Texas Southwestern Medical Center Research Articles

An Unobtrusive and Lightweight Ear-worn System for Continuous Epileptic Seizure Detection

Epilepsy is one of the most common neurological diseases globally (around 50M people globally). Fortunately, up to 70% of people with epilepsy could live seizure-free if properly diagnosed and treated, and a reliable technique to monitor the onset of seizures could improve the quality of life of patients who are constantly facing the fear of random seizure attacks. The current gold standard, video-EEG (v-EEG), involves attaching over 20 electrodes to the scalp, is costly, requires hospitalization, trained professionals, and is uncomfortable for patients. To address this gap, we developed EarSD , a lightweight and unobtrusive ear-worn system to detect seizure onsets by measuring physiological signals behind the ears. This system can be integrated into earphones, headphones, or hearing aids, providing a convenient solution for continuous monitoring. EarSD is an integrated custom-built sensing - computing - communication ear-worn platform to capture seizure signals, remove the noises caused by motion artifacts and environmental impacts, and stream the collected data wirelessly to the computer/mobile phone nearby. EarSD 's ML algorithm, running on a server, identifies seizure-associated signatures and detects onset events. We evaluated the proposed system in both in-lab and in-hospital experiments at the University of Texas Southwestern Medical Center with epileptic seizure patients, confirming its usability and practicality.

Mycophenolate mofetil for the treatment of cicatrizing conjunctivitis secondary to ocular pemphigoid

PurposeTo characterize the use of mycophenolate mofetil (MMF) in a large cohort of patients undergoing treatment for ocular mucous membrane pemphigoid (ocMMP). DesignThis was a retrospective consecutive observational chart review of patients with cicatrizing conjunctivitis associated with pemphigoid (ocMMP) at the University of Texas Southwestern Medical Center in Dallas, TX from 2016 to 2023 who underwent treatment with MMF. MethodsData collection included patient demographics, medical and ocular history, clinical findings, slit lamp photographs, biopsy results, additional testing, disease stage, time on MMF, patient response to treatment, and side effects of treatment. The data was analyzed with logistic regression using IBM SPSS (version 29). The dependent variable was remission status. ResultsA total of 52 patients with cicatrizing conjunctivitis associated with pemphigoid were treated with MMF, of which 37 (71.2 %) patients had biopsy proven disease. Of the cohort, 29 (55.8 %) patients were female and 23 (44.2 %) patients were male. The mean age at initiation of MMF therapy was 65.1 years (range 35–93). The best degree of response achieved by each patient in our cohort was as follows: no response (4, 7.7 %), partial response (28, 53.8 %), clinical remission with steroids (4, 7.7 %), steroid-free remission (14, 26.9 %), and durable drug-free remission (2, 3.8 %). The mean time of treatment with MMF was 35.5 months (range 2–118), with a mean follow up time of 42.7 months (range 3–123). The mean time to clinical remission was 6.7 months (range 1–18), while the mean time to steroid-free remission was 7.2 months (range 2–18). Of the entire cohort, 16 (30.8 %) patients reported side effects. The most common side effect was nausea (7 patients). There was one adverse event (anemia, 1, 1.9 %). Overall, 30 (57.7 %) patients discontinued MMF, most commonly due to side effects (11 patients) or inadequate disease control (11 patients). ConclusionMycophenolate mofetil (MMF) can be beneficial in ocMMP as a steroid-sparing alternative. Although effective, side effects and discontinuation of treatment were common.

