Digital Commons Network^™

Rad Reduction Reveals Therapeutic Potential Of Targeting Cardiomyocyte L-Type Calcium Channel Regulation For Heart Failure, Garrett Elmore

Theses and Dissertations--Physiology

Heart failure (HF) is prevalent and is predicted to increase with the aging population. Dilated cardiomyopathy (DCM) is a common cause of systolic HF. Current therapies fail to address principal issues: compromised systolic function and dysfunctional Ca²⁺ handling. No therapeutic approach exists for direct, positive modulation of cardiomyocyte L-type calcium channels (LTCC). RAD (Ras associated with diabetes) is a key regulator of the cardiac LTCC. RAD is a downstream phosphorylated target of the ß-adrenergic receptor (ß-AR)/cAMP/protein kinase A pathway; phosphorylation augments LTCC activity, contributing to chronotropy, inotropy, and lusitropy. RAD overexpression results in LTCC inhibition, whereas knockout positively modulates …

Asymmetric Synthesis Of The Hiv Protease Inhibitor Tmc-126 And An Anti-Malarial Agent Via A Titanium Tetrachloride Mediated Asymmetric Glycolate Aldol Addition Reaction. Redefining The Curtius Rearrangement Reaction Via Dehomologation Of Carboxylic Acids Bearing Alpha-Leaving Groups, Kweku Amaning Affram

Theses and Dissertations

Acquired Immune Deficiency Syndrome (AIDS) and malaria are two devastating infectious diseases caused by HIV and Plasmodium parasites. AIDS is caused by HIV-1 and HIV-2, transmitted through sexual contact, blood transfusions, needle sharing, and perinatal routes. Malaria, caused by plasmodium parasites through mosquito bites. Today, millions of people around the world have been infected with HIV and malaria and much research has been done to treat it. However, despite advancements in therapeutic options, these diseases remain a significant global health threat, particularly in developing countries due to the emergence of drug-resistant strains for both HIV and malaria complicating eradication efforts. …

The Role Of Sptbn1 Protein In Microglia Cells Actin Structure And Hiv-1 Infection, Rachel Pecka

Graduate Theses/Dissertations

Human immunodeficiency virus (HIV) directly attacks the host immune system by infecting and replicating in CD4-presenting immune cells. Like most viral pathogens, HIV utilizes cellular machinery to assist in viral entry, transport, and export. One of the components HIV is known to utilize for replication is the actin cytoskeleton. By directly binding to actin or actin-binding proteins, HIV can manipulate structural dynamics within the cell. The way HIV hijacks actin for replication post-viral fusion isn’t fully understood, especially during viral transport to the nucleus. A 2013 study conducted by Dai et al. found that lowering the expression of the cellular …

Ciliary Arl14b In Vision, Alexis Breann Crockett

Graduate Theses, Dissertations, and Problem Reports (ETD)

Primary cilia are highly specialized organelles that regulate signaling, trafficking, and sensory perception across multiple tissues, including the retina. The small GTPase ADP Ribosylation Factor-Like Protein 13B (ARL13B) is an atypical ARF-family protein enriched in cilia. ARL13B acts as a guanine exchange factor (GEF) for another small GTPase ARF-like Protein 3 (ARL3). Mutations in ARL13B cause Joubert syndrome, a ciliopathy characterized by brain malformation, developmental delays, and retinal degeneration. Despite ARL13B’s known ciliary localization and clinical relevance, ARL13B’s precise functions in cilia remain poorly defined. This dissertation investigates the cilia-specific roles and GEF-specific roles of ARL13B in photoreceptors using two …

Characteristics Contributing To The Risk Of Diabulimia In Adults Living In The United States, Danielle L. Van Hout

All Master's Theses

The purpose of this study was to determine the prevalence and factors that contribute to the risk of diabulimia by using the validated Diabetes Eating Problem Survey-Revised (DEPS-R) (Markowitz et al., 2009) screening tool in adults living in the U.S., as well as to examine differences in individuals at-risk and not-at-risk for diabulimia. This observational study involved a 30-question Qualtrics survey containing the DEPS-R distributed via various social media outlets and flyers on the CWU Ellensburg campus. Participants were required to be 18 years or older, diagnosed with T1DM for more than one year, and live in the U.S to …

