Digital Commons Network^™

Targeting Plasma Membrane Phosphatidylserine Content To Inhibit Oncogenic Kras Function, Walaa E. Kattan

Dissertations and Theses (Open Access)

The small GTPase KRAS, which is frequently mutated in human cancers, must be localized to the plasma membrane (PM) for biological activity. We recently showed that the KRAS C-terminal membrane anchor exhibits exquisite lipid-binding specificity for select species of phosphatidylserine (PtdSer). We therefore investigated whether reducing PM PtdSer content is sufficient to abrogate KRAS oncogenesis. Oxysterol-related binding proteins ORP5 and ORP8 exchange PtdSer synthesized in the ER for phosphatidylinositol-4-phosphate (PI4P) synthesized in the PM. We show that depletion of ORP5 or ORP8 reduced PM PtdSer levels, resulting in extensive mislocalization of KRAS from the PM. Concordantly, ORP5 or ORP8 depletion …

Synthetic Essentiality Of Tdo2 In Apc-Mutated Colorectal Cancer, Rumi Lee

Dissertations and Theses (Open Access)

Inactivation of the adenomatous polyposis coli (APC) tumor suppressor is

common genetic event across many cancers and serves a critical initiating

event in the majority of sporadic colorectal cancers (CRC). The WNT/APC

pathway remains an elusive target for cancer, prompting us to explore

orthogonal strategies to identify specific vulnerabilities for APC-deficient

CRC and other cancers. Using the concept of synthetic essentiality (SE), we

sought to identify essential effectors of APC deficiency with the goal of

expanding targetable vulnerabilities in CRC. We identified Tryptophan 2,3-

dioxygenase 2 (TDO2) as an SE gene for APC-deficient cancers.

Mechanistically, APC loss results in TCF4/b-catenin-mediated …

Library Brown Bag Webinar At The Tmc Library, Beatriz Varman

TMC Library Newsletter (2015-)

The TMC Library is Offering the Following "Brown Bag" Webinar Introduction to Archives and the McGovern Historical Center Tuesday, September 21st, 2021 from noon - 12:30 pm.

Epithelial Memory Of Resolved Inflammation Limits Tissue Damage While Promoting Pancreatic Tumorigenesis, I-Lin Ho

Dissertations and Theses (Open Access)

Inflammation is a major risk factor for pancreatic ductal adenocarcinoma. When occurring in the context of pancreatitis, mutations of KRAS accelerate tumor development. We discovered that long after its complete resolution, a transient inflammatory event primes pancreatic epithelial cells to subsequent transformation by oncogenic KRAS. Upon recovery from acute inflammation, epithelial cells of the pancreas display an enduring adaptive response associated with sustained transcriptional and epigenetic reprogramming. Such adaptation enables the prompt reactivation of acinar-to-ductal metaplasia (ADM) upon subsequent inflammatory events, thus efficiently limiting tissue damage via rapid decrease of zymogen production. We propose that since activating mutations of KRAS …

Manipulating Enhancer Rna Activity To Study Their Roles In Gene Regulation And Cancer, Zian Liao

Dissertations and Theses (Open Access)

Enhancers are essential regulatory elements that precisely control gene transcription during development and disease. Especially in cancer, enhancers modulate tumor gene expression, and in some cases directly drive tumorigenesis. With the recent advances in next-generation sequencing, researchers discovered that active enhancers are pervasively transcribed into RNAs, which are named enhancer RNAs (eRNAs). Studies have suggested that eRNAs have a functional role in the enhancer action mechanism. Studying their roles will provide a new understanding of gene regulation and cancer development. In my MS study, I focused on using novel methods to study eRNA functions. Using a breast-cancer-specific eRNA, I have …

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 …

Metabolomics Profiling Of Patients With A-Β+ Ketosis-Prone Diabetes During Diabetic Ketoacidosis, Farook Jahoor, Jean W Hsu, Paras B Mehta, Kelly R Keene, Ruchi Gaba, Surya Narayan Mulukutla, Eunice Caducoy, W Frank Peacock, Sanjeet G Patel, Rasmus Bennet, Ake Lernmark, Ashok Balasubramanyam

