Digital Commons Network^™

Haplotype-Informed Allelic Imbalance Detection From Rna In Cancer, Zuhal Ozcan

Dissertations and Theses (Open Access)

Comprehensive genomic and transcriptomic characterization of tumors has uncovered enrichment for distinct aneuploidy and expression patterns, demonstrating the utility of molecular based classification of cancers and their subtypes. Existing cohorts with transcriptomic profiling from next-generation sequencing contain an untapped potential to also relate genomics with rich clinical phenotypes. Yet, derivation of somatic copy number and expression profiles from analyses of RNA has remained elusive. Further, DNA analysis in these cohorts is not always feasible due to limited tissue availability or financial constraints. Here, we present a statistical approach that overcomes these challenges using haplotype information to aid detection of somatic …

Regulation Of Systemic And Cellular Metabolism In Prostate Cancer By Camkk2 And Elucidation Of Atgl’S Role In Disease Progression, Dominik Awad

Dissertations and Theses (Open Access)

The androgen receptor (AR) is the major driver of prostate cancer; hence, men with progressing disease are treated with androgen deprivation therapy (ADT). However, the majority of patients will relapse within 2-3 years due to multiple AR reactivation mechanisms. Thus, AR and the processes downstream of the receptor remain central drivers of prostate cancer. A direct target of AR is CAMKK2, a gene coding for the serine/threonine kinase Ca^2+/calmodulin-dependent protein kinase kinase 2 (CAMKK2), a protein upregulated in advanced prostate cancer. CAMKK2 modulates many of its pathological effects through the phosphorylation and activation of the 5' AMP-activated …

Absolute Quantification Of Tc-99m Activity Distributions Using A Planar Molecular Breast Imaging Commercial System, Benjamin P. Lopez

Dissertations and Theses (Open Access)

Molecular breast imaging (MBI) uses two dedicated-breast semiconductor detectors to visualize the preferential uptake of technetium-99m-sestamibi (^99mTc-sestamibi) by breast cancer cells relative to surrounding benign breast tissues. Clinically, MBI is used primarily as a supplementary tool to standard-of-care mammography because of its improved detection of breast cancers, especially in women with mammographically-dense breasts. Because of a lack of image corrections, MBI applications are currently limited to qualitative evaluations of relative pixel intensities between image regions with suspected lesions and normal tissue.

The objective of this dissertation was to use Monte Carlo simulations to better characterize the MBI imaging …

Perceptions And Roles Of Genetic Counselors In Perinatal Palliative Care: Where Are We Now?, Amanda Chamberlain

Dissertations and Theses (Open Access)

After the identification of a life-limiting fetal diagnosis, a perinatal palliative care (PPC) team can provide specialized medical care and emotional support for the family throughout the pregnancy and after delivery. Although the growth of the field of PPC over the last ten years is well-documented, there is only one study to date that explores the experiences of genetic counselors with regards to PPC. This study seeks to further the understanding of genetic counselors’ current perceptions of, experiences with, and roles in the delivery of PPC.

An edited version of the Perinatal Palliative Care Perceptions and Barriers Scale was used …

Unraveling The Effects Of Aerobic Exercise And Erk5 Signaling In The Solid Tumor Microenvironment Using Murine Models, Hannah Savage

Dissertations and Theses (Open Access)

Solid tumors are comprised of multiple cell types which communicate and work together to promote tumor progression. Advances in the treatment of solid tumors have armed clinicians with more efficacious pharmacologic agents and combinations. However, a focus on drug adjuvants in the treatment of solid cancer has left gaps in knowledge regarding non-pharmacologic treatment adjuvants, like aerobic exercise. The current dissertation investigates pharmacologic and non-pharmacologic based approaches to remodel the solid tumor microenvironment landscape and alter therapeutic efficacy. We disassemble compartments of the tumor microenvironment, including tumor vasculature and immune infiltrate, using mouse models and single cell techniques, to elucidate …

Decoding Copy Number Substructure And Evolution From Single Cell Genomics, Darlan Conterno Minussi

Dissertations and Theses (Open Access)