Sex-Specific Roles Of The Adipocyte Mineralocorticoid Receptor In Obesity And Early Life Stress, Meghan B. Turner

Theses and Dissertations--Pharmacology and Nutritional Sciences

Obesity is a burgeoning health epidemic caused by chronic overnutrition and exacerbated by genetic, environmental and developmental factors. The adipocyte mineralocorticoid receptor (MR), a transcriptionally active nuclear receptor, is speculated to contribute to metabolic dysfunction in the obese state. MR expression is increased in obese adipose tissue, and MR modulates the expression of fat-derived hormones such as leptin and adiponectin. In women, obesity can be exacerbated by early life stress, such as adverse childhood experiences (ACEs). Studies show that women display a positive association between cumulative ACE exposures and increased body mass index. Previously, we demonstrated that maternal separation and …

Tissue Kallikrein 1 Cleaves Complement Factor C3 And Activates The Alternative Complement Pathway, Sarah E. Sartain, Andrew Yee, Paula Jacobi

Research Data

Hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), characterized by microvascular endothelial damage and severe renal injury, negatively affects HSCT survivorship with high mortality and long-term renal morbidity. After HSCT, innate immunity and inflammation are often dysregulated. The alternative complement pathway (AP) of the innate immune system is overactivated in HSCT-TMA, but the mechanisms of its initiation are poorly described. Complement component C3 of the AP can be cleaved by proteases outside of the AP. Because mRNA expression of tissue kallikrein 1 (KLK1), an inflammatory serine protease that produces kinins, has been found to be markedly elevated in the renal endothelium …

Aneurysmal Dilatation Following Common Femoral Artery Directional Atherectomy, Timothy H.H. Kam, Bryan P. Yan, Guangming Tan

Journal of the Hong Kong College of Cardiology

Aneurysmal dilatation is an uncommon but serious complication of directional atherectomy for heavily calcified lower extremity arterial disease. In the absence of established treatment guidelines, this case report describes the successful endovascular management of a common femoral artery aneurysm following directional atherectomy using covered stents.

Effects Of Round-Up On The Environment, Sandra J. Marcu

Journal of Earth and Life Science

Many people around the world have used and still currently use Roundup but are unaware of the effects it has on the environment. Roundup is a spray on application weedkiller that is widely used around the world today both residentially and commercially. It enables its user to grow a garden or a field of crops with a no-tilling approach to eliminate weeds. It is a well-known and popular choice for killing weeds that has been around since the mid 1970’s (Oca, 2017). John Franz, a Monsanto scientist discovered that glyphosate (main ingredient in Roundup) was an herbicide or weedkiller, and …

Treatment Sequence With Tebentafusp And Immune Checkpoint Inhibitors In Patients With Metastatic Uveal Melanoma And Metastatic Gna11/Gnaq Mutant Melanocytic Tumors, Florentia Dimitriou, Marlana Orloff, Erica Koch Hein, Phil Cheng, Isaac Hughes, Ester Simeone, Kamaneh Montazeri, Piyush Grover, Inderjit Mehmi, Camille Gerard, Caroline Gaudy-Marqueste, Jean-Jacques Grob, Olivier Michielin, Omid Hamid, Georgina Long, Ryan Sullivan, Ellen Kapiteijn, Douglas Johnson, Paolo Ascierto, Anthony Joshua, Richard Carvajal, Marcus Butler, Jessica Hassel, Reinhard Dummer

Kimmel Cancer Center Faculty Papers

BACKGROUND: Metastatic uveal melanoma (mUM) is rare. Immune checkpoint inhibitors (ICIs) have shown modest efficacy in mUM. Tebentafusp prolonged overall survival (OS) in a phase 3 study. We aimed to investigate the efficacy and safety of the sequence of tebentafusp and ICIs.

METHODS: Patients with HLA-A * 02:01 positive mUM, or metastatic GNA11/GNAQ mutant melanocytic tumors treated with tebentafusp followed by ICIs (group 1) or the inverse sequence (group 2) at any treatment line were retrospectively identified. The primary objective was OS rate at 2 years.