Faculty, Staff and Students Publications

When stable and near-normoglycemic, patients with “A−β+” ketosis-prone diabetes (KPD) manifest accelerated leucine catabolism and blunted ketone oxidation, which may underlie their proclivity to develop diabetic ketoacidosis (DKA). To understand metabolic derangements in A−β+ KPD patients during DKA, we compared serum metabolomics profiles of adults during acute hyperglycemic crises, without (n = 21) or with (n = 74) DKA, and healthy control subjects (n = 17). Based on 65 kDa GAD islet autoantibody status, C-peptide, and clinical features, 53 DKA patients were categorized as having KPD and 21 type 1 diabetes (T1D); 21 nonketotic patients were categorized as …

The Immunoregulatory Landscape Of Human Tuberculosis Granulomas, Evan Li, Antony Rodriguez, Amber U Luong, David Allen, John Morgan Knight, Farrah Kheradmand, David B Corry

Faculty, Staff and Student Publications

The allergic airway diseases chronic rhinosinusitis (CRS), allergic fungal rhinosinusitis (AFRS), asthma, allergic bronchopulmonary mycosis/aspergillosis (ABPM/A), and cystic fibrosis (CF) share a common immunological signature marked by T H 2 and TH 17 cell predominant immune responses, the production of IgE antibody, and atypical inflammatory cell infiltrate that includes eosinophils and other innate immune effector cells. Severe forms of these disorders have long been recognized as being related to hypersensitivity reactions to environmental fungi. Increasingly however,environmental fungi are assuming a more primary role in the etiology of these disorders, with airway mycosis, a type of non-invasive airway fungal infection,recognized as …

Conserved Non-Pocket Interactions Drive The Diversity Of Peptide Presentation By Mhc Class I Molecules, Kyle Jackson

Dissertations and Theses (Open Access)

Cytotoxic T-lymphocytes (CTL) can lyse infected or transformed cells through recognition of peptides presented on human leukocyte antigen (HLA) molecules. A thorough understanding of peptide-HLA interactions is needed for improvement of CTL-based immunotherapies. We observed that aspartic acid (D) and glutamic acid (E) at peptide position 4 are highly prevalent in HLA-I peptide ligands, and discovered that they interact with arginine (R) in position 65 and lysine (L) in position 66 of the α1 helix of the binding groove in HLA-A*0201 and HLA-A*2402. Since this interaction differed from well-characterized peptide-HLA anchor interactions mediated by peptide position 2 and the C-terminus, …

Pedsql™ Gastroparesis Symptoms Module Domain And Item Development: Qualitative Methods, James W Varni, Robert J Shulman, Mariella M Self, Liz Febo-Rodriguez, Heather Charron, Kent Williams, Sam Nurko, Rachel L Rosen, Bruno P Chumpitazi

Children’s Nutrition Research Center Staff Publications

Objectives: Like adults, children suffer from gastroparesis; however, there are currently no validated instruments to determine the impact of gastroparesis in pediatric patients. The objective of this study was to develop the items and domains to support the content validity of the new Pediatric Quality of Life Inventory (PedsQL™) Gastroparesis Symptoms Module.

Methods: Patients were recruited from the National Institute of Diabetes and Digestive and Kidney Diseases Pediatric Gastroparesis Registry. The qualitative methods involved an iterative process comprising a literature review of existing questionnaires and gastroparesis clinical research, an expert review panel of pediatric gastroenterologists who provided feedback on the …

Recommendations For The Use Of The Veggie Meter® For Spectroscopy-Based Skin Carotenoid Measurements In The Research Setting, Marcela D Radtke, Mykaela Poe, Jodi Stookey, Stephanie Jilcott Pitts, Nancy E Moran, Matthew J Landry, Lewis P Rubin, Virginia C Stage, Rachel E Scherr

Children’s Nutrition Research Center Staff Publications

Carotenoids are a class of phytochemical compounds found in a variety of fruits and vegetables (F/V) and, therefore, are commonly used as a biomarker for F/V intake. The Veggie Meter® is a noninvasive research-grade instrument that detects and quantifies carotenoids in the skin. To determine current practices and examine variability among users, a survey was administered to researchers using the device (n = 19, response rate = 35.8%) and variation in anatomical site preparation, calibration, number of measurements, measurement site, and documentation was observed. A protocol was developed in partnership with Veggie Meter® users to outline the preparation, calibration, …

The Association Between Outdoor Artificial Light At Night And Breast Cancer Risk In Black And White Women In The Southern Community Cohort Study, Qian Xiao, Gretchen L Gierach, Cici Bauer, William J Blot, Peter James, Rena R Jones

Faculty, Staff and Student Publications

No abstract provided.

