Digital Commons Network^™

Pharmacodynamics, Efficacy, And Safety Of Intraputaminal Eladocagene Exuparvovec Administered To Pediatric Patients With Aromatic L-Amino Acid Decarboxylase Deficiency Using An Mr-Compatible Cannula: 48 Weeks Of Follow-Up, Daniel J Curry, Phillip L Pearl, Scellig S D Stone, Donald L Gilbert, Sudhakar Vadivelu, Bruria Ben-Zeev, Matthew Vestal, Muhammad Zafar, Chun-Hwei Tai, Sheng-Che Chou, Zion Zibly, Lior Ungar, Mered Parnes, Mariam Hull, Lisa Emrick, Christian Werner, Alexis Krolick, Vinay Penematsa, Antonia Wang, Rezwanur Rahman, Lee Golden, Yin-Hsiu Chien, Paul Wuh-Liang Hwu

Faculty, Staff and Students Publications

Aromatic ʟ‐amino acid decarboxylase (AADC) deficiency is a rare pediatric neurotransmitter disorder that typically necessitates lifelong care, and that carries a risk of childhood mortality. Eladocagene exuparvovec gene therapy is designed to restore AADC production. Study GT‐002 (NCT04903288) is a phase 2, multicenter, open‐label trial assessing the pharmacodynamics, safety, and efficacy of eladocagene exuparvovec administered to the putamen bilaterally in pediatric patients with AADC deficiency using a magnetic resonance (MR)‐compatible cannula. Patients received eladocagene exuparvovec at 1.8 × 1011 vector genomes via the SmartFlow MR‐compatible cannula in a single operative session. Endpoints include the change from baseline in …

How Does Frailty Impact Peri-Operative And Speech Recognition Outcomes For Cochlear Implants In Veterans?, Kaitlyn A Brooks, Benjamin D Lovin, Alex D Sweeney, Angela S Peng, Nathan R Lindquist

Faculty, Staff and Students Publications

Objective: To investigate the association of frailty with post-cochlear implant (CI) admission, morbidity, and CI-aided word recognition outcomes in veterans.

Study design: Retrospective cohort.

Setting: Single-institution tertiary care Veterans Health Administration (VHA) hospital.

Methods: Veterans who underwent cochlear implantation between 1998 to 2024 were included. The Modified 5-Item Frailty Index (mFI-5) score was used to characterize preoperative frailty. Outcomes of interest were admission from post-anesthesia care unit (PACU), relative risk (RR) of admission among frail patients, and relationship between frailty and post-CI word recognition score (WRS). Ordinal data were analyzed via logistic regression and Chi square tests; a multivariate linear …

Lean On Me: Social Factors And Diabetes Outcomes Among Young Adults With Type 1 Diabetes Prior To Transitioning To Adult Care, Caroline M Roberts, Samantha A Carreon, Charles G Minard, Sarah K Lyons, Randi Streisand, Barbara J Anderson, Tricia S Tang, Siripoom Mckay, Katherine Gallagher, Sridevi Devaraj, Marisa E Hilliard

Faculty, Staff and Students Publications

Aims: Little is known about how different aspects of social relationships relate to diabetes self-management and glycaemic outcomes in young adults with type 1 diabetes (T1D). We examined relationships of general and diabetes-specific social variables with diabetes self-management and HbA1c. We hypothesized diabetes-specific factors would more strongly associate with self-management and HbA1c than general social factors.

Methods: We analysed baseline data from 100 young adults with T1D (Mage = 19.9 ± 1.3 years) enrolled in a randomized controlled trial of a paediatric to adult care transition intervention. We examined associations of self-reported general and diabetes-specific social factors with self-reported self-management …

Toward Scientific Rigor: Setting Standards For Indirect Calorimetry Analysis And Reporting, Elizabeth L Lieu, Mark A Herman, Sean M Hartig

Faculty, Staff and Students Publications

Indirect calorimetry determines energy expenditure by measuring respiratory gas exchange. The approach is based on the principle that nutrient metabolism consumes O2 and produces CO2 and water in predictable ratios that can be compared with heat production. Due to the impracticality and high cost of direct calorimetry, indirect calorimetry is the major approach for modern metabolic studies in preclinical models. Despite the broad adoption of this method in rodent phenotyping, the field has lacked standardized methods for analyzing, representing, and sharing these data, limiting scientific progress. The recent review in Nature Metabolism by the International Indirect Calorimetry Consensus Committee (IICCC) …

Comparing Observed With Self-Reported Hand Hygiene Adherence Among Bedside Nurses And Physicians At Two Hospitals In The United States, Prathit A Kulkarni, M Todd Greene, Sanjay Saint, Karen E Fowler, Serene Jacob, Laura Dillon, Michelle Espiritu, Nathan Houchens, Huberta T Cozart, Barbara W Trautner

Faculty, Staff and Students Publications

Background: Hand hygiene is a core component of infection prevention in healthcare settings. One potential reason for lack of adherence to recommended hand hygiene practices is erroneous self-perception. We aimed to compare perceptions about hand hygiene compliance with objective data.

