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Immunosuppression and Epigenetic Therapy: Amyloid Precursor-Like Protein 2-Mediated Macrophage Dynamics and Histone Deacetylase Inhibition in Neuroblastoma
No full textAmyloid precursor-like protein 2 (APLP2) has been previously associated with pro-tumor phenotypes in cancer cells, and these studies investigate the expression and functions of this protein in macrophages. Collective findings demonstrated increased APLP2 expression in U937 monocyte-like cells following cytokine-induced differentiation to macrophage-like cells. Analysis of human mRNA data revealed elevated APLP2 levels in M2/anti-inflammatory (pro-tumor) macrophages compared to M1/pro-inflammatory (anti-tumor) macrophages. Consistent with the mRNA data, immunoblotting confirmed higher APLP2 protein expression in mouse M2 macrophages. Through comparison of macrophages from wild-type and APLP2-knockout mice, we correlated alterations in inflammation-associated markers with the presence of APLP2, which suggests that APLP2 influences macrophage polarization dynamics between M0/unpolarized and pro- and anti- inflammatory states. Notably, intratumoral infiltration of M2/anti-inflammatory macrophages has been reported in several cancers, including the pediatric cancer neuroblastoma (NB), and NB-conditioned media induced macrophage polarization resembling APLP2-mediated profiles. These findings implicate APLP2 in shaping macrophage dynamics, potentially contributing to tumor-associated immunosuppression.
The immunosuppressive tumor microenvironment in NB is a contributor to poor outcomes for patients, with high-risk patients facing a five-year survival rate of ~50%. New therapeutic strategies are needed for NB, and histone deacetylase (HDAC) inhibitors have emerged as promising anti-cancer agents due to their ability to modulate gene expression and tumor phenotypes. These studies assessed M344, an HDAC inhibitor, for its therapeutic efficacy in NB. Analysis of clinical NB data showed higher HDAC transcript expression in advanced-stage tumors relative to early-stage samples, and M344 treatment increased histone acetylation. M344 also exerted anti-proliferative and pro-apoptotic effects on NB cells through G0/G1 cell cycle arrest and pro-apoptotic caspase activation. Compared to vorinostat, an HDAC inhibitor in clinical use for lymphoma and clinical trials for NB, M344 demonstrated superior cytostatic and cytotoxic effects, as well as reduction of NB cell migration. In vivo, metronomic M344 dosing significantly suppressed tumor growth and extended survival in NB-bearing mice. Additionally, M344 enhanced tolerability of topotecan and prevented tumor rebound when combined with cyclophosphamide. These findings position M344 as a potent candidate for NB therapy, with improved tumor suppression, reduced toxicities, and potential to enhance long-term outcomes in patients
Labeled
Get PDFTo explore the extent to which stigma permeates the field of psychiatry, this project, entitled “LABELED”, involved writing a series of structured poems for ten commonly stigmatized mental illnesses: anorexia nervosa, antisocial personality disorder, attention-deficit hyperactivity disorder, bipolar disorder, borderline personality disorder, generalized anxiety disorder, major depressive disorder, obsessive-compulsive disorder, schizophrenia, and substance use disorder. The shortest poems in each set focus on stereotypes and first impressions commonly held about these disorders while the longer poems center around the identity of these individuals beyond their diagnoses. Amongst each set of poems, there is a recontextualization of the words shared between them to further demonstrate the deconstruction of negative stereotypes and humanization of the patients that occurs after going beyond one’s initial assumptions.
