Texas Digital Library
UT Southwestern Medical Center Institutional Repository (University of Texas)Not a member yet
10274 research outputs found
Sort by
Cell Type-Specific Contributions of FOXP1 to Human Cortical Development
No full textPages vi-xv are misnumbered as pages v-xiv, pages 89-129 are misnumbered as pages 87-127, and pages 130-174 are misnumbered as pages 124-168.The human neocortex consists of diverse cell types that are genetically pre-programmed to organize themselves in a human-specific manner throughout development. Some of the human specific features are reflected in the composition and behavioral patterns of cell types under strict spatiotemporal guidance by gene regulators such as transcription factors, which are acquired through evolution. Any defects in early cortical development can be detrimental and often result in irreversible neurodevelopmental disorders (NDDs). In our study, we wanted to understand human cortical development through a transcription factor, FOXP1, whose mutant forms are implicated in autism spectrum disorder (ASD) and intellectual disability (ID). FOXP1 is enriched in the human basal radial glial cells (bRGCs) and intermediate progenitor cells (IPCs) in the developing neocortex. These cell types are uniquely capable of sustained self-renewal and neurogenesis during early corticogenesis and rapidly decrease in number in later neurogenesis. I hypothesize that FOXP1 regulates gene expression programs in these specific cell types for the proper development of the neocortex. Progress in learning about the role of FOXP1 in different cell types in early corticogenesis has been limited due to technical challenges. However, with the advent of human brain developmental model systems and single-cell technologies, we can successfully interrogate cellular and molecular mechanisms in the rapidly developing human neocortex at single cell resolution. In this thesis, I present work I have done to understand human cortical development in the context of evolution and developmental disorders through the molecular window of FOXP1. In chapter 1, I summarize our current understandings on human neocortical development. This is a modified version of a review article I wrote summarizing scientific findings from many primary publications and several in-depth review articles on important topics, such as cellular and molecular mechanisms governing cortical progenitor proliferation, cell lineage progression, neuronal specification, and arealization, across multiple gyrencephalic and lissencephalic species. Chapter 2 is a literature review on the role of FOXP1 in corticogenesis and FOXP1-relevant NDDs. The contents in chapter 1 and 2 are designed to provide sufficient background information for my experimental hypothesis, design, results and discussion that are presented in chapter 3. Lastly, chapter 4 contains additional results, discussion and future directions, which includes my opinions and criticisms on my own work as well as recommendations for future experiments
Feasibility and Acceptability of Utilizing a Single Session Problem-Solving Intervention with Caregivers of Pediatric Patients Receiving Chronic Transfusion to Treat Sickle Cell Disease
Get PDFPages 85-99 are misnumbered as pages 84-98.INTRODUCTION: For patients and caregivers of patients receiving chronic red blood cell transfusions (CT) to treat sickle cell disease (SCD), few studies have investigated the use of single session interventions, and none to address problem-solving in a single session. Feasibility and acceptability of such an intervention with caregivers of pediatric patients who receive CT to treat SCD were investigated. Efficacy was also explored.
METHOD: Participants were twenty caregivers (95% female; 95% Black/African American, Mage = 42.45 years) and patients (55% male; 95% Black/African American, Mage = 13.55 years) who were approached either during their CT appointment or via a HIPAA-approved telehealth platform while at home. Participants in the intervention group received a single session problem-solving intervention (SSPSI) during their second visit, and all participants completed self-report measures during each of the four research visits.
RESULTS: Data indicate 54% of participants approached agreed to participate in the study and 80% of participants who enrolled were retained through the end of the study. Regarding acceptability, 100% of participant pairs in the intervention group found the intervention to be acceptable at each visit of the study.
DISCUSSION: Caregivers and patients were able to utilize this patient and family-centered, culturally sensitive SSPSI to identify strategies to address problems they were experiencing. The study demonstrated feasibility and acceptability of the SSPSI. Further investigation is needed to further investigate efficacy of such an intervention with this population. Utilizing a SSPSI with caregivers and patients who receive CT to treat SCD appears to be feasible and acceptable, within the specific setting investigated, in addressing problem-solving with this patient population
Magnetic Resonance Prediction of Severe Placenta Accreta Spectrum in Pregnancy: Validation of a Radiomic Features
No full textThe 62nd Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 30, 2024, 3-6 p.m., D1.700 Lecture Hall)INTRODUCTION: Placenta accreta spectrum (PAS) or placental invasion into the uterine myometrium in women with previous cesarean delivery has become increasingly prevalent, affecting 1 in 500 pregnancies. Depending on the severity of placental invasion, patient management may involve a total hysterectomy at the time of cesarean delivery. We previously identified radiomic features from PAS-suspected MR images that were highly predictive of patient surgical outcome. After developing the algorithm, we needed to establish a validation cohort to test the radiomic model, a necessary step for reproducibility and generalization.
