Medicine and Health Sciences Commons^™

Chronic Environmental Exposure To Metal Mixtures In Tribal Populations And Potential Immune System Effects, Jennifer Ong

Biomedical Sciences ETDs

Hardrock mining in the United States (US) has left a legacy of mixed metal mine waste sites. Wastes may contain multiple metals of health concern, including arsenic, cadmium, lead, mercury, and uranium, among others. Mining waste sites are disproportionately located on or contiguous to the watersheds of tribal lands. Due to proximity, and because of reliance on natural resources to maintain traditional diets and customs, Native American communities’ contact with multiple metals is often increased. Two impacted communities are the Cheyenne River Sioux Tribe (CRST) and Navajo Nation. Both tribes have expressed concerns that metals in mine waste adversely affect …

The Role Of Omega-3 Polyunsaturated Fatty Acids In Blood Pressure Regulation And Secondhand Smoke-Induced Vascular Dysfunction, Emily Anna Wheeler

Biomedical Sciences ETDs

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) may lower cardiovascular disease risk by reducing blood pressure (BP). We hypothesized that fat-1 transgenic mice, which convert n-6 PUFAs to n-3 PUFAs, would have improved vascular function in BP regulation and following secondhand smoke (SHS) exposure, compared to wild type (WT) mice.

BP was recorded in mice fed an n-6 PUFA, or standard chow diet. On the n-6 PUFA diet fat-1 mice had a lower mean arterial pressure and a greater decrease in diastolic BP when treated with an ACE inhibitor, compared to WT mice. No differences were observed on the chow diet. …

The Role Of Adaptive Immunity In Chronic Hypoxia-Induced Pulmonary Hypertension, Levi David Maston

Biomedical Sciences ETDs

Inflammation is a prominent pathologic feature in pulmonary arterial hypertension as demonstrated by pulmonary vascular infiltration of inflammatory cells, including T and B lymphocytes. However, the contribution of the adaptive immune system is not well characterized in pulmonary hypertension (PH) caused by chronic hypoxia (CH). Inflammatory cells, through various mechanisms, have the capability to increase pulmonary vascular resistance in various disease states. CD4⁺T cells have the potential to play a significant role in the disease process initiated by hypoxia. CD4⁺T cells are largely responsible for orchestrating downstream immune processes and are critical in focusing and amplifying …

Cyclic Amp Efflux Inhibition As A Potential Therapeutic Target For Acute Leukemia: Small Molecule Discovery And Validation, Dominique R. Perez

Biomedical Sciences ETDs

Evasion of apoptosis and resistance to chemotherapy are major therapeutic challenges for acute leukemias. Presumably as a means to promote cell survival, multiple elements of the cyclic AMP (cAMP) pathway are aberrantly regulated in acute leukemias. Furthermore, increased intracellular cAMP (icAMP) is known to induce apoptosis. Therefore, modulation of icAMP has long been a target in leukemias. The central hypothesis of this dissertation is that malignant cells produce and remove excess intracellular cAMP to evade apoptosis and promote survival. Consequently, inhibition of cAMP efflux could selectively trigger leukemia cell death. We designed a novel assay to assess icAMP efflux from …

Improving Proton Pump Inhibitor Prescription Practices As A Means To Decreasing Nosocomial Infections, Jens Langsjoen

Biomedical Sciences ETDs

Proton pump inhibitors (PPIs) are commonly prescribed to treat stomach acid related illnesses, but increase the risk of hospital acquired infections. Measuring hospital PPI overuse trends and provider willingness to adopt PPI reduction interventions can inform the feasibility of reducing PPI overuse. We: (1) interviewed physicians, pharmacists and IT leaders to determine options for hospital PPI reduction, (2) analyzed electronic health record data to determine patterns of PPI overuse, and (3) surveyed providers regarding their willingness to adopt PPI reduction interventions. PPI use was inappropriate in 32% of inpatient encounters locally and 38% nationally. ICU exposure increased the odds of …

Intratypic Genetic Variability Of Human Adenovirus Type 4: Implication For Viral Pathogenesis, Camden Roy Bair

Biomedical Sciences ETDs

Human adenovirus type 4 (HAdV-E4) is a causative agent of acute respiratory disease and conjunctivitis worldwide. Two major lineages of HAdV-E4 genomic variants have been identified by their distinct BamHI restriction profiles: prototype-like (p-like) strains and the a-like genomic variants. Recent molecular epidemiology studies have shown a predominance of a-like genomic variants detected in association with disease which suggests a-like strains have a fitness advantage or they may be more pathogenic. The impact of HAdV-E4 intratypic genetic variability on in vitro and in vivo phenotypes relevant to pathogenesis is a major gap in knowledge. I hypothesize that HAdV-E4 comprises two …

