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Regulation of Liver Homeostasis and Regeneration
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.Although hepatocytes and biliary epithelial cells are slow-cycling during normal homeostasis, liver tissue is remarkably regenerative, and can quickly proliferate to recover from injury. However, this regenerative capacity is often dysregulated in chronic liver diseases and liver cancer. Understanding the regulation of liver homeostasis and regeneration will provide solid scientific ground to develop therapies for patients. The first part of the thesis was to investigate two unique characteristics that cause cellular heterogeneity in the liver, hepatic zonation and polyploidy, under liver homeostasis and regeneration. To determine whether the zonal heterogeneity leads to differences in regenerative capacity, the Igfbp2-CreER line was generated to lineage trace midlobular hepatocytes. The results showed that the midlobular cells preferentially contribute to tissue maintenance and regeneration. The liver is also known for a high percentage of polyploid cells. To investigate its functional roles, the inducible Anln knockdown mouse model was used to induce hepatic ploidy. In super-polyploid mice with 97% polyploid hepatocytes, the regenerative capacity, tissue fitness, gene regulation and mitotic errors were unchanged. Moreover, the mice were substantially protected from tumorigenesis induced by mutagen and chronic liver injuries. The second goal of my thesis is to identify secreted growth regulators of regeneration. I used in vivo CRISPR knockout screening to identify Secreted Phosphoprotein 2 (SPP2) as a negative regulator of liver regeneration. Spp2 loss-of-function mice showed protection against acute liver failure but also against chronic fatty liver disease and chemically induced fibrosis. Biochemical studies revealed multiple candidate interaction partners for Spp2, and among these, integrins are potential mediators of some Spp2 phenotypes. Altogether, this study offers new ways to discover, validate, and characterize secreted factors
Moving beyond the tip of the iceberg: emerging concepts in tuberculosis infection and disease
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
Treatment Options of Lung Nodules in Wilms Tumor Patients at a Single Institution from 2000 to 2023
Get PDFThe 63rd Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 28, 2025; 3-6 p.m.; D1.700 Lecture Hall)BACKGROUND: Wilms Tumor (WT) is a common pediatric cancer typically seen in children under 5 yrs. Stage IV is characterized by metastasis primarily to the lung requiring nephrectomy, chemotherapy and possibly lung irradiation and/or surgical biopsy. In this study, we examine stage IV WT and define outcomes based on individual therapeutic approaches.
METHODS: 61 children (mean 4.52 yrs / 4 mo. - 14 yrs.) treated for WT between 2000 to 2023 at a single institution were identified. Number, size, and treatment of Stage IV lung nodules before and after various treatments were compared.
RESULTS: 36 of 61 WT patients (59%) had Stage IV disease. 3 out of 36 (8%) received post-nephrectomy chemotherapy only; 1 (3%) had chemotherapy/surgery combination; 19 (53%) had chemotherapy/radiation combination; and 13 (36%) had chemotherapy/radiation/surgery combination.
28 Stage IV patients (78%) had greater than 3 lung nodules with a pre-nephrectomy average nodule size of 10.7 mm. After treatment(s), persistent nodules averaged 1.6 mm (85% size reduction), and 44% of patients had no nodules remaining.
14 out of 36 Stage IV patients had eventual biopsy of nodules with 7 of the 14 positive for metastasis. One had post-chemo surgical biopsy with resection of one (benign) nodule. Of 13 children who had chemo/rad/surgery treatments, 3 had chemo followed by surgical biopsy for persistent (malignant) nodules, then whole lung irradiation within one-month post-op. 10 pts had chemo / irradiation, followed by biopsy of persistent/recurrent nodules. In this group, 9 of 10 had a biopsy within a year after irradiation, while 1 had a biopsy 3 yrs after radiation (benign). In total, 4/10 delayed biopsies demonstrated persistent or recurrent metastasis. Five-year mortality for all 36 Stage IV pts was 14%.
