Texas Digital Library
UT Southwestern Medical Center Institutional Repository (University of Texas)Not a member yet
10274 research outputs found
Sort by
Deception
Get PDFcan the cat be trusted? sometimes I wonder what is going on at home when I'm at work! pets can be playful and mischievou
Effect of Fragmentation of Cancer Care on Treatment Use and Survival in Hepatocellular Carcinoma
No full textThe general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.BACKGROUND: Fragmentation of care (FC) refers to treatment received at multiple facilities. Implications of FC include increased health care costs and amplification of existing healthcare disparities. This study aimed to identify patient and hospital-level factors associated with FC and analyze the effect of FC on patient outcome measures (overall survival and time to treatment).
OBJECTIVE: Fragmented care in HCC patients is associated with worse overall survival and increased time to treatment compared to patients receiving non-fragmented care.
METHODS: The Texas Cancer Registry (TCR) was queried from 2004-2015 for a 12-year study span. Patient- and hospital-level factors were characterized within 2 groups: patients receiving fragmented care (FC) and those receiving non-fragmented care (NFC). Cox proportional hazards regression models were used to identify those factors that were independently and significantly associated with overall survival and time to treatment. Kaplan-Meier curves were generated to evaluate differences in overall survival between the FC and NFC groups, as well as between every type of transition within the FC group (stratified on the basis of safety net hospital status or volume status). All statistical analyses were performed with SPSS.
RESULTS: Of our cohort (n = 4329), 72.6% received NFC, and 27.4% received FC. In comparison to patients receiving NFC, patients receiving FC had larger median tumor sizes at diagnosis (≥4 cm, 52.6% vs 35.2%; p < .001). NFC patients also tended to present with regional or metastatic disease (35.9% vs 26.7%; P < .001). A subset analysis of patients with localized stage HCC who received curative therapy showed that FC was associated with decreased odds of curative therapy (odds ratio, 0.83; 95% confidence interval [CI], 0.7-0.9). In this subgroup analysis, FC was associated with worse OS (median survival, 67 vs 43 months; HR, 1.2; 95% CI, 1.0-1.4) and increased TTT (HR, 0.74; 95% CI, 0.7-0.8). Ultimately, in our global cohort, FC was associated with worse OS (hazard ratio [HR], 1.14; 95% CI, 1.05-1.24) and increased TTT (HR, 0.76; 95% CI, 0.7-0.8).
CONCLUSION: Patients receiving FC had worse OS and increased TTT compared to patients receiving NFC. Several patient and hospital-level factors were found to be associated with FC, including age, insurance, non-safety net hospital status, accreditation, and disease stage. This work has implications for encouraging initiatives geared toward increasing care coordination, especially when managing cancer. Future work may aim to elucidate the reasons for the associations described and delineate steps by which to mitigate FC in the context of these factors
An Imaging Approach to Examine Telomere Dynamics and Regulation of Gene Expression with Aging
Get PDFTelomeres are repetitive non-coding nucleotide sequences (TTAGGG)n capping the ends of chromosomes. Improved methods to measure the shortest (not just average) telomere lengths (TLs) are needed. Progressive telomere shortening with increasing age has been associated with shifts in gene expression through models such as the telomere position effect (TPE), which suggests reduced interference of the telomere with transcriptional activity of increasingly more distant genes. A modification of the TPE model, referred to as Telomere Position Effects over Long Distance (TPE-OLD), explains why some genes 1-10 MB from a telomere are still affected by TPE, but genes closer to the telomere are not. Therefore, demonstrating the regulatory roles of telomere length shortening on genes with accurate TL measurement will improve our understanding to the 3D genomic DNA landscape including telomeres.
In this doctoral dissertation, I developed a user-friendly software for automatic electrophoresis gel quantification and contributed to developing the Telomere Shortest Length Assay (TeSLA), a technique that detects telomeres from all chromosome ends from <1 kb to 18 kb using small amounts of input DNA. Using cells with more TL information provided by TeSLA, I conducted an imaging approach to systematically examine the occurrence of TPE-OLD at the single cell level. Compared to existing methods, the pipeline allows rapid analysis of hundreds to thousands of cells, which is necessary to establish TPE-OLD as an acceptable mechanism of gene expression regulation.