Tauopathies, Novel Optogenetic Tools, And The Future Of Artificial Intellience In Medicine., Jessica L. Binder

Biomedical Sciences ETDs

To this day, there is no cure for Alzheimer’s disease (AD) and related dementias (ADRD). With the daunting rise at an exponential rate of ADRD burden and related deaths, the necessity to find a new line of attack is vital. Pathological accumulation of microtubule associated protein tau in neurons is a major neuropathological hallmark of Alzheimer’s disease (AD) and related tauopathies. Attempts have been made to promote clearance of pathological tau (p-Tau) from neurons via autophagy. Transcription factor EB (TFEB) has shown to clear p-Tau from neurons via autophagy. However, sustained TFEB activation and autophagy can create burden on cellular …

Identification Of A Novel Class Of Er-Selective Ligands Lacking Cross-Reactivity To Gper, Richard A. Pepermans

Biomedical Sciences ETDs

Estrogen plays multiple roles in health and disease, exerting its effects through the classical estrogen receptors (ERα and ERβ) and the G protein‑coupled estrogen receptor (GPER). Current ER‑targeting ligands, including the therapeutic ERα antagonist tamoxifen, have been shown to cross‑activate GPER. This cross‑activation is hypothesized to contribute to clinically observed endocrine resistance in breast cancer, highlighting the potential benefit of truly ER‑selective antagonists. We report the identification of a novel class of ER‑selective ligands that lack cross‑reactivity towards GPER, identifying a truly ER‑selective agonist (AB‑1) and antagonist (AB‑82P). Importantly, AB‑82P degrades a clinically relevant ERα mutant and exhibits inhibitory effects …

Determining The Pathological Effects Of Prenatal Alcohol Exposure On Peripheral Neuropathy Via Spinal And Peripheral Immune Mechanisms, Joshua J. Sanchez

Biomedical Sciences ETDs

Previous studies have suggested that children with Fetal Alcohol Spectrum Disorder (FASD) display hypersensitivity to light touch. In support of this notion, we have demonstrated that applying a chronic constriction injury (CCI) to the sciatic nerve of rats that have prenatal alcohol exposure (PAE) results in heightened sensitivity to light touch, clinically termed allodynia. These observations coincided with heightened glial activation and enhanced peripheral immune reactivity. Considering allodynia is known to be mediated by both peripheral immune responses and spinal glial activation, it is reasonable to speculate that allodynia following PAE may be mediated through an alteration of immune reactivity. …

Utilizing Quantitative Fluorescence Microscopy To Study Oncogenesis, Ellen W. Hatch

Biomedical Sciences ETDs

Quantitative fluorescence microscopy is a highly technical, swiftly evolving field of methodologies that are uniquely able to probe the nano-scale biological environment. With these optimized, advanced technologies available, scientists and medical providers are equipped to illuminate a plethora of puzzles in science and medicine through the multiplexing and high spatiotemporal resolution offered. Here I first exploit these capabilities to study a rare cancer with multiplex immunohistofluorescence (IHF) to confirm cell type and undocumented protein expression that may have implications for our understanding of the biology of mast cells and the potential efficacy of treatment and symptom management in mast cell …

Determining Mediators Of Naive T Cell Motility And Dc Association In The Lymph Node, Janie R. Byrum

Biomedical Sciences ETDs

To become activated and perform effector functions, naive T cells move within lymph nodes to scan dendritic cells presenting antigen. Previous work has shown naive T cell activation is promoted by interleukin 7 in vivo, and it does so by regulating the T cell:dendritic cell interaction. Our work identifies a novel role for IL-7 in mediating naive T cell motility in the lymph node and promoting T cell association with DCs. Additionally, we have developed a method for analyzing microscopy images, regionalized normalized mutual information, to assess intercellular associations between T cells and other cells within the lymph node. Dendritic …

Mechanisms Of Arsenic-Induced Suppression Of Early Red Blood Cell Development, Sebastian Medina

Biomedical Sciences ETDs

Anemia adversely impacts the health of more than a billion people worldwide. A strong association between anemia and arsenic exposure has been reported in epidemiological studies from multiple countries. However, the mechanistic bases for the association between arsenic exposure and anemia is not fully understood. In this study, we found an inverse association between drinking water arsenic exposures and clinical indicators of anemia (i.e., red blood cell counts and hematocrit/packet cell volumes) in a cohort of men from rural Bangladesh enrolled in the Health Effects of Arsenic Longitudinal Study.