Methods: Direct observations of hand hygiene performance by nurses and physicians during typical workflow in inpatient general medicine wards were conducted from 12 September 2022 to 27 October 2022 at two academic Veterans Affairs medical centers. Participants were surveyed regarding perceptions about their hand hygiene performance relative to recommended practices.

Results: Among nurses, hand hygiene was performed in 1,397/3,690 (37.9%) …

Interpretable Ensemble Machine Learning Prediction Of Nonadherence And The Risk Of Nonpersistence Of Targeted Disease-Modifying Antirheumatic Agents In Older Adults With Rheumatoid Arthritis, Yinan Huang, Sandeep K Agarwal

Faculty, Staff and Students Publications

Purpose: Ensemble machine learning (ML) demonstrated potential for improving predictions based on big health care data. We developed and validated interpretable ensemble ML models in evaluating the nonadherence and nonpersistence of biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in rheumatoid arthritis (RA).

Methods: This retrospective study used 5% Medicare claims data including older (aged ≥65 years) patients initiating b/tsDMARDs (the index date) between 2013 and 2019, who were diagnosed with RA (the International Classification of Diseases, Ninth and Tenth revision codes). Nonadherence, defined as medication possession ratio < 80%, was evaluated during the 12-month follow-up. Nonpersistence was defined as duration (in days) from the index date until treatment gap ≥60 days during the follow-up period, with death and insurance disenrollment as censoring criteria. Data were split into 75% for model training and 25% for evaluation, with patients' demographics and clinical characteristics measured in the baseline period. Machine learning ensemble classification models (random forest, eXtreme Gradient Boosting [XGBoost], and prediction rule ensembles [PRE]) evaluated the binary nonadherence outcome and ML ensemble survival models (random survival forest, XGBoost survival, and PRE survival) assessed time until nonpersistence. Using the testing cohort, concordance index (C-index) was reported for the ML survival models and AUC was reported for ML classification models.

Findings: We identified 3927 eligible patients with RA (mean age 73 ± …

Predictive Validity Of The Obsessive-Compulsive Inventory-4 And Florida Obsessive-Compulsive Inventory-Ii Severity Scale, Eric A Storch, Ryan J Mccarty, Maya Zehavi, Mahnoor Ahmad, Vanessa Zavala Cruz, Dayan Berrones, Josselyn S Muñoz, Diana Obando, Servando Rodriguez Barajas, Renee M Frederick, Jacey L Anderberg, Hannah C Moore, Marcos E Ochoa-Panaifo, Mayra C Martinez Mallen, Ogechi C Onyeka, Andrew D Wiese, Melisa N Sagarnaga, Joseph F Mcguire, Ygor Arzeno Ferrão, Latin American Trans-Ancestry Initiative For Ocd Genomics (Latino), Wayne K Goodman, James J Crowley, Brazilian Obsessive-Compulsive Spectrum Disorder Working Group (Gttoc)

Faculty, Staff and Students Publications

Efficient and accurate screening tools are crucial for improving early identification and treatment outcomes among individuals with obsessive-compulsive disorder (OCD). This study evaluated the sensitivity and specificity of two OCD screening measures: the Obsessive-Compulsive Inventory-4 (OCI-4) and the Florida Obsessive-Compulsive Inventory-II (FOCI-II) severity scale. The measures were administered in a large transnational sample of Spanish speaking Latin American adults (N = 1696) with elevated obsessive-compulsive symptomatology. Participants completed diagnostic interviews (MINI and Y-BOCS) and self-report assessments across 23 sites in 11 countries. Both measures significantly distinguished OCD from non-OCD cases, with the FOCI-II demonstrating somewhat better predictive performance (AUC = …

The Diagnostic Performance Of The Basic Versus The Detailed Telomere Flow Fish Test In Young Patients With Aplastic Anaemia, Nicholas F Decleene, Duc T Nguyen, Susan E Kirk, Hannah L Helber, Ghadir S Sasa, Alison A Bertuch

Faculty, Staff and Students Publications

Identifying telomere biology disorders (TBDs) in patients with aplastic anaemia (AA) is essential for guiding appropriate care. Telomere length (TL) measurement by flow cytometry with fluorescence in situ hybridization supports diagnosis, but the real-world performance of the basic test (lymphocytes and granulocytes) versus the detailed test (which includes four lymphocyte subsets) remains unclear. We retrospectively reviewed 439 patients who underwent detailed TL testing at our institution from 2008 to 2022. Haematological disease was present in 87%, with AA comprising 56%. We classified 23 subjects with TBD independently of TL, only one of whom had severe AA (SAA) at initial presentation. …