PURPOSE: To validate the radiomic features previously found to correlate with the need for cesarean hysterectomy in patients with a high-risk for placenta accreta spectrum (PAS).
METHOD: We performed an IRB approved retrospective review of 53 pregnancies from 2019 to 2023 of patients with clinically suspected PAS who had MR studies. Volumetric placental, uterus, and internal os regions of interest (ROIs) were manually segmented under the supervision of a board- certified radiologist with 30 years of OBGYN MR experience. Radiomic features were extracted following the image biomarker standardization initiative guideline using the pyRadiomics package. Placental Location within the Uterus (PLU) was described by a customized radiomic feature, determined as the angle between 2 vectors, with the tail being the epicenter of the uterus to the internal os and the epicenter of the placenta.
RESULT: From our study, 25 patients (32.8±5.5 y/o) required cesarean hysterectomy with pathologic confirmation of PAS while 28 (33.0±5.6 y/o) underwent regular cesarean delivery. Estimated blood loss and gestational age at delivery were significantly different between groups (p<0.05). PLU and several other radiomic features were significantly different between those who required hysterectomy after cesarean delivery compared to those who did not in this new validation cohort of patients (p<0.05).
DISCUSSION: We demonstrated that Placental Location within the Uterus (PLU) and other radiomic variables were predictive in detecting patients that needed hysterectomy in a validation cohort. This is an important step toward the development of a reliable, reproducible, and generalizable radiomic model for the prediction of PAS severe enough to result in cesarean hysterectomy.Southwestern Medical Foundatio
Joy
No full textThe author submitted this entry in the 10-Word Story category (Amateur division) for the 2024 On My Own Time (OMOT) Art Show.My brother-in-law is about to get married, and all of the joy and excitement of this time in their lives is permeating the entire family
Assessing Disease Severity in Cutaneous Lupus Patients Using Natural Language Processing
Get PDFThe 62nd Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 30, 2024, 3-6 p.m., D1.700 Lecture Hall)BACKGROUND: Cutaneous lupus erythematous (CLE) is an autoimmune skin disorder that manifests as inflammatory cutaneous lesions commonly in photosensitive areas. It is often chronic in nature, with exacerbations that can lead to hyperpigmentation and scarring. One tool used to measure disease activity and damage in CLE patients is the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score. There has been little work done previously using natural language processing (NLP) in dermatology to assess disease severity, though there is promising potential for its use given the role of narrative data in dermatology.
OBJECTIVE: We aim to develop a NLP model that interprets physical examination (PE) documentation in CLE patients and computes disease severity scores in the form of CLASI activity and damage scores.
METHODS: Dataset was derived from 50 patients enrolled in the UTSW CLE registry. 89 clinical exams of 24 patients were used in a training set, used to train the NLP model. 35 clinical exams of 26 patients were selected for a validation set, used to test the model's accuracy in prediction. An entity dictionary was defined that provided rules for labeling vocabulary pertinent to CLASI scores within the PE note. This was used to label the relationships between entities in the training and validation sets. The BERT (Bidirectional Encoder Representations from Transformers) model was trained to predict all entities and relationships in the notes, based on which the CLASI scores were calculated. After training, the model was applied to the validation set. In evaluation, scores generated from the model were compared to the ground-truth CLASI scores based on human annotation.
RESULTS: The model-predicted scores had a correlation of 0.79 and 0.86 with the ground truth on the activity and damage scores, respectively, in the training set, and a 0.61 and 0.79 correlation in the validation set. The model had 0.84 and above for accuracy, recall, precision and F1 within the sub-goal of determining the category of score severity (high or low), for both training and validation sets.
CONCLUSIONS: Using PE notes as the input, a BERT-based NLP model can be trained to predict CLASI scores in CLE patients. If successfully implemented, this algorithm can significantly increase the volume of real-world data available for CLE research by efficiently processing PE notes in the EHR. Future steps are to increase the size and representation of the training set to improve accuracy and external validity of BERT's predictions.Southwestern Medical Foundatio
Effect of ULK1 Inhibition on Corneal Epithelial Cells During Pseudomonas aeruginosa Infection
Get PDFThe 62nd Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 30, 2024, 3-6 p.m., D1.700 Lecture Hall)Each year the Medical Student Research Program awards students for the best oral presentation and the best poster presentation as judged by faculty across campus. This author received an award as one of the best poster presentations at this forum.INTRODUCTION: Pseudomonas aeruginosa (PA) keratitis is a severe infection of the cornea that can lead to blindness. Studies in our lab have shown that PA exploits autophagy, a major cellular degradation process, in corneal epithelial cells (hTCEpi cells) to promote intracellular survival. We have further shown that the inhibition of autophagy by the Unc 51-like kinase (Ulk1), an enzyme that mediates formation of the autophagosome, reduces intracellular levels of PA. More recently, we have demonstrated that PA infection negatively impacts host mitochondria. ULK1/2 has been reported to translocate to mitochondria to mediate mitophagy however, a role for ULK1/2 in mitochondrial homeostasis during infection has not yet been explored. In this study, we investigated the effects of the inhibition of Ulk1 during PA infection on host mitochondria.