Each section is distinguished by a derogatory term that has historically been used to refer to these patients, highlighting what is all too often the very first impression one has of these patients. The poems in each set are named for descriptions of what may be observed in an initial presentation to an emergency department, a new patient visit at an outpatient clinic, and finally the established patient visit to model a patient’s navigation through the healthcare system. The progressive lengthening and greater inclusion of detail in the longer poems mirrors how we get to deepen our understanding of patients as we spend more time with them.https://digitalcommons.unmc.edu/emet_posters/1046/thumbnail.jp
CXCR4 Cell and Lymphoid Targeted CRISPR-Cas9 Lipid Nanoparticles Facilitate HIV-1 Proviral DNA Excision in CD4+ T cells
No full textAdvancements in antiretroviral therapy (ART) have enabled those people living with HIV-1 (PLWH) to live a life free from the many complications of viral infection. However, the daily use of medications for the person’s lifetime and the associated social stigma are impactful for cost and access. Moreover, type one HIV (HIV-1) is latent in multiple tissue and cell reservoirs resulting in viral rebound and the emergence of viral resistance. The latter is followed by ART interruption. However, to date, a ‘cure’ for HIV-1 remains elusive. With these needs in mind, we have developed targeted lipid nanoparticles (T-LNPs) as a means to improve delivery that can lead to viral elimination. Although viral and nanoparticle approaches were developed to deliver clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 formulations, a safe and effective means to preclude off-target toxicities is not available. Changing the chemical composition and surface functionality of LNPs can selectively deliver CRISPR/Cas9-guide RNA (gRNA) complex. We demonstrated that LNPs that target the CXCR4 receptor can selectively excise integrated viral DNA in laboratory cell models and primary CD4+ T cells, therefore, can be used for delivery to HIV-infected cells and tissues in animal models of persistent human infection. Moreover, we altered the tropism of LNPs to deliver to extrahepatic organs, specifically the spleen. Therefore, it can be tuned to effectively deliver to HIV-1 organ reservoirs as well. Finally, we have shown that that this two-pronged approach can excise viral DNA from infected humanized mice. In summary, our studies provided a proof-of- concept that we can deliver gene-editing therapies safely and effectively to difficult-to-reach latent HIV-1 reservoirs for viral DNA excision
Molecular Mechanisms of Aberrant Metabolism in Pancreatic Cancer Aggressiveness and Metastasis
Get PDFPancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer known for being one of the most fatal, with a 5-year survival rate of only 10%. This highlights the urgent need to better understand its underlying biology. In recent years, there has been increasing interest in and research into the metabolic characteristics of pancreatic cancer, driven by strong evidence indicating that metabolic reprogramming is crucial in the initiation, progression, and resistance to therapy of the tumor. As our knowledge of the metabolic complexities of pancreatic cancer grows, this area has become increasingly important, offering potential opportunities for early detection, targeted therapies, and personalized treatment approaches in the battle against this challenging disease.
This dissertation has investigated the role and mechanism of two proteins in increasing the aggressiveness of Pancreatic Ductal Adenocarcinoma (PDAC). While several publications have reported different axes affecting and rewiring metabolism in PDAC, my thesis primarily focuses on understanding the impact of abnormal protein expressions on metastatic and aggressive properties of PDAC. We identified a novel protein expressed specifically in aggressive PDAC.
My first set of results addresses the effects that aberrant PAF1 expression has on PDAC metabolism. A correlation analysis using Polymerase associated factor-1 (PAF1) as the selected gene for Pancreatic Cancer (PC) sample type and customized the corGSEA to the hallmark. The analysis revealed that PAF1 expression in Pancreatic Cancer (PC) is enriched and statistically significant in various metabolic pathways, xii including oxidative phosphorylation and glycolysis. Additionally, loss of PAF1 expression resulted in reduced Lactate Dehydrogenase A (LDHA) expression, Extracellular Acidification rate (ECAR), and increased Oxygen Consumption Rate (OCR) rates. Further analysis showed that PAF1 interacts with Hypoxia-Induced Factor 1 (HIF1α) and together regulates the transcription of LDHA.