Clinical Outcomes Following Stereotactic Mri-Guided Laser Ablation In Children With Tuberous Sclerosis Complex And Intractable Epilepsy, Chelsey Ortman, Rohini Coorg, Irfan Ali, Dave Clarke, Gloria Diaz-Medina, Kimberly Houck, Akshat Katyayan, Laura Masters, Deepankar Mohanty, Anuranjita Nayak, Michael Quach, Vijay M Ravindra, James J Riviello, Sonali Sen, Elaine Seto, Danielle Takacs, Cristina Trandafir, John T Freiling, Karen Evankovich, Yingchao Yuan, Kalman A Katlowitz, Daniel Curry, Howard L Weiner, Anne Anderson

Faculty, Staff and Students Publications

Objective: In children with tuberous sclerosis complex (TSC) and drug-resistant epilepsy (DRE), magnetic resonance imaging-guided stereotactic laser ablation (SLA) therapy offers less-invasive treatment compared to craniotomy and resection. Our study seeks to further expand on the long-term outcomes in patients with TSC-related DRE who have undergone SLA.

Methods: Patients with TSC and DRE treated with SLA, between July 1, 2016 and January 1, 2022, at our institution were identified retrospectively. Reduction in number of anti-seizure medications (ASMs), developmental improvement as reported by the patients' families, seizure frequency measured in surgically targeted seizure type and total seizures per day, and Engel …

Defining The Society Of Pediatric Liver Transplantation (Split) Research Agenda: A Delphi Consensus Project, Sharad I Wadhwani, Pooja Reddy Spector, Amy G Feldman, Katryn N Furuya, Kayla Hartjes, Chaowapong Jarasvaraparn, Beau Kelly, Stacee M Lerret, Krupa Mysore, Arti Pawaria, Philip Rosenthal, Amy Shui, Voytek Slowik, Sarah Taylor, Jennifer Vittorio, Pamela L Valentino

Faculty, Staff and Students Publications

Background: Despite major advances in surgical and medical management, only one-third of pediatric liver transplant (LT) recipients remain morbidity-free at 10 years. The Society of Pediatric Liver Transplantation (SPLIT) published a research agenda over 10 years ago, and much progress has been made since then. An updated consensus-driven SPLIT research agenda could guide future research and funding priorities. We aimed to identify and prioritize key research needs across the continuum of pediatric LT care using a modified Delphi consensus approach.

Methods: We conducted a three-round modified Delphi process among SPLIT members. In round 1, participants submitted open-ended research priorities. In …

Segmental And Multifocal Isolated Dystonias: Similarities And Differences, Hyder A Jinnah, Vittorio Velucci, Daniele Belvisi, Gamze Kilic-Berkmen, Joel S Perlmutter, Laura J Wright, Christine Klein, Jeanne S Feuerstein, Steven Bellows, Joseph Jankovic, Cynthia Comella, Richard L Barbano, Aparna Wagle Shukla, Stephen G Reich, Mark S Ledoux, Alberto J Espay, Kevin R Duque, Florence C F Chang, Victor S C Fung, Sarah Pirio-Richardson, Carmen Terranova, Emile S Moukheiber, Sarah Idrissi, Barbara Vitucci, Susan H Fox, Samuel Frank, Natividad Stover, Brian D Berman, Rachel Saunders-Pullman, William G Ondo, Christopher L Groth, Marcello Esposito, Laura Avanzino, Francesco Bono, Roberto Erro, Marcello Mario Mascia, Antonella Muroni, Alfredo Berardelli, Giovanni Defazio

Faculty, Staff and Students Publications

Background: Whether the traditional distinction between segmental and multifocal dystonia is clinically or scientifically useful remains unclear.

Objective: To evaluate whether idiopathic isolated adult-onset segmental and multifocal dystonia can be differentiated based on clinical features other than the contiguity of affected body regions.

Methods: We compared data on segmental and multifocal dystonia from two large dystonia databases established in the USA and Italy that used similar criteria for patient recruitment and assessment.