Aneuploidy is a prominent feature in Triple-Negative Breast Cancers (TNBC), however, the evolution of genotypes during tumor expansion remains poorly understood. The prevalent model of TNBC evolution is the Punctuated Copy Number Evolution (PCNE), in which tumors undergo a period of elevated genomic instability, acquiring complex genomic rearrangements within a short timeframe followed by clonal stasis. However, these observations rely on limited cell numbers and inherent experimental bias from first-generation single cell technologies. Therefore, the evolutionary trajectory after the punctuated burst remains unknown. To address this question, we sequenced 9,765 cells from 8 primary TNBCs and 6,413 cells from 4 …

Grk3 Connects Angiogenesis And Neuroendocrine Differentiation In Prostate Cancer By Activating Hdac2 That Epigenetically Represses Tsp1 And Rest, Samira Naderinezhad

Dissertations and Theses (Open Access)

Prostate cancer (PCa) is the second most frequent cancer and the second leading cause of mortality in men in the United States. Neuroendocrine prostate cancer (NEPC) is the aggressive subset of castration-resistant prostate cancer (CRPC), found in ~20% lethal CRPC. The mechanisms underlying the progression of PCa to NEPC are still largely unclear, and new drug targets are desperately needed. NEPC is highly vascularized (angiogenic) and characterized by high expression of neuroendocrine markers. However, direct molecular links connecting angiogenesis and neuroendocrine differentiation are elusive.

Since epigenetic regulation has been implicated in NEPC progression, we examined expression patterns of 147 epigenetic …

Development Of Graphical Models And Statistical Physics Motivated Approaches To Genomic Investigations, Yashwanth Lagisetty

Dissertations and Theses (Open Access)

Identifying genes involved in disease pathology has been a goal of genomic research since the early days of the field. However, as technology improves and the body of research grows, we are faced with more questions than answers. Among these is the pressing matter of our incomplete understanding of the genetic underpinnings of complex diseases. Many hypotheses offer explanations as to why direct and independent analyses of variants, as done in genome-wide association studies (GWAS), may not fully elucidate disease genetics. These range from pointing out flaws in statistical testing to invoking the complex dynamics of epigenetic processes. In the …

Bhlhe40: Required For Tumor Microenvironment Remodeling And Immune Checkpoint Therapy Efficacy, Avery Salmon, Avery J. Salmon

Dissertations and Theses (Open Access)

Advancements in immunotherapy treatments have become essential in the treatment of various cancers, such as those with high tumor burden like melanoma(Brahmer et al., 2012; Hodi et al., 2010). Immunotherapy, specifically immune checkpoint therapy (ICT) provides antagonist effect on specific immune checkpoints to control effector T cell functions(Pardoll, 2012). This therapy allows for the modulation of anti-tumor responses through the use of monoclonal antibodies, such as anti-CTLA-4 or anti-PD-1 that block the receptors from binding with their ligands, thus allowing for CD4⁺ and CD8⁺ T cell priming and activation(Wei et al., 2017). However, the required epigenetic and transcriptional …

Genomewide Crispr/Cas9 Screen Identifies Network Of Protein Complexes That Regulate Trim24, Lalit Patel

Dissertations and Theses (Open Access)

TRIM24 is an oncogenic chromatin reader that is frequently overexpressed in human tumors and associated with poor prognosis. However, TRIM24 is rarely mutated, duplicated, or rearranged in cancer. This raises questions about how TRIM24 is regulated and whether changes in its regulation are responsible for its activity in cancer.

To investigate this possibility, I performed a genomewide CRISPR/Cas9 screen library using fluorescence activated cell sorting (FACS) to identify regulators of TRIM24. The screen was enabled by two innovations. I engineered cells with an in-frame knock-in of mClover3 to the endogenous copy of TRIM24 to allow fluorescent monitoring of TRIM24 expression …

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 …

Body Temperature And Diet As Drivers Of Obesity Development, Jessie Morrill

Dissertations and Theses (Open Access)