METHODS: Telomerase-immortalized human corneal epithelial (hTCEpi) cells were used for this study. Cells were cultured in serum-free defined keratinocyte media with growth supplements. Cells were inoculated with 106 CFU/ml of PA in log growth phase with or without treatment with 1 ï�M of the Ulk1/2 inhibitor MRT68921. Intracellular levels of PA were quantified using a gentamicin survival assay. Oxygen consumption and mitochondrial polarization were assessed using Seahorse metabolic flux analysis and tetraethyl-benzimidazolyl-carbocyanine iodide (JC-1), respectively. Levels of pro-inflammatory cytokines were assessed using ELISA. Untargeted metabolomics was performed using mass spectrometry. Cellular changes were further evaluated using transmission electron microscopy (TEM).
RESULTS: PA infection induced robust mitochondrial depolarization. There was a corresponding increase in secretion of IL-6 and IL-8. Treatment with MRT68921 restored mitochondrial polarization and reduced IL-6, but had no effect on IL-8. MRT68921 also reduced intracellular levels of PA. TEM demonstrated robust mitochondrial fission during PA infection. Treatment with MRT68921 preserved mitochondrial structure and polarization during PA infection.
CONCLUSIONS: Taken together, these data suggest that Ulk1/2 modulates the host mitochondrial response to PA infection. Further studies are needed to determine the mechanism by which MRT68921 preserves mitochondrial function and its potential use as an adjunct therapeutic for PA-mediated keratitis.Southwestern Medical Foundatio
My Queen
Get PDFThe author submitted this entry in the Open Verse Poetry category (Amateur division) for the 2024 On My Own Time (OMOT) Art Show.My inspiration for writing the poem "My Queen" was to model writing elegy poetry for my 7th grade ELA students. My mother had recently passed away and I decided it would be an honorable memory. I didn't have a lot of time to fully process the reality of life without her nor really grieve, because I had a main role in preparing as well as participating in her funeral services, and afterwards, I could not take more time off from work. Writing this poem was very therapeutic for me, and even more so when I read it aloud in class to my students. When I finished reading it, the entire class gave me a standing ovation and many of them (including me) were visibly filled with raw emotions (tears). When they completed their elegy poetry, it was very apparent that my previous moment of transparency had quite a positive influence on their commitment to produce amazing heart-warming poetry
Deciphering AXL-Driven Molecular Mechanisms of EMT
Get PDFPages xviii-xix are misnumbered as pages xix-xx.Cellular plasticity, a feature associated with epithelial-to-mesenchymal transition (EMT), contributes to tumor cell survival, migration, invasion, and therapy resistance. Across human cancer, tumors that are high grade, poorly differentiated, and have undergone EMT carry a worse prognosis with a high likelihood of metastasis and poor outcome. AXL, a receptor tyrosine kinase (RTK), drives EMT and is implicated in tumor progression, metastasis, and therapy resistance in multiple cancer types including pancreatic cancer (PDA) and breast cancer. We investigated the contribution of TANK-binding kinase 1 (TBK1) to PDA progression and report that TBK1 supports the growth and metastasis of KRAS-mutant PDA by driving an epithelial plasticity program in tumor cells that enhances invasive and metastatic capacity. We identified that the receptor tyrosine kinase AXL induces TBK1 activity in a Ras-RalB-dependent manner. Furthermore, we report that AXL activation stimulates TBK1 binding and phosphorylation of the specific AKT isoform, AKT3 at S472. Activation of AKT3 drives the binding of AKT3 to slug/snail, where the complex is translocated into the nucleus. The binding of AKT3 to slug/snail protects the EMT-TFs from proteasomal degradation thus leading to an increase in EMT. These data suggest that the translocation of AKT3 to the nucleus is required for AXL-driven EMT and metastasis. Congruently, nuclear AKT3 expression correlates with worse outcome in aggressive breast. These results suggest that selective AKT3 targeting represents a novel therapeutic avenue for treating aggressive cancer that may avoid toxicity associated with pan-AKT inhibition. Additionally, our findings suggest that interruption of the AXL-TBK1-AKT3 cascade, has potential therapeutic efficacy in AXL positive metastatic cancer
HPV-Positive and HPV-Negative Vulvar Squamous Cell Carcinoma Are Biologically, but Not Clinically, Distinct
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.This dissertation is adapted from the associated publication of a year-long research project in which the author was the first author referenced in the citation below. "Per Elsevier regarding an article published in The Journal of Investigative Dermatology, [the author retains] the right to include this report in a thesis or dissertation, provided it is not published commercially. Permission is not required, but a reference is needed."BACKGROUND: Vulvar squamous cell carcinoma (VSCC) pathogenesis is traditionally defined by the presence or absence of human papillomavirus (HPV), but the definition of these groups and their molecular characteristics remains ambiguous across studies.