My second set of results identified a novel protein, GDA, and its role in the metabolic reprogramming of PDAC. Using an aggressive PC cell line and a normal pancreas cell line, RNA sequencing revealed an increased fold change in expression for GDA, which is an enzyme involved in the purine salvage pathway. This was confirmed using multiple analyses (RT-PCR, ddPCR, western blot, and immunohistochemistry) to confirm expression variation in several PC cell lines. Validation of the role of the protein was confirmed through the depletion of the protein and by performing multiple in vivo and in vitro experiments. In addition, we identified a mechanism of action and an inhibitor capable of reducing the expression of these proteins and, ultimately, the proliferation of pancreatic cancer cells. Overall, my work contextualized the roles of two proteins (PAF1 and GDA) in aberrant metabolism to fuel PDAC aggressiveness. The unique mechanisms I discovered provide a potential mode of action to develop therapeutics for PDAC
Apolipoprotein E4, Tauopathy, and Brain Injury: Molecular Insights into Alzheimer\u27s Disease Pathology
No full textAlzheimer’s disease (AD) is the world’s leading cause of dementia, characterized by progressive atrophy of the hippocampal and cortical brain regions, synapse damage and loss, and a buildup of senile plaques and neurofibrillary tangles composed of β-amyloid peptides and hyperphosphorylated tau, respectively. While age is the most significant risk factor for developing AD, apolipoprotein E4 (APOE4) is the strongest genetic risk factor for AD. Although it is known that APOE4 influences tau pathology, the molecular mechanisms by which APOE4 drives AD pathogenesis and progression remain unclear. In addition to intrinsic contributions to AD, there are many extrinsic factors that can induce AD phenotypes. An example is traumatic brain injury (TBI) which can occur in many different aspects of life. In short, TBI is characterized by mechanical damage to the brain tissue followed by secondary events that further disturb important molecular processes later in recovery. A specific connection to AD is the induction of tau hyperphosphorylation at the site of injury following TBI. This modified tau can then aggregate and spread to adjacent brain regions, causing AD-relevant tau burden. Further, APOE4 carriers appear to experience worse outcomes after TBI. How TBI leads to subsequent AD development and the interrelationship between TBI and other AD-related contributors such as APOE4 and tau are areas of active investigation. The work in this thesis details the connections between APOE4 genetic risk, non-mutant human tau pathology, and TBI-induced secondary events and how they relate to the molecular underpinnings of AD pathogenesis and progression
Cardiac Patient Care Coordination: A Comprehensive Literature Review on Outcomes
No full textCare coordination is a vital aspect of the U.S. primary care landscape. Care Coordination is the deliberate process of managing a patient across different provider settings and services and is a vital part of chronic patient care. Most primary care providers (PCPs) today have moved to adopt some form of patient-centered care that serves as the central hub for coordinating and managing a patient\u27s complete healthcare journey. PCPs\u27 access to specialist records and their familiarity with their patients\u27 long-term disease courses uniquely position them as the prime coordinators of patient care. Care coordination is becoming increasingly important in cardiac care as it has been shown to lead to positive health outcomes. Heart disease is the number one cause of death worldwide, while also contributing to higher rates of emergency room visits, hospitalizations, and higher costs. Heart disease also contributes to increased noncardiac comorbidities, like lung disease and diabetes, and a high number of prescription medications. With the amount of both primary care and specialty doctor visits, tests and procedures, and prescription medications, care coordination is the perfect tool to properly manage the care of a patient with heart disease. Care coordination has been shown to lower the rate of emergency room visits, readmissions to the hospital, and a faster return to work rate for patients who have a cardiac disease. This literature review summarized the evidence of various cardiac care coordination interventions, specifically applied to patients with heart diseases, focusing on the effectiveness of nurse-led multidisciplinary teams, frequency of follow-up, and the timing and accuracy of patient information flow. By synthesizing existing research, this review showed that care coordination interventions positively influence patient health outcomes, including reducing hospital readmissions, improving patient satisfaction, enhancing quality of life, and reducing costs
A Comprehensive Literature Review of Barriers to Hormone Therapy Utilization: Strategies for Improving Menopause Management in Women Aged 40-60