I examined two human genes, for which TPE-OLD has been described before, ISG15 (Interferon Stimulated Gene 15) and TERT (TElomerase Reverse Transcriptase). For both genes I found less interaction with the telomere on the same chromosome in old cells compared to young cells. Experimentally elongated telomeres in old cells rescued the level of telomere interaction for both genes. However, the dependency of the interactions on the age progression from young to old cells varied. One model for the differences between ISG15 and TERT may relate to the markedly distinct interstitial telomeric sequence arrangement in the two genes. Overall, this provides a strong rationale for the role of telomere length shortening in the regulation of gene expression
Interplay Between Tryptophan Metabolites and the Virulence Factors of Enteric Pathogens
No full textThe human gut consists of a complex milieu of several small molecules that helps in shaping its overall chemistry and biogeography. Trillions of bacteria, collectively known as the gut microbiota, colonize this landscape and occupy a specific niche. Small molecules derived from diet, gut microbial metabolism, and host metabolic activity have an impact on dictating the underlying gut microbiome composition. Gut bacterial populations effectively sense these molecular signatures and modulate gene expression to colonize this niche. An invading intestinal pathogen, to effectively colonize the gut, must sense and respond to the molecular signatures in the gut, which leads to effective colonization and infection.
Diet is the principal source of energy by the intake of three main nutrients: carbohydrates, proteins, and fats. Tryptophan is an essential amino acid taken from the diet and plays an important role in protein biosynthesis. Tryptophan is also metabolized to different small molecules and its metabolic products are known to be present in high concentrations in the body. Upon ingestion, tryptophan is readily available in the luminal environment of the gut. Abundant levels of tryptophan are also absorbed by intestinal epithelial cells and is made available in different cellular compartments for normal physiological processes.
Tryptophan present in the gut lumen can be further metabolized to numerous small molecules by the action of the gut microbial metabolic activity. Indole is one of the most abundant tryptophan-derived metabolites present in the gut and is absorbed by the host epithelial cells. The host can also metabolize tryptophan to various small molecules including serotonin that is made available in the gut lumen upon release from the host cells. Bacteria in the gut sense these bacterial and host-derived small molecules to colonize and maintain their niche. Similarly, an invading food-borne pathogen such as Enterohemorrhagic Escherichia coli (EHEC), which causes gastroenteritis by primarily colonizing the human colon, sense these small molecules and respond in a way that is conducive for its colonization and virulence gene expression. The role of these highly abundant tryptophan-derived small molecules in dictating the infectivity of an enteric pathogen remains unknown. Because the concentrations of these small molecules naturally present in the body are in the range of the drug concentrations that are used to treat certain diseases, it is possible to repurpose the information gained from these studies to treat intestinal infections.