Combination Of Oncolytic Adenoviruses, T-Cell Activation, And Blockade Of Ido Metabolic Circuitry For The Treatment Of Glioma, Teresa Nguyen

Dissertations and Theses (Open Access)

Glioblastoma is the most common malignant primary brain tumor in adults; the current aggressive treatment results in a 5% five-year survival rate. More effective therapies should be developed. One promising alternative is oncolytic adenovirus, Delta-24-RGD, which elicits cancer cell lysis and immunogenic cell death. In fact, Delta-24-RGD produced complete responses in 20% of recurrent glioblastoma patients through immune mechanisms that activate anti-tumor cytotoxic properties of T-cells. This cytolytic effect can further be enhanced by adding immune agonists, namely OX40L, which engages the OX40 receptor to co-stimulate activated T cells for enhanced proliferation. Hence, we produced the next generation of Delta-24-RGD, …

Identification And Characterization Of De Novo Germline Tp53 Mutation Carriers In Families With Li-Fraumeni Syndrome, Carlos C. Vera Recio

Dissertations and Theses (Open Access)

Li-Fraumeni syndrome (LFS) is an inherited cancer syndrome caused by a deleterious mutation in TP53. An estimated 48% of LFS patients present due to a de novo mutation (DNM) in TP53. The knowledge of DNM status, DNM or familial mutation (FM), of an LFS patient requires genetic testing of both parents which is often inaccessible, making de novo LFS patients difficult to study. Famdenovo.TP53 is a Mendelian Risk prediction model used to predict DNM status of TP53 mutation carriers based on the cancer-family history and several input genetic parameters, including disease-gene penetrance. The good predictive performance of Famdenovo.TP53 was demonstrated …

Unveiling Global Roles Of G-Quadruplexes And G4-22 In Human Genetics, Ruth Barros De Paula

Dissertations and Theses (Open Access)

G-quadruplexes are non-B DNA structures formed by four or more runs of repeated guanines that confer unique features to living organism’s genomes. These sequences are enriched in regulatory regions, such as promoters and 5’ UTRs, and have distinct regulatory roles in both health and disease states. Even though previous studies showed the impact of G4 in gene expression, none of them summarized the location-specific effect of G4. Also, there is no broad understanding about the most common G4 repeat in the human genome, named here as G4-22, and how it links to the evolution of mammals and their biology. In …

Automation Of Radiation Treatment Planning For Cervical Cancer, Dong Joo Rhee

Dissertations and Theses (Open Access)

Cervical cancer is one of the most common cancer in low- and middle-income countries (LMICs). The mortality rate can be reduced if radiation treatment becomes widely available. However, due to the lack of radiation treatment facilities and human resources, many cervical cancer patients in Africa are not able to receive timely treatments or advanced therapies. To increase the availability of radiation treatment in low-and middle-income countries (LMICs) including African countries, many attempts have been made to reduce the cost of medical linear accelerators. However, increasing the number of treatment machines would not instantly resolve the issues, as there would be …

Quantitative Magnetic Resonance Imaging For The Early Prediction Of Treatment Response In Triple Negative Breast Cancer, Benjamin C. Musall

Dissertations and Theses (Open Access)

Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer which lacks upregulated hormone receptors. Because of this, it is not vulnerable to clinically available targeted therapies. When treated with standard of care neoadjuvant systemic therapy (NAST), TNBC only shows approximately a 40% rate of pathologic complete response (pCR). A biomarker which could predict TNBC response to NAST early during treatment would be useful, as it would allow for non-responders to be triaged to alternative therapies and potentially allow for the treatment of responders to be de-escalated.

