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Exploring the untapped nexus of ethics and health facility design
Get PDFTuesday, January 10, 2023; noon to 1 p.m. (Central Time); via Zoom. "Exploring the Untapped Nexus of Ethics and Health Facility Design". Diana C. Anderson, MD, MArch, Instructor, Neurology, Boston University School of Medicine and Principal, Healthcare Design, Jacobs, Boston, Massachusetts; William J. Hercules, MArch, Licensed Architect, Founder and CEO, WJH Health, Orlando, Florida; Stowe Locke Teti, MA, HEC-C, Clinical Ethicist, Inova Fairfax Medical Campus, Falls Church, Virginia; and David A. Deemer, MD, MA, Internal Medicine Resident and Ethicist, University of Wisconsin Hospitals & Clinics, Madison, WisconsinArchitecture inherently reflects the normative preferences of its time. This certainly applies to healthcare architecture, where design concepts have intentional and decades-long effects on patients, families, and staff. Employing healthcare architecture to alter behaviors, mediate interpersonal interactions, and affect patient outcomes make it an ethical matter. We propose that advances in design science and our understanding of its powerful effects warrant a shift in how we think about space, and that the built environment in healthcare is analogous to a medical intervention. As such, all responsible stakeholders should openly discuss and thoroughly scrutinize the intentional use of the built environment to affect perceptions and change behaviors of patients, residents to a similar standard as conventional medical therapies. We highlight prominent examples of such architectural interventions, analyze their implementation, and offer perspective on how medicine and architecture can create ethically responsible spaces.UT Southwestern--Program in Ethic
Inhibitory Control of Contextual Fear Memory and Memory Specificity
Get PDFThe brain functions are supported by close interactions between excitation and inhibition. Inhibition contributes to neural computation by gating information flow, tuning the gain of the network, and modulating the output strength of the system. The inhibition in the brain is mainly achieved by GABAergic inhibitory neurons which exert their effect by acting on multiple types of GABA receptors. In this dissertation, I examined the roles of specific types of GABAergic neurons and GABA receptors in learning and memory. The study consists of three major components. In the first component (Chapter 2), I developed a novel technique to selectively target and control GABAergic interneurons (NDNF cells) distributed at the SLM of the hippocampus. With this technique, I found that the activities of NDNF cells increased during memory encoding and decreased during retrieval. Enhancing their activity improved memory encoding but impaired memory retrieval. I further discovered that NDNF cells coordinate memory encoding and retrieval by differentially regulating the two major excitatory inputs to the CA1 region of the hippocampus. In the second component (Chapter 3), I identified a single nucleotide deletion in the gene of a subunit of GABA receptors - Gabra2 that reduces contextual fear memory in C57BL/6J by using quantitative trait locus analysis. In the third component (Chapter 4), I found a change in GABAB receptor-mediated feedforward inhibition led to distinct hippocampal responses to environmental stimuli. This difference further led to distinct hippocampal representation and generalization of contextual fear memory. These studies were carried out at genetic, molecular, circuit, and behavioral levels, and involved a combination of techniques including genetic mapping, in vivo recording, circuit manipulation, and behavior analysis. They exemplify how inhibition shapes neuronal activity and animal behavior. They also provide valuable tools and ideas for future research on the function of inhibition in the brain. The knowledge gained through these studies on how the brain inhibitory network interacts with excitatory neurons to regulate memory facilitates our understanding of the cognitive processes in the brain
Dendritic Cells Suppress Pathogen-Induced Inflammasome Activation to Prime Naïve T Cells
