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Microbubble-Assisted Ultrasound Guided Immunotherapy of Cancer: A Novel Microbubble Platform for Cancer Immunotherapy
Full text linkThe recent success of immunotherapy for treatment-refractory metastatic melanoma, lung cancer, and renal cell carcinoma has provided a new hope that immunotherapy can be generalized to a broader range of cancers. However, many cancers do not respond to immunotherapy, which has limited its use to a subset of patients. There is now greater recognition that generating optimal antitumor immunity requires activating both innate and adaptive immune systems. The cytosolic innate immune sensor cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has recently emerged as a potential therapeutic target to boost antitumor immune responses. cGAS-STING is crucial for priming adaptive antitumor immunity through antigen-presenting cells (APCs). Natural agonists such as cyclic dinucleotides (CDNs) activate the cGAS-STING pathway, but their clinical translation is impeded by poor cytosolic entry and serum stability, low specificity, and rapid tissue clearance. Furthermore, off-target STING activation can cause widespread inflammation and dose-dependent T cell death, thus facilitating tumor immune evasion and further hindering the clinical translation of STING agonists. Addressing this clinical need requires a platform that enables targeted, on-demand, and cytosolic delivery of CDNs.
In this dissertation, I will report the design, characterization, and efficacy of a novel ultrasound (US)-guided cancer immunotherapy platform using nanocomplexes composed of 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) electrostatically bound to biocompatible branched cationic biopolymers that are conjugated onto APC-targeting microbubbles (MBs). The nanocomplex-conjugated MBs (ncMBs) engaged with APCs and efficiently delivered cGAMP into the cytosol via sonoporation, resulting in activation of cGAS-STING and downstream proinflammatory pathways that efficiently prime antigen-specific T cells. This bridging of innate and adaptive immunity inhibited tumor growth in both localized and metastatic murine cancer models. Our findings demonstrate that targeted local activation of STING in APCs under US stimulation results in systemic antitumor immunity and improves the therapeutic efficacy of checkpoint blockade, thus paving the way towards novel image-guided strategies for targeted immunotherapy of cancer. Future studies will look at utilizing ncMBs with clinically approved US scanners and loading various drugs, as this versatile platform has the potential to facilitate the targeted delivery of a variety of payloads
Clinical features, metabolic and autoimmune derangements in acquired partial lipodystrophy (Barraquer-Simons Syndrome)
No full textThe attached file includes the Lipodystrophy Demographic and Health History Questionnaire, and this submission meets the Extended Data Sets and Supplemental Materials requirements that are included in author guidelines for the Journal of Clinical Endocrinology & Metabolism (Print ISSN 0021-972X, Online ISSN 1945-7197)
Understanding Contraceptive Preferences at the Time of Abortion Among Patients in a Legally Restrictive Setting
Full text linkBACKGROUND: Abortion clinics frequently offer contraceptive counseling, but it is unclear if this is in line with patient preferences or satisfies an unmet need. A better understanding of patient attitudes towards contraceptive care and counseling during abortion care, and desires around seeking contraceptive care after abortion, may inform more patient-centered practices.
OBJECTIVE: To examine preferences for contraceptive counseling and access among patients seeking abortion in a legally restrictive setting.
METHODS: In this cross-sectional, mixed-methods study, 181 patients at an abortion clinic in Dallas, Texas completed anonymous, self-administered surveys from June-July 2018. We analyzed the survey data descriptively. In June 2019, we conducted 40 phone interviews with a set of participants who had recently sought abortion care at the clinic to gain further insight into their ideal preferences for contraceptive care, identify barriers they faced to accessing their preferred contraceptive method after abortion, and explore their understanding of contraceptive counseling. Interviews lasted about 20 minutes and were recorded using a voice recorder for transcription purposes. Data were coded using thematic analysis.
RESULTS: Of the 389 patients offered a survey, 46.5% agreed to participate (n = 181). 33.1% of respondents indicated they preferred to obtain birth control from somewhere near their home. 29.3% indicated they preferred to obtain birth control from the same physician they visit for their other health care needs. Most (81.8%) were uninterested in contraceptive counseling at their abortion visit. Of these, over half (52.0%) did not want to follow up for contraceptive counseling or services.