Quantitative Magnetic Resonance Imaging (MRI) may be used to probe and …

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 …

Understanding The Pathogenesis Of Renal Medullary Carcinoma, Melinda Soeung

Dissertations and Theses (Open Access)

Renal medullary carcinoma (RMC) is a lethal cancer that predominantly affects young individuals with sickle cell trait (SCT). It is not currently understood why RMC only affects certain individuals with SCT. We found that patients with RMC more frequently participated in high-intensity exercise than matched controls. Using mouse models of SCT, we demonstrated the significant increase of renal hypoxia in the right kidney following high- but not moderate-intensity exercise. We also demonstrated in cell culture studies that SMARCB1 is ubiquitinated for proteasome-mediated degradation in hypoxia, and the re-expression of SMARCB1 leads to compromised proliferation in renal cells specifically in the …

Dissecting The Mechanisms Of Venetoclax Resistance In Myelodysplastic Syndromes, Shuaitong Chen

Dissertations and Theses (Open Access)

Myelodysplastic syndromes (MDS) are a class of heterogeneous clonal hematopoietic disorders. The current standard of care for MDS is the hypomethylating agent (HMA)-based therapy. However, only 50 percent of the patients respond, with transient effects and no approved second-line treatment options after their diseases progress to acute myeloid leukemia (AML). The mechanisms that govern HMA failure are unknown. Recently, we unveiled that MDS are maintained and propagated by two different immunophenotypically distinct hierarchical cellular organizations of MDS hematopoietic stem and progenitor cells (HSPCs) through the upregulation of specific survival pathways. This finding allowed us to potentially stratify MDS patients into …

Virulence And Biofilm Formation In Candida Albicans Are Inhibited By Short Peptide Subunits Of Entv, Shane Cristy

Dissertations and Theses (Open Access)

Candida albicans, the most clinically significant fungal pathogen, commonly causes topical mucosal infections such as oral cavity and urogenital tract infections. It also less frequently causes severe invasive and bloodstream infections. Invasive infections are most prevalent amongst patients with compromised innate immune responses, such as those receiving chemotherapy or recovering from surgery. C. albicans can also form biofilms on implanted medical devices. Fungal infections are difficult to treat due to the paucity of therapeutic options, and this problem is compounded by the resistance properties of biofilm infections.

Candida albicans exists as a member of the commensal flora of the …

The Importance Of Dna Repair Capacity To (And A Model To Predict) Cell Radiosensitivity To Ions, David B. Flint, David B. Flint

Dissertations and Theses (Open Access)

Radiation therapy with ions has a number of advantages over conventional radiation therapy with photons, including favorable depth-dose distributions, greater relative biological effectiveness (RBE) and a lesser dependence on a number of biological factors known to affect radiosensitivity to photons, including DNA repair capacity. Thus, it is expected that an additional benefit of using ions is that they mitigate the great heterogeneities in treatment responses commonly observed in photon therapies.

However, by analyzing the cell survival of human cancer cell lines exposed to clinically relevant photon, proton, and carbon ion beams, we show there is not significantly less relative variability …

The Microsatellite Instability High Endometrial Tumor Microenvironment And Identifying Predictive Biomarkers Of Response To Pembrolizumab, Jeffrey How

Dissertations and Theses (Open Access)

Objective: Half of patients with microsatellite instability high (MSI-H) endometrial cancer are treatment-refractory to pembrolizumab. We sought to evaluate the MSI-H endometrial tumor samples to examine differences in the tumor microenvironment (TME) and identify transcriptomic signatures associated with response/resistance to pembrolizumab. Methods: Archival tumor samples from MSI-H endometrial cancer patients treated at MD Anderson Cancer Center were obtained. Tissue samples originating from patients who did not receive pembrolizumab treatment (“untreated cohort ”; n = 11) were analyzed via RNA sequencing (RNA-seq). Pre-treatment archival tumor samples (“treated cohort”; n = 23) from patients who were later treated with pembrolizumab were collected …

Dissecting Tumor Heterogeneity In Lung Cancer, Aparna Padhye

Dissertations and Theses (Open Access)

Lung cancer is a heterogeneous disease composed of genetically and phenotypically distinct tumor cells as well as a heterogeneous microenvironment consisting of non-cancer cells and extracellular matrix. Constant interactions among these components ultimately leads to a complex tumor tissue that is ever evolving and poses a therapeutic challenge for sustained benefit. Strategies for targeting lung cancers are largely guided by the genetic alterations identified in the tumor specimens. However, in order to gain a better understanding of lung cancer progression and develop effective treatment modalities, studying tumor in context of its microenvironment is crucial. The first aim of this project …

Understanding The Role Of Arglu1 In Interferon Signaling Activation In Breast Cancer, Phuoc Nguyen

Dissertations and Theses (Open Access)

