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Inhibition of Karyopherin-β1-Mediated Nuclear Import of Lineage-Defining Transcription Factors in Small Cell Lung Cancer
No full textSmall cell lung cancer (SCLC) is an aggressive neuroendocrine tumor that accounts for approximately 16% of lung cancer diagnoses. Recent genomic studies support the classification of this disease into four different subtypes based on the expression of the lineage-defining transcription factors ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1 (SCLC-Y). Together, the SCLC-A and SCLC-N subtypes account for a majority of SCLC. ASCL1 and NEUROD1 are Class II bHLH transcription factors that command the expression of SCLC oncogenes and are known to drive distinct transcriptional programs, conferring SCLC-A and SCLC-N with different molecular and physiological features. ASCL1 has also been shown to be required for tumor formation in SCLC mouse models, and, where tested, both ASCL1 and NEUROD1 play key roles in maintaining growth of SCLC-A and SCLC-N cell lines. Together, these findings suggest that strategies to inhibit ASCL1 and NEUROD1 activity may represent an attractive SCLC therapy, and provide new insight into the underlying plasticity of the major SCLC subtypes. ASCL1 and NEUROD1 are translated in the cytoplasm and must be transported into the nucleus in order to regulate gene expression. Interestingly, it has been shown that NEUROD1 is selectively imported into the nucleus via the nuclear transport receptor Karyopherin-β1, or KPNB1 (also known as Importin-β1) in several mouse and human cell lines. Additionally, a muscle-specific bHLH transcription factor, MYOD, has also been shown to be imported into the nucleus by KPNB1, suggesting a common nuclear import mechanism for Class II bHLH transcription factors. However, whether ASCL1 is also imported into the nucleus via the same mechanism, and whether the nuclear import of NEUROD1 is mediated by KPNB1 in the setting of SCLC, had not been tested. Here, I 1. identified KPNB1 as a nuclear import receptor for ASCL1 and NEUROD1 in SCLC, 2. showed that KPNB1 inhibition disrupts SCLC- A patient derived xenograft (PDX) growth in vivo, and preferentially disrupts the growth of ASCL1/NEUROD1+ SCLC in vitro, and 3. compared the changes in gene expression following the inhibition of ASCL1 or KPNB1 activity across in vitro and in vivo models of SCLC
Improving Adherence to an Integrated Spontaneous Awakening and Spontaneous Breathing Trial Protocol
Get PDFBACKGROUND: Integration of nursing-driven spontaneous awakening trial (SAT) and respiratory therapy-driven spontaneous breathing trial (SBT) protocols for patients on mechanical ventilation in the intensive care unit (ICU) is associated with fewer ventilator days, shorter ICU stays, and reduced hospital length-of-stay. However, institutional adherence is often suboptimal due to the complexity and multidisciplinary nature of these integrated protocols. This project aims to describe baseline compliance with our institution's SAT/SBT protocol, identify factors influencing compliance, and increase adherence to the existing SAT/SBT protocol in the ICU to a goal of greater than 95% compliance by August 2023.
LOCAL PROBLEM: Data from a retrospective chart review indicated a SAT screen rate of 63.8% and a SBT screen rate of 85%. Therefore, the SAT/SBT protocol adherence at our institution is sub-optimal.
METHODS: Initially, we determined baseline adherence rates through a retrospective chart review of SAT and SBT documentation. Specifically, we identified the rates of correctly performed SAT and SBT screenings for all eligible patients and the subsequent rates of correct SAT and SBT performance for patients who passed the appropriate screening. We then sought to identify factors influencing adherence to the SBT/SAT protocol by employing an ethnographic approach, including: (a) process mapping of the integrated SAT/SBT protocol, (b) literature-driven surveys using the Likert scale to assess potential barriers to protocol adherence, (d) informal interviews with nurses and respiratory therapists, and (e) direct observation in the medical ICU. Individual factors identified were organized using the Systems Engineering Initiative for Patient Safety (SEIPS) sociotechnical framework. The SEIPS model allowed for further design of targeted interventions to improve protocol adherence.