Results: Compared to segmental dystonia, multifocal dystonia was characterized by a higher proportion of men, a younger age at dystonia onset, a greater frequency of upper limb dystonia, …

Linkage Disequilibrium Score Regression Identifies Genetic Correlations Between Hepatocellular Carcinoma And Clinically Relevant Traits, Younghun Han, Vikram R Shaw, Jinyoung Byun, Aaron P Thrift, Catherine Zhu, Donghui Li, Rikita I Hatia, Robin Kate Kelley, Sean P Cleary, Anna S Lok, Paige M Bracci, Jennifer B Permuth, Roxana Bucur, Jennifer Knox, Jian-Min Yuan, Amit G Singal, Prasun K Jalal, R Mark Ghobrial, Yuko Kono, Dimpy P Shah, Mindie H Nguyen, Neehar D Parikh, Richard Kim, Hui-Chen Wu, Hashem El-Serag, Ping Chang, Yun Shin Chun, Jian Gu, Chad Huff, Asif Rashid, Lu-Yu Hwang, Alison P Klein, Saira A Khaderi, Ahmed O Kaseb, Kathrine A Mcglynn, Lewis R Roberts, Manal M Hassan, Christopher I Amos

Faculty, Staff and Students Publications

Hepatocellular carcinoma (HCC) mortality is increasing globally, partly due to the growing prevalence of nonviral liver diseases. Genome-wide association studies (GWAS) have identified genetic variants associated with HCC development. Leveraging GWAS summary statistics and linkage disequilibrium score regression (LDSR), we investigated disease co-development with hepatitis C virus-negative (HCV-negative) HCC to provide unique insights into HCC etiology and prioritize relationships for further causal inquiry. We utilized the LDSR statistical framework to estimate the genetic correlation and heritability between HCV-negative HCC with 901 epidemiologic, behavioral, and clinical traits from the United Kingdom Biobank (UKBB). First, we set the threshold for observed scale …

Responsive Neurostimulation In Children, Adolescents, And Young Adults-Longitudinal Effectiveness And Safety, Steven T Lee, Shital Patel, Cemal Karakas, Kimberly Houck, Cristina Trandafir, Matthew J Mcginley, Deepankar Mohanty, James J Riviello, Howard L Weiner, Daniel Curry, Irfan Ali

Faculty, Staff and Students Publications

Drug-resistant epilepsy (DRE) remains challenging to treat, and seizure control often fluctuates over time. Responsive neurostimulation (RNS) is increasingly used in pediatric and young adult populations, yet long-term effectiveness and safety data are limited. We evaluated longitudinal seizure control trajectories and safety of RNS in children, adolescents, and young adults treated at our center. Seizure frequency was assessed at approximately 6-month intervals from serial follow-up visits through the most recent follow-up, with each sampled visit categorized by ≥ 50 % (all-responder, AR) or ≥90 % (super-responder, SR) seizure reduction. We examined the persistence and durability of seizure control and used …

Proteomic Signatures Of Cardiac Dysfunction Among People With Diabetes: The Atherosclerosis Risk In Communities Study, Justin B Echouffo-Tcheugui, Chiadi E Ndumele, Jingsha Chen, Mary R Rooney, Keenan A Walker, Pascal Schlosser, Kuni Matsushita, Morgan E Grams, Christie C Ballantyne, Ron C Hoogeveen, Eric Boerwinkle, Bing Yu, Amil M Shah, Ruth F Dubin, Rajat Deo, Yue Ren, Jerome I Rotter, Kent D Taylor, Wendy S Post, Peter Ganz, Elizabeth Selvin, Josef Coresh

Faculty, Staff and Students Publications

Background: To investigate the proteomic signatures of heart failure (HF) in diabetes. The underlying mechanisms of the elevated risk of HF in diabetes are unknown.

Methods: In 10 189 ARIC study (Atherosclerosis Risk in Communities) participants free of HF (mean age 57±7 years, 56% women, 22% Black adults, 14% with diabetes), we conducted discovery and internal validation for the associations of 4955 plasma proteins with HF by diabetes status. We performed (1) Cox regression to identify proteins associated with HF by diabetes status, (2) external validation in the MESA study (Multi-Ethnic Study of Atherosclerosis, n=5233, 633 with diabetes), and (3) …

Segmental Tracheal Resection For Thyroid Cancer: Perioperative Morbidity, Locoregional Control, And Survival, Anastasios Maniakas, David C Wilde, Isabelle Fournier, Emily K Hyde, Li Xu, Jennifer R Wang, Neil D Gross, Erich M Sturgis, Victoria Banuchi, Naifa L Busaidy, Maria E Cabanillas, Priyanka Iyer, Ramona Dadu, Steven G Waguespack, Mimi I Hu, G Brandon Gunn, Michael Kwon, Salmaan Ahmed, Michelle D Williams, Mark E Zafereo

Faculty, Staff and Student Publications

Background: Segmental tracheal resection is rarely needed for advanced thyroid cancer but is among the most complex, high-risk thyroid surgeries.

Methods: Retrospective study of patients undergoing segmental tracheal resection for thyroid cancer at MD Anderson Cancer Center (2005-2024).