6366 Elevated Baseline Triglycerides As an Independent Risk Factor For Coronary Artery Disease

Abstract Disclosure: E. Askar: None. H. Moran: None. D. Bleich: None. Introduction: Diabetes is considered a coronary artery disease (CAD) risk equivalent. Studies have shown that the baseline level of triglycerides plays a role in cardiovascular risk independent of LDL levels lowered with statins. Numerous studies demonstrate that, in the general population, coronary artery calcium (CAC) scoring predicts and reclassifies cardiovascular disease (CVD) events, even in the absence of other risk factors. Here, we present a case of a 65 -year-old Caucasian male with elevated baseline triglycerides and a high CAC score, increasing his CVD risk despite the normalization of his triglycerides with statin therapy.Case presentation: A 65-year-old Caucasian male with a history of hypertension, hyperlipidemia, and diabetes presented to our endocrinology clinic for the management of hyperlipidemia and diabetes. His medications included empagliflozin 10 mg daily, repaglinide 1 mg three times a day, atorvastatin 20 mg daily, and amlodipine 10 mg daily. He had no complaints, and the physical examination was unremarkable. His recent HbA1c was 7.4%. Six months prior to presentation, he was found to have elevated triglycerides of 253 mg/dL (normal range: 10-149 mg/dL), low HDL of 34 mg/dL (normal range: >39 mg/dL), LDL of 84 mg/dL (normal range: 0-99 mg/dL), and total cholesterol of 167 mg/dL (normal range: 100-200 mg/dL). At that time, he was started on atorvastatin, and his recent triglycerides and HDL levels normalized. He was referred for CAC scoring, and the result was 2733 , which is above the 90th percentile for men between the ages of 65 and 69. As a result, he was further referred to a coronary angiogram. Conclusion: McGarry at the University of Texas Southwestern Medical Center was the first to describe the elevated triglyceride along with low HDL phenotype associated with insulin resistance. They explained this phenotype as a result of hepatic insulin resistance. Elevated insulin levels reduce the activity of lipoprotein lipase (LPL). As a result of that, the VLDL triglycerides rise, forming small dense LDL with a strong atherogenic potential.In the 2010 published ACCORD study, the effects of simvastatin alone versus simvastatin and fenofibrate were compared in 5500 Patients with type 2 diabetes. The experimental group did not exhibit any significant adverse cardiovascular events after eight years. However, the mean triglyceride was only 162 mg/dL. Consequently, no assumptions about the impact of the treatment on cardiovascular events in a more pertinent subset of people with greater baseline triglycerides could be made.While there has been controversy on the role of triglycerides in CVD, the idea of lowering triglycerides in diabetes patients with high triglycerides and low HDL to lower the risk of CVD is well supported. Presentation: 6/2/2024

Bringing PERT to Pediatrics: Initial Experience and Outcomes of a Pediatric Multidisciplinary Pulmonary Embolism Response Team (PERT)

IntroductionMultidisciplinary Pulmonary Embolism Response Teams (PERTs) streamline care of adults with life-threatening pulmonary embolism (PE). Given rarity of pediatric PE, developing a clinical, educational, and research PERT paradigm is a novel and underutilized concept in pediatrics. Research QuestionIs PERT feasible in pediatrics, and does it improve PE care? Study Design and MethodsA strategy-to-execution proposal to launch a pediatric PERT was developed for institutional buy-in. Key stakeholders collectively implemented PERT. Data were collected for the two-year pre- and post-PERT eras, and outcomes were compared. ResultsPERT implementation took 12 months. Our PERT, led by hematology, comprises of pediatric experts in emergency medicine, critical care, interventional cardiology, anesthesiology, and interventional radiology. Data on 30 patients pre-PERT and 31 post-PERT were analyzed. Pre-PERT, 10%(3/30), 13%(4/30), 20%(6/30), and 57%(17/30), and post-PERT, 3%(1/31), 10%(3/31), 16%(5/31), and 71%(22/31) were categorized as high-risk, intermediate-LOW risk, intermediate-HIGH risk, and low-risk PE, respectively. Post-PERT, there were 13 unique PERT activations. PERT was activated on all eligible PE patients and, additionally, on four low-risk PEs. Time-to-echocardiogram was shorter post-PERT (4.7 hrs vs 2 hrs, P=0.0147). Anticoagulation was ordered (90 min vs 54 min, P=0.003) and given sooner (154 min vs 113 min, P=0.049) post-PERT. There were no differences in time-to-reperfusion therapies (12 hrs pre-PERT vs 8.7 hrs post-PERT, P=0.1). Five (83.3%) of six eligible (intermediate-HIGH and high-risk) patients received reperfusion therapies in the post-PERT era compared to three (37.5%) of eight eligible patients in the pre-PERT era (P=0.0001). There were no differences in major bleeding, mortality, or length of stay in either era. InterpretationThe pediatric PERT paradigm was successfully created and adopted locally. Our PERT enhanced access to experts, facilitated timely advanced therapies, and held value for low-risk PE. The University of Texas Southwestern Medical Center (UTSW) and Children’s Health System of Texas pediatric PERT may serve as a best-practice model for streamlining care for pediatric PE.

A-039 Parathyroid Hormone and Vitamin D Follow an Inversely Correlated Serum Level

Abstract Background Parathyroid hormone (PTH) is a polypeptide responsible for regulating the physiological level of serum calcium through a complex homeostatic process closely associated with bone metabolism. In response to a decreased serum concentration of calcium, PTH level is increased leading to the elevation of calcium via bone resorption. Furthermore, Vitamin D (Vit-D) is a critical component of the endocrine system that also contributes to calcium homeostasis. Vit-D increases the level of serum calcium by stimulating intestinal absorption and renal reabsorption. Vit-D impacts the serum level of PTH by two distinct mechanisms. First indirectly, an increase in serum concentration of calcium, caused by Vit-D-mediated intestinal absorption and renal reabsorption disengages the process of PTH release through interaction with calcium-sensing receptors on parathyroid cells. Secondly, Vit-D directly interacts with parathyroid cells resulting in a reduced expression of PTH. Taken together, Vit-D is assumed to negatively impact the serum level of PTH. This study examined the homeostatic correlation between the circulating concentrations of Vit-D and PTH. Methods Retrospective serum concentrations of PTH and Vit-D were retrieved from the biochemical profiles of hospitalized and ambulatory patients who presented to or admitted at the tertiary care level hospital of University of Texas Southwestern Medical Center during the period between July-to-September of 2021. Correlation analysis between Vit-D and PTH was performed using GraphPad-PRISM-version-8. Results A total of 163 corresponding serum Vit-D and PTH values were obtained. Vit-D and PTH values displayed an inverse correlation (Figure 1). Pearson r values for linear and logarithmic trendlines (-0.6745 and -0.785, respectively) demonstrated a negative correlation between Vit-D and PTH. Conclusions Measuring Vit-D and PTH levels are critically important for assessing the homeostatic status of calcium. PTH level maintains an inverse relationship with Vit-D. Therefore, therapeutic targeting of Vit-D or PTH would mutually affect their concentration eventually reflected in calcium homeostasis.