In the present study, we focused on two highly abundant tryptophan-derived small molecules present in the gut. Indole is derived from bacterial metabolism while serotonin is present via the action of host metabolism of tryptophan. Indole and serotonin are structurally similar and therefore may have similar effects against a pathogen in vivo. Indeed, we identified that both indole and serotonin decrease the virulence of the human pathogen Enterohemorrhagic E. coli (EHEC) and the mouse pathogen Citrobacter rodentium. We used multiple strategies including genetic manipulation, pharmacological inhibitors, and knock-out murine models to show that both indole and serotonin are inhibitory signals for virulence gene expression in EHEC and C. rodentium. We further investigated the mechanism used by these pathogens to sense these signals. We identified the first bacterial receptor for both indole and serotonin, and showed that these signals are sensed by a bacterial membrane bound histidine kinase CpxA. Upon sensing indole or serotonin, CpxA dephosphorylates itself and the transcription factor CpxR. In its phosphorylated state, CpxR directly activates expression of the virulence genes, its dephosphorylation prevents its action, decreasing expression of these genes. Together, our studies highlight the importance of sensing small molecules and understanding the gut biogeography by invading pathogens to successfully colonize the gut
Locus Coeruleus-Dependent Dopamine Release in the Dorsal Hippocampus: Mechanisms and Modulation of Synaptic Plasticity
Get PDFLocus coeruleus (LC) neurons coordinate the overwhelming majority of norepinephrine (NE) signaling throughout the mammalian neocortex and hippocampus. Recent discoveries indicate that dopamine (DA), the biosynthetic precursor of NE, is also released from LC axons. These axons innervate most brain regions, and are especially prevalent in the rodent dorsal hippocampus, including area CA1. It was previously thought that the only supply of CA1 dopamine was the ventral tegmental area, but several recent studies have identified LC fibers as the main source of DA in this region. However, both the mechanism by which LC-DA is released, and whether or not it is released in sufficient quantities to influence DA-dependent processes in the hippocampus, remain unclear. These questions have major implications for theories concerning the molecular basis of learning, since the consolidation of episodic memories in CA1 requires activation of dopamine D1-like receptors. Therefore, the focus of this dissertation is to determine if LC-originating DA can modulate synaptic plasticity, and therefore learning and memory, in CA1 of the mouse hippocampus. We also sought to uncover the molecular mechanism of this LC-DA release.
The following experiments study the effects of LC-dopamine on CA1 function using optogenetic, electrophysiological, pharmacological, and behavioral approaches. We show that optogenetically evoked LC-DA release is sufficient to activate D1/D5 receptors (D1/5R) on CA1 pyramidal neurons and modulate synaptic potentiation at Schaffer collateral synapses, a necessary step for the consolidation of learning. In accordance with this, we find that LC-specific knockdown of DA synthesis can block learning at the behavioral level (Chapter 2). We also demonstrate that one possible LC-DA release mechanism is reverse transport through the norepinephrine transporter (NET), and advance the idea that presynaptic NMDA receptors on LC terminals may play a role in this release. Furthermore, as DA and NE should be co-released in dorsal CA1, we show that they act together to enhance synaptic strength (Chapter 3). Since LC activity is known to be involved in attention and memory, our results contribute new insight into how the LC can link attentional processes to memory formation at the molecular, circuit, and behavioral levels (Chapter 4)
Eosinophilic esophagitis: current and emerging therapeutics
Get PDFDetailed formal protocol with illustrations and extensive bibliography.A recording of the protocol presentation is available on UT Southwestern's Mediasite. Note: Access to the video is restricted to authorized UT Southwestern users only.UT Southwestern--Internal Medicin
The short history and tenuous future of "professionalism"
Get PDF[Note: The slide presentation is not available from this event.] Tuesday, December 13, 2022; noon to 1 p.m. (Central Time); via Zoom. "The Short History and Tenuous Future of 'Professionalism'". Matthew Wynia, M.D., M.P.H., Professor, CU School of Medicine and Colorado School of Public Health, and Director, Center for Bioethics and Humanities, University of Colorado, Anschutz Medical Campus.[Note: The slide presentation is not available from this event.] The concept of professionalism in health care is both newer and more fragile than many assume. The history, strengths, risks, and alternatives to professionalism should be understood if we hope to create a future in which health professionals work well together in teams to effectively and ethically serve our patients and communities.UT Southwestern--Program in Ethic
Deprescribing for older adults
Get PDFDetailed formal protocol with illustrations and extensive bibliography.A recording of the protocol presentation is available on UT Southwestern's Mediasite. Note: Access to the video is restricted to authorized UT Southwestern users only.UT Southwestern--Internal Medicin
Lies, damned lies, and evaluations: the quest for "high value" feedback
Get PDFDetailed formal protocol with illustrations and extensive bibliography.A recording of the protocol presentation is available on UT Southwestern's Mediasite. Note: Access to the video is restricted to authorized UT Southwestern users only.UT Southwestern--Internal Medicin
Comparing Ordinary
Get PDFThis poem juxtaposes human emotion with the remarkable, simultaneously marking it in a category of humility as well as the extraordinary experience it provides