Results: We identified 120 patients with a median follow-up of 4.6 years (range 0.02-16.38). Papillary thyroid cancer was most common (68%). The median number of tracheal rings resected was 4 (range 1-9). Seventeen (14%) patients had a new tracheostomy placed at the time of surgery, with 11 (9%) remaining trach-dependent at last follow-up. Twenty-six (22%) patients had a return to the operating …

Aav Gene Therapy For Mps Iva With Induction Of Immune Tolerance Via Oral Administration Of Epitope Peptides Of N-Acetylgalactosamine-6-Sulfate Sulfatase, Sampurna Saikia, Yasuhiko Ago, Fnu Nidhi, Shaukat Khan, Zhengyu Ma, Shunji Tomatsu

Department of Pediatrics Faculty Papers

Mucopolysaccharidosis IVA (MPS IVA) is caused by the accumulation of undegraded glycosaminoglycans due to the deficiency of the N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme. MPS IVA manifests as progressive systemic skeletal dysplasia. Gene therapy (GT) is potentially a one-time treatment in which the enzyme is continuously produced, circulated, and delivered to target tissues. However, immune responses to gene products can diminish therapeutic efficacy. We hypothesized that oral delivery of tolerogenic peptides induces immune tolerance to human GALNS (hGALNS) in MPS IVA mice, enhancing therapeutic efficacy. Neonatal mice deficient in mouse GALNS (mGALNS) were treated orally with three T-cell/B-cell epitope peptides or hGALNS …

In Vitro Studies Of The Effects Of Antithrombotic Zn-Dipicolylamine-Harboring Liposomes (Dpals) On Serum Albumin And Human Umbilical Vein Endothelial Cells, Michelle Tanujaya, Gianna Cai, Jia Patel, Zana Moldavsky, Yumna Ejaz, Malia Mahazabin Ahmed, Sangsang Duong, Lawrence E. Goldfinger, Koon Y. Pak, Brian D. Gray, Parkson Lee-Gau Chong

Cardeza Foundation for Hematologic Research

Thrombosis remains a leading cause of cardiovascular morbidity and mortality. During thrombosis, activated platelets and endothelial cells expose phosphatidylserine (PS) on their outer membranes, creating a surface that accelerates clot formation. Current antithrombotic therapies, such as heparin and warfarin, carry significant bleeding risks, highlighting the need for safer alternatives. In response, we developed a PS-targeting liposomal formulation composed of Zn-dipicolylamine (DPA)-cyanine-3[22,22] and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (molar ratio 3:97). This DPA-harboring liposome (DPAL) binds selectively to PS-rich surfaces such as activated platelets and has demonstrated efficacy in reducing thrombosis in mouse models, with minimal bleeding. In the present study, we examined the interaction …

Alpha And Beta Emitters In Translational Nuclear Medicine: Clinical Advances, Challenges, And Future Direction, Hanieh Karimi, Thomas H. Shaffer, Erik Stauff, Vinay V. R. Kandula, Heidi H. Kecskemethy, Lauren W. Averill, Xuyi Yue

Department of Radiology Faculty Papers

Radiopharmaceutical therapy (RPT) has emerged as a transformative modality in oncology, particularly for patients with metastatic or inoperable tumors. By leveraging molecularly targeted carriers conjugated to cytotoxic radionuclides, RPT enables precise delivery of ionizing radiation to tumor sites while minimizing off-target effects. Central to this approach are alpha (α) and beta (β) particle-emitting radionuclides. This review aims to provide a comprehensive overview of all clinically relevant alpha and beta emitters and incorporates the most recent advances from 2017-2025, offering a comprehensive and up-to-date perspective. Alpha and beta emitters hold significant promises for the future, especially in nuclear medicine, energy, and …

Multi-Ancestry Genome-Wide Association Study And Meta-Analysis Of Lung Function Decline, Bonnie K Patchen, Jingwen Zhang, Nathan Gaddis, Traci M Bartz, Jing Chen, Catherine Debban, Hampton Leonard, Ngoc Quynh H Nguyen, Jungkyun Seo, Courtney Tern, Richard Allen, Dawn L Demeo, Myriam Fornage, Carl Melbourne, Melyssa Minto, Matthew Moll, George T O'Connor, Tess Pottinger, Bruce M Psaty, Stephen S Rich, Jerome I Rotter, Edwin K Silverman, Jeran Stratford, Chengyue Zhang, R Graham Barr, Michael H Cho, Sina A Gharib, Ani Manichaikul, Kari North, Elizabeth C Oelsner, Eleanor M Simonsick, Martin D Tobin, Bing Yu, Seung Hoan Choi, Josée Dupuis, Patricia A Cassano, Dana B Hancock

The Brown Foundation: Institute of Molecular Medicine

Background

Despite evidence for a genetic component, few genetic associations with lung function decline have been identified. We aimed to evaluate genome-wide associations and putative downstream functionality of genetic variants for lung function decline.