Judge rules against former employee

Case name: Thornton v. The University of Texas Southwestern Medical Center, No. 3:22‐CV‐2079 (N.D. Tex. 05/29/24).

Neuronal Ceroid Lipofuscinoses Type 7 (CLN7)- A Case Series Reporting Cross Sectional and Retrospective Clinical Data to Evaluate Validity of Standardized Tools to Assess Disease Progression, Quality of Life, and Adaptive Skills.

This study evaluated the clinical characteristics of neuronal ceroid lipofuscinosis type 7 or CLN7 disease spectrum to characterize the clinical, electrophysiologic and neuroimaging phenotypes. We performed a single-center cross sectional data collection along with retrospective medical chart review in patients with a genetic diagnosis of CLN7. This study received ethical approval by the University of Texas Southwestern Medical Center Institutional Review Board. A total of 8 patients were included between the ages of 4 to 6 years. All patients had a genetic diagnosis of CLN7 with homozygous or compound heterozygous mutations in the MFSD8 gene. The information collected includes patient demographics, developmental history, neurological events including seizures and neurodevelopmental regression along with further evaluation of brain magnetic resonance imaging and electrophysiological findings. The clinical phenotype is described through cross sectional and retrospective data collection and standardized tools assessing quality of life and functional skills. Our findings in this cohort of CLN7 patients indicated that development is initially normal with onset of clinical symptoms as early as two years of age. Language problems were noted prior to or at the onset of seizures in all cases. Gait problems were noted prior to seizure onset in 3 of 8 patients, and at or within 6 months after the onset of seizures in 5 of 8 patients. All patients followed a progressive course of language, motor, and neurocognitive deterioration. Congruent with the medical history, our patients had significantly low scores on adaptive abilities. Natural history data such as this can be used to support future clinical trial designs.

Two-Stage Training Framework Using Multicontrast MRI Radiomics for IDH Mutation Status Prediction in Glioma.

Purpose To develop a radiomics framework for preoperative MRI-based prediction of isocitrate dehydrogenase (IDH) mutation status, a crucial glioma prognostic indicator. Materials and Methods Radiomics features (shape, first-order statistics, and texture) were extracted from the whole tumor or the combination of nonenhancing, necrosis, and edema regions. Segmentation masks were obtained via the federated tumor segmentation tool or the original data source. Boruta, a wrapper-based feature selection algorithm, identified relevant features. Addressing the imbalance between mutated and wild-type cases, multiple prediction models were trained on balanced data subsets using random forest or XGBoost and assembled to build the final classifier. The framework was evaluated using retrospective MRI scans from three public datasets (The Cancer Imaging Archive [TCIA, 227 patients], the University of California San Francisco Preoperative Diffuse Glioma MRI dataset [UCSF, 495 patients], and the Erasmus Glioma Database [EGD, 456 patients]) and internal datasets collected from the University of Texas Southwestern Medical Center (UTSW, 356 patients), New York University (NYU, 136 patients), and University of Wisconsin-Madison (UWM, 174 patients). TCIA and UTSW served as separate training sets, while the remaining data constituted the test set (1617 or 1488 testing cases, respectively). Results The best performing models trained on the TCIA dataset achieved area under the receiver operating characteristic curve (AUC) values of 0.89 for UTSW, 0.86 for NYU, 0.93 for UWM, 0.94 for UCSF, and 0.88 for EGD test sets. The best performing models trained on the UTSW dataset achieved slightly higher AUCs: 0.92 for TCIA, 0.88 for NYU, 0.96 for UWM, 0.93 for UCSF, and 0.90 for EGD. Conclusion This MRI radiomics-based framework shows promise for accurate preoperative prediction of IDH mutation status in patients with glioma. Keywords: Glioma, Isocitrate Dehydrogenase Mutation, IDH Mutation, Radiomics, MRI Supplemental material is available for this article. Published under a CC BY 4.0 license. See also commentary by Moassefi and Erickson in this issue.

