Analytical, Diagnostic and Therapeutic Techniques and Equipment Commons^™

The Role Of Ucp2 In Pancreatic Cancer Metabolism And Its Potential As A Radiosensitizer, Emily Rieff

Dissertations and Theses (Open Access)

Uncoupling protein 2 (UCP2) is a mitochondrial protein that regulates the flow of protons down the gradient established by the electron transport chain (ETC) without generating ATP, thus uncoupling the proton gradient from ATP generation. In tumors, specifically pancreatic cancer (PDAC), the ETC is highly stimulated to generate the copious ATP needed by the tumor to grow. However, extended ETC use increases reactive oxygen species (ROS), and if left unchecked, results in cell death. To evade this, PDAC employs antioxidant strategies, including upregulating UCP2 in tumor cells. In addition to its uncoupling function, UCP2 indirectly controls ROS levels by maintaining …

Functional Contribution Of Epithelial To Mesenchymal Transition Program On Krasg12d Targeting Efficacy In Pancreatic Cancer, Ana S. Maldonado

Dissertations and Theses (Open Access)

Functional contribution of epithelial to mesenchymal transition program on KRAS^G12D targeting efficacy in pancreatic cancer

Ana S. Maldonado, BS

Advisory Professor: Raghu Kalluri, M.D., Ph.D.

Pancreatic Ductal Adenocarcinoma (PDAC), a highly aggressive, metastatic, and therapeutically resistant form of pancreatic cancer has been projected to become the second-leading cause of cancer related mortality in the United States. This is driven by its detection difficulty, treatment efficacy, and asymptomatic nature, among other factors. PDAC is driven predominantly by KRAS^G12D mutations, which are responsible for the initial development of pancreatic intraepithelial neoplasia (Pan-IN) lesions, that are further maintained and progressed until …

Inclusion Of Adoption As A Pregnancy Management Option In Prenatal Genetic Counseling Practice, Emma Billings

Dissertations and Theses (Open Access)

Prenatal genetic counselors are essential to providing education, psychosocial support, and guidance on pregnancy options to patients who receive a fetal diagnosis of an anomaly or genetic condition. Therefore, genetic counselors should be well-educated on comprehensive pregnancy management options consisting of parenting, abortion, and adoption. The landscape of adoption education in genetic counseling practice was last characterized in 2010 by Perry and Henry, revealing substantial variability in both the inclusion of adoption-specific education in genetic counseling program (GCP) curricula and the discussion of pregnancy options with patients in prenatal practice. As a result, the authors published a call to action …

Gene Expression–Based Algorithms For The Identification Of Drug Combinations In Personalized Medicine, Lon Fong

Dissertations and Theses (Open Access)

Three of the major problems facing cancer therapeutics are 1) drug resistance, the intrinsic or acquired ability of cancer cells to evade the effect of the therapies used to treat them; 2) heterogeneity among individual patients’ disease at the molecular level and the resulting variability in therapeutic response; and 3) the limitations of genomics biomarkers in matching patients to the most effective therapy. One possible solution to drug resistance is the use of combination therapies rather than monotherapies. Use of multiple drugs, each with a different mechanism of action, lowers the chances that the cancer cells will develop or have …

The Diagnostic Odyssey Of Hypermobile Eds Patients: Diagnosis, Clinical Expectations, And Psychosocial Concerns, Madeline Alpar

Dissertations and Theses (Open Access)

Background: Ehlers-Danlos syndrome (EDS) is a highly variable, heritable connective tissue disorder. Hypermobile EDS (hEDS) is the most common subtype of EDS and has no identifiable underlying genetic etiology. Patients with clinical features of hEDS face a long diagnostic odyssey due to lack of genetic testing and wide clinical heterogeneity. Additionally, recent research has shown that genetic institutions limit evaluations for suspected hEDS, adding another barrier to care.

Methods: We developed an online patient survey to explore the diagnostic odyssey of hEDS for those who were diagnosed with or suspicious for hEDS. This survey included sections on demographics, diagnostic information …

Impact Of Personal, Familial, And Socioeconomic Factors On The Return Of Remotely Collected Samples For Genetic Testing, Jordan Zeiger

Dissertations and Theses (Open Access)

There are a multitude of barriers known to impact access to medical care in the United States. COVID-19 has changed and compounded these barriers and led to a shift in the setting of the genetic counseling (GC) appointment, and in sample types used for genetic testing, specifically with use of telemedicine and remotely collected saliva kits. Previous studies have described lack of patient follow-through in returning these kits. Though the understanding of barriers to medical care, including access to genetics services, is well described, there is little in the literature for how these barriers impact the return of remotely collected …

