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Role of Krox20 Transcription Factor and Krox20+ Stem Cells in Epithelial Tissue Development and Homeostasis
Get PDFResident stem cells (SCs) within tissues are important for normal homeostasis maintenance and wound repair. This is mediated by the ability of SCs to properly self-renew, maintain their identity, and differentiate. Epidermal SCs occupy exclusive niches, priming them for giving rise to specific portions of the of the interfollicular epidermis (IFE) and hair follicle (HF). During homeostasis, the bulge SCs generate the lower portion of the HF, while isthmus, junctional zone, and infundibular SCs give rise to the upper HF and IFE. Beyond their unique cell fate, these cells are also capable of generating other portions of the epidermis, but only during pathological conditions (e.g., wounding). In this study, we report a newly identified infundibular SCs, marked by transcription factor Krox20. While Krox20-expessing cells are limited to the infundibular niche, lineage tracing analysis shows that these cells differentiate to generate both the entire HF and the IFE during homeostasis. Notably, previously identified epidermal SCs are derived and continually replenished from Krox20 lineage cells. The ablation of K14-derived Krox20-expressing cells results in deformed HF structure and the lack of a hair shaft, as well as abnormal differentiation and stratification of the IFE. Taken together, these results highlight Krox20-expressing cells as epidermal SCs, crucial for HF and IFE homeostasis and maintenance. Notably, this study represents the first description of a SC population which give rise to both the HF and the IFE during homeostasis, representing a paradigm shift in the current understanding of epidermal SCs differentiation. To evaluate the role of the Krox20 protein in these cells, we ablated Krox20 expression in K14-derived epithelial cells, and found that this resulted in spontaneous hair loss, correlated with aberrant HF structure and epidermal differentiation. Interestingly, these mice also serendipitously developed squamous metaplasia of the ocular surface, resulting from the loss of Meibomian glands (MGs). Expression analyses showed that Krox20-expressing cells constitute stem/progenitor cells that are restricted to the ductal region of the MG, but differentiate to give rise to the entire MG structure. Overall, this study identifies Krox20 as a marker of resident SCs that are essential to continually replenish epithelial-derived tissues (e.g., the epidermis and the MG), with Krox20 expression playing an important role in the function of these cells
Melanocortin Peptides Coordinate Metabolic and Immune Responses
Get PDFPages 84-114 are misnumbered as pages 83-113.The melanocortin system has been studied for over a century. What began from the simple observation that pituitary lysates applied to tadpoles caused their skin to darken has evolved into the most-researched pathway regulating body weight today. Through decades of serendipitous findings, brute force positional cloning studies, and modern neuroscience techniques, researchers are finally unraveling the roles of the melanocortin system in regulating metabolism. Furthermore, work from James Lipton and colleagues at UT Southwestern over 40 years ago pioneered the melanocortin immunoregulation field. Here, I discuss my recent findings that the melanocortin alpha-melanocyte stimulating hormone (α-MSH) is a critical regulator of inflammation and thermogenesis in response to an immune challenge using a unique mouse model that cannot produce α-MSH. Next, I conduct a series of metabolic experiments to further dissect the melanocortin system in the hypothalamus. Using novel genetics tools, I investigate the role of α-MSH release from a subpopulation of hypothalamic neurons and find that this peptide is a critical autonomic regulator that controls leptin and insulin homeostasis and obesity. Together, these data underscore the importance of α-MSH in different aspects of physiology, which an active area of research for drug development that has had recent success. My findings build on this foundation and raise the possibility of expanding the therapeutic potential of the melanocortins to include acute or chronic inflammatory diseases and further our understanding of the neural mechanisms coordinating metabolism
Resurrection of the Public Universal Friend
Get PDFThe author submitted this entry in the Open Verse Poetry category (Professional division) for the 2025 On My Own Time™ (OMOT) Art Show.This poem came from a prompt to write about a historic figure. I learned about the Public Universal Friend, an 18th century Quaker preacher who adopted an androgynous appearance and refused to be addressed by gendered pronouns. As a nonbinary person, I felt the need to share the P.U.F.'s story through poetry, especially after learning about how historians tried to erase their identity. Even if the gender identification of "nonbinary" is more recent, we've always been around
In Many Forms, I AM Me!