CONCLUSIONS: Reduction in lung nodule size and numbers demonstrated success of standard treatments for post-nephrectomy Stage IV disease. However, despite standard nephrectomy/chemotherapy/lung radiation, surgical biopsy identified persistent/recurrent metastatic disease in 40% up to three yrs after initial therapy.Southwestern Medical Foundatio
Are we ready for psychedelic medicine? (The Daniel W. Foster, M.D., Visiting Lectureship in Medical Ethics)
No full textThe Daniel W. Foster, M.D. Visiting Lectureship In Medical Ethics (in conjunction with Ethics Grand Rounds). Tuesday, February 11, 2025; noon to 1 p.m. (Central Time); Room D1.502 or via Zoom. "Are We Ready for Psychedelic Medicine"? Amy L. McGuire, J.D., Ph.D., Leon Jaworski Professor of Biomedical Ethics and Director of the Center for Medical Ethics and Health Policy, Baylor College of Medicine.There is tremendous excitement about the therapeutic potential of psychedelic substances like MDMA and psilocybin, and impressive bi-partisan advocacy for access to these drugs, both within and outside of the healthcare system. Are healthcare providers ready for what many are calling "The Psychedelic Renaissance"? In this lecture, Dr. Amy McGuire will explore alternative pathways to access psychedelics in the U.S. and the appropriate role of healthcare gatekeeping. Drawing on her research on psychedelic retreat organizations and experience working with Indigenous communities in South America, Dr. McGuire will examine the potential risks of unregulated psychedelic use and explore what it means to approach psychedelic drug research with epistemic humility.UT Southwestern--Program in Ethic
Real-World Outcomes of Faricimab in Patients with Neovascular Age Related Macular Degeneration and Diabetic Macular Edema
Get PDFThe 63rd Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 28, 2025; 3-6 p.m.; D1.700 Lecture Hall)PURPOSE: The purpose of this study is to evaluate the real-world outcomes of intravitreal faricimab in previously treated patients with neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME).
DESIGN: Retrospective cohort study
PARTICIPANTS: Patients with the diagnosis of nAMD or DME who transitioned to faricimab treatment from bevacizumab, ranibizumab, or aflibercept and have at least 3 months of follow-up.
METHODS: Patients who initiated faricimab treatment from 1/1/2021- 12/31/2023 were identified from CPT and J codes. Medical records were reviewed up to 7/31/2024 for demographic information, visual acuity (VA), previously attempted treatments, treatment intervals, optical coherence tomography (OCT) findings including central macular thickness (CMT), and adverse events.
MAIN OUTCOME MEASURES: Changes in dosing interval length and visual acuity for nAMD and DME patients; additional tertiary outcome measure of CMT for DME patients.
RESULTS: A total of 84 patients and 102 eyes with nAMD and 20 patients and 31 eyes with DME were included. 77 nAMD eyes (75.5%) showed improved response with faricimab compared to the previous agent, 18 eyes (17.7%) showed no change, 3 eyes (2.9%) showed worse response, and 4 eyes (3.9%) had an adverse event (2 with retinal detachments and 2 with intraocular inflammation). For nAMD eyes, the average injection interval increased (6.3 to 9.2 weeks, p <0.01) and logMAR visual acuity (VA) remained stable (0.40 to 0.39, p=0.41) before and after switching to faricimab. 18 DME eyes (58.1%) showed improved response with faricimab, 13 (41.9%) showed no change, and none showed worse response. There were no adverse events in the DME group. For DME eyes, there was a statistically significant decrease in logMAR VA (0.43 vs 0.26, p <0.01) and central macular thickness (372.9 vs. 313.8, p<0.001), but no change in interval length (7.3 vs 10.3, p=0.76) before and after faricimab treatment.
CONCLUSIONS: nAMD and DME patients who were switched to faricimab from a different agent showed an improved response to the new medication.Southwestern Medical Foundatio
Topological Regulation of TM4SF20
Get PDFTransmembrane proteins must adopt proper topology to perform their functions. It was previously demonstrated that ceramide regulates TM4SF20 (transmembrane 4 L6 family 20) by altering the topology of the transmembrane protein, but the underlying mechanism remains obscure. This regulatory mechanism, denoted regulated alternative translocation (RAT), depends on a GXXXN motif present in the first transmembrane helix of TM4SF20. In the first part, using site-directed mutagenesis, I show that Asn-26 in the motif is crucial for RAT of TM4SF20, as it cannot be replaced even by Gln. In contrast, Gly-22 could be substituted by other small residues such as Ala and Ser without affecting RAT of TM4SF20. I further demonstrate that the GXXXN motif alone is insufficient to induce RAT because TM4SF4, a relative of TM4SF20 that also contains the motif in the first transmembrane helix, does not undergo RAT. Using TM4SF40-TM4SF20 chimeras, I determined that Pro-29 is also important for RAT of the protein: Replacing Pro-29 together with either Leu-25 or Val-17 of TM4SF20 with the corresponding residues of TM4SF4 abolished RAT of TM4SF20. Because Val-17, Gly-22, Leu-25, Asn-26, and Pro-29 are