Metabolic disease and obesity affect millions of individuals worldwide and the prevalence of obesity is expected to continue to rise. Mechanisms underlying diet-induced metabolic disease and obesity are complex and are largely unknown. In this dissertation research, we aimed to make advances toward understanding how body temperature and high-fat diet consumption contribute to the development of obesity. Herein, we describe the progress that was made toward three research projects. In the first project, we develop novel animal models to determine the impact of reduced body temperature on obesity development and also demonstrate that severe obesity can be reversed through increased …

Yap And Taz Are Required For Neural Crest-Derived Cardiovascular Development, Shannon Erhardt

Dissertations and Theses (Open Access)

Congenital heart defects (CHDs) are the most common human birth defect, occurring in ~1/100 newborns, and are a leading cause of early infant death. Cardiac neural crest cells (NCCs) are a migratory and multipotent cell population known to aid in the development of the cardiac outflow tract (OFT), valves, and interventricular septum, during embryogenesis. Yap and Taz are downstream effectors of the fundamental Hippo signaling pathway and are vital for proper organ and tissue development, yet their role in neural crest (NC)-derived heart formation is still largely unknown. We generated Yap and Taz conditional knockout (CKO) mice using a Cre-lox …

The Role Of The Hypoxia-Inducible Factor 2 In Pancreatic Cancer: Mechanisms Of Tumor Immunosuppression And Intestinal Radioprotection, Carolina Garcia Garcia

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with dismal prognosis. The only curative option for patients is surgery, but over 80% of patients are not surgical candidates. Unfortunately, PDAC is resistant to the three remaining options. PDAC is characterized by a profoundly hypoxic and immunosuppressive stroma, which contributes to its therapeutic recalcitrance. Alpha-smooth muscle actin+ (αSMA+) cancer-associated fibroblasts (CAFs) are the most abundant stromal component, as well as mediators of stromal deposition. The hypoxia-inducible factors (HIF1 and HIF2) coordinate responses to hypoxia, yet, despite their known association to poor patient outcomes, their functions within the PDAC tumor microenvironment (TME) …

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 …

Lipid Composition And Configuration Drive Biophysical Properties Of The Mammalian Plasma Membrane, Jessica L. Symons

Dissertations and Theses (Open Access)

In the 1970s, it was established that phospholipid (PL) classes are asymmetrically distributed across the (PM) leaflets. Recapitulating strategies coupled with newly developed, high-resolution shotgun lipidomics, our lab confirmed PL class asymmetry and surprisingly measured the endoplasmic leaflet to contain double the number of PLs vs. the exoplasmic leaflet. My re-analysis of classical studies show that PM PL abundance imbalance has been a consistent finding across decades of literature. This is surprising, because bilayers do not tolerate interleaflet area imbalances to the degree that this imbalance would suggest, which prompted us to consider the existence of an elusive membrane resident …

Non-Photic Mechanisms Of Entrainment In Bmal1 Deficient Conditions, Jamie Tran

Dissertations and Theses (Open Access)

Maintaining our internal circadian (i.e. 24 -hour) clock is imperative to our daily biological and mental well-being. Large epidemiological studies have shown that disruptions of our circadian rhythms can lead to poor mental health, metabolic diseases, and various types of cancer. Various external cues that have become a part of the modern times such as electricity, shift -work, rapid travel across various time zones, easier access to nutritionally unbalanced food items, and various rigid social demands have deleterious effects on our internal clock, and generally reduce robustness of the circadian clock. The two following projects aim to examine two fundamental …

The Novel Role Of Dnmbp In Kidney Development, Brandy Walker

Dissertations and Theses (Open Access)

Congenital anomalies of the kidney and urinary tract (CAKUT) accounts for nearly one-fourth of all birth defects and more than 40% of pediatric end-stage renal disease, yet only 10-20% of CAKUT cases have a known monogenetic cause. Human kidneys are composed of up to a million epithelial tubules called nephrons. Disruption of nephron development is one of the many congenital anomalies that cause CAKUT, often resulting in chronic or end-stage renal disease which requires transplant. During nephron epithelialization, the formation of stable cadherin-mediated adhesion junctions is essential for maintaining cell-cell contacts. To understand the cell behaviors underlying abnormalities in renal …

Induced Cytotoxicity In Crebbp/Ep300mut Head And Neck Squamous Cell Carcinoma, Thomaia Pamplin

Dissertations and Theses (Open Access)

INDUCED CYOTOXICTY IN CREBBP/EP300mut HEAD AND NECK SQUAMOUS CELL CARCINOMA

Thomaia Pamplin

Advisor: Curtis Pickering, Ph.D.

