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The Molecular Basis of Tissue Elasticity and Force Balance During Drosophila Gastrulation
Get PDFThe mechanics of folding any material rely on two things: the physical forces forming the fold and the material properties of the substance being folded. When working in biological tissue such as an early Drosophila embryo, there is no existing way to directly measure morphogenetic forces, and the relative contributions of forces in various cellular domains remain unknown. To begin, I studied gastrulation in a genetic background where basal membranes never form and cells remain open to the yolk sack throughout the course of VF formation. Strikingly, the VF is still capable of forming in this background. I extensively characterize this phenotype by a combination of electron microscopy and immunofluorescence. My observations rule out a class of popular models of VF formation that would generically predict no folding in the absence of basal membranes. To address this discrepancy, we propose that viscous shear forces play a major role in allowing the furrow to form. We have developed a new computational model that takes cytoplasmic viscous shear into account. In accordance with our observations, our model predicts that basal membranes are dispensable for VF formation. Tissue material properties such as elasticity are also key to fold shape. In vivo tissue deformation experiments show that embryonic tissue is elastic in the stages leading up to gastrulation. Inhibiting F-actin polymerization severely decreases elasticity. I propose that different characteristics of F-actin networks - e.g. branching, remodeling, and crosslinking - are variably responsible for conferring elasticity. It is unclear whether the presence of active forces along actin filaments contributes to tissue elasticity. To this end, I engineered the auxin-inducible degron system to degrade the foremost source of active forces in F-actin networks: myosin II. My design allows us to specifically degrade Drosophila myosin II in under 1hr in vivo. This will allow us to precisely quantify the contribution of myosin II to not only tissue elasticity, but any other feature or developmental process of interest
Re-Designing Cancer Immunotherapy to Enhance Anti-Tumor Immunity
Get PDFImmunotherapy has transformed the field of oncology. However, clinical challenges of toxicity and low response rate offer opportunities to develop novel, rational strategies to integrate into current clinical oncology treatment. To address these challenges, we designed a novel local mesenchymal stromal cell (MSC) based immunotherapy to study the immune tumor microenvironment (TME), and optimized radiotherapy delivery with cGAMP and systemic α-PD-L1 immunotherapies. Using MSC, we delivered various forms of anti-CD3 and/or co-signals to explore their contribution to re-activate T cells inside the TME. Combined α-CD3 and CD40L rather than CD80 leads to superior anti-tumor efficacy compared to either alone. Mechanistically, TCR activation of pre-existing CD8+ T cells synergizes with CD40L activation of DCs inside the TME to control tumor growth. We found exogenous TCR signals can better re-activate TIL, but distal tumor control required T cells from the draining lymph node. This study supplies further evidence that TCR signaling for T cell re-activation in the TME is defective but can be rescued by proper exogenous signals, indicating the importance of the local tumor microenvironment on anti-cancer immunity. To approach the problem from another angle, we chose to optimize delivery of radiotherapy for enhanced immune stimulation. Treating radiotherapy like a vaccination in situ, we tested the hypothesis that spacing radiation doses by 10 days would allow for enhanced anti-tumor immunity. This new ablative radiation dosing scheme "personalized ultra-fractionated stereotactic adaptive radiotherapy" (PULSAR) was tested in combination with α-PD-L1 therapy and cGAMP treatment in immune activated and resistant syngeneic immunocompetent mouse models of cancer. We report that both radiation and immunotherapy sequencing as well as radiotherapy fraction spacing affects the combination treatment response. Better tumor control was achieved by giving α-PD-L1 therapy during or after radiation. Spacing fractions 10 days apart (PULSAR) achieved better tumor control when combined with α-PD-L1 and cGAMP immunotherapies than traditional single day spacing. These results illustrate that radiotherapy dosing and scheduling impacts tumor control in combination with two different immunotherapies. These pre-clinical investigations demonstrate that modifying the tumor microenvironment toward immune stimulation by local delivery of exogenous TCR signaling and radiation can lead to novel effective immunotherapy
The End
Get PDFThe author submitted this entry in the 10-Word Story category (Amateur division) for the 2024 On My Own Time (OMOT) Art Show.This was inspired from witnessing a death of a patient, as a nursing student about 35 years ago. I was filled with grief and cried a lot. The sight and the sound are still embedded in my heart and mind. It may be because this the first time I have ever seen someone dying