RESULTS: Factors influencing adherence were identified from survey responses by 63 nurses and 26 respiratory therapists, 30 hours of direct observation, and tabulated comments from surveys and informal interviews. Prominent factors influencing compliance included knowledge of the protocol, protocol variation across intensive care units, accessibility of the protocol, ease of documentation in the electronic medical record (EMR), and the exclusion of nurses and respiratory therapists in physician-led ICU rounds.
CONCLUSION: Data from a retrospective chart review and ethnographic investigation of SAT/SBT protocols indicated sub-optimal adherence. Further investigation into the specific factors influencing adherence allowed us to propose specific interventions to improve performance. Such future interventions will include: (a) EMR redesign using feedback obtained in our investigation to improve accessibility and allow reliable surveillance of protocol adherence, (b) enhanced, standardized multidisciplinary ICU rounds, (c) protocol education sessions, (d) continuous monitoring of protocol metrics with intermittent feedback provided to staff, and (e) a Quality Assurance and Performance Improvement Workgroup dedicated to regular engagement of key stakeholders for process improvement
Interaction of Quantal Inhibitory and Excitatory Neurotransmission in Regulation of Synaptic Homeostasis via Molecular Signaling
Get PDFThe processing and flow of information through brain circuits is undeniably shaped by individual neurons and synapses. The type of synapse between any two given neurons determines the reliability, speed, and strength of signal transfer. Therefore, studying the organization and signaling capacity of the variety of synapses present in our nervous system is critical to understanding how information is shaped and communicated between neurons. Neurotransmission can be classified into two broad types: spontaneous and evoked. Much of the work examining these types of neurotransmission and their properties has been done in excitatory synapses. Yet the variety of inhibitory neurons is so vast that Ramon y Cajal referred to them as the "Butterflies of the Soul." In order to help paint a more complete picture of the brain, this PhD thesis is focused on the structure, function, and regulation of synapses and neurotransmission, with a focus on inhibitory synapses.
We first expanded the tools available to study synapses by demonstrating that lentiviral CRISPR could be used in postmitotic cells to knockout synaptic proteins and study non-cell autonomous phenotypes. Next, we took advantage of the use-dependent properties of the GABAA receptor antagonist picrotoxin, demonstrating that this drug could be used to interrogate inhibitory synapse parameters, such as presynaptic release probability. By utilizing picrotoxin, we were able to examine the postsynaptic organization of spontaneous and evoked neurotransmission at inhibitory synapses, and discovered a partial segregation of the postsynaptic receptors activated by evoked and spontaneous neurotransmission. This result implied that spontaneous and evoked neurotransmission at inhibitory synapses may have partially non-overlapping functions. Because the function of inhibitory spontaneous neurotransmission is largely unknown, we next examined the signaling capacity of inhibitory spontaneous neurotransmission. We discovered that modulation of inhibitory, but not excitatory, spontaneous neurotransmission alters transcription of certain activity-induced genes, including Bdnf. Furthermore, blockade of inhibitory spontaneous neurotransmission leads to downscaling of excitatory synapses through a BDNF-dependent mechanism. Finally, we examined the regulation of synapse function by miRNAs regulated by MeCP2, a gene in which loss of function mutations are the primary cause of Rett Syndrome. We characterized the effects of two candidate miRNAs on synapse function. One of these miRNAs, miR-101a, has opposing impacts on excitatory and inhibitory synapses, suggesting a role in regulating excitatory/inhibitory balance, a feature that is often altered in ASD and ASD-like disorders such as Rett Syndrome. In summary, we have contributed to the study of synapses by expanding the tools available, improving understanding of inhibitory synapse structure and function, and examining the broad regulatory capacity of certain miRNAs over synaptic function
A Lesson Hard Learned
Get PDFThe author submitted this entry in the Creative Non-Fiction category (Amateur division) for the 2023 On My Own Time (OMOT) Art Show.A last parting lesson passed from father to son
Assessing Self-Care Perception in Patients Living with Type 2 Diabetes and Their Physicians
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: Type 2 diabetes mellitus (T2D) is chronic illness affecting millions in the United States. Patients living with T2D require highly individualized care and significant patient effort. This effort is comprised of the patient's self-care with regards to medication, diet, lifestyle, and mental health. Self-efficacy is a patient's ability to feel agency over their illness and therefore feel able to maintain self-care. Previous literature suggests that improving a patient's self-efficacy through various behavioral health interventions may improve a patient's ability to manage their T2D. Additionally, interventions on self-efficacy are thought to work regardless of health literacy level and might be a generalizable intervention. However, while validated surveys assessing patient diabetes distress, quality-of-life, social determinants of health, adverse childhood events, and more exist, no literature was found attempting to understand a patient's perspective on their self-care, and by extension, their self-efficacy. Under the premise that consistent beliefs between patient and physician regarding self-care are necessary to make meaningful plans promoting self-care and self-efficacy, the authors developed the term self-care perception consistency to assess relationship between patient and physician perceptions of a patient's self-care.