Background: Head and neck squamous cell carcinoma HNSCC is the most common malignancy in the head and neck. Most cases are found in advanced stages and depending on the location can be treated with surgical resection and/or radiation (XRT), chemotherapy, or chemoradiation. Our lab groups have identified that HNSCC with a mutation in its CREBBP/EP300 genes can be sensitized to XRT when the histone acetyltransferase activity of CREBBP/EP300 is inhibited. This radiosensitization manifests in the form of increased cell death for …

New Pubmed Videos Available, Joanne Romano

TMC Library Newsletter (2015-)

Are you new to PubMed? Do you Need a Refresher on how to Search? Are you a more advanced searcher and need to refine your search results?

Take a look at the newest PubMed videos available at The TMC Library.

Digital Commons@Tmc, Alice Sherwood

TMC Library Newsletter (2015-)

DigitalCommons@TMC is an open-access resource with more than 7,450 articles, making almost all full-text content accessible worldwide. If you are affiliated with a TMC institution when the work is created, and you own the copyright of the research publication, you can contribute to this repository. Most research can be submitted electronically, you would need a Bepress account prior to submitting your research. Some publications may not allow authors to submit directly, and there is also generally a 12-month embargo period for dissertation submission.

Welcome New And Returning Students, Beatriz Varman

TMC Library Newsletter (2015-)

The TMC Library provides the following services to assist students with their research.
Do you have an assignment that requires searching the library databases, but you are not sure where to start? We are here to help. The Student Services page has the information you need to get you started.

Factors Associated With Parental Acceptance Of Covid-19 Vaccination: A Multicenter Pediatric Emergency Department Cross-Sectional Analysis, David Rayburn, Stephanie A Eucker, Nicole L Nadeau, Lisa A Drago, Danielle Cullen, Sarah Dennis Meskill, Suzanne Bialeck, Michael Gillman

Faculty, Staff and Students Publications

STUDY OBJECTIVE: During the delta surge of the COVID-19 pandemic in 2021, we sought to identify characteristics and beliefs associated with COVID-19 vaccination acceptance in parents of pediatric emergency department (ED) patients.

METHODS: We conducted a cross-sectional survey-based study of the parents of children aged 3 to 16 years presenting to 1 of 9 pediatric EDs from June to August 2021 to assess the parental acceptance of COVID-19 vaccines. Using multiple variable regression, we ascertained which factors were associated with parental and pediatric COVID-19 vaccination acceptance.

RESULTS: Of 1,491 parents approached, 1,298 (87%) participated, of whom 50% of the parents …

Chronic Granulomatous Disease-Like Presentation Of A Child With Autosomal Recessive Pkcδ Deficiency, Sarada L Nandiwada, Kruthi Murthy, Anne Puel, Jean-Laurent Casanova, Javier Chinen, Jacinta Bustamante

Faculty, Staff and Students Publications

BACKGROUND: Autosomal recessive (AR) PKCδ deficiency is a rare inborn error of immunity (IEI) characterized by autoimmunity and susceptibility to bacterial, fungal, and viral infections. PKCδ is involved in the intracellular production of reactive oxidative species (ROS).

MATERIAL AND METHODS: We studied a 5-year old girl presenting with a history of Burkholderia cepacia infection. She had no history of autoimmunity, lymphocyte counts were normal, and no auto-antibodies were detected in her plasma. We performed a targeted panel analysis of 407 immunity-related genes and immunological investigations of the underlying genetic condition in this patient.