Inferno
No full textThe author submitted this entry in the Open Verse Poetry category (Amateur division) for the 2024 On My Own Time (OMOT) Art Show.Reworked from a draft that was based on fires in Northern California that engulfed numerous redwoods, the piece took on a more personal note when fires recently ravaged Ruidoso, New Mexico, which is a short drive from my mother and stepfather. The images and videos I received from them were so disheartening, knowing how horribly it impacted the local ecosystems and countless lives, which were upended by the heavy smoke and fires. Here, I imagine two brothers stuck in a hopeless situation, forced to endure the inevitable nature of mortality. And while so many forms of green will rise through the ashes, it doesn't make the loss and pain any easier to handle
Broken Heart
Get PDFThe author submitted this entry in the Open Verse Poetry category (Professional division) for the 2024 On My Own Time (OMOT) Art Show.This poem came from a writing exercise that had me assuming the perspective of an inanimate object. I wound up going into a science fiction direction and thought about the trope of a man with a robot lover
Pathologic Fracture Secondary to Acute Hematogenous Osteomyelitis in Children in New Zealand
No full textBACKGROUND: Acute hematogenous osteomyelitis is a common pediatric musculoskeletal infection that has been well studied in the literature. Moderate to severe cases of osteomyelitis may weaken and destabilize the bone architecture leading to complications like pathologic fracture. The purpose of this study was to investigate the risk factors for the development of pathologic fracture following acute hematogenous osteomyelitis for children in New Zealand.
METHODS: Nine patients who were treated for a pathologic long-bone fracture secondary to Staphylococcus aureus osteomyelitis between January 2009 to December 2019 at the Starship Children's Hospital in Auckland, New Zealand were identified. These patients were compared with a age and sex matched control group of twenty-seven children with Staphylococcus aureus osteomyelitis without a pathologic fracture. A retrospective review of patient's clinical records, lab and microbiological findings was performed.
RESULTS: Patients who developed a fracture presented with osteomyelitis at a mean age of 5.3 years (range, 0.1 to 8.6 years). The mean time from initial osteomyelitis onset to pathologic fracture was 49 days (range, nine to 116 days). Patients with an increased NZ deprivation score and those of Pacific-Islander ethnicity differed significantly between the two groups. For initial clinical presentation, it was found that swelling, reduced range of motion and erythema, and higher CRP levels showed significant differences between the two groups. Length of stay, PICU admission and increased readmissions also showed significant differences between the two groups. The management strategy of the pathologic fracture group was also presented.
CONCLUSIONS: Patients presenting with more severe acute infections are at significant risk of pathologic fracture following osteomyelitis. Prophylactic treatment plans such as early immobilization and casting may be necessary in patients presenting with these risk factors to prevent the long and difficult treatment of pathologic fracture
Asthma with metabolic comorbidity: management challenges and novel treatment options
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
Understanding liability risk from healthcare AI tools
No full text[Note: The video and slides are both not available from this event.] Tuesday, September 10, 2024; noon to 1 p.m. (Central Time); Room NB2.100A or via Zoom. "Understanding Liability Risk from Healthcare AI Tools". Michelle M. Mello, J.D., Ph.D., Professor of Law at Stanford Law School and Professor of Health Policy at Stanford University School of Medicine.[Note: The video and slides are both not available from this event.] When use of a healthcare AI tool leads to patient harm, who is responsible? This session will examine how liability may arise in AI guided care and how courts are grappling with the challenges of adjudicating liability for software-related injuries. It will offer guidance for assessing the potential liability risk associated with different AI tools and tips for risk management.UT Southwestern--Program in Ethic
Delivery Continuity and Neonatal Disposition to Birthing Parent in Individuals with Substance Use Disorder at Parkland Health
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)OBJECTIVE: Infants born to individuals with substance use disorder (SUD) are at increased risk of removal from their parent. Individuals with SUD in pregnancy receive obstetric care by a multidisciplinary care team (MCT) at our safety-net hospital. We evaluated factors associated with delivery continuity and neonatal discharge to birthing parent among patients with SUD.