RESULTS: 131 patients were included; 51 in group 1 and 80 in group 2. …

Alpha-Synuclein Interaction With Gedunin, Tony Matundura Nyabayo

Graduate Theses/Dissertations

Parkinson’s disease (PD) and other Proteinopathies develop when α-synuclein misfolds and aggregates into toxic amyloids. While existing treatments for PD are primarily focused on managing its symptoms, a viable solution for slowing down the progress of Parkinson’s disease involves targeting the toxic α-synuclein amyloids. Gedunin, a natural inhibitor of heat shock protein 90, has been extensively used to treat malaria. Also, recent research investigations have shed light on its potential beyond malaria therapy, indicating that Gedunin may offer a possible solution for treating a variety of neurodegenerative diseases. Using plate-based assays, we examined how Gedunin influences α-synuclein fibrillation and its …

Characterizing A Rad23 Dependent Ultraviolet Radiation Resistance In Tetrahymena Thermophila, Emma June Liimatta

Graduate Theses/Dissertations

In 2020, 10 million deaths were attributed to cancer, with multidrug resistance being responsible for over 90% of deaths in cancer patients receiving treatment. This study utilized the model organism Tetrahymena thermophila to study how cells become resistant to Ultraviolet Radiation (UV) radiation, a process similar to multidrug resistance, specifically focusing on the nucleotide excision repair and ubiquitin shuttle protein Rad23. The National Cancer Institute documented 30-60% of cancers tested had a mutation in RAD23. Knockdown of RAD23 in Tetrahymena thermophila demonstrated a UV resistance phenotype with decreased nucleotide excision repair and differential expression of proteins active within caspase-independent …

The Role Of Host Factor Sptbn1 In Hiv-1 Capsid Uncoating In Human Microglial Cells, Callie Marie Fry

Graduate Theses/Dissertations

HIV-1 is the virus that causes acquired immunodeficiency syndrome (AIDS), and currently, there is no cure once an individual is infected. The development of new drugs targeting HIV-1 replication steps is essential for keeping viral loads low or undetectable to prevent further transmission. An attractive replication step for new drug targets is viral capsid uncoating, where the virus loses the protein structure encapsulating the genome. The exact mechanism of capsid uncoating is unknown; however, several host-factors may be involved including protein SPTBN1. Recent studies have shown a significant decrease in viral infectivity when SPTBN1 is knocked down, yet its role …

One And Half Versus Bi-Ventricular Repair In Pediatric E Bstein Anomaly, Short-Term Outcomes Retrospective Analysis, Rania Abushokka, Hanan Mohammed Hassan, Ahmed Meawad, Ahmed Algebaly

Journal of Medicine in Scientific Research

-Background: The application of one and half-ventricular repair in Ebstein anomaly(EA) should be considered, in association with effective cone repair, to reduce the volume preload on a dysfunctional right ventricle, and to take the benefit of obtaining ante-grade pulmonary blood flow. The one and half-ventricular repair that applied in patients with hypoplastic sub pulmonic ventricle can alternate effectively the Fontan pathway. This provides pulsatility in pulmonary circulation. However, pressure elevation in superior vena cava (SVC) and right atrial hypertension can occur in patient’s undergone one and half ventricular repair. Aim The aim of this study to evaluate the short-term outcomes …

Structural And Interpersonal Determinants Of Covid-19 Vaccine Uptake In Vulnerable Populations Of The United States, Alyea Wood

Capstone Showcase

Since its introduction in late 2020, the uptake of the COVID-19 vaccine has had the lowest rates in marginalized populations like minorities, elderly, and those of low socioeconomic status. Decreased rates of vaccination uptake in these groups has resulted in increased burden of disease and subsequently higher rates of hospitalization and death. Many inequities in poor COVID-19 health outcomes can be explained by examining common predictive factors that determine vaccination rates in these United States populations. This special article research aims to explore these various predictive factors with the goal to provide targeted strategies to boost COVID-19 vaccination rates, especially …

Caspases Protect Against Hyperglycemia Induced Necroptosis-Like Cell Death In Brain Endothelial Cells, Aleena S. Mathew

Theses and Dissertations

Acute diabetes characterized by high spikes in blood glucose levels in association with severe hyperglycemia can lead to an increased risk of ischemic stroke in the brain. To better understand high blood glucose levels, hyperglycemia, in the brain we explored its effects on endothelial cells. Endothelial cells line the inner walls of blood vessels and are directly impacted in hyperglycemia. Brain endothelial cells are a major component of the blood brain barrier (BBB) which tightly regulates the brain’s microenvironment. The type of cell death such as apoptosis, caspase dependent, or necroptosis, caspase independent, can exacerbate diabetes associated complications. There is …