Interviews revealed that nearly half (47.5%) of participants were unable to obtain their first-choice contraceptive method. Of these, 57.9% identified cost as the primary barrier to accessing their first-choice method. Patients were most interested in accessing contraceptive care through in-office visits (52.5%), whether regular (71.4%) or one-time visits (28.6%). Most participants (82.5%) were able to correctly describe contraceptive counseling in their own words--some characterized it as a simple delivery of information regarding contraception, others as a more nuanced exchange tailored to each patient's needs. The aspects of counseling participants were most interested in were side effects of methods (69.2%), followed by efficacy (17.9%). Participants were most interested in receiving counseling either through verbal explanation (56.4%) or through websites or videos (59.0%). Nearly half (48.7%) indicated a preference for obtaining contraceptive counseling at the clinic, whereas 20.5% indicated a preference for receiving this information at home. 23% had no preference between the two or felt that both were appropriate sites in which to receive this counseling.
CONCLUSION: Among survey respondents, most lacked interest in contraceptive counseling at the time of their abortion visit. Those interested in follow-up preferred a resource handout over other options, such as a follow-up visit or phone call. Qualitative analysis revealed that most patients have a clear understanding of what contraceptive counseling entails, and that while some felt that the abortion clinic appointment was an appropriate setting to begin the conversation around contraceptive counseling, others expressed a preference for receiving this information at home, in a less overwhelming or time-bound setting.
This research highlights important patient preferences that can guide patient-centered approaches in abortion care settings. Patients may not desire contraceptive counseling at their abortion visit and may prefer to receive it from primary care providers. These preferences can best be honored by facilitating access when requested, such as through comprehensive resources and referrals to primary care providers. Additionally, patient-centered counseling should honor patient preferences regarding contraception and empower patients in their decision-making process. Additional research examining patient perceptions of what contraceptive counseling entails and exploring the possibility of contraceptive coercion can be helpful in making counseling protocols more patient-centered. Given the setting of this study, these findings would be particularly informative for patients seeking abortion and contraceptive care in other settings that are similarly legally restricted
Difficult cases of testoterone replacement therapy in male hypogonadism
Full text linkDetailed 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 Role of DnaJC7 in Modulating Tau Aggregation in the Cell
No full textAppendix A contains a previously published manuscript, which is referenced below as a related citation.Tauopathies are a diverse group of neurodegenerative diseases characterized by the abnormal accumulation of misfolded tau protein. The most recognized tauopathy, Alzheimer's Disease, is estimated to affect more than 30 million people worldwide. Mutations that increase the propensity for tau to adopt an aggregation-prone conformation have been identified in familial forms of tauopathies, further emphasizing the causal role of tau misfolding in these neurodegenerative diseases. The Diamond Lab has pioneered the prion model as a hypothesis for how tau can template, or seed, its misfolded conformation onto inert tau protein, thus enabling further aggregation. However, the fate of these aggregates and the key players that may interact with them after they have formed remains poorly understood. We reveal that DnaJC7, a co-chaperone of the J domain protein (JDP) family, engages with tau aggregates and is involved in their clearance from the cell. Additionally, I conducted a genetic screen to knockout all JDPs in our tau biosensor cells to show that DnaJC7 and DnaJB6 are unique in their ability to mitigate tau aggregation in the cell. Further, I show that DnaJC7 KO leads to increased seeding of multiple tau seed sources in the biosensor cells, suggesting that DnaJC7 may serve to protect the endogenous inert tau, in agreement with our previous work showing that DnaJC7 preferentially binds inert monomeric tau over seeding-competent tau. I also surveyed the effects of recently identified ALS-associated mutations in DnaJC7 on intracellular tau seeding to show that five of these mutations increase tau seeding. Surprisingly, the T341P mutant shifts the tau seeding profile to resemble that of a mutant unable to stimulate Hsp70 substrate binding, providing insights into the pathogenic mechanism of this mutation. The work presented here underscores the specific role that DnaJC7 plays in modulating tau aggregation in the cell. Further characterization of the DnaJC7:tau interaction may reveal novel preventative and therapeutic strategies for several neurodegenerative diseases