Methods

We conducted genome-wide association study (GWAS) analyses of decline in FEV1, FVC, and FEV1/FVC in 52,056 White (N = 44,988), Black (N = 5,788), Hispanic (N = 550), and Chinese American (N = 730) participants across seven general population cohorts. GWAS analyses were stratified by cohort, ancestry, and sex. Results were combined in cross-ancestry and ancestry-specific meta-analyses. Significant variants available in …

Profiling The Genomic Landscape And Evolutionary History Of Polyploid Giant Cancer Cells In Undifferentiated Pleomorphic Sarcomas, Amy L Bowes, Sara Waise, Tom Lesluyes, Thomas Butters, Christie English, Haixi Yan, Annelien Verfaillie, Christopher Davies, Jianan Chen, Emma Nye, Richard Stone, Jiten Manji, Adrienne M Flanagan, Jonas Demeulemeester, Maxime Tarabichi, Nischalan Pillay, Peter Van Loo

Faculty, Staff and Student Publications

Polyploid giant cancer cells (PGCCs), characterised by multinucleation and atypical nuclear morphology, are a common feature of undifferentiated pleomorphic sarcomas. While PGCCs may be a critical substrate for cancer evolution, their formation pathways and genomic consequences remain underexplored. In this study, we characterise PGCCs in ten pleomorphic sarcomas and use topographic single-cell DNA sequencing (scDNA-seq) to investigate their genomic landscape. We selected PGCCs based on their nuclear morphology, including mononucleated or multinucleated bizarre, misshapen nuclei, and analysed them at single-cell resolution. Histopathological analysis showed that PGCCs were often randomly distributed throughout the tumour and did not appear in clusters, suggesting …

Profiling The Genomic Landscape And Evolutionary History Of Polyploid Giant Cancer Cells In Undifferentiated Pleomorphic Sarcomas, Amy L Bowes, Sara Waise, Tom Lesluyes, Thomas Butters, Christie English, Haixi Yan, Annelien Verfaillie, Christopher Davies, Jianan Chen, Emma Nye, Richard Stone, Jiten Manji, Adrienne M Flanagan, Jonas Demeulemeester, Maxime Tarabichi, Nischalan Pillay, Peter Van Loo

Faculty, Staff and Student Publications

Polyploid giant cancer cells (PGCCs), characterised by multinucleation and atypical nuclear morphology, are a common feature of undifferentiated pleomorphic sarcomas. While PGCCs may be a critical substrate for cancer evolution, their formation pathways and genomic consequences remain underexplored. In this study, we characterise PGCCs in ten pleomorphic sarcomas and use topographic single-cell DNA sequencing (scDNA-seq) to investigate their genomic landscape. We selected PGCCs based on their nuclear morphology, including mononucleated or multinucleated bizarre, misshapen nuclei, and analysed them at single-cell resolution. Histopathological analysis showed that PGCCs were often randomly distributed throughout the tumour and did not appear in clusters, suggesting …

Aggregation Of Gene Regulatory Information And Knowledge On Fair Principles Enables Discovery Of Pathogenic Gene Regulatory Variants, Keyang Yu, Haoquan Zhao, Andrea S Wilderman, Tierra R Farris, Jessie E Arce, David Chen, Andrew R Jackson, Yiran Guo, Qi Li, Bosko Jevtic, Dubravka Jevtic, Vuk Milinovic, Yuankun Zhu, Jeremy Costanza, Eric D Wenger, Christopher Nemarich, Lisa Anderson, Aleksandar Mihajlović, Kristin Ardlie, Shaine A Morris, Matthew E Roth, Deanne M Taylor, Adam C Resnick, Lilei Zhang, Aleksandar Milosavljevic

Faculty, Staff and Students Publications

Motivation: Methods for sharing gene regulatory information and knowledge on FAIR principles, particularly in the context of tissue-specific gene regulation, remain poorly defined and implemented, hampering discovery and clinical genetic diagnosis.

Results: We specified FAIR principles for tissue-specific gene regulatory information and knowledge; implemented them by developing a registry of regulatory elements and aggregating FAIR gene regulatory information from several major sources; developed computational tools that utilize these FAIR resources; and demonstrated their utility by associating gene regulatory variants with major subtypes of congenital heart disease.

A Comparative Effectiveness Trial For Universal Psychosocial Screening With The Psychosocial Assessment Tool (Pat) Across 18 Childhood Cancer Programs In The United States: Adoption, Penetration, And Health Equity, Lamia P. Barakat, Michele A. Scialla, Nithyasri Ramaswamy, Janet A. Deatrick, Kamyar Arasteh, Eric Sandler, Shannon N. Hammer, Anne E. Kazak

Department of Pediatrics Faculty Papers

BACKGROUND: Universal, systematic psychosocial screening in childhood cancer assures care matched to need and achieves a Standard of Psychosocial Care. It is accomplished inconsistently due to barriers at the family, provider, and institution level, potentially contributing to disparities in care and outcomes. We conducted a comparative effectiveness trial of two implementation strategies of an established measure (Psychosocial Assessment Tool; PAT3.0) across 18 children's cancer programs to identify strategies that resulted in higher levels of screening in English and Spanish (penetration, health equity). We also examined uptake at the institution level (adoption).

