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To Rise
Get PDFThe author submitted this entry in the 10-Word Story category (Amateur division) for the 2025 On My Own Time™ (OMOT) Art Show.Inspired by the morning wake-up alarm
Patterns of Loading Dose Use in Biologic Therapies for Hidradenitis Suppurativa and Psoriasis
Get PDFThis thesis includes 2 separate documents: [Part One] A Study of Female and Minority Representation in Clinical Trials and [Part Two] Patterns of Loading Dose Use in Biologic Therapies for Hidradenitis Suppurativa and Psoriasis.[Female and Minority Representation in Clinical Trials for Hidradenitis Suppurativa and Psoriasis]
BACKGROUND: It is well established that females and minorities are under-represented in clinical research despite legislative efforts to promote their inclusion. Several studies have found this trend to be true in clinical trials for hidradenitis suppurativa (HS) and psoriasis (PsO).
OBJECTIVE: To identify any differences in demographic breakdowns of HS and PsO patients between healthcare settings to uncover any causative healthcare disparities.
METHODS: This systematic review reports racial, ethnic, and sex makeup of HS and PsO patient populations across the emergency department (ED), inpatient, clinical trial, and registry settings. 95% confidence intervals are used as proxies of statistical significance to compare demographic breakdowns between settings.
RESULTS: Female, Hispanic, and Black patients were under-represented in HS clinical trials compared to their population prevalences (Female: 63.7% (61.4-66.0%) vs. 73.5% (72.8-74.3%); Hispanic: 3.8% (1.4-6.3%) vs. 12.0% (11.4-12.6%); Black: 9.1% (6.3-11.8% vs. 20.3% (19.6%-20.9%)). White patients were over-represented (76.6% (72.5-80.6%) vs. 59.9% (59.1%-60.7%)). Female and Black patients were under-represented in PsO clinical trials compared to their population prevalences (Female: 33.0% (32.6-33.5%) vs. 54.8% (49.8-59.8%); Black: 2.2% (2.0-2.4%) vs. 5.7% (3.4-8.0%)). Black patients were over-represented in the inpatient and emergency department (ED) settings in HS (inpatient vs. emergency department vs. population prevalence: 49.9% (49.3-50.6%) vs. 49.9% (49.7-50.1%) vs. 20.3% (19.6-20.9%) and in the inpatient setting in PsO (inpatient vs. population prevalence: 19.8% (19.1-20.6%) vs. 5.7% (3.4-8.0%).
CONCLUSION: The finding that females and minority groups are under-represented in HS and PsO clinical trials is consistent with the published literature. Black patients appear to be over-represented in the acute care setting compared to other groups, the reason for which is likely multifactorial.[Patterns of Loading Dose Use in Biologic Therapies for Hidradenitis Suppurativa and Psoriasis]
BACKGROUND: There are few published studies directly comparing the clinical effectiveness of biologic therapy regimens with loading doses to those without loading doses, and there is no clear pattern of loading dose use. Published reasons for the use of loading doses include faster achievement of therapeutic drug levels, reduced time to clinical response, prevention or neutralization of anti-drug antibodies, and the need for more drug to gain control of an inflammatory disease than maintain control.
OBJECTIVE: To identify any patterns of loading dose use in biologic therapies.
METHODS: All FDA-approved biologic therapies for plaque psoriasis and their recommended regimens in all indications were tabulated (Table 1). The total amount of drug recommended in weeks one through twelve and thirteen through twenty-four were considered the loading dose and maintenance dose, respectively. The amount of drug recommended in each twelve-week period was normalized by dividing by the maximum amount of each biologic drug recommended for any indication in that same period. For each indication and twelve-week period, normalized values were added, and the sum was divided by the total number of approved biologic therapies in that indication. This yielded the average recommended biologic dose for a given indication in each 12-week period. These average doses were classified into quartiles by comparing them to other indications within the same 12-week period. A high dose of biologic therapy was considered to fall within quartile one or two and a low dose, within quartile three or four.
RESULTS: In HS, PsO, and uveitis, high loading and maintenance doses were recommended relative to other indications. In Crohn's disease and ulcerative colitis, high loading doses and low maintenance doses were recommended. In rheumatoid arthritis and psoriatic arthritis, low loading doses and high maintenance doses were recommended. In non-axial spondyloarthritis, low loading and maintenance doses were recommended.