Potentiation Of The Immune Checkpoint Blockade Response By Metabolic Modulation Is Predictable Using Molecular Imaging, Renee L. Chin

Dissertations and Theses (Open Access)

Unregulated cell division is a hallmark of cancer. The high metabolic needs of the tumor cells result in nutrient depletion and produce a hostile tumor microenvironment (TME) for antitumor immune cells, protecting the tumor from immune cell-mediated control and immunotherapy. Two of these environmental factors, acidosis and hypoxia, are commonly found in solid cancers. In my thesis, I posited that modulation of tumor acidosis and hypoxia can serve as biomarkers by indicating immunogenicity and tumor sensitivity to immune checkpoint blockade (ICB) as monitored using molecular imaging. Esomeprazole was found to promote tumor immunogenicity and induce tumor control when used to …

Infrastructure Development For Personalized Risk Prediction To Reduce Cardiovascular Disease In Childhood Cancer Survivors, Suman Shrestha

Dissertations and Theses (Open Access)

Although childhood cancer survivors have lengthy life expectancies, they run the risk of experiencing long-term health issues as a result of their treatment. The most frequent non-cancerous cause of morbidity and mortality for these survivors is cardiac disease. Radiation therapy (RT) has been linked in numerous cohort studies to a higher chance of developing a late cardiac disease in these survivors, and this risk rises with higher mean heart doses and increased RT exposure to larger cardiac volumes. Since, the heart is a heterogeneous organ made up of several distinct substructures, RT dose received by the entire heart does not …

Cell-Free Dna Sequencing In Multiple Myeloma, Russell Irwin

Dissertations and Theses (Open Access)

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

Development Of Advanced Mr-Guided Adaptive Radiation Therapy Methods For Head & Neck Cancers On The 1.5t Mr-Linac, Brigid Mcdonald

Dissertations and Theses (Open Access)

The 1.5T hybrid MRI/linear accelerator (MR-linac) has recently been introduced into clinical practice and used for the treatment of head and neck cancers (HNC). This device enables on-line adaptive radiation therapy (ART) based on anatomical changes throughout treatment and variations in patient position. This novel technology also has the potential for advanced ART strategies such as dose-optimized ART, in which the treatment plan is optimized based on the accumulated dose over previous fractions, or biological image-guided ART, in which the plan is adapted based on individual tumor response as measured through quantitative imaging techniques such as diffusion-weighted imaging (DWI). The …

Roles Of Oxidative Stress And Dna Methylation In Cigarette Smoking-Induced Accelerated Acute Myeloid Leukemia Progression, Mary Figueroa

Dissertations and Theses (Open Access)

Acute myeloid leukemia (AML) is a commonly diagnosed cancer in smokers. When current or former smokers have AML, they have worse survival compared to never smoking patients. This has been observed clinically for decades, but then it is unknown how smoking leads to worsened AML survival. Smoking causes oxidative stress and altered DNA methylation that persists for decades in peripheral blood mononuclear cells, but these changes from smoking have not been evaluated in the context of AML. We hypothesize that smoking-induced molecular changes, including altered DNA methylation associated with poor AML prognosis, promote AML. We developed a novel model to …

Targeting Metabolic Adaptations To Anti-Angiogenic Therapy In Ovarian Cancer, Deanna M. Glassman, Deanna Glassman

Dissertations and Theses (Open Access)

ABSTRACT

Background: Ovarian cancer is the most lethal gynecologic malignancy. Despite modest clinical improvements with anti-VEGF antibody (AVA) therapy, adaptive resistance is nearly ubiquitous and additional therapeutic options are limited. A dependence on glutamine metabolism, via the enzyme glutaminase (GLS), is a known mechanism of adaptive resistance.

Purpose: To assess the efficacy of a glutaminase inhibitor as a means of exploiting the metabolic vulnerability of glutamine dependence that develops as a result of adaptive resistance to AVA therapy.

Experimental Design: We used a glutaminase inhibitor (GLSi) synthesized at MD Anderson Cancer Center for all in vitro and in vivo experiments. …

Nanoparticles For Biomedical Applications, Joseph Kim

Dissertations and Theses (Open Access)

This thesis presents development and evaluation of the potential of three new nanoparticles for biomedical applications. With the rapid growth of the field of nanoscience, researchers have explored developing nanoparticles for various biomedical applications, including imaging, therapy, and drug delivery. This thesis demonstrates the development of two C­₆₀ fullerene based nanoparticles and one boron based nanoparticle to answer key questions related to their biological potential.

