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Inflammation and cardiovascular risk: insights from rheumatoid arthritis
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
Tumor Infiltrating Lymphocytes (TILs) as a Predictive Marker of Pathological Complete Response (pCR) in a Diverse Patient Population with Early Triple Negative Breast Cancer (TNBC) Treated with the Neoadjuvant Real-World KEYNOTE-522 Regimen
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)Each year the Medical Student Research Program awards students for the best oral presentation and the best poster presentation as judged by faculty across campus. This author received an award as one of the best poster presentations at this forum.Triple-negative breast cancer (TNBC) is a heterogeneous, aggressive subtype of breast cancer with poor prognosis. In July 2021, based on the KEYNOTE-522 trial, the FDA approved neoadjuvant pembrolizumab with chemotherapy for high-risk early-stage TNBC. The K522 regimen demonstrated an increased pathological complete response (pCR) rate of 64.8% compared to only chemotherapy. The presence of tumor-infiltrating lymphocytes (TILs) has been identified as a predictive biomarker of pCR and improved survival in patients with TNBC. This retrospective study assessed a diverse early-stage TNBC cohort to determine whether TILs predict response to neoadjuvant pembrolizumab in the K522 regimen in different subgroups.
We reviewed records of 184 early TNBC patients who received neoadjuvant treatment with K522 regimen. Descriptive statistics were used to report the following patient variables: age, presence of TILs, grade, tumor and nodal status, ethnicity, pCR and residual cancer burden (RCB). Two proportion Z-tests and Chi-squared tests for independence were used to compare pCR rate between demographics. Univariate logistic regression was used to evaluate association between presence of TILs, grade, and residual cancer burden.
In our patient population, 34.8% self-identified as Caucasian, 31.0% Hispanic, 25.5% Black, and 8.7% Other. There was no significant difference in pCR rate or presence of reported TILs across ethnicities. In total, 57% achieved a pCR; TILs were observed in 52.8% of pathology reports. Presence of TILs was associated with a significantly improved pCR rate of 70% compared to individuals without TILs (p=0.0027). Controlling for tumor grade, patients with TILs were 2.67 times more likely to have RCB of either 0 or 1 (p=0.005). Patients with grade 3 TNBC were 2.89 times more likely to have an RCB of 0 or 1 (p=0.0131). Notably, Hispanic patients with TILs had an increased rate of pCR than Hispanic patients without TILs (p=0.0323). No other ethnic group showed statistical association with TILs and pCR. Unlike the predominantly Caucasian K522 trial, our cohort included significant Hispanic and Black populations, which may explain our lower pCR rate of 57%, as studies indicate Black patients often have lower pCR rates.
These findings suggest that TILs may serve as a predictive marker of treatment response in early-stage TNBC. Higher pCR rates among Hispanic patients with TILs suggest that TILs could guide treatment de-escalation for certain subgroups. Changes to the current guidelines to include standardized TIL reporting in pathology current guidelines are necessary, along with larger studies for further validation.Southwestern Medical Foundatio
The University of Texas Southwestern Medical Center 63rd Annual Medical Student Research Forum
No full textThe 63rd Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 28, 2025; 3-6 p.m.; D1.700 Lecture Hall)This 155-page booklet includes a list of oral presentations, a table of contents to the abstracts, and the abstracts divided into three categories: Basic Research and Disease Models; Clinical Research; and Quality Improvement, Global Health, Medical Education, Community Health, and Research Design.Southwestern Medical Foundatio
Histone Lysine Demethylase KDM4A as a Therapeutic Target for Small Cell Lung Cancer
Full text linkSmall cell lung cancer (SCLC) arises from neuroendocrine cells within the lung. Along with deletion or loss-of-function RB1 and TP53 mutations, which occur in almost all cases, subsets of SCLC are driven by specific lineage transcription factors including ASCL1, NEUROD1, POU2F3, or YAP1. The expression of various MYC family members leads to further inter-tumor heterogeneity. Despite this heterogeneity in SCLC, the current treatment for SCLC is lineage-transcription-factor-subtype agnostic. Although most patients are initially responsive to first-line etoposide and platin chemotherapy, they soon develop resistance, and no effective second-line therapy is currently available. A recent large NCI screen showed that over 60 SCLC cell line models responded to > 500 investigational drugs in a manner highly correlated with etoposide responses, suggesting that none of these drugs would provide benefits against SCLC beyond those of current chemotherapy. By analyzing publicly available data from shRNA and CRISPR screens in addition to our own RNA-seq expression data, I identified KDM4A as a potential candidate to target in SCLC. To underscore the potential of KDM4A as an anti-SCLC target, I tested the response phenotypes of etoposide and three JmjC KDM inhibitors using a panel of SCLC cell lines representing all the SCLC transcription factor subtypes and found that SCLC responses to JmjC KDM inhibitors did not correlate with their responses to etoposide. Furthermore, I found that upon treatment with the pan-JmjC KDM inhibitor JIB-04, many genes in the ER stress signaling pathways were upregulated in SCLC cell lines, suggesting that this is the mechanistic path leading to SCLC death following Jumonji inhibition. Additional analysis revealed that JIB-04-resistant cells also activated pro-survival pathways such as mTOR to overcome the effects of JIB-04 treatment. I also found that the loss of KDM4A in a SCLC cell line led to slower proliferation and activity in the ER stress signaling pathway. In summary, I identified Jumonji enzymes as viable targets to treat the SCLC, adding a new therapeutic option to the treatment paradigm. Furthermore, new possible therapeutic combinations, including that of Jumonji inhibitors with mTOR inhibitors, could prove to be beneficial to treat SCLC
Study of Glycan-Mediated Interactions by Photocrosslinking GlcNAc and GalNAc Analogs
Full text linkGlycans, along with nucleic acids, proteins and lipids, are essential elements of life. Glycans are involved in multiple biological processes, such as cell signaling, cell adhesion and host pathogen interactions, many of which are achieved through interactions with other molecules, especially glycan binding proteins. However, there are multiple challenges in the study of glycan-mediated interactions. One of the main challenges in glycobiology is the low affinity of glycan binding events, making them difficult to characterize. To address this challenge, diazirine-functionalized sugar analogs that can be metabolically incorporated into cellular glycans were designed. Upon UV irradiation, a covalent bond forms between the diazirine group and nearby molecules. The formation of a covalent bond makes it easier to characterize glycan-mediated interactions using various methods, including Western blot, immunoprecipitation and proteomics. In this thesis, I will focus on diazirine-functionalized N-acetylglucosamine (GlcNAc) and N-acetylgalactosamine (GalNAc) analogs, GlcNDAz and GalNDAz. I will demonstrate the incorporation of GlcNDAz into N-linked glycans using complementary methods and the applications of GlcNDAz in identification of binding partners of two glycan binding proteins, galectin-1 and cholera toxin B subunit. In addition, I will demonstrate the preliminary results I have on GalNDAz incorporation and photocrosslinking, which indicate that GalNDAz may be incorporated into cellular glycans.