Follow-up studies in mice, revealed that 60-day exposure to trivalent inorganic …

Comprehensive Sequencing With Surface Tagmentation Based Technology, Kuan Feng

Biomedical Sciences ETDs

Next-generation sequencing technologies (NGS) have undergone extensive improvements since the invention of the 454 sequencing system in 2005. With tremendous progress in throughput, speed and a dramatic reduction in per-base cost, DNA sequencing is widely used in basic science as well as translational research. However, it is still a challenge to acquire a complete human genome. The long-range information is often missing due to the short length of NGS reads, which leaves many gaps in between scaffolds rather than an entire piece for each chromosome. Moreover, without the long-range information, haplotype-resolved genome sequencing and structural variant detection can be difficult, …

The Tetraspanin Cd82 Regulates Hematopoietic Stem Cell Fitness And Bone Marrow Retention, Chelsea Saito-Reis

Biomedical Sciences ETDs

The maintenance of the hematopoietic stem and progenitor cell (HSPC) population is critical to sustaining the adult blood and immune system throughout an organism’s lifespan. The bone marrow microenvironment plays a key role in the regulation of HSPC maintenance and functions. Previous work from our lab has identified the tetraspanin CD82 as an important modulator of HSPC interactions with the bone marrow niche. However, the mechanisms as to how CD82 contributes to the maintenance, trafficking and retention of HSPCs with the niche remained unclear. First, we investigated how CD82 promotes HSPC quiescence, homing and engraftment using a global CD82 knock …

Niemann-Pick C1, Its Connection To Obesity, And Its Impact On Human Evolution, Joseph Joshua Castillo

Biomedical Sciences ETDs

Niemann-Pick type-C disease is a rare autosomal recessive neurodegenerative disease that classically presents in the first decade, leading to ataxia, vertical-gaze palsy, loss of communication skills, epileptic seizures, and eventually death. The stark reality about NPC disease underlines the important role the NPC1 protein plays in whole-body lipid homeostasis. It is no surprise, then, that the NPC1 gene has been associated with other diseases as well, such as obesity, diabetes, and Ebola virus infection. In this manuscript, a connection will be made that intertwines genetics, biochemical and molecular mechanisms, physiology, and evolutionary pressures, and will explain how a gene, discovered …

Developing Droplet Based 3d Cell Culture Methods To Enable Investigations Of The Chemical Tumor Microenvironment, Jacqueline A. De Lora

Biomedical Sciences ETDs

Adaptation of cancer cells to changes in the biochemical microenvironment in an expanding tumor mass is a crucial aspect of malignant progression, tumor metabolism, and drug efficacy. In vitro, it is challenging to mimic the evolution of biochemical gradients and the cellular heterogeneity that characterizes cancer tissues found in vivo. It is well accepted that more realistic and controllable in vitro 3D model systems are required to improve the overall cancer research paradigm and thus improve on the translation of results, but multidisciplinary approaches are needed for these advances. This work develops such approaches and demonstrates that new droplet-based cell-encapsulation …

Inpatient Initiated Methadone For Chronic Non-Cancer Pain At The University Of New Mexico, Steven Fishburn

Biomedical Sciences ETDs

ABSTRACT

Introduction

Inpatient initiation of methadone is ideal due to associated risks of cardiac arrhythmias and a high incidence of overdose. Evidence based guidelines have been developed for initiation of methadone for chronic noncancer pain (CNCP). The purpose of this study is to describe the frequency of pretreatment testing and high-risk prescribing in patients initiated on methadone at the University of New Mexico Hospital (UNMH).

Methods

A retrospective observational study was conducted using electronic health record data from UNMH, a southwest tertiary care center. We collected data on frequency of (1) pretreatment testing and (2) discharges with concomitant high-risk prescriptions. …

Regulations Of Pathogenic Cd4+ T Helper Lymphocytes In Inflammatory Diseases, Handong Zheng

Biomedical Sciences ETDs

In this comprehensive project, three interrelated studies with distinct foci were employed to understand the regulations of specific CD4⁺ T helper cell population in inflammatory diseases.