In the first part of the thesis, we describe synthesis and characterization of a pure boron nanoparticle containing asolectin phospholipid-based liposome construct prepared using a water-in-oil emulsion method, as a novel alternative agent for …

Lgr5 Regulation Of Stat3 Signaling And Drug Resistance In Colorectal Cancer, Tressie Posey, Tressie Alexandra Posey

Dissertations and Theses (Open Access)

LGR5 Regulation of STAT3 Signaling and Drug Resistance in Colorectal Cancer

Tressie Alexandra Capri Posey B.S.

Advisory Professor: Kendra Carmon, Ph.D.

The greatest difficulty in treating colorectal cancer (CRC) is the development of drug resistance which leads to relapse after treatment and progression to metastasis. Cancer stem cells (CSCs) are believed to drive relapse because of their capacity to self-renew, acquire resistance mechanisms, and differentiate promoting tumor growth and heterogeneity. Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), is a bona-fide marker of CSCs and has been considered a viable target for CSC specific therapeutic development. While we showed targeting LGR5 …

Effect Of Lactoferrin To Increase Drug Permeability Of Primary Pulmonary Mycobacterial Granulomas, Thao Nguyen, Thao Kt Nguyen

Dissertations and Theses (Open Access)

Despite extensive research and worldwide eradication efforts, Mycobacterium tuberculosis (Mtb) remains a major infectious pathogen to the human population with about 10 million cases of infection per year globally. The host-pathogen interaction, pulmonary granuloma formation, and Mtb adaptions result in increased complexity of the disease. Granulomas are formed by active immune responses generated during Mtb infection, and serve to contain and limit bacterial dissemination. The major mycobacterial surface mycolic acid, trehalose 6,6'-dimycolate (TDM), functions in multiple ways to enhance immune cell recruitment of sites of infection, to induce inflammation and granulomatous responses, and to initiate survival strategies for …

Development Of Quantitative Molecular Photoacoustic Imaging For Noninvasive Cancer Diagnostics, Cayla Zandbergen

Dissertations and Theses (Open Access)

Traditional diagnostic imaging provides clinicians with anatomical information that guides both diagnosis and treatment planning; however, once a tumor has progressed enough to be visible, it has often reached an advanced stage. Molecular imaging techniques allow for real-time visualization of chemical and biological processes via imaging of specific biomarkers, which can facilitate detection of malignancies before they become visible. One biomarker of interest is blood oxygen saturation (SO₂) due to its correlation with hypoxia, which is associated with increased tumor malignancy; some studies have also established SO₂ as an independent biomarker of disease progression. Additionally, because cancerous …

Imaging Based Prediction Of Pathology In Adult Diffuse Glioma With Applications To Therapy And Prognosis, Evan Gates

Dissertations and Theses (Open Access)

The overall aggressiveness of a glioma is measured by histologic and molecular analysis of tissue samples. However, the well-known spatial heterogeneity in gliomas limits the ability for clinicians to use that information to make spatially specific treatment decisions. Magnetic resonance imaging (MRI) visualizes and assesses the tumor. But, the exact degree to which MRI correlates with the actual underlying tissue characteristics is not known.

In this work, we derive quantitative relationships between imaging and underlying pathology. These relations increase the value of MRI by allowing it to be a better surrogate for underlying pathology and they allow evaluation of the …

Investigating Diffusion Tensor Imaging Correlates Of Cognitive Impairment In Idiopathic Normal Pressure Hydrocephalus And Alzheimer's Disease, Omar Hasan, Omar Hasan

Dissertations and Theses (Open Access)

Modest expansion of the human brain cerebrospinal fluid (CSF)-filled ventricles is normal with aging, and because of this, it can be difficult for physicians to accurately diagnose and treat enlarged ventricles (ventriculomegaly), called hydrocephalus¹ (fluid or water in the brain) Ventriculomegaly occurs due to an obstruction (such as a blood clot or tumor), or a change in CSF absorption². Primary hydrocephalus, also called idiopathic normal pressure hydrocephalus (iNPH), is non-obstructive and may be comorbid with other neurodegenerative diseases such as Alzheimer’s disease (AD) or frontotemporal dementia (FTD). Clinically, it can be difficult to tell whether the pathophysiological …

Longitudinal Clonal Lineage Dynamics And Functional Characterization Of Pancreatic Cancer Chemo-Resistance And Metastasization, Chieh-Yuan Li

Dissertations and Theses (Open Access)