Abstract PO1-19-08: Phase I trial of pegylated liposomal doxorubicin chemotherapy in combination with CD40 agonist and Flt3 ligand in metastatic triple-negative breast cancer

Abstract Background: Only a subset of patients with metastatic triple-negative breast cancers (TNBC) demonstrate response to FDA approved PD-1 immune checkpoint blockade (ICB), and few have durable responses. Data suggests that breast cancers have defects in antigen presentation and that antigen presenting cells especially the cDC1 subtype of dendritic cells (DCs) are required for response to ICB. CD40 agonists activate antigen presenting cells including DCs and B cells and repolarize macrophages to an anti-tumor phenotype. Flt3 ligand is a growth factor that increases differentiation and expansion of DCs. We recently demonstrated in pre-clinical TNBC models that the combination of liposomal doxorubicin chemotherapy, a CD40 agonist, and a Flt3 ligand improves outcomes compared to alternate combinations. Methods: This is a single arm phase I pilot study of liposomal doxorubicin, CDX-1140 (CD40 agonist monoclonal antibody), and CDX-301 (recombinant Flt3 ligand) combination therapy in patients with metastatic or unresectable locally advanced metastatic TNBC. Patients will be randomized to 3 lead-in arms (triplet therapy, doublet immunotherapy only, or liposomal doxorubicin only) for one cycle prior to receiving triplet therapy with tissue biopsies done before and after the lead-in treatment. CDX-301 will be given for only two cycles; liposomal-doxorubicin and CDX-1140 will be continued until disease progression or clinically limiting toxicities. Primary endpoint is determination of a recommended phase II dose based on treatment-related adverse events and dose-limiting toxicities. Secondary endpoints include anti-tumor immune response after triplet therapy, after immunotherapy alone, and after liposomal doxorubicin alone; median progression-free survival, overall response rate, duration of response, and clinical benefit rate. Key eligibility criteria are unresectable stage III or stage IV TNBC (ER ≤10%, PR ≤10%, HER2/neu negative), 1st to 3rd line treatment for metastatic disease (1st line patients need to be PD-L1 negative by 22C3 assay), measurable disease by RECIST 1.1 criteria, consent for pre-treatment and on-treatment biopsies of amenable soft tissue tumor lesions, no prior treatment with an anti-CD40 antibody or a Flt3 ligand, no anthracycline treatment in the metastatic setting, no prior progression while on anthracycline-based therapy or within 6 months of completing neoadjuvant chemotherapy, and no history of non-infectious pneumonitis or current pneumonitis. This trial will enroll up to 45 patients across multiple sites (NCT05029999) and is currently open at University of Texas Southwestern Medical Center, Texas Oncology, University of Chicago, University of Texas San Antonio, Sarah Cannon Research Institute, and Johns Hopkins. Citation Format: Sangeetha Reddy, Joyce O'Shaughnessy, Navid Sadeghi, Samira Syed, Cesar Santa-Maria, Virginia Kaklamani, Nan Chen, Denise Yardley, Yisheng Fang, Isaac Chan, Nisha Unni, Sarah Kashanian, Namrata Peswani, Shahbano Shakeel, Meredith Carter, Kelly Kyle, Farjana Fattah, Chul Ahn, Ina Patel, Joshua Gruber, Dawn Klemow, Glenda Delgado, Nicole Sinclair, Michael Yellin, Heather McArthur, Rita Nanda, Suzanne Conzen, Carlos Arteaga. Phase I trial of pegylated liposomal doxorubicin chemotherapy in combination with CD40 agonist and Flt3 ligand in metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-08.

Synthesizing 3D Multi-Contrast Brain Tumor MRIs Using Tumor Mask Conditioning.

Data scarcity and data imbalance are two major challenges in training deep learning models on medical images, such as brain tumor MRI data. The recent advancements in generative artificial intelligence have opened new possibilities for synthetically generating MRI data, including brain tumor MRI scans. This approach can be a potential solution to mitigate the data scarcity problem and enhance training data availability. This work focused on adapting the 2D latent diffusion models to generate 3D multi-contrast brain tumor MRI data with a tumor mask as the condition. The framework comprises two components: a 3D autoencoder model for perceptual compression and a conditional 3D Diffusion Probabilistic Model (DPM) for generating high-quality and diverse multi-contrast brain tumor MRI samples, guided by a conditional tumor mask. Unlike existing works that focused on generating either 2D multi-contrast or 3D single-contrast MRI samples, our models generate multi-contrast 3D MRI samples. We also integrated a conditional module within the UNet backbone of the DPM to capture the semantic class-dependent data distribution driven by the provided tumor mask to generate MRI brain tumor samples based on a specific brain tumor mask. We trained our models using two brain tumor datasets: The Cancer Genome Atlas (TCGA) public dataset and an internal dataset from the University of Texas Southwestern Medical Center (UTSW). The models were able to generate high-quality 3D multi-contrast brain tumor MRI samples with the tumor location aligned by the input condition mask. The quality of the generated images was evaluated using the Fréchet Inception Distance (FID) score. This work has the potential to mitigate the scarcity of brain tumor data and improve the performance of deep learning models involving brain tumor MRI data.