Get PDFActivation of inflammasome leads to pyroptotic cell death thereby eliminating the replicative niche of virulent pathogens, a process integral to innate immunity. While inflammasome-associated cytokines such as IL-1β and IL-18 have an established role in T cell function, whether inflammasome activation in dendritic cells (DCs) is critical for T cell priming is not clear. Here, we find that lymphoid organ resident conventional DCs (cDCs) actively suppress inflammasome activation to prevent pyroptotic cell death. This protection from inflammasome-induced cell death preserves the ability of cDCs to prime both CD4 and CD8 T cells. Transcription factors IRF8 and IRF4, in cDC1s and cDC2s respectively, mediate this suppression of inflammasome activation by limiting the expression of inflammasome-associated genes. Additionally, overexpression of either of IRF4 or IRF8 is sufficient to inhibit inflammasome activation in macrophages, cells that are normally permissive to inflammasome activation. Furthermore, we find that reduced expression of IRF8 leads to aberrant inflammasome activation in cDC1s which hampers their ability to prime CD8 T cells. These results uncover the importance as well as the molecular mechanism of inflammasome suppression in cDCs and ascribe a novel post-developmental role for IRF4 and IRF8 in cDC function
Crosstalk Signaling Between cAMP and mTORC1
Get PDFThe mammalian target of rapamycin complex 1 (mTORC1) senses multiple stimuli to regulate anabolic and catabolic processes. G-protein-coupled receptors (GPCRs) paired to Gs proteins increase cyclic adenosine 3'5' monophosphate (cAMP) to activate protein kinase A (PKA), which phosphorylates Raptor at Ser 791 resulting in potent mTORC1 inhibition. We identified a novel mTORC1-interacting protein called A-kinase anchoring protein 8L (AKAP8L). Using biochemical assays, we found that the N-terminal region of AKAP8L binds to mTORC1 in the cytoplasm. Importantly, loss of AKAP8L decreased mTORC1-mediated processes such as translation, cell growth and cell proliferation. AKAPs anchor protein kinase A (PKA) through PKA regulatory subunits, and we show that AKAP8L can anchor PKA through regulatory subunit I (RI). Full-length AKAP8L restored mTORC1-regulated biology, whereas AKAP8L missing the N-terminal region that confers interaction with mTORC1 did not. Additionally, we have shown that H89 (N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide), a well-characterized ATP-mimetic kinase inhibitor, renders the phosphorylation of S6K1 and AKT resistant to mTOR inhibitors across multiple cell lines. Moreover, H89 prevented the dephosphorylation of AKT and S6K1 under nutrient depleted conditions. PKA and other known H89-targeted kinases do not alter the phosphorylation status of S6K1 and AKT. Pharmacological inhibition of some phosphatases also enhanced S6K1 and AKT phosphorylation. These findings suggest a new unknown target for H89 by which it sustains the phosphorylation status of S6K1 and AKT, resulting in mTOR signaling. Lastly, we identified A-kinase anchoring protein 13 (AKAP13) as a crucial scaffold involved in GPCR-Gs signaling to mTORC1. AKAP13 potently enhances Raptor Ser 791 phosphorylation and inhibits mTORC1 activity. Consistently, in cells where Raptor Ser 791 is mutated to Ala, AKAP13 is unable to supress mTORC1 activity. AKAP13 mediates mTORC1-induced cell proliferation, cell size and colony formation. Interestingly, AKAP13 expression inversely correlates with mTORC1 activation and positively correlates with overall lung adenocarcinoma patient survival. Our results place the GPCR-Gas signaling pathway to mTORC1 as a potential target that may be beneficial for human diseases with hyperactivated mTORC1
FGF23 at the intersection of phosphate and iron homeostasis
No full textDetailed 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 cost of dying in America
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
The Role of the WWTR1(TAZ)-CAMTA1 Gene Fusion in Epithelioid Hemangioendothelioma
No full textEpithelioid hemangioendothelioma (EHE) is a devastating and mysterious vascular cancer which has no known definitive treatment. Due to a lack of valid animal or cell-based models of EHE, progress toward understanding and treating this cancer has been severely limited. However, recent studies have determined that 90% of patients exhibit a lone, characteristic in-frame gene fusion, TAZ(WWTR1)-CAMTA1. While expression of the TAZ-CAMTA1 fusion protein has been validated as a biomarker of EHE, it remains unknown whether this genetic abnormality is a passenger or a driver of EHE. In this project, I present the first genetically-engineered mouse model (GEMM) of EHE, showing that the expression of