Characterization of cell type-specific molecular heterogeneity in cancer using multi-omic approaches

Tumors are composed of heterogeneous cell types each with its own unique molecular profiles. Recent advances in single cell genomics technologies have begun to increase our understanding of the molecular heterogeneity that exists in tumors with particular focus on gene expression and chromatin accessibility profiles. However, due to limitations in methods for certain sample types and high cost for single cell genomics, bulk tumor molecular profiling has been and remains widely used. In addition, other facets of single cell epigenomic profiling, particularly methylation and hydroxymethylation, remains underexplored. Thus, investigations to understand the cell type specific epigenetic heterogeneity and the cooperation among various molecular layers to regulate tumorigenesis are needed. In this thesis, I utilize a multi-omic approach integrating DNA methylation, hydroxymethylation, chromatin accessibility, and gene expression profiles to investigate unique single cell type-specific features in 1) epithelial-to-mesenchymal transition and in 2) pediatric central nervous system tumors. First, I demonstrate the shared and distinct epigenetic profiles that are associated with single cells undergoing epithelial-to-mesenchymal transition. With a multi-omic approach, I identify increased hydroxymethylation in binding motifs of transcription factors critical in regulating epithelial-to-mesenchymal transition. Then, I shift my focus to characterize the cellular heterogeneity in pediatric central nervous system tumors and transcriptomic alterations associated with these tumors, while accounting for cell type composition, with single nuclei gene expression data. I detect novel pediatric central nervous system tumor associated genes that are differentially expressed. Finally, I illustrate the cytosine modification alterations that occur predominantly in the progenitorlike cell types of pediatric central nervous system tumors with a multi-omic approach. I determine associations between cell type-specific hydroxymethylation alterations with cell type-specific gene expression changes. Together, these findings emphasize the need for consideration of cellular identity to determine molecular heterogeneity that exist in various cancer contexts. Moreover, these works collectively suggest the utility of multiomic approaches to uncover novel insights in underlying tumor biology

Effects of team-based medication management on prescribing patterns, outcomes, and costs in veterans with diabetes

In response to persistent shortages of primary care physicians, researchers have suggested increased use of non-physician providers to mitigate the consequences of the strained supply of physicians. As more health care systems implement a team-based approach in treating patients, better understanding the pattern of team care and its effects on outcomes and cost is critical in transitioning away from physician-centric care. This dissertation focuses on the prescribing component of care to explore the effects of team medication management on prescribing patterns, clinical outcomes, and care costs in Veterans with diabetes. In Chapter 2 I examine the outpatient prescribing patterns of oral antidiabetic drugs (OADs) over a 2-year period among patients who receive sole-provider prescribing or team-based prescribing. I find that team-prescribing patients receive significantly more sulfonylureas and metformin/sulfonyl urea combinations, suggesting that team prescribing may respond to patients’ needs quicker and intensify treatment earlier by switching or augmenting the initial medication. To determine the effect of prescribing modality on health outcomes, I compare mean changes in diabetes-related lab measures between the sole-provider models and team-prescribing models in Study 2. I perform 2-stage least squares regression to estimate the change in outcome measures from baseline to follow-up and find that while patients receiving NP prescribing achieve significantly greater reductions in glucose level compared to those receiving physician prescribing, the differences in HbA1c, glucose, and LDL reductions between team prescribing patients and sole-provider patients are insignificant. In Study 3 I explore the effect of prescribing model on health care costs. I use generalized linear modeling to estimate mean total outpatient cost among patients managed under different prescribing models. In addition, I perform logistic regression to estimate the likelihood of incurring any inpatient cost. I find no significant differences in mean outpatient cost or the likelihood of incurring any inpatient cost between sole-provider prescribing and team prescribing, suggesting that prescribing modality may not be associated with care costs. Evidence from this dissertation suggests that while team prescribing appears to provide more responsive medication management, it does not result in significant improvements in health outcomes or affect overall care costs.2019-10-23T00:00:00

The Interface Between ER and Mitochondria: Molecular Compositions and Functions

Mitochondria and endoplasmic reticulum (ER) are essential organelles in eukaryotic cells, which play key roles in various biological pathways. Mitochondria are responsible for ATP production, maintenance of Ca2+ homeostasis and regulation of apoptosis, while ER is involved in protein folding, lipid metabolism as well as Ca2+ homeostasis. These organelles have their own functions, but they also communicate via mitochondrial-associated ER membrane (MAM) to provide another level of regulations in energy production, lipid process, Ca2+ buffering, and apoptosis. Hence, defects in MAM alter cell survival and death. Here, we review components forming the molecular junctions of MAM and how MAM regulates cellular functions. Furthermore, we discuss the effects of impaired ER-mitochondrial communication in various neurodegenerative diseases