Gain-Of-Function Tp53 Mutations Induce Non-Canonical Nf-Κb Transcriptional Targets To Promote Tumor Development, Kelsey A. Yutan

Scripps Senior Theses

Background: Gain-of-function TP53 mutations have previously been shown to induce chromosomal instability (CIN) in cancer cells, triggering the cGAS-STING innate immune response and subsequently activating the non-canonical NF-κB (NC-NF-κB) signaling pathway. This signaling cascade promotes cancer cell metastasis and an immunosuppressive tumor microenvironment (TME), significantly impacting tumor development and progression. However, the precise downstream mechanisms by which the mutp53-CIN-cGAS-STING-NC-NF-κB signaling pathway facilitates tumor development and progression remain poorly understood. Here, our objective was to identify direct downstream targets of mutp53-CIN-cGAS-STING-induced NC-NF-κB signaling that potentially impact the TME to promote the development and progression of oral squamous cell carcinoma.

Methods …

Exploring Psychological Implications Of The Contemporary Lung Transplant, Isaac C. Machar

Williams Honors College, Honors Research Projects

Since its inception in 1963 at the University of Mississippi Medical Center, more than 50,000 lung transplant procedures have been performed. During its 50-year anniversary, 2023 saw just over 3,000 lung transplants performed in the United Sates. However, as this procedure continues to increase in execution each year, it is critical that the psychological implications of this procedure are explored. In this paper, I hope to develop an understanding of the psychological background of contemporary lung transplantation. Reviewing the lung and double lung transplant, the goal is to apply biopsychology principles to the field. Background information about transplant science is …

Astrocyte Specific Enhancers In The Cortex And Striatum Of Mice, Mikaela Kottelich

Williams Honors College, Honors Research Projects

Among glial cells, astrocytes have a prevalent influence on supporting neuronal function and overall brain health. Specifically targeting this cell type for disease treatment is an existing issue. Other cell types tend to express the desired treatment, which is not always wanted and can lead to unintended, negative consequences. Astrocytes contribute largely to maintaining the blood brain barrier, which is disrupted in Parkinson’s disease. Certain genes are thought to be the reason for this disruption, so if they can be specifically targeted in astrocytes with a specific enhancer, the disruption of the disease could be reversed. In our experiment, we …

Key Considerations For Combination Therapy In Alzheimer’S Clinical Trials: Perspectives From An Expert Advisory Board Convened By The Alzheimer’S Drug Discovery Foundation, Jeffrey Cummings, Michael Gold, Mark Mintun, Michael Irizarry, Andrew Von Eschenbach, Suzanne Hendrix, Donald Berry, Cristina Sampaio, Kaycee Sink, Jaren Landen, Miia Kivipelto, Michael Grundman, Steven E Arnold, Allan Green, Katherine Partrick, Laura Nisenbaum, Aaron Burstein, Howard Fillit

Faculty, Staff and Student Publications

There is growing consensus in the Alzheimer's community that combination therapy will be needed to maximize therapeutic benefits through the course of the disease. However, combination therapy raises complex questions and decisions for study sponsors, from preclinical research through clinical trial design to regulatory, statistical, and operational considerations. In January 2024, the Alzheimer's Drug Discovery Foundation convened an expert advisory board to discuss the key considerations in each of these areas. Experts agreed on the need to prioritize a combination therapy approach that encompasses a wide range of targets associated with aging and the underlying biology of Alzheimer's disease. Progress …

Skinrisk Ai, Spencer Simms

Williams Honors College, Honors Research Projects

SkinRisk AI is an exploration of the opportunities for implementing machine learning (ML) and artificial intelligence (AI) in the medical technology field, specifically in the early detection of skin cancer. This project presents the design, development, and evaluation of a mobile application that allows users to capture images of skin lesions and receive a machine learning assisted risk assessment. The system combines a convolutional neural network (CNN) for image analysis with an intuitive mobile app built using Flutter, FastAPI, and Supabase to deliver real time screening.