Get PDFThe author submitted this entry in the Open Verse Poetry category (Amateur division) for the 2025 On My Own Time™ (OMOT) Art Show.This piece was inspired by my real-life alter egos: Doomp (my bold college nickname), Jhays (the day-to-day me), Mutha (my title as Bulb's mom), and Jhaysmine/Jasmine (my given name and the root of it all). It's a verbal reflection of womanhood and identity. It's a reminder that no matter the title, I still get it done. That even while juggling roles, responsibilities, and dreams, I'm still me. This piece speaks to the strength it takes to show up, and the importance of not forgetting who you are in the process. It's for every woman doing "too much" and still doing it well
Structural Interplay of Anesthetics and Paralytics on Muscle Nicotinic Receptors
Get PDFGeneral anesthetics and neuromuscular blockers are used together during surgery to stabilize patients in an unconscious state. Anesthetics act mainly by potentiating inhibitory ion channels and inhibiting excitatory ion channels, with the net effect of dampening nervous system excitability. Neuromuscular blockers act by antagonizing nicotinic acetylcholine receptors at the motor endplate; these excitatory ligand-gated ion channels are also inhibited by general anesthetics. The mechanisms by which anesthetics and neuromuscular blockers inhibit nicotinic receptors are poorly understood but underlie safe and effective surgeries. Here we took a direct structural approach to define how a commonly used anesthetic and two neuromuscular blockers act on a muscle-type nicotinic receptor. Nicotinic acetylcholine receptors participate in neuro-muscular transmission and are the drivers of muscle contraction at the neuro-muscular junction. We discovered that the intravenous anesthetic etomidate binds at an intrasubunit site in the transmembrane domain and stabilizes a non-conducting, desensitized state of the channel. The depolarizing neuromuscular blocker succinylcholine also stabilizes a desensitized channel but does so through binding to the classical neurotransmitter site. Rocuronium binds in this same neurotransmitter site but locks the receptor in a resting, non-conducting state. Together, this study reveals a novel structural mechanism for how general anesthetics work on excitatory nicotinic receptors and further rationalizes clinical observations in how general anesthetics and neuromuscular blockers interact.
Nicotinic receptors are also found throughout the nervous system in different stoichiometries. The inclusion of different subunits allows for fine tuning of the receptor function. An intriguing sub class of nAChR subunits, called accessory subunits co-assemble with the neuronal nAChRs and are thought not to contribute to the endogenous ACh binding site. Their incorporation into the neuronal nAChR however changes channel function but how that is achieved remains unknown as these subunits are particularly tough to express and study. For the second part of my thesis, I discuss my work on the neuronal nicotinic receptor carrying the α5 accessory subunit. The α5 subunit was incorporated into the ganglionic α3β4 receptor and recombinantly expressed. The accessory subunit occupied one site in the pentamer but did not seem to form a neurotransmitter site
Doctor's Visit
No full textThe author submitted this entry in the Open Verse Poetry category (Amateur division) for the 2025 On My Own Time™ (OMOT) Art Show.A poem for our sweet dog (Honey), who thought it was just another ride, but was tricked and taken to the vet for a teeth extraction..
Stoplights
Get PDFThe author submitted this entry in the Open Verse Poetry category (Amateur division) for the 2025 On My Own Time™ (OMOT) Art Show.The event of this poem defines the before and after of my lif
Measurement and Applicants of Incidental Coronary Calcium on Chest CT Scans
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.Pages 1-16 are misnumbered as pages 2-17, and pages 17-32 are misnumbered as pages 19-34.The utility of coronary artery calcium (CAC) to better identify and stratify risk profiles for individuals at risk for ASCVD has introduced numerous modalities and scoring systems for characterizing calcium burden. Recently, identification of CAC on a non-gated, standard non-cardiac CT (NCCT) scan has provided new opportunities to characterize the burden for a larger cohort of patients. The advent of NCCT has introduced the need for a new, standardized scoring system with possibilities including an ordinal, visual, and modified Agatston score. Additionally, various machine learning approaches have created novel ways to identify calcification on NCCT scans, further automating and streamlining the pipeline. Finally, considering the growing research advising an NCCT derived CAC score is likely able to inform early statin initiation, future considerations include identifying specific patient populations to target and devising a standardized approach for NCCT derived CAC score reading and clinician-facing reporting
Aligning Patients' Defibrillator Status with their Goals of Care: A Multidisciplinary Quality Improvement Project at Parkland Hospital
Get PDFBACKGROUND: Implantable Cardioverter Defibrillators (ICDs) are life-prolonging devices that prevent death from life-threatening arrythmias. Over 150,000 devices are implanted in the US each year. Given the possibility of patient goals evolving over their life course, current national guidelines direct providers to explore goals-of-care and ICD deactivation with patients. However, many patients never have these conversations with their providers, especially in underserved patient populations where healthcare resources may already be limited. As a result, a significant portion of patients continue to have their ICD shock settings "on" and remain at risk for unwanted painful ICD shocks towards their end of life, which can inflict unnecessary suffering on both patients and their caregivers.