OBJECTIVE: The hypothesis of this project was that HPV-positive and HPV-negative VSCC are distinct diagnoses with unique biomarkers and clinically distinct behaviors. The objective was to determine the clinical and biologic relevance of these two groups in VSCC.
METHODS: A retrospective cohort analysis of 36 patients with invasive VSCC was performed where HPV status was determined using RNA in situ hybridization (ISH) and polymerase chain reaction (PCR). Clinical annotation, p16 immunohistochemistry (IHC), programmed death ligand-1 (PD-L1) IHC, HPV16 circular E7 RNA (circE7) detection, and RNA-sequencing (RNA-seq) of the cases was performed.
RESULTS: A combination of ISH and PCR identified 20 cases (55.6%) as HPV-positive. HPV-status did not impact overall survival (HR: 1.36, 95% CI: 0.307 to 6.037, p=0.6857) or progression-free survival (HR: 1.12, 95% CI: 0.388 to 3.22, p=0.8367), and no significant clinical differences were found between the groups. PD-L1 expression did not correlate with HPV status, but increased expression of PD-L1 correlated with worse overall survival. Transcriptomic analyses (n=23) revealed distinct groups, defined by HPV status, with multiple differentially expressed genes previously implicated in HPV-induced cancers. HPV-positive tumors showed higher global expression of endogenous circular RNAs (circRNAs), including several circRNAs that have previously been implicated in the pathogenesis of other cancers.
CONCLUSIONS: In summary, this retrospective cohort analysis did not detect clinical differences between HPV-positive and HPV-negative cases or an association with biomarkers, PD-L1 and circE7. The transcriptomic analysis of VSCC confirmed the biological distinction between these two groups in VSCC and suggested specific diagnostic and therapeutic targets for future studies, including several circRNAs
Group Intervention for Resiliency and Posttraumatic Growth Following Sexual Trauma in Women Veterans
Get PDFWomen service members have higher rates of childhood sexual trauma in comparison to civilian women and almost 50 percent of women reported joining the military to escape stressful home environments. Women Veterans also experience a myriad of traumatic stressors while in the military, including high rates of Military Sexual Trauma (MST), combat exposure, deployments, and/or perceived personal danger which can increase the risk of developing Posttraumatic Stress Disorder (PTSD). Research with Veteran populations demonstrates that individuals with a history of trauma who experience psychological distress are more likely to be exposed to future trauma and that multiple traumatic events across the lifespan can have an aggregate negative impact on well-being, particularly in the post-deployment adjustment stage, often depleting them of important coping resources. Furthermore, women Veterans with combat exposure and/or MST experience PTSD differently than civilian women or military men, and therefore may require tailored and integrative treatments.
The current evidenced-based treatments offered at the VA do not necessarily target aspects of resiliency. Studies have shown that interventions that are based in resiliency may reduce susceptibility to Posttraumatic symptoms, depression and suicide, and mediate the development of mental illness following trauma exposure. Interventions that focus on resiliency and posttraumatic growth (PTG) may help decrease symptom presentation, increase quality of life, and reduce the utilization and/or cost of care.
This pilot project developed and implemented a resiliency group intervention manual and client workbook specifically tailored to women Veterans with histories of military sexual trauma in a clinical treatment setting. We evaluated feasibility and explored the impact of the psychoeducation group as it relates to overall knowledge and utility of resiliency skills. Outcome measures of enrollment rate, completion rate, drop-out rate and a knowledge/satisfaction questionnaire showed that the resiliency skill building psychoeducation group was feasible and acceptable. Data also showed that that the intervention positively increased scores related to resilience and posttraumatic growth, reduced clinical symptoms as assessed by the PCL-5 and PHQ-9, and improved quality of life in women Veterans that have experienced MST