An interview with Sandra Schmid – Chief Scientific Officer of the Chan Zuckerberg Biohub

ABSTRACT Sandra Schmid is the Chief Scientific Officer of the Chan Zuckerberg Biohub in San Francisco, USA. She was previously Professor and Chair of the Cell Biology Department at the University of Texas Southwestern Medical Center, and Chair of the Department of Cell Biology at Scripps Research Institute, CA, USA. Sandra's research over the years has focused on the biochemical dissection of the endocytic pathway, in particular the role of dynamin and the mechanisms of clathrin-mediated endocytosis. We chatted to Sandy to find out more about her career, her role as an advocate for women in science, and her recent transition to the Chan Zuckerberg Biohub.

Is patient‐reported symptom onset associated with odontogenic infection severity?

AbstractIntroductionThe purpose of this study was to determine if there is a relation between odontogenic infection severity score (OISS) and the time interval from patient‐reported symptom onset to emergency department (ED) presentation. The working hypothesis was that higher OISSs would be found in patients who developed symptoms and delayed ED presentation compared with patients who presented earlier.Materials and MethodsThe study population was composed of consecutive patients who were admitted to the University of Texas Southwestern Medical Center and surgically treated in the operating room for severe odontogenic infections from January 2016 to December 2020. Odontogenic infection severity was measured using a numerical severity index. Three cohort groups were predefined to evaluate the relation between patient‐reported symptom onset in days and OISS.ResultsThere were 115 patients who met the inclusion and exclusion criteria. There was no significant difference in the OISSs between the three cohorts. In patients who received antibiotics prior to ED presentation, there was no difference in OISS. Male sex and diabetes diagnosis were related to higher OISSs.ConclusionsPatient‐reported symptom onset is unrelated to OISS in patients treated surgically for severe odontogenic infections. Other patient‐specific factors such as diabetes diagnosis are related to higher OISSs.

Delta Radiomic Features Predict Resection Margin Status and Overall Survival in Neoadjuvant-Treated Pancreatic Cancer Patients.

Neoadjuvant therapy (NAT) emerged as the standard of care for patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgery; however, surgery is morbid, and tools to predict resection margin status (RMS) and prognosis in the preoperative setting are needed. Radiomic models, specifically delta radiomic features (DRFs), may provide insight into treatment dynamics to improve preoperative predictions. We retrospectively collected clinical, pathological, and surgical data (patients with resectable, borderline, locally advanced, and metastatic disease), and pre/post-NAT contrast-enhanced computed tomography (CT) scans from PDAC patients at the University of Texas Southwestern Medical Center (UTSW; discovery) and Humanitas Hospital (validation cohort). Gross tumor volume was contoured from CT scans, and 257 radiomics features were extracted. DRFs were calculated by direct subtraction of pre/post-NAT radiomic features. Cox proportional models and binary prediction models, including/excluding clinical variables, were constructed to predict overall survival (OS), disease-free survival (DFS), and RMS. The discovery and validation cohorts comprised 58 and 31 patients, respectively. Both cohorts had similar clinical characteristics, apart from differences in NAT (FOLFIRINOX vs. gemcitabine/nab-paclitaxel; p<0.05) and type of surgery resections (pancreatoduodenectomy, distal or total pancreatectomy; p<0.05). The model that combined clinical variables (pre-NAT carbohydrate antigen (CA)19-9, the change in CA19-9 after NAT (∆CA19-9), and resectability status) and DRFs outperformed the clinical feature-based models and other radiomics feature-based models in predicting OS (UTSW: 0.73; Humanitas: 0.66), DFS (UTSW: 0.75; Humanitas: 0.64), and RMS (UTSW 0.73; Humanitas: 0.69). Our externally validated, predictive/prognostic delta-radiomics models, which incorporate clinical variables, show promise in predicting the risk of predicting RMS in NAT-treated PDAC patients and their OS or DFS.

An open chat with… Josep Rizo.

Josep Rizo is a Professor of Biophysics, Biochemistry and Pharmacology at the University of Texas Southwestern Medical Center, where he is Virginia Lazenby O'Hara Chair in Biochemistry. He is particularly interested in the study of the mechanisms of neurotransmitter release and intracellular membrane fusion using structural biology, a variety of biophysical techniques and reconstitution approaches. Jose has been a part of the FEBS Open Bio Editorial Board since 2021. In this interview, he shares his insights into developments in the field of neurotransmitter release, describes his move from Spain to the United States, and discusses how sometimes you need to use both logic and scientific hunches.