Motivated by the rising skin cancer rates and importance of early detection, SkinRisk AI …

Critical Analysis Of Gestational Diabetes Risk Factors: A Systematic Review, Madison Keich, Madeleine Ray, Mia Ross

Williams Honors College, Honors Research Projects

Gestational Diabetes Mellitus (GDM) is a common complication of pregnancy that causes an increased blood sugar that can affect both the mother's and baby’s health. A variety of factors can increase the risk of developing the disease, including race, socioeconomic status, and prenatal education. Each of these factors contributes to the experience of one’s maternal care. Expecting mothers may not understand how significant GDM is, and its potential to result in negative outcomes. It is important to review these factors, acknowledge them, and help reduce health disparities caused by them. Nurses are vital to assessing and delivering patient education on …

The Quality-Of-Life Benefits And Risk Of Isotretinoin (Accutane) In Acne Treatment: A Systematic Review, Noelia Valencia Zuniga

Honors Undergraduate Theses

Acne vulgaris is a prevalent dermatological condition, particularly affecting adolescents and young adults. While often treated as a cosmetic issue, acne can significantly impair a patient's mental health and overall quality of life (QoL). Isotretinoin, commonly known as Accutane, is widely regarded as the most effective treatment for severe and persistent acne. However, its use is controversial due to a range of potential side effects, including psychiatric symptoms, teratogenicity, and other systemic complications. To better understand the risk-benefit profile of isotretinoin in acne treatment, we conducted a systematic review, focusing on the QoL benefits and risks associated with its use. …

The Incidence Of Postmenopausal Breast Cancer In Relation To Occupational Exposure To Textile Fibers And Dusts In Montreal, Canada, 2008-2011, Maymouna Myriam Ka, France Labrèche, Mark S. Goldberg, Vikki Ho

Études primaires

Objective To estimate the associations between occupational exposure to textile fibers/dusts, and incidence of postmenopausal invasive breast cancer.

Methods

A population-based case-control study conducted in Montreal (2008 − 2011) identified hospital cases (N = 695) and population controls (N = 608) from the electoral list. Occupational hygienists examined participants’ occupations and tasks, and attributed exposures to several textile fibers. For all tumors and according to biomolecular subtypes, odds ratios (OR) and 95% confidence intervals (95%CI) were estimated using logistic regression models with different exposure indices, adjusting for potential confounders.

Results

Ever exposure to cotton dust was associated with an increased …

Antibiotic Resistance: The Growing Threats And Potential Solutions, Olisaemeka Zikora Akunne, Blessing Nkechi Emmanuel, Umar Faruk Saidu, Ayobami Sunday Akinnawo, Nasiru Ademola Adeyemi, Livia Chinaza Egoh, Malami Aishatu Muhammad, Olusegun Ayo Ade-Adekunle, Deborah Ahuoyiza Peter, Anne Amina Freitas

Department of Biomedical and Translational Sciences Faculty Publications

Antibiotic resistance (AR) has become a critical global health crisis, threatening the efficacy of antibiotics and increasing healthcare costs, morbidity, and mortality. The One Health approach, which emphasizes the interconnectedness of human, animal, and environmental health, is increasingly recognized as an essential framework for addressing the complex drivers of AR. This review explores the mechanisms of resistance, such as genetic mutations, horizontal gene transfer, and biofilm formation, along with contributing factors such as the overuse of antibiotics in healthcare and agriculture. We assess both traditional and emerging strategies to combat AR, including antimicrobial stewardship, the development of new antibiotics, and …

Cellular And Molecular Mechanisms Of Lung Regeneration, Repair, And Fibrosis, Volume Ii, Yong Qiu, Xiao Xiao Tang, Shigeyuki Shichino, Prem Prakash Kushwaha, Yan Y. Sanders, Remo Castro Russo, Chunheng Mo

Department of Biomedical and Translational Sciences Faculty Publications

[Introduction] Organ fibrosis represents a substantial a major contributor to global disease burden, implicated in over 30% of cases leading to disability-associated and fatal conditions. Among these conditions, idiopathic pulmonary fibrosis (IPF) stands as a progressive and frequently fatal interstitial lung disease characterized by aberrant extracellular matrix deposition and parenchymal scarring. The prognosis for IPF patients is poor, with a median survival time of just 3–5 years (Bhattacharya and Ramachandran, 2023; Lederer and Martinez, 2018, Ma et al., 2024, Wei et al., 2024). Current FDA-approved therapeutics, Pirfenidone and Nintedanib, demonstrate capacity to attenuate functional decline in pulmonary fibrosis but remain …