OBJECTIVE: Our project aim is to ensure 100% of patients at Parkland Hospital with ICDs have alignment between the shocking function of their device and their goals of care by January 1, 2024.
METHODS: A Quality Improvement (QI) effort was undertaken at Parkland Hospital to increase alignment of patients' ICD on/off status with their goals-of-care. The DMAIC methodology (Define, Measure, Act, Improve, Control) was selected to guide the QI effort. First, a cohort of 113 patients with ICDs at Parkland were identified using an existing palliative care registry. From that cohort, a retrospective chart review was conducted to assess medical and demographic data. Additional data was collected about existing patient educational tools. Next, patient knowledge, goals, and experiences were assessed using a survey adapted from validated published tools. Of the 113 patients in the registry, 26 patients completed the phone survey. Based on knowledge gaps identified in the survey, a patient education video was created, alongside updates within the EPIC electronic medical record system, to streamline the process of ICD discussions and deactivation. Multiple iterative PDSA cycles were undertaken to implement the education video and EPIC tools into providers' workflow.
RESULTS: From 2019 to 2023, the project progressed through each of the DMAIC stages:
Define: In our 113 patients, 75% were male, 48% were Black, 26% were Hispanic, and 19% were uninsured or requiring financial assistance at Parkland. From the 113 patients, 26 patients ultimately completed the phone survey, of whom 27% spoke English as a second language and 80% had a high school degree or less. Of note, nearly 40% of this original 113 patients passed away in the five months between initial identification and phone survey, indicating a very ill and near end of life patient population for whom goals of care discussions are especially crucial. Existing education material were primarily written documents, featured a range of reading levels, featured White-appearing individuals, and very few included Spanish language versions.
Measure: Of the 26 patients who completed the phone interview survey, only 31% of patients correctly identified that deactivation of ICDs did not require surgery, only 54% were aware that the heart does not stop beating after deactivation, and only 19% correctly stated ICD deactivation does not require pacemaker function to also be deactivated. These scores were lower than reports in prior published literature.
Act: An expert multidisciplinary committee was convened to evaluate the data, synthesize root cause analyses, and determine interventions.
Improve: A patient-centered ICD educational video was created, featuring Parkland patients, animations about key concepts, and versions in English and Spanish. In addition to the video, efforts were undertaken to standardize the processes for goals of care discussion/ICD deactivation (including EPIC order sets, consult placements, and process maps). Several iterative PDSA cycles were conducted to assess how best to integrate these tools into provider workflow.
Control: Evaluation of the patient education video and EPIC integration is currently ongoing.
CONCLUSION: Our QI effort is the first to address the specific goals of care discussion challenges of Parkland patients with ICDs as they near the end of life. This project utilized a patient-centered design approach to develop educational content that was intentionally inclusive and accessible to Parkland patients, as well as addressed their main common knowledge gaps. Through our efforts, we hope to empower patients at Parkland with the knowledge and tools to become active participants in their own care plans. Ultimately, we hope this project reinforces the importance of centering the voice of our patients at the core of our medical decisions, system designs, and improvement processes
Increased Risk of Cutaneous Immune-Related Adverse Events in Patients Treated with Talimogene Laherparepvec and Immune Checkpoint Inhibitors: A Multi-Hospital Cohort Study
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: Previous studies have shown that combining immune checkpoint inhibitors (ICIs) with Talimogene Laherparepvec (TVEC) may improve antitumor responses. However, the risk of developing cutaneous immune-related adverse events (cirAEs) in patients treated with ICI and TVEC has not been studied.
OBJECTIVE: To evaluate the differences in cirAE development between patients treated with ICI alone and both ICI and TVEC (ICI+TVEC).
METHODS: Patients with cutaneous malignancy receiving ICI with or without TVEC therapy at the Massachusetts General Brigham healthcare system were included. CirAE development, time from ICI initiation to cirAE, cirAE grade, cirAE morphology, and survival were analyzed. Pearson's chi-squared test or Fisher's exact test for categorical variables and t-test or Kruskal-Wallis test for continuous variables were used. To account for immortal time bias, we performed adjusted time-varying Cox proportional hazards modeling.
RESULTS: The rate of cirAE development was 32.3% and 38.7% for ICI only and ICI+TVEC, respectively. After adjusting for covariates, ICI+TVEC was associated with a 2-fold increased risk of cirAE development (HR: 2.03, p=0.006) compared to patients receiving ICI therapy alone.
LIMITATIONS: The retrospective nature and limited sample size from a tertiary-level academic center.
CONCLUSION: These findings underscore potential opportunities for dermatologists and oncologists in counseling and monitoring patients