2065. Efficacy of D-peptide-conjugated Antisense Compounds Against Pseudomonas aeruginosa

Abstract Background Pseudomonas aeruginosa (PA) causes significant morbidity and mortality in immunocompromised hosts and those with cystic fibrosis. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) are antisense compounds designed to target specific genes and prevent translation. PPMOs with L-isomer peptides (L-PPMOs) were previously shown to have in vitro and in vivo activity. However, L-PPMOs are vulnerable to degradation by host proteases. We hypothesize that PPMOs with a D-isomer peptide (D-PPMOs) may be a more stable and potent alternative. We aimed to characterize the activity of L- and D-isomers in PA strains using planktonic and biofilm assays as well as an infected mouse model. Methods All L- and D-PPMOs were synthesized by Sarepta Therapeutics, Inc. We tested L- and D-isomers of the (RXR)4XB (X for 6-aminohexanoic acid and B for β-Ala) and R6G peptide [(Arg)6-Gly]. PMOs for rpsJ (ribosomal protein) and acpP (fatty acid synthesis protein) were conjugated to the 3’ end of each peptide. Minimum inhibitory concentration (MIC) assays were performed in unique lab and clinical (including MDR) isolates using MOPS medium. Strain PAO1 biofilms were grown in MBEC plates for 24 hours, with PPMOs then dosed every 8 hours for 24 hours, followed by colony enumeration. For in vivo studies, mice were infected with strain PA103 intratracheally and given intranasal PPMO at 6 hours post-infection. Lung burden was determined at 24 hours post-infection. Results MIC values of D-R6G-RpsJ and D-R6G-AcpP were comparable to their L-isomers, but D-RXR-RpsJ showed an improved MIC90 of 0.5 μM compared to the L-RXR-RpsJ MIC90 of 16 μM (Table 1). Both isomers demonstrated reduction of 48-hour biofilm to various degrees. D-PPMO biofilm reduction ranged from 1.5 logs to &amp;gt; 3 logs (D-R6G-AcpP and D-RXR-RpsJ, respectively). L-PPMO biofilm reduction ranged from 2 logs to &amp;gt; 4 logs. D-PPMOs were superior to their L-PPMO counterparts in our delayed in vivo acute pneumonia model, with most D-PPMOs resulting in an additional 50% decrease in lung burden. Conclusion D-PPMOs show similar or improved activity in vitro and in vivo when compared to L-PPMOs at the same dosage. Future studies will investigate the pharmacology of D-PPMOs, as they may represent a more biologically robust alternative to L-PPMOs for PA infections. Disclosures David E. Greenberg, MD, University of Texas Southwestern Medical Center: Dr. Greenberg has numerous patents on PPMOs

Distinct SF3B1 Allele HEAT Repeat Location Is Associated with Co-Occurring Mutation Patterns in MDS