Pathogenic TH17 cells play an essential role in the initiation and development of both human multiple sclerosis (MS) and animal experimental autoimmune encephalomyelitis (EAE). Nevertheless, the underlying mechanism by which the pathogenicity of TH17 cells is controlled in the autoimmune neuro-inflammation remains unclear. In aim 1, we revealed that lumican (Lum), an extracellular matrix (ECM) protein, negatively regulates encephalitic TH17 cell responses. Our findings highlighted a TH17 cell-intrinsic effect of Lum in suppressing …

Studying Egfr Signaling Through Single Molecule Imaging And Computational Modeling, Emanuel Salazar Cavazos

Biomedical Sciences ETDs

Signaling through the Epidermal Growth Factor Receptor (EGFR) plays an important role in both physiological and cancer-related processes. In this work, single-molecule microscopy measurements and computational modeling were closely integrated to better understand the mechanisms that regulate EGFR signaling. Technical improvements were made over the previously described Single-Molecule Pull-down (SiMPull) assay to facilitate direct detection of the phosphorylation state of thousands of individual receptors, and thereby estimate both the fraction of receptors phosphorylated at specific tyrosine residues and the frequency of multisite phosphorylation. These improvements enabled the first direct detection of multisite phosphorylation on full-length Epidermal Growth Factor Receptor (EGFR), …

Shape And Surface Chemistry Dictate Cellular Internalization Pathways Of Mesoporous Silica Nanoparticles., Annikka Jensen

Biomedical Sciences ETDs

Advances in the field of nanoparticle biomedical applications have made large strides towards achieving targeted deliver­y of therapeutics and imaging agents. However, less is understood on how the shape of a targeted nanoparticle will alter the level of cellular internalization. The research conducted herein demonstrated that by encasing the bare MSNP with a zwitterionic supported lipid bilayer, referred to as a protocell, the aspect ratio of the MSNP was maintained. However, the non-targeted protocell’s conformal coating drastically diminished the ability of the cell’s active sensory system to recognize the protocell. This finding indicates the cell envokes non-specific macropinocytosis in response …

Effect Of Exercise Interventions On Fatigue For Breast Cancer: A Systematic Review And Meta-Analysis, Julien Succar

Biomedical Sciences ETDs

We conducted a systematic review and meta-analysis on the effect of different exercise interventions on fatigue in patients with breast cancer undergoing active therapy. We found that exercise generally improves fatigue outcomes at 12 weeks after initiation of the exercise intervention. Aerobic exercise intervention improved fatigue, but anaerobic and combination regimens did not show improvement compared to controls. Moreover, no exercise intensity was found to be superior compared to controls. Our findings revealed that there is a need for standardization of exercise regimens in studies in order to identify the most effective exercise regimen.

Designing Synthetic Environments To Control Valvular Interstital Cells In Vitro, Kent E. Coombs

Biomedical Sciences ETDs

Aortic valve disease (AVD) is a large contributor to health costs in the United States affecting 2.8% of the population greater than 75 years old. With a growing elderly population due to medical advances, AVD will continue to rise in prevalence over time. Current treatments for AVD are insufficient due to a lack of preventative therapies and the bioprosthetic valves used for surgical replacement have major limitations. Tissue engineered heart valves (TEHVs) present an ideal solution to current AVD needs because of their biocompatibility, capability to integrate with the host’s tissue, and ability to utilize the natural repair mechanisms of …

Intestinal Permeability And Microbial Dysbiosis In Acute Coronary Syndrome (Miacs Study), Tarik Alhmoud

Biomedical Sciences ETDs

Background: Acute Coronary Syndrome (ACS) is a leading cause of morbidity and mortality. Metabolic syndrome and obesity are major risk factors for atherosclerosis and ACS. Dysbiosis plays an important role in metabolic syndrome and obesity. Studies show a markedly increased risk of heart attacks in patients with high levels of the pro-atherogenic metabolite trimethylamine-N-Oxide (TMAO). TMAO is produced by the intestinal microbial flora through metabolism of dietary phospholipids; Gram-negative bacteria (Phylum Proteobacteria) is the major source of TMAO metabolism. Patients with obesity and metabolic syndrome have a defective intestinal tight-junctional (TJ) barrier, which allows paracellular permeation of luminal antigens such …

V-Atpase Roles In Prostate Cancer, Yamhilette Licon Munoz

Biomedical Sciences ETDs

Vacuolar ATPase (V-ATPase) is responsible for maintaining the acidic pH of the endomembrane system in eukaryotic cells. V-ATPase active transport of protons generates the differential luminal pH in lysosomes, endosomes, and the Golgi. In addition to intracellular V-ATPase, cancer cells have V-ATPase at the plasma membrane. Plasmalemmal V-ATPase acidifies the extracellular milieu and enhances cell motility and invasion, evidence that V-ATPase contributes to tumorigenic phenotypes. We studied V-ATPase cellular functions in prostate cancer (PCa), the most commonly diagnosed cancer for men in the United States. V-ATPase inhibitors decreased invasion and migration of PCa cells. In aggressive PCa cell lines, C4-2B …