CONCLUSION: The use of loading doses was found to cluster by specialty. The reason for this pattern is unclear and may have several possible explanations
Humanizing drug discovery II: improving success rates for first-in-class medicines
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
She Thrives
No full textPrompt: "What does your voice sound like when it is free, powerful, and truly heard?"Defying the odds in a society and culture that expect you to stay quiet takes courage. It means finding peace within yourself, embracing your voice, and choosing to use it boldly in pursuit of what truly matters to you. It's about rewriting the narrative, and doing so with purpose and passion
Improving quality of life for people with cirrhosis
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
AAN brain death practice guidelines: what's old, what's new, and what's next
Get PDFTuesday, December 10, 2024; noon to 1 p.m. (Central Time); Room NB2,100A or via Zoom. "AAN Brain Death Practice Guidelines: What's Old, What's New, and What's Next." Michael Rubin, M.D., Associate Professor of Neurology-Neuro Critical Care, The University of Texas Southwestern Medical Center.The American Academy of Neurology 2023 Brain Death Practice Guideline is the third in a series of position papers designed to establish standards of practice for death determination by neurologic criteria. These guidelines have been shaped by the development and implementation of the Uniform Determination of Death Act as well as court cases and a rigorous debate in the neurology and ethics literature. The stakeholders are many and include clinicians, researchers, policy makers, lawyers, clergy, and philosophers. While some elements of this debate are resolved, many are left undecided. I am going to review the historic evolution of death determination, explain our current state, and then offer informed speculation as to what the future may bring.UT Southwestern--Program in Ethic
Late Presentation of Complications of Mid-Urethral Sling and Outcomes after Sub-Urethral Sling Removal
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: Mid-urethral slings (MUS) are common procedures for surgical management of stress urinary incontinence (SUI) in women and have recognized complications, which are often underdiagnosed if they occur late and may result in complex care even after sub-urethral sling removal (SSR). This study focused on the evaluation of MUS complications occurring 10+ years after placement, and outcomes after sling release.
METHODS: Demographics, past medical history, original MUS operative note, presenting symptoms, pre-SSR evaluation, peri-operative complications, post-SSR symptoms at last visit, were collected from EMR (EPIC) for patients who underwent SSR at least 10 years after MUS placement. For those not seen in the past 2 years, a standardized phone interview using validated questionnaires was performed by a neutral investigator not involved in the care of these patients.
RESULTS: From 2006 to 2023, 58 patients met study criteria with mean age of 65 ± 10.5 years and predominantly Caucasian (91%). Nine were reached by phone and 4 were lost to follow-up. Time from initial MUS procedure to SSR removal was 16.7 ± 3.9 years. Most MUS were TVT (76%), followed by TOT (18%). At presentation, 90% of patients reported pain, 86% dyspareunia, 69% recurrent UTI, 52% SUI, and 53% urge urinary incontinence. Multiple presenting symptoms were observed in 83% of patients. At a mean follow-up of 2.2 years, SSR resulted in resolution of pain in 50% of patients, dyspareunia in 50%, recurrent UTI in 60%, SUI in 29%, and urge urinary incontinence in 37%, for each respective initial symptom. Some patients reported de novo pain (3%), UTIs (2%), SUI (9%) or urge urinary incontinence (7%). 7% required subsequent surgery for UI or persistent pain-related issues.
CONCLUSIONS: It is important that pelvic reconstructive surgeons monitor patients who receive MUS over time and counsel patients considering MUS on these potential risks.Southwestern Medical Foundatio
Glutamine Antagonism and Its Utility as a Therapeutic Modality in Cancer
Get PDFGlutamine metabolism is important in cancer as it fuels the TCA cycle, plays a role in redox homeostasis, and contributes to the production of nucleotides, amino acids, and lipids for survival, making glutamine metabolism a promising target in cancer therapy. The work outlined in this dissertation focuses on understanding the mechanism of the broad glutamine metabolism inhibitor, 6-diazo-5-oxo-L-norleucine (DON) and its prodrug, JHU-083, while comparing them to the effects of CB-839, a specific glutaminase inhibitor. DON is one of the oldest and well-known glutamine antagonists and can effectively limit tumor growth in a preclinical setting. Unfortunately, DON was removed from early phase clinical trials due to unacceptable toxicity in the gastrointestinal tract (GI). Thus, DON prodrugs were recently developed to be inactive until cleaved by cathepsins enriched in the tumors or by plasma esterases, bypassing toxicity in the GI tract.
Using isotope tracer studies in cancer cells and mouse xenograft models, I found that DON and JHU-083 mainly inhibit glutamine-derived nitrogen labeling in purines but unexpectedly does not limit the contribution of glutamine-derived carbon labeling of tricarboxylic acid (TCA) cycle metabolites. Additionally, I found that DON and JHU-083 can limit the levels of purines but not the levels of most TCA cycle metabolites. These findings suggest that these drugs are poor inhibitors of glutaminase in the cancer cell lines tested and that DON and JHU-083 mainly target purine metabolism.