Background: In 2022, the WHO classified a new subtype of myelodysplastic neoplasms (MDS) with low blast count and SF3B1 mutation called MDS- SF3B1. SF3B1 is the major subunit of the SF3B spliceosome complex and is responsible for recognizing 3' splice sites in pre-mRNA for processing into mature mRNA. Mutations in SF3B1 have also been observed in other myeloid neoplasms. While MDS- SF3B1 has been associated with a better survival outcome, allelic variants such as SF3B1 K666N are associated with higher-risk MDS, transformation to AML and decreased OS. Additionally, SF3B1 E592K is more likely to be co-mutated with RUNX1, with a worse prognosis. Thus, not all SF3B1 allelic variants should be treated the same. The IPSS-M model incorporates SF3B1 mutations with different weights depending on co-mutations (i.e. isolated del(5q) or BCOR, BCORL1, RUNX1, NRAS, STAG2, SRSF2 mutations) but did not find a difference based on SF3B1 hotspot mutation. However, these and other studies have focused on specific amino acid substitutions but have not taken into consideration the protein domain structure of SF3B1. Using a large cohort of SF3B1-mutant myeloid malignancies, we determined whether HEAT repeat domain location was associated with differences between SF3B1-mutant myeloid neoplasms when comparing co-mutations and clinical characteristics. Methods: Bone marrow, peripheral blood, or FFPE tissue samples from a cohort of 2,996 unique patients with a suspected myeloid neoplasm from 6/30/2020-5/30/2023 were sequenced using a DNA 297 gene myeloid panel. We also analyzed a separate cohort of 112 patients from Sylvester Comprehensive Cancer Center (SCCC) and the University of Texas Southwestern Medical Center (UTSW) from 06/01/2017-06/30/2023 to validate the findings and assess for associations with clinical parameters such as blast count, time to disease progression, and survival. Statistics were performed using Chi-Square. SF3B1 has 22 HEAT repeats with SF3B1 mutations occurring predominately in HEAT Domains 2-6. For this study, we used UniProt definitions of amino acids 569-603 (HEAT2), 604-641 (HEAT3), 643-677 (HEAT4), 680-718 (HEAT5), and 763-801 (HEAT6) as shown in Figure 1. Results: Out of 2,996 myeloid neoplasm patients with SF3B1 mutations, the SF3B1 allele with the highest prevalence was K700E, which falls into HEAT repeat number 5, followed by K666N/R/T and H662Q in HEAT repeat number 4, and R635C in HEAT repeat number 3. Mutations in HEAT repeat 2 and 6 were less common. Several genes were significantly co-mutated in different SF3B1 heat domains, including ASXL1 (11%, p-value =&amp;lt;0.00001), CUX1 (4.7%, p-value = &amp;lt;0.00001), DNMT3A (22.5%, p-value = &amp;lt;0.00001), EZH2 (4.3%, p-value = 0.07), JAK2 (11.2%, p-value= &amp;lt;0.00001), RUNX1 (7.8%, p-value = &amp;lt;0.00001), STAG2 (3.2%, p-value = &amp;lt;0.00001), and TET2 (28.2%, p-value = 0.003) shown in Table 1. The most common co-mutations within each HEAT domain were: HEAT2- ASXL1 (80.0%), RUNX1 (55%), and STAG2 (25%); HEAT3- TET2 (29.5%), DNMT3A (17.5%), and ASXL1 (12.6%); HEAT4- TET2 (24%), D NMT3A (15.2%), and JAK2 (16.9%); HEAT5- TET2 (31.4%) and DNMT3A (31%);and HEAT6- TET2 (28.9%), ASXL1 (15.8%), DMNT3A (14.5%), and EZH2(10.5%). In a separate cohort of 112 patients with clinical follow-up, 97 were diagnosed with MDS- SF3B1: 53 (55%) were male and the average age at diagnosis of 70 years (range: 27-89 years old). A total of 88 patients had 297 gene myeloid panel information, which revealed a similar HEAT repeat distribution: HEAT3 (19%), HEAT4 (27%), HEAT5 (45%), and HEAT6 (6%). The median OS of the entire cohort was 10.5 years (CI 95% 4.93-NE). With a median follow-up of 2 years; 75, 81, 63 and 80% of patients were alive in HEAT 3, 4, 5 and 6, respectively. Conclusion: Distinct SF3B1 alleles defined by HEAT repeat location reflect distinct co-mutation patterns and may play a role in the biology of myeloid disorders. The relatively most enriched co-mutation patterns included: ASXL1 and RUNX1 in HEAT2, JAK2 in HEAT4, and EZH2 in HEAT6. Despite numerical differences in survival larger multicenter patient cohorts are needed to further define how distinct SF3B1 allelic variants and their HEAT repeat location correlate with prognosis and outcome in MDS and other myeloid neoplasms. In addition, further research is need into whether distinct SF3B1 alleles result in differences in RNA splicing signatures that may influence interactions with co-occurring mutations and disease biology.

IPSS-M - Use for Predicting Survival and Progression in Patients with Ccus - a Retrospective Multi-Institutional Study