In recent years, technological advancements, such as next-generation sequencing and single-cell interrogation techniques, have enriched our understanding in tumor heterogeneity. By dissecting tumors and characterizing clonal lineages, we are better understanding the intricacies of tumor evolution. Tumors are represented by the presence of and dynamic interactions amongst clonal lineages. Each lineage and each cell contributes to tumor dynamics through intrinsic and extrinsic mechanisms, and the variable responses of clones to perturbations in the environment, especially therapeutics, underlie disease progression and relapse. Thus, there exists a pressing need to understand the molecular mechanisms that determine the functional heterogeneity of tumor sub-clones …

Development Of A Ct Metal Artifact Management Algorithm For Proton Therapy Planning (Ampp) For Head And Neck Cancer Patients, Daniela Branco

Dissertations and Theses (Open Access)

Purpose: Dental amalgams (high Z materials) are common sources of artifacts in Head and Neck (HN) images. Commercial artifact reduction techniques have been offered, but many are impractical, produce inaccurate CT images or are not clinically available, thus not widely implemented. The goal of this work is to use CT gantry tilts to develop and evaluate a stereoscopic HN metal artifact management algorithm and investigate its improvement in proton treatment planning.

Methods: The in-house CT metal artifact management method for proton planning (AMPP) uses two angled CT scans to generate a single image set with no metal artifacts posterior …

Characterization Of Treatment Planning System Photon Beam Modeling Errors In Iroc Houston Phantom Irradiations, Mallory Glenn

Dissertations and Theses (Open Access)

In radiation therapy, proper commissioning of the treatment planning system’s (TPS) dose calculation algorithm is critical because any errors in this process impact all treatment plans prepared in the system. Previously, TPS errors have been identified as a major cause for poor phantom irradiation performance, which may also mean that patients are treated suboptimally. The purpose of this work was to investigate the TPS beam modeling developed by the radiotherapy community to understand where inconsistencies may arise, which variables are most susceptible to variations, and in what way changing these variables can alter dose calculations.

Using the Imaging and Radiation …

Investigating The Metabolic Progression Of Glioblastoma With Hyperpolarized Magnetic Resonance, Travis Salzillo

Dissertations and Theses (Open Access)

Rapid diagnosis and therapeutic monitoring of aggressive diseases such as glioblastoma (GBM) can improve patient survival by providing physicians the time to optimally deliver treatment. This includes early in development, while the tumor is still manageable, or following initial therapy, when alternative treatments should be considered. The main goal of this project was to determine whether metabolic imaging with hyperpolarized magnetic resonance spectroscopy (MRS) could detect changes in tumor progression more rapidly than conventional anatomic magnetic resonance imaging (MRI) in patient-derived GBM murine models. To comprehensively capture the dynamic nature of cancer metabolism, in vivo pyruvate-to-lactate conversion with hyperpolarized MRI, …

Molecular Mechanisms Of Antimicrobial Resistance In Multi-Drug Resistant Enterococci, Ayesha Khan

Dissertations and Theses (Open Access)

Antibiotic resistance is a major global public health threat. Enterococci are recalcitrant, nosocomial pathogens that can be intrinsically resistant to valuable antibiotics, like beta-lactams, or evolve resistance to all existing antimicrobials. The LiaFSR system regulates resistance to cell membrane (CM) stressors like daptomycin (DAP), a front-line drug for multi-drug resistant infections. DAP resistance (DAP-R) in E. faecalis is mediated by CM phospholipid alterations. Emergence of DAP-R often leads to b-lactam resensitization, a phenomenon called the seesaw effect. The molecular mechanism of DAP-R and the seesaw effect are unknown. Here we show that LiaX is a surface exposed protein whose C-terminal …

Identification And Molecular Analysis Of Dna In Exosomes, Jena Tavormina

Dissertations and Theses (Open Access)

Exosomes are heterogeneous nanoparticles 50-150nm in diameter. Exosomes contain many functional cargo components, such as protein, DNA, and RNA. While protein and RNA exosome content has been extensively studied, very little work has been done to characterize exosomal DNA. Here, we demonstrate that exosomal DNA is heterogeneous and its packaging into exosomes is dependent on the cell of origin. Furthermore, through a rigorous assessment of various isolation methods, we identify Size Exclusion Chromatography (SEC) as the best method for the isolation of exosomal DNA for downstream applications. Additionally, we evaluate the methylation status of exosomal DNA and demonstrate that exosomal …

Evaluating The Therapeutic Efficacy Of Grb2 Inhibition In Ovarian Malignancies, Olivia Lara

Dissertations and Theses (Open Access)

Purpose: Adaptor proteins such as growth factor receptor-bound protein-2 (Grb2) play important roles in cancer cell signaling. In the present study, we examined the biological effects of liposomal antisense oligodeoxynucleotide that blocks Grb2 expression (L-Grb2) in ovarian cancer models.