STUDY DESIGN: This is a retrospective cohort study of pregnant patients with SUD who accessed Parkland Health (PHHS) between July 28, 2021 and June 25, 2022. We compared MCT interactions among patients who did and did not deliver at PHHS as well as neonatal disposition and outcomes for infants born to individuals with SUD and with specifically opioid use disorder (OUD).
RESULTS: Among 256 pregnant individuals with SUD who accessed care in our system, 144 (56%) received care by our MCT during pregnancy or at the delivery hospitalization. 98 of these patients delivered at PHHS and 46 delivered elsewhere (68% vs 32%, p<0.001). Significantly more eligible individuals who delivered at PHHS accepted medication-assisted treatment (MAT) compared to those who did not (88% vs 70%, p=0.025). Of 139 patients with SUD who delivered at PHHS, 91 (65%) infants were discharged home with the birthing parent. Parents who went home with their infants were more likely to use cannabis (33% vs 4%, p<0.001) and less likely to use opioids (34% vs 63%, p=0.003). They attended more prenatal visits (median [IQR] 9 [5,11] vs 1 [0,4], p<0.001) and met less frequently with our multidisciplinary team providing integrated SUD treatment (1 [0,10] vs 4 [1, 14.5], p=0.026). Neonates discharged with the birthing parent were less likely to have a positive meconium (7% vs 75%, p<0.001) or urine toxicology (2% vs 67%, p<0.001) and were less likely to have a 5-minute Apgar <4 (0% vs 4%, p=0.04). Of 62 patients with OUD, 31 (50%) were discharged with their neonate. Those who used opioids alone were more likely than individuals with opioid-polysubstance misuse to retain charge of their infant (78% vs 43%, p=0.018).
CONCLUSION: Increased interactions and MAT with a team specializing in care of pregnant patients with SUD is associated with delivery continuity. Neonatal disposition and outcomes are influenced more by maternal drug of choice and prenatal care attendance than by MCT interactions because of variance in SUD complexity. Opioid-polysubstance misuse is associated with separation of maternal infant dyad.Southwestern Medical Foundatio
Effectiveness of a Print Books Request Program
Get PDFBACKGROUND: Schusterman Library is a small library in the University of Oklahoma system serving 1200 students. Interlibrary loan users can recommend purchasing a book they order through ILL. The library purchases many of these. Is this a successful, cost-effective program? To find out, we asked these questions: (1) "What were the circulation statistics?", (2) "How soon after purchase were books loaned?", and (3) "What were program costs, especially compared to all books purchased in the same period?" METHODS: ILL books recommended for purchase between October 10, 2020, and July 2, 2024, were compared to acquisitions records to see which had been purchased. Of those, we determined cost and circulation statistics and compared them to all books purchased in the same period. RESULTS: 142 of 168 books recommended through ILL were purchased. Mean cost was USD 65.43. Of those, 78, or 55%, circulated. Cost per use was USD 68.34. The mean cost for all books purchased (1376) during the same period was USD 45.86. Percentage of those circulating (612) was 44%. Cost per use was USD 38.15. Average time between receipt of recommended books and first loan was 51 days, compared to an average of 185 days to first loan for all books purchased. DISCUSSION: While costs for recommended books were higher than those for all books purchased, loan percentage was higher and time to first loan was shorter for recommended books. The program appears to be successful in terms of user behavior, although program costs are higher than baseline costs