the TAZ-CAMTA1 protein in endothelial cells is sufficient to drive the formation of EHE-like tumors in the lungs of mice. Furthermore, I demonstrate that the cessation of TAZ-CAMTA1 expression leads to the regression of these vascular tumors. I also demonstrate that TAZ-CAMTA1 transforms the MS1 endothelial cell line and that subcutaneous transplantation of these cells into nude mice leads to the formation of solid, progressive EHE-like vascular tumors that have the capacity to metastasize to the lung. Utilizing these two novel models of EHE, I unravel the gene program of TAZ-CAMTA1 and demonstrate that TAZ-CAMTA1 drives a gene signature similar to TAZ, the key effector of the Hippo pathway. Expression of an activated TAZ in endothelial cells is also sufficient to drive EHE-like vascular tumors in mice, and genetic blockade of the transcriptional partners of TAZ, the TEAD family of transcription factors, prevents the formation of TAZ-CAMTA1-induced vascular tumors. Next, I show that TAZ-CAMTA1 induces an angiogenic and regenerative-like gene program in endothelial cells. I validate that TAZ-CAMTA1 exhibits gain-of-function activities by having increased resistance to proteasomal degradation and increased nuclear enrichment over TAZ. Lastly, I show that TAZ-CAMTA1 still maintains its binding to the Hippo pathway proteins which are known to negatively regulate TAZ. In summary, I generate two novel models that pinpoint TAZ-CAMTA1 as the key driver of EHE and utilize these models to suggest several new lines of investigation for the treatment of patients with EHE
Evaluating the Clinical and Financial Impact of Multi-Gene Panel Testing
Get PDFBACKGROUND: Medical management of advanced cancers is increasingly guided by predictive biomarkers. Tumor mutation testing using commercial assays examining select gene panels is now incorporated in the standard work-up of advanced cancers. With some exceptions, existing and emerging biomarkers remain inadequate clinical tools for many patients, and anecdotal evidence and small phase trials have driven much of the enthusiasm for biomarker-driven treatments. The purpose of this study is to assess predictive clinical factors of successful gene mutation testing and to determine whether tumor mutation testing directly impacts clinical practice.
METHODS: All submitted test requests from UT Southwestern faculty to Foundation One were abstracted for test success and mutation results. Patients were cross-referenced in the EPIC electronic health record information. To evaluate practice changes and patient outcomes after one-year of follow-up, we collected data from the first 100 patients that underwent next generation sequencing testing (excluding PD-L1 testing) in 2020.
RESULTS: Among the 100 patients studied, the typical patient was close to older age (mean age 58.7 years), female (56%), Caucasian (52%), insured (71%), and with stage 3 or 4 cancer (79%). The most common tumor types were breast (20%), colorectal (18%), and myelodysplastic syndrome (9%). 20% of patients (20/100) were found to have an actionable mutation and 2 patients were enrolled in clinical trials due to Foundation Medicine testing. Among the 20 patients with an actionable mutation, 5 of them (25%) had a change in therapy. All of these patients responded to the change in therapy with stable disease, and while three of them started the therapy within a month of the Foundation testing resulting, the other two waited 5 and 11 months. The fifth patient was actually found to not have disease but was placed on a maintenance therapy as a result of the testing.
CONCLUSIONS: While precision medicine offers the promise of better understanding genomic drivers of disease, it is unclear if the benefits of such an approach outweigh the risk on a population level and if resulting changes in patient care are superior as compared investigator-chosen therapies. Medical oncologists should continue to apply intelligent and judicious use of Foundation Medicine testing
Space II
Get PDFThe author submitted this entry in the Open Verse Poetry category (Amateur division) for the 2023 On My Own Time (OMOT) Art Show.I had failed to realize that in my writings the overarching theme was space. Although it's a poem about longing, at the time I wrote this I wasn't really feeling loss or want. Words thrown on paper, really
Improving survival & reducing racial disparities in cardiac arrest
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