METHODS: Sites were randomized to Strategy I (web-based training …

Hiv Infection, Neurotoxicity, Inflammation, Premature Aging, And Therapeutic Challenges To Plwh: An Overview, Mudit Tyagi, Ulhas P. Naik, Kratika Tyagi, Madhulika Sharma, Gagan Kaushal, Alok Bhushan, Michael Bukrinsky, Priya Tyagi

Department of Medicine Faculty Papers

HIV infection remains a major global health challenge due to its complex pathogenesis and lifelong persistence in people living with HIV (PLWH). A central barrier to eradication is the virus's ability to establish long-lived latent reservoirs in different tissues, including the central nervous system (CNS), where it evades immune clearance and antiretroviral therapy (ART). These reservoirs, seeded early during infection, fuel viral rebound if ART is interrupted, requiring lifelong treatment. In the CNS, HIV persists despite systemic viral suppression because of limited ART penetration across the blood-brain barrier (BBB), and infection of long-lived cells such as microglia and perivascular macrophages. …

Recognizing Structural And Social Determinants Of Health In The Diagnosis And Care Of Dementia, Shana D Stites, Sharnita Midgett, Nisha Patel, Kimberly Halberstadter, Rosalie Schumann, Marissa L Streitz, Yidan Shi, John C Morris, Jason Flatt, Crystal M Glover, Dawn Mechanic-Hamilton

2020-Current year OA Pubs

Structural and social determinants of health are environmental conditions that affect individuals' health and functioning across the life course. These determinants are salient factors at the apex of individual psychology, community variables, and larger sociological factors, exerting prominent effects on individuals' wellbeing. The National Institute on Aging seeks to understand their influence on aging and Alzheimer's disease. We propose that the benefits of doing so may reach beyond knowledge of disease mechanisms - it may also improve clinical outcomes. We describe efforts introducing structural and social determinants of health data into the national network of Alzheimer's disease research centers. We …

Supporting Evidence-Based Responses To Emotional Needs In Emphysema (Serene): Protocol For A Randomized, Open-Label Mechanistic Trial Comparing Coping Skills Training And Disease-Specific Education For Depressive Symptoms Conducted In United States Health Systems, Joanna L. Hart, Daniel Carter, Chloe Hinton, James Grilli, Lily A. Brown, Nora Brier, Yingying Lu, Casey Whitman, Michael O. Harhay, Michael Sims, Carmen Alvarez, Lisa R. Miller-Matero, C. Virginia O'Hayer

Department of Psychiatry and Human Behavior Faculty Papers

BACKGROUND: Depressive symptoms and anxiety are highly prevalent among people with chronic obstructive pulmonary disease (COPD), strongly associated with poor outcomes, and rarely recognized or treated. Integrating families into interventions may amplify supportive care treatment effects and overcome common challenges, yet this strategy is understudied. The Supporting Evidence-based Responses to Emotional Needs in Emphysema (SERENE) trial's main objective is to identify the mechanisms through which a family-partnered Coping Skills Training (CST) reduces depressive symptoms among patients with COPD, testing five putative mechanisms: family relationship quality, patient and caregiver self-efficacy, patient loneliness, and caregiver psychological distress.

METHODS: SERENE will enroll 375 …

The Path Forward For T Cell Engagers In Patients With Prostate Cancer, Sumit K. Subudhi, Bilal A. Siddiqui, Kevin K. Zarrabi, William K. Kelly, Charles G. Drake

Department of Medical Oncology Faculty Papers

T cell engagers (TCEs) recruit T cells to the tumor microenvironment (TME) to induce antitumor immune responses. TCEs have demonstrated promising clinical responses in patients with metastatic castration-resistant prostate cancer and have advanced into phase 3 clinical trials. Here we provide an overview of the mechanisms of action of TCEs, including both CD3-targeted and CD28-targeted agents, and review the clinical development of these agents for prostate cancer. We propose a path forward for TCEs in prostate cancer, in which innovative clinical trials will facilitate a biological understanding of mechanisms of efficacy and toxicity to inform: (1) development of predictive biomarkers …

Concordance Analysis Of Dna And Rna Profiling: The Md Anderson Impact2 Study In Precision Oncology, Stephanie T Schmidt, Mehmet A Baysal, Siqing Fu, David S Hong, Sarina A Piha-Paul, Aung Naing, Jordi Rodon Ahnert, Timothy A Yap, Ecaterina Elena Dumbrava, Jennifer Beck, Funda Meric-Bernstam, Apostolia Maria Tsimberidou