Mathematical Modeling Of Nanoparticle Biodistribution, Prashant Dogra

Biomedical Sciences ETDs

The prospects of nanoparticle-based drug delivery and imaging have been hindered by insufficient understanding of the effects of nanoparticle physicochemical properties on their in vivo disposition. Here, we present an integrative mathematical modeling and in vivo imaging approach to quantify the relationship between nanoparticle physicochemical properties, namely, size, surface charge, and surface chemistry, on their in vivo disposition kinetics in healthy rats. We developed simple master equations in closed-form to accurately represent the time-dependent concentration of nanoparticles in different regions of the body and obtain functional relationships for predictive purpose to support rational design of nanomedicine. We further used …

Cholesterol Regulation Of Pulmonary Endothelial Calcium Entry Following Chronic Hypoxia, Bojun Zhang

Biomedical Sciences ETDs

Chronic hypoxia (CH)-induced pulmonary hypertension (PH) is associated with diminished ATP-induced endothelial Ca2+ entry as well as membrane cholesterol in pulmonary arteries. Store-operated Ca2+ entry (SOCE) and depolarization-induced Ca2+ entry are major components of the response to ATP and are similarly decreased after CH. Because endothelium-dependent vasodilation is closely associated with pulmonary endothelial [Ca2+]i, the blunted agonist-induced Ca2+ influx in pulmonary artery endothelial cells (PAEC) may contribute to the development of CH-induced PH. Interestingly, impaired agonist-induced Ca2+ influx in PAEC following CH can be restored by membrane cholesterol supplementation. In the current studies, we hypothesized that impaired Ca2+ entry in …

Post-Transcriptional Regulation Of Addiction-Related Behaviors: Opposing Roles Of Nucleus Accumbens Mir-495 And Hud, Robert J. Oliver Jr

Biomedical Sciences ETDs

Substance use Disorders (SUDs) are characterized by chronic relapse after periods without symptoms. This has been hypothesized to stem from persistent alterations in corticolimbic circuit function and structure caused by drug-induced alterations in addiction-related gene (ARG) expression. Transcriptional and epigenetic regulation of ARGs and addiction-like behaviors have been well characterized but the role of post-transcriptional regulation is an understudied, yet promising field. RNA binding proteins (RBPs) are one post-transcriptional regulator of mRNA stability. HuD is a neuronal specific RBP that stabilizes mRNAs and is regulated by neuronal activity and cocaine. Another type of post-transcriptional regulator, microRNAs (miRNAs), are non-coding RNAs …

Patient Centered Family Planning Care, Lauren Thaxton Md, Mba

Biomedical Sciences ETDs

The Institute of Medicine defines six important domains of health care quality: safety, efficacy, timeliness, efficiency, equitable delivery and patient-centeredness. Quality family planning care aims to provide individuals with the tools needed to engage in healthy and satisfying sex lives while planning and spacing pregnancies to achieve desired family size. The field of family planning strongly relies on the domain of patient-centeredness as individual values and preferences guide clinical care. Yet large gaps in knowledge exist in understanding how to improve patients’ clinical experience. This hybrid thesis posits avenues for improving the quality and patient-centeredness of clinical care.

Quality care …

Exploring Biological Heterogeneity And Its Consequences At Tissue And Cellular Scales Through Mathematical And Computational Modeling, Romica Kerketta

Biomedical Sciences ETDs

This dissertation explores the effects of heterogeneity across different biological scales in cancer as well as normal cells. At the tissue scale, we investigated the variability present in the tumor microenvironment and its effect on patient chemotherapeutic outcomes using a mathematical model of drug transport. We found that parameters such as tumor blood perfusion and radius of blood vessel had an impact on the tumor cytotoxicity. This indicated that the physical microenvironment of the tumor is an important regulator of the tumor response to chemotherapy. At the cellular scale, we investigated the heterogeneity present on the membrane landscape of ErbB2 …

Photography And Catalogue Of Cutaneous Vascular Malformations Of Patients With Ccm1- Chm Cerebral Cavernous Malformations, Athanasios K. Manole

Biomedical Sciences ETDs

Due to a genetic mutation, a rare and potentially fatal disease has spread throughout New Mexico. This disease, Familial Cerebral Cavernous Malformation (FCCM1-CHM), is due to a mutation that affects peoples of Hispanic heritage in New Mexico. The FCCM disease is characterized by the development of dilated, thin walled, leaky vessels that occur in the brain and spinal cord. As a result of this genetic mutation, the lesions in the blood vessels of the brain and spinal cord are highly susceptible to hemorrhaging into surrounding tissue. This can lead to headaches, seizure, and possibly death. Researchers at the University of …