Chapter 1 introduces the background of this thesis, including basics of glycans and lectins, metabolic glycan engineering, photocrosslinking groups and photocrosslinking sugar analogs. In chapter 2, the incorporation of GlcNDAz into cellular N-linked glycans is demonstrated. Chapter 3 focuses on applications of GlcNDAz in crosslinking of galectin-1 and cholera toxin B subunit, and in identification of their binding partners by crosslinking and proteomics. Chapter 4 includes the preliminary data on applications of GlcNDAz in identification of galectin-1 binding partners during lysosomal damage and the function of galectin-1 in cellular response to lysosomal damage. In chapter 5, the preliminary results on GalNDAz incorporation and photocrosslinking are examined
Beginnings and Ends
Full text linkThe author submitted this entry in the 10-Word Story category (Amateur division) for the 2025 On My Own Time™ (OMOT) Art Show.I've always been fascinated by the life of a star and how beautiful destructive chaos can give birth to life through stardus
Precision in drug allergy: from mechanisms to the bedside
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
Face in the Clouds
Full text linkThe author submitted this entry in the AI Literature category (Amateur division) for the 2025 On My Own Time™ (OMOT) Art Show.The specific prompt that the author submitted to the AI system to generate the story is available as a separate document.Lying in the grass, looking up at the clouds, I had an idea for a story. I spoke it out loud, using speech-to-text to save my ramblings. When I got home, the text was busy and hard to parse through. I used ChatGPT to organize my thoughts, with this story as a result
Outcast
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.Being involved in animal rescue is hard, and I feel particularly useless because I am unable to foster. California (where Devore shelter is located) and Texas often have to euthanize animals due to lack of space or resources. I wrote this after reaching a breaking point with seeing so many cats lose their lives and almost losing a cat I did try to rescue on my own. Thankfully policy changes has helped Devore's case a bit, but more work needs to be done everywhere to help the animals that get dumped
Elucidating the Impact of Endogenous Proteins on Lipid Nanoparticle Organ-Targeting Outcomes
Full text linkRibonucleic acid (RNA) biomolecules can be used for the prevention and treatment of various diseases by gene silencing, gene expression, and gene editing approaches. As RNA can be easily degraded by nucleases and does not readily cross the cell membrane to access the cytosol, where it is biologically active, a delivery system is necessary to circumnavigate these obstacles and ensure targeting of the proper cell type(s). Presently, lipid nanoparticles (LNPs) represent the most clinically-advanced system for delivery of multiple classes of RNA, including small interfering RNA (siRNA), messenger RNA (mRNA), and guide RNAs for genome editing. Despite this progress, precise control of delivery to a desired organ to access specific cell type(s) is necessary as RNA remains largely limited to applications involving localized routes of administration, such as vaccination, or disease targets in the liver due to significant hepatic accumulation of LNPs following intravenous administration.
This dissertation aims to elucidate the biological interactions that enable extrahepatic RNA delivery by LNPs via systemic injection. The preferential liver delivery of LNPs results from interactions with plasma proteins involved in endogenous cholesterol transport. Building on this foundation, I characterized the targeting mechanism of selective organ targeting (SORT) nanoparticles, an LNP platform for tissue-specific RNA delivery to therapeutically-relevant cells of the liver, spleen, or lungs after intravenous injection. I discovered that the biophysical class of a 5th lipid added to the LNP, termed a SORT molecule, alters the LNP's biodistribution, ionization behavior, and plasma protein interactions. Furthermore, I provide evidence for an endogenous targeting mechanism wherein binding of distinct proteins to the nanoparticle surface facilitates tissue-specific RNA delivery through interactions between surface-bound proteins and cognate receptors highly expressed by cells in the target organ. Further studies on a specific chemical series of SORT molecules within the same biophysical class revealed that a nuanced relationship exists between LNP chemistry, plasma protein interactions, and the tissue-specificity of mRNA delivery. Collectively, these findings lay the foundation for an innovative paradigm - endogenous targeting - wherein the molecular composition of a nanoparticle is rationally engineered to promote binding of specific plasma proteins that yield a desired delivery outcome