RESULTS: Consistent with a history suggestive of …

A Sensor-Controlled Digital Game For Heart Failure Self-Care Based On Behavioral Change Frameworks, Katelyn Leggio, Matthew O'Hair, Emily T Hebért Arsers, Grace Lee, Tom Baranowski

Faculty, Staff and Students Publications

Self-care behaviors are critical to manage the adverse impact of heart failure disease. However, engaging in self-care behaviors such as physical activity or daily weight-monitoring can be difficult due to lack of knowledge or motivation. Digital games can serve as an alternative to traditional patient education to provide information and motivate engagement in critical self-care behaviors. In this paper, we describe a sensor-controlled digital game (SCDG) in which game play is driven by the player's real life self-care behaviors. We also present the design and development of the next iteration of the SCDG based on playtesting results and behavioral theoretical …

Becoming A Doctor During A Pandemic: Impact On Medical Student Social Identity Formation, Ruifei Wang, Connor T Hoch, Nadia Ismail, Jennifer Christner

Faculty, Staff and Students Publications

The COVID-19 pandemic required modifications to undergraduate medical education that likely affected medical students' social identity formation (SIF). SIF is shaped by experiences throughout the medical education continuum. This commentary explores factors potentially affecting medical student SIF during the COVID-19 pandemic focusing on students' perceptions of being part of the healthcare team, their role in medicine, and their engagement during the pandemic. Based on such considerations, we propose that educators should aim to design effective learning environments to support a full educational experience that encompasses acquiring medical knowledge and building strong social identities even during a pandemic.

Implementation Of A Virtual Huddle To Support Patient Care During The Covid-19 Pandemic, Andrew Hunter, Elwyn Welch, Stephen Bujarski, Christina Kao, Lavannya Pandit, Kanta Velamuri, Venkata D Bandi

Faculty, Staff and Students Publications

BACKGROUND: During a surge of COVID-19 cases, the volume of acute care patients with hypoxemic respiratory failure placed a high burden of responsibility on internal medicine, pulmonary and critical care medicine, and clinical pharmacy services.

OBSERVATIONS: We describe the COVID-19 Tele-Huddle Program, a novel approach to communication between key stakeholders in COVID-19 patient care through a daily video conferencing huddle. The program was implemented during a 4-week surge in COVID-19 cases at a large, academic medical center in Houston, Texas. Data collected during the COVID-19 Tele-Huddle Program included the type and number of interventions implemented, number of patients discussed, and …

Roles And Responsibilities Of Medicine Subinternship Directors : Medicine Subinternship Director Roles, Irene Alexandraki, Nadia Ismail, Michael Kisielewski, Jackcy Jacob, Katherine Walsh, Diane L Levine, Karen Szauter, Harish Jasti, Amber T Pincavage, Jeffrey Larochelle, Susan A Glod

Faculty, Staff and Students Publications

BACKGROUND: The internal medicine (IM) subinternship (also referred to as acting internship) plays a crucial part in preparing medical students for residency. The roles, responsibilities, and support provided to subinternship directors have not been described.

OBJECTIVE: We sought to describe the current role of IM subinternship directors with respect to their responsibilities, salary support, and reporting structure.

DESIGN: Nationally representative, annually recurring thematic survey of IM core clerkship directors with membership in an academic professional association as of September 2017.

PARTICIPANTS: A total of 129 core clinical medicine clerkship directors at Liaison Committee on Medical Education fully accredited U.S./U.S.-territory-based medical …

Integrated Multi-Omic Characterization Of Congenital Heart Disease, Yuka Morikawa, Thomas J Martin, Emma J Birks, Kenneth S Campbell, Jeanne Nerbonne, Kory Lavine, Lalita Wadhwa, Jun Wang, Diwakar Turaga, Iki Adachi, James F Martin

Faculty, Staff and Students Publications

The heart, the first organ to develop in the embryo, undergoes complex morphogenesis that when defective results in congenital heart disease (CHD). With current therapies, more than 90% of patients with CHD survive into adulthood, but many suffer premature death from heart failure and non-cardiac causes1. Here, to gain insight into this disease progression, we performed single-nucleus RNA sequencing on 157,273 nuclei from control hearts and hearts from patients with CHD, including those with hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot, two common forms of cyanotic CHD lesions, as well as dilated and hypertrophic cardiomyopathies. We …