Background: Clonal cytopenia of undetermined significance (CCUS) is characterized by the presence of a clone with somatic mutations in genes associated with myeloid neoplasms (MN) or abnormal cytogenetics, along with unexplained and persistent cytopenias in the absence of significant marrow dysplasia. CCUS is considered a premalignant state with a risk of progression to MN. The clinical outcomes of patients (pts) with high risk CCUS (Weeks et al, NEJM Evidence 2023) may be similar that of some patients with myelodysplastic syndromes (MDS). This study aims to predict the outcomes of CCUS patients using the molecular international prognostic scoring system (IPSS-M) developed for MDS. Methods: A retrospective analysis was conducted in patients diagnosed with CCUS between 2015 and 2023, we included patients harboring pathogenic mutations (MUT) identified through next-generation sequencing (NGS) testing at two institutions: Mayo Clinic and the University of Texas Southwestern Medical Center, Dallas, TX, USA were included. Progression was considered present if patients with CCUS progressed into myeloid neoplasm at follow up. Statistical analysis was performed using JMP® 17.1.0 Software. IPSS-M risk scores were calculated via the IPSS-M Risk Calculator (mds-risk-model.com). Results: A total of 103 patients were included in the study. The median age was 72 years, the majority were male patients (73%), and the median bone marrow blast % at the time of NGS was 1%. Forty-five % had an isolated mutation in a single gene, and 55% had co-mutations in ≥1 gene. The median number of mutations was 2 (range 1 - 5), occurring across 43 different genes. The most common mutations were in TET2 (N=28; 27%), ASXL1 (N=21; 20%), SRSF2 (N=21; 20%), U2AF1 (N=18; 17%), DNMT3A (N=16; 16%), and TP53 (N=12; 12%). Additionally, 25% of patients had an abnormal karyotype. Hematologic and genetic characteristics are summarized in (Table 1A). The median IPSS-M score was -0.9 (-3 to +2.34) and the median IPSS- Revised (R) score was 2 (0 - 6). The majority of patients had low (L) IPSS-M risk category (53%), followed by moderate low (ML) (19%) and very low (VL) (17%). Per IPSS-R, the majority had low-risk category (47%), followed by VL (38%) and intermediate (14%). Overall, 26 (25%) pt died after a median follow-up of 34 months and 21% progressed to MN (MDS 14 &amp; CMML 8), and 1 patient with MDS and 1 with CMML progressed to secondary AML (2%). The median overall survival (mOS) was not reached, with a 2-year estimated (YE) OS and leukemia-free survival (LFS) of 80%. Predictive Power: When utilizing the IPSS-M risk category ( L, M, H) * by combining the risk categories into L *(L+VL), M * (ML+MH), and H *(H+VH) to overcome the low sample size limitation, it significantly predicted OS (p &amp;lt; .0001) ( Figure 1A) and median MN-free survival (FS) (p &amp;lt; .0001) ( Figure 1B). The 2YE-OS rates by IPSS-M risk category were as follows: VL - 93%, L - 87%, ML - 75%, high (H) - 25%, very high (VH) - 0% and the 2YE-OS rates by IPSS-M ( L, M, H) are summarized in Table 1B. IPSS-M hazard ratio (HR) for OS was 1.6 for ( M*) compared to 25 for ( H *) risk category (p &amp;lt; .0001). The ( L *) category, being the largest, was used as the reference level. Conclusion: This study provides the first real-world experience of using the IPSS-M and a modified version of the IPSS-M ( L, M, H) * risk category model to predict survival and progression into MN in CCUS (MUT) pt. The IPSS-M risk category was found to be a significant predictor of OS and MN-free survival. We propose that larger cohorts are needed to validate our findings.

An interview with Jared Rutter.

Jared Rutter's group studies the mechanisms by which cells sense their metabolic environment and integrate these signals to influence cell behaviors. Jared completed his PhD at the University of Texas Southwestern Medical Center, USA, where he stayed on to begin his independent research career as the first Sara and Frank McKnight Independent Fellow. He established his own lab at the University of Utah, USA, where he is now Distinguished Professor of Biochemistry and an HHMI Investigator. Jared is a Guest Editor for Development's special issue on Metabolic and Nutritional Control of Development and Regeneration. We caught up with him to find out more about his research, his experiences with translating this work to the clinic and the importance of placing metabolism research in the broader biological context.

SAT265 Stearoyl CoA Desaturase Knockdown Increases Saturated And Monounsaturated Fatty Acid Concentrations In SDHB KD Cells But Not In hPheo1 Wild-type Progenitor Cells

Abstract Disclosure: H.K. Ghayee: Other; Self; Royalties form the University of Texas Southwestern Medical Center. N. Bala: None. Y. Xu: None. S.G. Tevosian: None. M. Kozuch: None. N.D. Denslow: None. A.A. Alli: None. Introduction: Pheochromocytoma and paraganglioma (PPGL) patients with mutations in the succinate dehydrogenase B subunit (SDHB) frequently develop metastatic lesions and have a poor prognosis. The stearoyl-CoA desaturase 1 (SCD1) protein plays an important role in lipid metabolism. SCD1 inhibitors have shown great potential as new treatments for various diseases including cancer. Hypothesis: siRNA mediated knockdown of SCD1 compared to non-targeting siRNA would result in differences in the concentrations of saturated fatty acids and monounsaturated fatty acids in SDHB KD cells compared to hPheo1 wild-type (WT) progenitor cells. Methods: Fatty acid concentrations were assessed by fatty acid methyl ester (FAME) analysis. SCD1 expression was assessed by quantitative polymerase chain reaction (qPCR) and Western blotting analysis. Results: Analyses showed a significant decrease in SCD1 in SDHB KD cells compared to hPheo1 WT cells. Fatty acid methyl ester analysis showed the concentrations of the saturated fatty acids myristic acid, palmitic acid, and stearic acid, and the monounsaturated fatty acids palmitoleic acid and oleic acid are increased at least 2-fold in SDHB KD cells transfected with SCD1 siRNA compared to non-targeting siRNA. Conclusions: Fatty acid changes noted in hPheo1 SDHB KD cells were not seen in hPheo1 WT cells after siRNA mediated knockdown of SCD1. This suggests that SDHB deficiency and loss of FADH2 production interacts specifically with lipid desaturation pathways. Presentation: Saturday, June 17, 2023

Judge rules against former employee

Case name: Baker v. University of Texas Southwestern Medical Center, No. 3:19‐CV‐3020 (N.D. Tex. 06/27/23).