Role of Soluble [alpha]-Klotho in the Alleviation of Acute Lung Injury
Full text linkInhalational insults like smoke, toxic fumes, and particulate matter plague our modern environment. These insults can cause acute lung injury (ALI), a syndrome characterized by inflammation, increased permeability, and pulmonary infiltrates. Moderate ALI causes hypoxemia, leading to respiratory failure if left unattended. Patients with severe ALI develop acute respiratory distress syndrome and require supplemental oxygen or mechanical ventilation. Despite advances in critical care, mortality from ALI is 40%, and there is an urgent need for a solution. Soluble alpha-Klotho (herein termed Klotho) is a pleiotropic protein essential for tissue maintenance and protection. Transmembrane Klotho is synthesized mainly in the kidney and cleaved at the transmembrane site of renal tubules for circulation to extra-renal organs. The lung does not produce endogenous Klotho but relies on the protein delivered via venous blood return. Klotho-deficient mice lungs have higher oxidative stress, higher antioxidant demand, and varying airspace size and distribution. Systemically, Klotho-deficient mice develop premature organ degeneration and have a shorter lifespan than wild-type (WT) mice. However, constitutive overexpression of Klotho in transgenic-Klotho (Tg-Kl) mice improves longevity and reduces oxidative stress. Based on these findings, I tested the hypothesis that Klotho could act as a therapeutic to reduce inflammation and oxidative stress caused by ALI. First, to characterize Klotho actions in the lung, Tg-Kl mice were subjected to two experimental injury models, cigarette smoke or hyperoxia. Mouse bronchoalveolar lavage fluid (BALF) was assayed for oxidative damage to compare age, genotype, and exposure; fixed lungs were sectioned, stained, and the morphology examined. Next, exogenous Klotho was incorporated into poly-lactic-co-glycolic-acid (PLGA) nanoparticles (NPs), a vehicle chosen for its desired properties suitable for inhalational delivery. Klotho-containing PLGA NPs were characterized for inhalational delivery and screened in A549 cells exposed to cigarette smoke. WT or Klotho-insufficient (Kl/+) mice inhaled Klotho-containing NPs following exposure to hyperoxia-recovery. Inhalational studies used the same biomarker panel and morphology previously mentioned to assess outcomes. The experiments demonstrated that increased endogenous Klotho in Tg-Kl mice attenuated hyperoxia-induced oxidative damage, reduced inflammation, and prevented mortality. In addition, Klotho NPs prevented cytotoxicity and DNA damage in smoke-exposed A549 cells. Finally, Klotho cDNA NP-treated mice showed preserved lung morphology and reduced oxidative damage and mortality rates compared to vector-treated mice. These studies showed that Klotho exerts cytoprotective functions in the lung, alleviating ALI and further damage in the mouse model, and could therefore have clinically therapeutic potential
Re-defining autoimmune diseases: the pathway to prevention
Full text linkDetailed 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
Physician Burden and Time Delays in Initiating Immunomodulatory Therapy for Non-Infectious Uveitis and Inflammatory Eye Diseases
Full text linkThe 63rd Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 28, 2025; 3-6 p.m.; D1.700 Lecture Hall)PURPOSE: To assess the additional time and effort requirements and resultant time delays necessitated by insurance-mandated prior authorization for medications used in the treatment of uveitis and ocular inflammatory disease.
DESIGN: Retrospective observational study
PARTICIPANTS: Patients with uveitis and ocular inflammatory disease at the University of Texas Southwestern Medical Center in Dallas, TX for whom the uveitis specialist attempted approval for initiation of a new systemic immunomodulatory therapy between 02/01/2023 - 01/31/2024.
METHODS: Electronic medical records were reviewed to determine prior authorization requests, appeals, and relevant data related to the process required to initiate new immunomodulatory therapy. Infusion related medications were excluded for analysis.
MAIN OUTCOME MEASURES: Primary outcome measures were the success rate of obtaining the requested medication and time from medication request to initiation. Secondary measures included the number of additional steps required (e.g. appeals, peer-to-peer consultations), factors influencing medication approval (e.g. insurance subtype, medication class), and rates of reliance on patient assistance programs.