OBJECTIVE: The objective is to assess the consistency between patient and physician perceptions of patient self-care through a biopsychosocial and structural/social determinants of health lens.
METHODS: This study uses a cross-sectional, quantitative data set obtained by the Research Residency Network of Texas (RRNeT) through a 71-item survey study. This survey was completed across 12 Family Medicine residencies in Texas and included individuals between 18-75 who were living with T2D. Responses ranged from short free response to Likert-scale based questions and covered topics such as demographics, social determinants of health, patient self-care, diabetes distress, quality-of-life, adverse childhood events, and more. The physicians of each patient were asked to complete a shorter 10-item survey with broader analogous questions to the patient survey. This data was collected through RedCap and analyzed through RStudio.
RESULTS: The term self-care perception consistency was coined to describe the relationship between the patient's and physician's perception of the patient's self-care. Self-care perception consistency was found to be lacking 31.2% of the time. Only HgA1c (p<0.01) was inversely correlated with self-care perception consistency in both the univariate and multivariate analyses of demographic factors and social determinants of health. Additional analysis was completed to assess the relationship of HgA1c control, patient diabetes distress, patient quality-of-life, and the physician survey with self-care perception consistency. Self-care perception consistent and inconsistent groups were found to have significantly different HgA1c control distributions (p < 0.01) in the subset of patients that rated their self-care positively, but no significant difference was found in the group that rated their self-care negatively. Patient self-care ratings were best correlated with their diabetes distress (p<0.01) and HgA1c (p<0.01) while physician ratings of patient self-care were best correlated with their perception of HgA1c, perception of patient diabetes distress, perception of patient quality-of-life, and perception of patient social connectedness (p<0.01 for all). Notably, trending diabetes distress, quality-of-life, the physician survey, and social determinants of health across patient self-care ratings in self-care perception consistent versus inconsistent groups revealed that only the physician survey showed opposite trends across the consistent and inconsistent groups.
CONCLUSION: Self-care perception consistency was found to be lacking 31.2% of the time. Notably, HgA1c is correlated with patient and physician perceptions of patient self-care (p<0.01 for both); however, in instances of patient-physician self-care perception inconsistency, HgA1c is not correlated with patient self-care perception. Instead, diabetes distress remains predictive of patient self-care rating in all instances (p<0.01). Patient-physician self-care perception inconsistency is also associated with inconsistency in patient and physician perceptions of the patient's diabetes distress. As diabetes distress remains consistently correlated with patient self-care rating, using the validated diabetes distress survey-17 with an additional question regarding self-care may help physicians better understand patients and therefore target appropriate education and psychosocial interventions
Compensation Between Foxp Transcription Factors Maintains Proper Striatal Function
Get PDFSpiny projection neurons (SPNs) of the striatum are critical in integrating neurochemical information to coordinate motor and reward-based behavior. Mutations in the regulatory transcription factors expressed in SPNs can result in neurodevelopmental disorders (NDDs). Paralogous transcription factors Foxp1 and Foxp2, which are both expressed in the dopamine receptor 1 (D1) expressing SPNs, are known to have variants implicated in NDDs. Paralogous transcription factors are thought to have the ability to compensate for each other and previous work published by the lab supports the hypothesis that Foxp1 and Foxp2 have compensatory roles in D1 SPNs as well. For my dissertation work, I utilized mice with a D1-SPN specific loss of Foxp1, Foxp2, or both and a combination of behavior, electrophysiology, and cell type specific genomic analysis to address if there was compensation occurring. It is only upon the loss of both genes that motor behavior was impaired whereas Foxp1 mediated social behavior impairments were exacerbated upon the further loss of Foxp2 (Chapter Two). I also found that while loss of Foxp1 resulted in KLeak mediated