Recognizing DON and JHU-083 as effective purine metabolism inhibitors can offer insight into which cancer patients could benefit from these drugs. Relapsed small-cell lung cancer (SCLC) is characterized by an upregulation of de novo purine biosynthesis and have few durable therapies. Using metabolic tracing and untargeted metabolomics, I found that DON can inhibit purine metabolism in treatment-naïve and chemoresistant pairs of SCLC. In a mouse xenograft model of relapsed SCLC, JHU-083 induces a delay in tumor growth without overt side effects. My work provides an opportunity to explore JHU-083 as an anti-cancer therapy for diseases that depend on purine biosynthesis
Vanishing Act: Lymphatic Vessels and Disappearing Bones
No full textGeneralized lymphatic anomaly (GLA) and Gorham-Stout disease (GSD) are related diseases of the lymphatic system. Patients with GLA or GSD develop ectopic lymphatic vessels in bone and gradually lose bone. Despite growing interest in the development of tissue-specific lymphatics, the cellular origin of bone lymphatic endothelial cells (bLECs) is not known, and the development of bone lymphatics has not been fully characterized. In this dissertation, I review the latest advances in research on the development of the lymphatic system and human lymphatic diseases. I also present my work on the development of bone lymphatics in mouse models of GLA and GSD. I show by lineage-tracing that bLECs arise from pre-existing Prox1-positive LECs. I demonstrate that bone lymphatics develop in a stepwise manner, where regional lymphatics grow, breach the periosteum, and then invade bone. I also show that osteoclasts are closely associated with invading lymphatics and that lymphatic invasion of bone is impaired in mice that lack osteoclasts. Additionally, I demonstrate that rapamycin suppresses the formation of bone lymphatics in mouse models of GLA and GSD. These findings shed light on the development of bone lymphatics, a process that has puzzled investigators since Gorham and Stout published their landmark paper over 60 years ago. They also show that an emerging treatment for GLA and GSD patients can inhibit lymphatic invasion of bone
Regulation of the cGAS-STING Pathway: Non-Agonist Activation and Cellular Trafficking
Get PDFThe cGAS-STING pathway in the innate immune system plays an important role in infection and cancer. Exogenous or endogenous DNA and cyclic dinucleotides acutely activate cGAS-STING, leading to type I interferon (IFN) signaling. STING-mediated IFN signaling is dynamically regulated by STING trafficking from the ER to the Golgi then to the lysosome. Cofactors and cellular mechanisms that facilitate STING trafficking and signaling are incompletely understood. In the settings of cancer immunotherapy, STING agonists induce strong anti-tumor immunity in preclinical models and synergize with radiation, chemotherapy, and immune checkpoint inhibitor therapy. Evaluation of STING agonists in human clinical trials is ongoing, although early results did not yield satisfying prospects. Thus, novel approaches to activate STING signaling are needed.
One non-agonist approach for activating the cGAS-STING pathway is to inhibit cytosolic DNase TREX1, which would lead to the build-up of self-DNA in the cytosol and activation of cGAS. TREX1 expression is upregulated during radiation therapy and TREX1 knockdown promotes anti-tumor immunity. I developed a cell-free DNase assay that quantitatively monitors the enzymatic activity of TREX1. As a proof of concept, inhibition of TREX1 by an existing small molecule inhibitor Compound I induced type I IFN response in many cell types in vitro. I performed an HTS screen of 300K small molecules with the TREX1 DNase assay and identified several candidate TREX1 inhibitors that exhibit over 10-fold higher potency compared to Compound I. Top candidates were well tolerated in a cell-based toxicity assay, making them promising small molecules to activate the cGAS-STING pathway as a non-agonist approach (Chapter 2).
I also performed a proteomic screen to identify spatial-temporal regulators of STING during trafficking. Knockdown of several post-Golgi cofactors of STING activates tonic IFN signaling, suggesting that the cGAS-STING pathway is operational at homeostasis. This 'basal-flux' mode of STING activation requires functional cGAS and STING to maintain a basal immune state. Blocking of post-Golgi STING trafficking extends STING Golgi-dwell time and enhances STING signaling. I identified trans-Golgi coiled-coil protein GCC2 and Rab GTPase Rab14 as key regulators of STING Golgi-exit. Moreover, I found increased autoantibodies production in Gcc2-/- mice in a STING-dependent manner. As another non-agonist approach to activate the cGAS-STING pathway, I found that Gcc2KO and Rab14KO tumor cells elicited T cell- and type I IFN-dependent anti-tumor immunity in mice (Chapter 3).
In summary, studies in this thesis describe detailed cellular mechanisms of STING trafficking as well as signaling regulation and novel non-agonist approaches to activate the cGAS-STING pathway for cancer immunotherapy