Get PDFMenopause is a natural transition marked by the cessation of ovarian activity, often accompanied by vasomotor symptoms (VMS), genitourinary syndrome of menopause (GSM), and psychological changes that significantly impact women’s quality of life. Hormone therapy (HT) has been the primary treatment for managing menopausal symptoms, particularly VMS, providing substantial relief when initiated within 10 years of menopause. Despite its effectiveness, HT usage has declined dramatically over the past two decades primarily due to barriers such as stigma, safety, misinformation, provider hesitancy, financial barriers, and cultural beliefs. This comprehensive literature review explores key factors influencing HT decision-making, including the media’s role in amplifying health fears, physician influence on treatment access, and disparities in education and healthcare. Findings suggest that misinterpretations of the Women’s Health Initiative (WHI) study—a major clinical trial published in 2002—along with media-driven misinformation, inconsistent provider recommendations, insurance limitations, and cultural barriers have led many women to either seek alternative therapies or avoid treatment altogether. Addressing these barriers through evidence-based public health messaging, improved provider education, and greater access to affordable treatment options is crucial to ensuring informed decision-making and improving menopause care
Evaluation of the Usage and Effectiveness of the Gross Anatomy Osteology e-Learning Module
No full textSupplementary online learning modalities have reached near ubiquity in graduate health sciences education, yet evidence about their effectiveness remains mixed. The Department of Genetics, Cell Biology, and Anatomy at UNMC recently introduced their own bespoke electronic study platform called the Osteology e-Learning Module to aid gross anatomy students in the study of osteology. To assess its effectiveness, osteology and whole gross lab practical exam scores were compared in four different content units across three school year cohorts of graduate students in the same gross anatomy class. A survey was also distributed to one cohort to capture subjective information about the module. Overall, Osteology e-Learning Module usage was mildly associated with greater osteology and gross exam scores and more consistent exam scores across content units. Greater individual module usage did not correlate to higher exam scores. Students reported overall positive attitudes on the survey. Though this study assessed the effectiveness of the learning module, further study about the mechanism by which the module improved outcomes would add greater insight
A Comparison of Resurgence Following DRA and DRO
No full textResurgence, a form of behavioral relapse, occurs when a previously reduced target behavior reemerges after an alternative source of reinforcement is discontinued. Differential reinforcement of alternative behavior (DRA) and differential reinforcement of other behavior (DRO) are commonly used strategies to reduce undesired behaviors. Although both are effective, unanticipated periods of extinction (e.g., service lapses or staff turnover) may lead to resurgence of the original target behavior. Romano and St. Peter (2017) found that behavior reduced via DRO was more prone to resurgence than behavior reduced via DRA. However, their study used a different number of response options between conditions (one for DRO, two for DRA), which may have influenced the outcomes. The purpose of this study was to replicate and extend Romano and St. Peter by comparing resurgence following DRO and DRA in a human operant arrangement while controlling for the number of response options across conditions. Overall, results indicated that DRO did not lead to a greater likelihood or magnitude of resurgence compared to DRA when the number of response options was held constant. These findings provide valuable insights into the durability of reinforcement-based interventions, allowing clinicians to make more informed treatment decisions
A Landscape Analysis of Rapid Evidence Curation During the 2022 Sudan Virus Disease Outbreak in Uganda
Get PDFUganda\u27s 2022 Sudan Virus Disease (SVD) outbreak emphasized the need for rapid and effective evidence curation in public health emergencies. This analysis examines evidence curation practices during the SVD response, identifying challenges and assessing the timeliness and effectiveness of strategies in low-resource settings. While global responses to previous outbreaks, like COVID-19, have advanced evidence synthesis, the SVD outbreak revealed infrastructure and data integration gaps. The study aims to map the evidence curation landscape, focusing on models and tools, such as data-sharing platforms, mobile Polymerase Chain Reaction (PCR) labs, and Integrated Management Systems (IMS). It will also address gaps in surveillance, diagnostics, and real-time data integration. The findings will provide actionable recommendations to enhance rapid evidence curation and outbreak response strategies, with a focus on improving decision-making, collaboration, and data integration in under-resourced regions, such as Uganda