RESULTS: A total of 83 patients underwent 107 attempts for initiation of a new immunomodulatory therapy. Underlying uveitis disease entities were pemphigoid (30, 38%), anterior uveitis (10, 13%), intermediate uveitis (6, 8%), posterior uveitis (1, 1%), panuveitis (28, 35%), and scleritis (4, 5%). Medications attempted included methotrexate (22, 20.6%), mycophenolate mofetil (13, 12.1%), mycophenolic acid (4, 3.7%), adalimumab (37, 34.6%), baricitinib (18, 16.8%), tofacitinib (10, 9.3%), and tocilizumab (2, 1.9%). The majority (71%) of medications were considered "off-label".
Approval rates were 100% for on-label and 52.31% for off-label medications (p=0.033). Patients requesting off-label use medications were twice as likely to be denied and require an appeals process (1.07 vs 0.50; p=0.01). Average time to initiation was 28 days for on-label and 41 days for off-label medications (p=0.01). For off-label medications, private insurance approval rates were significantly higher than Medicare (59.52% vs 36.36%; p=0.05). Patient assistance programs were utilized to cover some or all medication costs in 63% of cases.
CONCLUSION: Prior authorization requirements present an under-recognized and considerable administrative burden on healthcare providers in obtaining vision-saving therapy for their patients. Denials result in substantial delays in initiating crucial vision-preserving treatment.Southwestern Medical Foundatio
Otsukimi
Full text linkThe author submitted this entry in the Open Verse Poetry category (Professional division) for the 2025 On My Own Time™ (OMOT) Art Show.This work received a First Place Award in the "Open Verse Poetry" category in the 2025 OMOT show.Shortly after I returned from a trip to Japan in 2023, I had a really stressful morning. I wound up watching an Instagram Live by the guitarist of Alice Nine, whom I saw live during my trip, and he was talking about it being Otsukimi, the Japanese moon viewing festival, and how we don't need to feel alone because we all look at the same moon. It brightened my day and inspired this contrapuntal poem
Understanding the Structure and Function of GABAA Receptors Using Cryo-Electron Microscopy
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 17-156 are misnumbered as pages 15-154.γ-Aminobutyric acid type A (GABAA) receptors are essential for maintaining the delicate balance of excitatory and inhibitory signaling in the brain, playing a pivotal role in regulating neuronal function and communication. These receptors are targeted by a wide range of therapeutic compounds, including anxiolytics, sedatives, and anticonvulsants, as well as endogenous neurosteroids that modulate their function. Among these neurosteroids, a subset acts as positive allosteric modulators of GABAA receptors, enhancing the inhibitory effects of GABA. Allopregnanolone, a prominent member of this group, is the only drug specifically approved for the treatment of postpartum depression, demonstrating the clinical relevance of these modulators.
While recent advances in structural, physiological, and photolabeling studies have provided a growing consensus on the binding sites of positive modulators, the exact mechanism by which they potentiate GABA activation remains a subject of ongoing investigation. In contrast, the binding sites, and modes of action of negative modulators, which are other neurosteroids that inhibit GABAA receptor function, are still under debate and require further elucidation.
The first part of this thesis describes the work I have done during the last two years, during which I determined structures of a synaptic GABAA receptor bound to allopregnanolone and two inhibitory sulfated neurosteroids, providing new insights into their respective modes of action. Our findings reveal that allopregnanolone binds at the receptor-bilayer interface, occupying a consensus potentiator site, while the inhibitory neurosteroids interact with the receptor at a distinct location within the pore. By employing molecular dynamics (MD) simulations and electrophysiological experiments, we propose a mechanistic model that accounts for the potentiating effects of allopregnanolone on channel activity. Furthermore, our results suggest that the primary mechanism underlying the inhibitory actions of sulfated neurosteroids is the obstruction of the pore, leading to reduced ion flow and channel activity. These findings contribute to our understanding of GABAA receptor modulation and may have implications for the development of novel therapeutic agents targeting these receptors