In the U.S., the highest number of new cancer cases belongs to breast cancer in women, and this cancer also bears the second-highest death rate in women. Despite significant progress in breast cancer treatment that has been made in the past several decades, innovative and efficient therapies are still needed to eradicate this deadly disease. Novel cancer immunotherapy with immune checkpoint blockade (ICB) could induce long-lasting responses and improve survival in hard-to-treat malignancies. Regrettably, only a fraction of breast cancer patients respond to this highly promising strategy. To improving ICB therapy in breast cancer treatment, IFN signaling induction is a …

Intranasal Hpv Peptide Vaccine Formulation Induces Potent Cytotoxic Cd8 T Cell Immunity For The Treatment Of Genital Hpv Tumors, Gloria Sierra

Dissertations and Theses (Open Access)

Human Papillomavirus (HPV) induced cancers continue to affect millions of women worldwide, with the five year survival rate hovering just under 60% in some demographics. Therefore there is an unmet need to develop effective, yet, easily administered therapies to treat established HPV genital lesions. Even though immune checkpoint therapy (ICT) is a promising treatment option in some HPV+ cancers, the high cost and associated toxicities are still major concerns for their widespread application. HPV cancers are textbook candidates for therapeutic vaccination intervention because they’re driven by the expression of viral oncoproteins E6 and E7, which serve as ideal tumor specific …

Regulation Of Lung Mesenchymal Cells By Epithelial Wnt Ligands, Odemaris Narvaez Del Pilar

Dissertations and Theses (Open Access)

The mesenchyme comprises of heterogeneous cell populations that support neighboring structures and are integral to intercellular signaling. Despite such importance, mesenchymal cells are poorly defined morphologically and molecularly. Their signaling regulation is not well understood, lagging their counterparts in the epithelial, endothelial, and immune lineages. Leveraging single-cell RNA-seq, three-dimensional imaging, and lineage tracing, first, we delineated different lung mesenchymal cell types and classified them into three-proximal-distal axes in the neonatal and adult murine lung. Each axis is associated to the structure they support – the endothelium, epithelium and interstitium. We also identified two subpopulations of neonatal lung myofibroblasts – ductal …

Identification And Targeting Of Downstream Ar-Camkk2-Mediated Mechanisms For The Treatment Of Advanced Prostate Cancer, Chenchu Lin

Dissertations and Theses (Open Access)

The androgen receptor (AR) is the primary driver of prostate cancer and, therefore, AR-regulated signaling events are essential for the development and progression of the disease. Despite their initial effectiveness, drugs targeting AR eventually fail as sustained inhibition of receptor activity remains a challenge. Previously, Ca²⁺/calmodulin-dependent protein kinase kinase 2 (CAMKK2) was identified as an essential downstream component of AR signaling in prostate cancer that correspondingly tracked with disease progression. While the importance of CAMKK2 in AR-mediated prostate cancer progression has been established, our understanding of the events downstream that promote the disease remains incomplete. Here, I elucidated …

Trim24 Promotes Mammary Tumor Development By Upregulating Metabolic Reducing Power, Shucheng Miao

Dissertations and Theses (Open Access)

Metabolic reprograming is an emerging hallmark of cancer cells. Changes in cellular metabolism can contribute to cancer cell survival and tumor progression. Tripartite motif-containing protein 24 (TRIM24) is an E3 ligase for p53, a nuclear receptor co-regulator, and a histone reader. Over expression of TRIM24 correlates with poor overall survival of breast cancer patients. Previously, our lab created a mouse model that conditionally over-expresses (COE) TRIM24 protein in mammary epithelia (Trim24^COE) and develops carcinosarcoma or metaplastic mammary tumors (70% of all Trim24^COE tumors), a rare and aggressive triple-negative subtype called metaplastic TNBC in humans (MpBC). RNA-sequencing …

Micrornas As A Therapeutic Target To Regulate Microglial Activation In Post­ Stroke Isolation In Aged Male Mice, Anik Banerjee

Dissertations and Theses (Open Access)

Introduction:

It is increasingly recognized that social Isolation (SI) leads to a wide array of behavioral and cognitive deficits. Isolation and loneliness are linked to all-cause mortality, as well as mortality from stroke and other vascular diseases. In addition, isolated or lonely individuals have significantly poorer cognitive and functional outcomes following stroke and have higher rates of stroke recurrence. These detrimental effects have also been recapitulated in animal models; animals isolated prior to, or at the time of stroke, have larger infarcts than pair-housed mice. However, the mechanisms mediating the effects of social factors on stroke recovery are unknown. An …