Hiv Protein Tat Dysregulates Multiple Pathways In Human Ipscs- Derived Microglia, Liam Liyang Guo, Robert Jiang, Yan Cheng, Brooke Russell, Yan Y. Sanders, Ming-Lei Guo

Department of Biomedical and Translational Sciences Faculty Publications

In the era of combined antiretroviral therapy, around 50% of chronic HIV (+) individuals show varying degrees of memory and cognitive deficiency (NeuroHIV), a phenomenon of accelerated brain aging. HIV protein transactivator of transcription (TAT) has been well-accepted as a risk factor contributing to NeuroHIV through dysregulating microglia (Mg) functions. Previous studies have demonstrated that HIV-TAT can affect lipid metabolism, immune responses, autophagy, and senescence in rodent Mg. However, due to the significant species differences between rodent and human Mg (hMg), it is essential to take caution when interpreting the results obtained from rodent models into human conditions. For the …

Association Of Helicobacter Pylori Infection With Pediatric Asthma In Palestine, Alaa Hrizat, Amal A Shahin, Banan M Mafarjeh, Mohammad A Atawneh, Kamel Gharaibeh, Nisreen Rumman, Mutaz Sultan

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Purpose: Significant debate exists on the association between Helicobacter pylori infection and childhood asthma. We aimed to explore this association in a cohort of children in Palestine while estimating the prevalence of H. pylori in this population. Methods: We conducted a prospective case-control study among children aged 6–15 years in Palestine, including 44 asthma cases diagnosed by pediatric pulmonologists and 99 age-matched healthy controls recruited through cluster sampling from schools. H. pylori status was determined using a stool antigen test. Asthma severity was assessed using the International Study of Asthma and Allergies in Childhood questionnaire. Data on recent antibiotic use, …

Prevalence Of Electrocardiographic Changes And Risk Factors For Qtc Prolongation Among Steady State Sickle Cell Disease Patients: Cooperative Study Of Sickle Cell Disease, Mohammed B. Nawaiseh, Rund R. Haddadin, Yara B. Nawaiseh, Mohammad Z. Salameh, Abdallah A. Shurman, Osama Abu-Shawer, Asma I. Aljesrawi, Ibrahim A. Abuelbeh, Allaa Roto, Hadil Zureigat, Lana Mango, Munir Q. Zaqqa, Hanna K. Al-Makhamreh, Nakhleh Abu-Yaghi

Department of Medicine Faculty Publications

Objectives: Sickle cell disease (SCD) is associated with several cardiovascular adverse events. Corrected QT (QTc) interval prolongation is one of the potential life-threatening complications that predispose patients to sudden cardiac death. This study aims to assess the prevalence of electrocardiogram (ECG) changes and to investigate risk factors associated with increased propensity of QTc prolongation. Methods: This study utilized data from the Cooperative Study of Sickle Cell Disease Cardiac Ancillary Study. QT intervals were corrected using the Bazett formula, and prolongation was defined using sex-specific thresholds. The study population included African American patients with steady-state SCD across four clinical centers located …

Multi-Level Factors Associated With Low Dose Computed Tomography Lung Cancer Screening In The United States, Tung Sung Tseng, Chien Ching Li, Hui Yi Lin, Kelsey N. Witmeier, Chaoyi Zeng, Yu Wen Chiu, Michael D. Celestin, Edward J. Trapido

School of Public Health Faculty Publications

Low-dose computed tomography (LDCT) screening is recommended for high-risk smokers to decrease lung cancer-related mortality and increase prognosis. In the U.S., the uptake of LDCT screening among eligible smokers is suboptimal. The impacts of social-environmental and individual factors on LDCT screening uptake using nationally representative dataset recommendations are understudied. The current study investigated multi-level factors associated with LDCT screening using national data. Methods: The 2017-2021 Behavioral Risk Factor Surveillance System (BRFSS) data, social determinants of health (SDOH) and other state-level variables (Medicaid expansion status and the number of screening facilities using American Lung Association (ALA) 's State of Lung Cancer) …