hyperexcitability of D1-SPNs, this too was further impaired with the additional loss of Foxp2 (Chapter Three). Viral mediated re-expression of Foxp1 in the double knockouts was sufficient to restore both behavioral and electrophysiological impairments to baseline. I further studied the contribution of Foxp1 and Foxp2 to regulation of downstream targets genes using single-nuclei RNA-seq and found that in both juvenile and adult D1-SPNs, loss of both transcription factors resulted in differential expression of hundreds of genes (Chapter Four). I was able to use these experiments to also investigate how loss of these transcription factors from the D1-SPNs impacted gene expression in other cell-types (Chapter Five). I also utilized single-nuclei ATAC-Seq and again found that loss of both genes resulted in large scale dysregulation of chromatin state not seen in the single knockouts, including in regions enriched for Fox motifs (Chapter Six). I also began to address the open question of what the direct binding targets of Foxp1 and Foxp2 are using the newly developed CUT&RUN technique (Chapter Seven). The findings from my experiments point towards a form of compensation between Foxp1 and Foxp2 where one transcription factor maintains striatal function upon the loss of the other, which I discuss more in depth (Chapter Eight). I also discuss my involvement in a project where we further study the role of Foxp1 in D1- and D2-SPNs, which I am working on in collaboration with Dr. Nitin Khandelwal (Chapter Nine). I conclude by discussing the implications of my findings and suggest recommendations for further study (Chapter Ten)
Teaching the old dog new tricks: efforts to reform clinical trial design and conduct
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
Quantitative Analysis of Barriers and Facilitators to Adopting Tenecteplase
Get PDFThe objective of this study is to identify barriers and facilitators to TNK implementation at hospitals within the state of Texas and present them in a quantifiable presentation.This poster was presented at the 9th Annual Neuro and Intensive Care: Review, Workshops and Controversies 2023 in Orlando, Florida, on May 12, 2023.INTRODUCTION: Tenecteplase (TNK) is an emerging treatment for acute ischemic stroke (AIS) being adopted in place of alteplase (ALT). Compared to ALT, TNK has a longer half-life, shorter administration time, lower cost, and similarly high efficacy in treating large vessel occlusion. Nevertheless, there are barriers to TNK adoption as a treatment for AIS.
OBJECTIVES: The objective of this study is to identify barriers and facilitators to TNK implementation at hospitals within the state of Texas and present them in a quantifiable presentation.
MATERIALS & METHODS: This study examines questionnaire responses from 40 hospitals to examine barriers and facilitators to transition from ALT to TNK. Surveys were done via teleconference with stroke coordinators and physicians associated with the Lone Star Stroke Research Consortium and other regional Texas hospitals. The consortium comprises participants from 6 hub hospitals and 28 spoke hospitals including community-based facilities to Comprehensive Stroke Centers (CSC). Interviews lasting 10-20 minutes were conducted where nominal variables like hospital bed information, stroke information, thrombolytic use, and ordinal variables were recorded utilizing a Likert questionnaire. The participants were blinded to the survey questions to reduce bias.
DISCUSSION/RESULTS: The 40 Texas hospitals had a mean of 40 ED beds, 49 stroke beds, 685 annual stroke admissions out of which 14.5%, were hemorrhagic, 18% Transient Ischemic Attack (TIA) and 66.5% AIS respectively. There were 20 (50%) CSC hospitals, 2 (5%) thrombectomy capable, 16 (40%) primary stroke centers, and 2 (5%) were acute stroke ready hospitals. Compared to hospitals that successfully adopted TNK, non-adopters had significantly different views on the barrier of adequate evidence (P <.05), TNK delivery times (P<.05), and legal issues regarding giving TNK (P<.05). However, hospitals were similar in respect to the barriers of having a TNK policy (P=.094), buy-in from administration (P=.276), the cost of TNK (P=.089), and the willingness of pharmacy to adopt TNK (P=.242).
SUMMARY/CONCLUSION: There is a generalizable pattern of barriers and facilitators from the perspective of stroke coordinators and physicians. The results will be used to develop a TNK adoption Toolkit
Lung cancer screening: yes we can
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
Building trust in a time of turmoil
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