predicted to reside along the same surface of the transmembrane helix, our results suggest that interactions with other proteins mediated by this surface during translocation may be critical for RAT of TM4SF20. In the second part, I revealed the mechanism behind RAT of TM4SF20. TM4SF20 is synthesized in the endoplasmic reticulum (ER) with a cytosolic C terminus and a luminal loop before the last transmembrane helix where N132, N148, and N163 are glycosylated. In the absence of ceramide, the sequence surrounding glycosylated N163 but not N132 is retrotranslocated from lumen to cytosol independent of ER-associated degradation. Accompanying this retrotranslocation, the C terminus of the protein is relocated from cytosol to lumen. Ceramide delays the retrotranslocation process, causing accumulation of the protein that is originally synthesized. These findings suggest that N-linked glycans, although synthesized in the lumens, may be exposed to cytosol through retrotranslocation, a reaction that may play a crucial role in topological regulation of transmembrane proteins
Engineering Lipid Nanoparticle-Mediated Delivery of Nucleic Acids to Lymphoid Organs and Immune Cells
Get PDFRibonucleic acids (RNA) and deoxyribonucleic acids (DNA) hold promise for continued application in the treatment of genetic diseases. Short interfering RNA (siRNA) and microRNA (miRNAs) have been used to silence disease-causing genes. Longer messenger RNA (mRNA) and plasmid DNA (pDNA) have been used to deliver genes whose absence resulted in disease. RNA and DNA are both large hydrophilic macromolecules that are susceptible to degradation by nucleases and can induce immune responses when injected directly into the bloodstream. Moreover, due to their physicochemical properties, nucleic acids are unable to cross biological membranes to reach the cytosol or the nucleus. Viral and non-viral vectors are needed for the protection and effective delivery of nucleic acids. Lipid nanoparticles (LNPs) are an established essential platform for nucleic acid delivery. Efforts have led to the development of vaccines that protect against SARS-CoV-2 infection using LNPs to deliver mRNA coding for the viral spike protein. Significant challenges with LNP-mediated nucleic acid delivery include avoiding entrapment in the endosome and enabling extrahepatic delivery. This dissertation reports the engineering of LNPs for the delivery of mRNA and DNA to lymphoid organs such as the spleen and immune cells including T cells and neutrophils. Phospholipids containing phosphoethanolamine (PE) head groups likely increase endosomal escape due to their fusogenic properties. Additionally, it was found that negatively charged phospholipids drive spleen tropism. The use of a spleen selective organ targeting (SORT) formulation containing a negatively charged lipid transfected T cells in vivo. This formulation produced in situ Chimeric Antigen Receptor (CAR) T cells by delivery of mRNA encoding an anti-CD19 CAR. An in vivo Design of Experiment (DOE) to optimize LNPs for spleen pDNA delivery indicated ionizable lipids have the highest delivery efficacy of pDNA to the spleen, compared to cationic lipids. Additionally, higher molar ratios of phospholipid in relationship to the ionizable lipid increased pDNA delivery to neutrophils in the spleen. Overall, the results highlight how the chemistry and the composition of LNPs influences endosomal escape, organ tropism and cell targeting to obtain LNPs with unique therapeutic potential
Analysis of Meiotic Cancer Testis Antigens and Their Contribution to Tumorigenesis
Get PDFTumors frequently activate the expression of genes that are only otherwise required for meiosis. These Cancer Testes Antigens (CTAs) have been found to play critical roles in multiple cellular processes when aberrantly expressed in cancer. Here I found that the CTAs SPO11, GAGE and HORMAD1 play critical roles in cell survival, modulating response to DNA damaging agents, and DNA replication stress mitigation respectively. More specifically, we find HORMAD1 is critical for protecting stalled DNA replication forks in LUAD. Loss of HORMAD1 leads to nascent DNA degradation, an event which is mediated by the MRE11-DNA2-BLM pathway. Moreover, following exogenous induction of DNA replication stress, HORMAD1 deleted cells accumulate single stranded DNA (ssDNA). We find that these phenotypes are the result of a lack of RAD51 and BRCA2 loading onto stalled replication forks. Ultimately, loss of HORMAD1 leads to increased DNA breaks and chromosomal aberrations in response to replication stress. Collectively, our work supports the hypothesis that CTAs become abnormally expressed in cancer to buttress oncogenic behaviors and given their restrictive expression to the testes and tumors, they are unique targets with a broad therapeutic window
Life's Breath
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 observing and participating in the process of mechanical intubation
Echoes of the Universe
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 poem reflects my life's journey, exploring the essence of human existence by letting go of imposed definitions and embracing our connection to the cosmos and a deeper purpose