Experimental Design: Murine orthotopic models of ovarian cancer (OVCAR5 and SKOV3ip1) were used to study the biological effects of L-Grb2 on tumor growth. In vitro experiments (cell viability assay, Western blot analysis, siRNA transfection, and reverse phase protein array) were carried out to elucidate the mechanism and potential predictors of tumor response to L-Grb2.

Results: Treatment with L-Grb2 decreased tumor growth …

Multimodality Somatostatin Analog For Fluorescence-Guided Surgery In Cancer, Servando Hernandez Vargas

Dissertations and Theses (Open Access)

Cancer surgery remains the primary curative treatment for most solid cancers and has major therapeutic implications for patients with neuroendocrine tumors (NETs). Anatomical and functional imaging technologies are widely used during the pre- and postoperative stages, but intraoperative disease recognition relies on direct visual inspection and the hands of surgeons. The limited number of clinical tools for real-time intraoperative visual feedback restricts the ability to remove the complete cancer source and is partially responsible for the high rate of disease recurrence in patients. Intraoperative imaging with fluorescent contrast agents has the potential to improve the ability of surgeons to detect …

Development Of Automated Radiotherapy Treatment Planning For Cervical And Breast Cancer For Resource-Constrained Clinics, Kelly Kisling

Dissertations and Theses (Open Access)

Globally, cancer rates are on the rise, especially in low- and middle-income countries (LMICs). However, many of these countries lack access to radiotherapy, which is due in part to a substantial shortage of the staff necessary to deliver safe and effective radiotherapy. This staff shortage could be mitigated by the automation of the radiation treatment planning process. To this end, we developed automated planning for cervical and postmastectomy breast cancer radiotherapy, the two most common types of cancer in women in many LMICs.

For radiotherapy of cervical cancer in resource-constrained clinics, the recommended treatment technique is a four-field box. We …

Simvastatin Does Not Sensitize Ibc3 Her2+ Inflammatory Breast Cancer Brain Metastases To Whole Brain Irradiation In An Immunocompromised Mouse Model, Swaminathan Kumar

Dissertations and Theses (Open Access)

Retrospective data analysis suggests that inflammatory breast cancer (IBC) patients who take statins have better locoregional control after radiotherapy than those who do not [23]. Our lab has previously demonstrated that simvastatin radiosensitizes IBC cells in vitro [23], and brain metastases have strong expression of cholesterol-regulation genes compared to lung metastases in vivo [unpublished]. Delaying whole-brain irradiation (WBI) beyond 21 days is insufficient to reduce the incidence of brain metastases (developed by injecting IBC3 cells through the tail vein) in our mouse model because even high rates of cell killing leave substantial cell volume in established metastases [unpublished].

With the …

Discovery And Effects Of Pharmacological Inhibition Of The E3 Ligase Skp2 By Small Molecule Protein-Protein Interaction Disruptors, John K. Morrow

Dissertations and Theses (Open Access)

Skp2 (S-phase kinase-associated protein 2), one component of the SCF E3 ubiquitin ligase complex, directly interacts with Skp1 and indirectly associates with Cullin1 and Rbx1 to bridge the E2 conjugating enzyme with its protein substrate to execute its E3 ligase activity. Skp2 is an Fbox protein (due to it containing an Fbox domain) and it is the rate-limiting component of the SCF complex. Skp2 targets several cell-cycle regulatory proteins for ubiquitination and degradation; most notable and significant for cancer are the cyclin-dependent kinase inhibitor, p27. Skp2 is an oncogene and studies have shown that over-expression of Skp2 leads to increased …

Evaluating The Therapeutic Efficacy Of Restoring Wild-Type P53 Activity In P53-Mutant Tumors, Connie A. Larsson

Dissertations and Theses (Open Access)

The p53 transcription factor is the most frequently altered in human cancers usually via missense mutations that undermine its transcriptional activity. Clinically, TP53 mutations have been shown to be remarkably predictive of refractoriness to treatment, resulting in poor outcome. Consequently, the development of p53 pathway activating agents is rapidly evolving and gaining more attention in cancer therapeutics research, with several small molecule compounds currently in preclinical and clinical trials. However, it remains largely unknown what types or proportions of p53-mutant tumors will respond to p53 restoration-based therapies.

Using a mouse model of Li Fraumeni syndrome, we genetically restored wild-type …