Faculty, Staff and Student Publications

DNA profiling is an established method for cancer treatment selection, while RNA profiling remains investigational. We explored associations between DNA and RNA alterations and between the number of genes with altered expression and overall survival (OS) using patient data from IMPACT2 (NCT02152254), a randomized study evaluating molecular profiling for guiding cancer therapy across tumor types. Molecular profiling, including DNA next-generation sequencing, was performed on all 829 patients in the IMPACT2 study. RNA profiling was performed by Tempus for 253 of 829 patients. We evaluated the concordance between DNA and RNA profiling, analyzed OS in 217 treated patients with …

Risk Stratification Of Low-Dose Cytarabine And Venetoclax In Patients With Aml Ineligible For Intensive Chemotherapy, Andrew H Wei, Panayiotis Panayiotidis, Pau Montesinos, Kamel Laribi, Vladimir Ivanov, Inho Kim, Jan Novak, Rebecca Champion, Walter Fiedler, Maria Pagoni, Julie Bergeron, Stephen B Ting, Jing-Zhou Hou, Takahiro Yamauchi, Jianxiang Wang, Stephen A Strickland, Michael R Savona, Tara L Lin, Anoop Enjeti, Ing Soo Tiong, Sangmin Lee, Gail J Roboz, Relja Popovic, Qi Jiang, Zihuan Liu, Yan Sun, Wellington Mendes, Brenda Chyla, Courtney D Dinardo

Faculty, Staff and Student Publications

Prognostic risk categorization aids treatment selection for patients with acute myeloid leukemia (AML). Although the European LeukemiaNet (ELN) classifications (2017 and 2022) for AML have been used to stratify outcomes for patients receiving intensive chemotherapy, their application to patients receiving less intensive therapy, such as azacitidine plus venetoclax, has been less satisfactory. In response, a 4-gene classifier that stratifies older patients with AML unfit for intensive chemotherapy into those with higher benefit (wild type), intermediate benefit (FLT3-internal tandem duplication [ITD] or NRAS/KRAS mutation), or lower benefit (TP53 mutation) after azacitidine plus venetoclax treatment was developed. We hypothesized that this 4-gene …

Novel Csf Biomarkers For Facilitating Diagnosis Of Cns-Hlh From Other Neuroinflammatory Disorders, Sharat Chandra, Kenneth D Greis, Somchai Chutipongtanate, Nathan Luebbering, Aaron Webster, Kelsey E Poisson, Kristen S Fisher, Kristi Smiley, Rebecca A Marsh, Michael B Jordan, Stella M Davies

Faculty, Staff and Students Publications

Central nervous system (CNS)-hemophagocytic lymphohistiocytosis (HLH) can mimic other neuroinflammatory disorders (ONID), often leading to misdiagnosis. Current diagnostic studies do not reliably distinguish CNS-HLH from ONID. We hypothesized that novel cerebrospinal fluid (CSF) biomarkers identified using unbiased proteomic analysis can facilitate diagnosis of CNS-HLH from ONID. Banked CSF samples were categorized into 3 groups, CNS-HLH, ONID, and controls without CNS inflammation. Proteomic analysis was performed on 25 samples per group (total N = 75). Proteins demonstrating significant changes (>1.5-fold higher and P< .05) in the CNS-HLH compared with ONID and associated with HLH pathophysiology were selected as candidate biomarkers. Cross-platform validation of candidate biomarkers, along with known biomarkers CXCL9 and osteopontin, was performed using enzyme-linked immunosorbent assay (ELISA). One hundred twenty-two proteins were identified on CSF proteomic analysis at 99% confidence. Of these, 10 proteins demonstrated a >1.5-fold change with a P< .05 in CNS-HLH compared with ONID. SerpinG1, lysozyme, and CD14 were selected as candidate biomarkers. ELISA confirmed significant elevation of all 5 biomarkers in CNS-HLH relative to ONID. Median SerpinG1 levels were1242.9 ng/mL in CNS-HLH vs 292.2 ng/mL in ONID (P ≤ .001), lysozyme 222.2 ng/mL vs 65.6 ng/mL (P = .001), and CD14 180.3 ng/mL vs 64.5 ng/mL (P ≤ .001). Median CXCL9 levels were 223.7 ng/mL in CNS-HLH vs 15.5 ng/mL in ONID (P ≤ .001), and osteopontin levels were 356.5 ng/mL vs 92.9 ng/mL (P = .001). These findings demonstrate that novel CSF biomarkers SerpinG1, lysozyme, CD14, and CXCL9 can facilitate diagnosis of CNS-HLH from ONID.