Digital Commons Network^™

Identification Of A Cytokine Biomarker For Prognostic Modeling Of Breast Cancer-Related Lymphedema, Alison J Wu, Neil Lin, Jie Su, Cherie Lin, Madison-Shira Hossack, Wei Shi, Farnoosh Abbas-Aghababazadeh, Wei Xu, Benjamin Haibe-Kains, Simona F Shaitelman, Melissa B Aldrich, Fei-Fei Liu, Jennifer Y Y Kwan

Faculty, Staff and Student Publications

Lymphedema is a chronic complication of breast cancer treatment, and early intervention is crucial to reduce morbidity. This study evaluated the role of blood-based cytokine biomarkers in the prognostication of breast cancer-related lymphedema (BCRL) to improve risk prediction. A secondary analysis of inflammatory biomarkers for BCRL was performed using a previously published cohort of 147 breast cancer patients who had undergone serum cytokine profiling during their treatment at the Princess Margaret Cancer Centre from 2010-2014. Prognostic cytokine variables for lymphedema were selected by regression analysis and independence from known clinical risk factors. Regression-based modeling was employed to integrate prognostic variables …

Endothelial Oncogenic Kras Mutation Drives The Dynamics Of Microglia And Macrophages In Brain Arteriovenous Malformation, Hyejin Park, Jung-Eun Park, Bridger H Freeman, Bosco Seong Kyu Yang, Shun-Ming Ting, Alexander K Suh, Jude Pj Savarraj, Shuning Huang, Jakob Körbelin, Huimahn Alex Choi, Sean P Marrelli, Jaroslaw Aronowski, Peng Roc Chen, Eunhee Kim, Eun S Park

Faculty, Staff and Student Publications

Mutation of KRAS in endothelial cells (KRAS-EC) leads to intracerebral hemorrhage (ICH) in brain arteriovenous malformations (bAVM), resulting in severe disabilities or even death. However, it is unclear what causes this hemorrhagic conversion of bAVM. Here, using a locally established, clinically-relevant sporadic bAVM mouse model, created by overexpressing mutant KRAS (KRASG12V) in the brain EC, we demonstrate that KRAS-EC act as trigger for microglia (MG) activation and infiltration of macrophages (Mϕ). Using three-dimensional immunostaining approach with cleared human and mouse bAVM tissues, we demonstrate an abundance of MG/Mϕ around the bAVM nidus. The presence of MG/Mϕ are correlated to the …

Bi-Allelic Variants In Neuronal Adhesion Molecule Astrotactin 1 Gene Astn1 Cause Diverse Neurodevelopmental Disorders, Jesse M Levine, Daniel G Calame, Riccardo Sangermano, Haowei Du, Ahmed Saad, Jasmin Lisfeld, Tatjana Bierhals, Jonas Denecke, Eyyup Uctepe, Merve Yoldas Celik, Ahmet Yesilyurt, Hilal Yildiz Er, Elif Yilmaz Gulec, Aziza Mushiba, Naif Almontashiri, Pawel Gawlinski, Wojciech Wiszniewski, Ender Karaca, Lama Alabdi, Davut Pehlivan, Dana Marafi, Maha S Zaki, Fowzan S Alkuraya, Joseph G Gleeson, Shalini N Jhangiani, Richard A Gibbs, Jennifer E Posey, Kinga M Bujakowska, James R Lupski

Faculty, Staff and Students Publications

ASTN1 encodes astrotactin 1, a neuronal-glial ligand in the developing brain that promotes neuronal migration along radial glia in brain structures with laminar organization, such as the cerebral cortex, hippocampus, and cerebellum. In mouse models, disruption of Astn1 results in neuronal migration deficits, a mild reduction in cerebellar volume, and balance and coordination deficits. In humans, bi-allelic ASTN1 variants have been identified in nine individuals with neurodevelopmental disorders (NDDs) with or without brain malformations. ASTN1 additionally interacts with astrotactin 2 (ASTN2) to implement neuronal migration; ASTN2 deletions associate with NDDs with reduced penetrance. Here, we describe eighteen individuals with NDDs …

Multiparent Recombinant Inbred Lines Crossed To A Tester Provide Novel Insights Into Sources Of Cis And Trans Regulation Of Gene Expression, Fabio Marroni, Alison M Morse, Adalena V Nanni, Nadja Nolte, Patricka Williams-Simon, Luis G León-Novelo, Rita M Graze, Paul Schmidt, Elizabeth King, Lauren M Mcintyre

Faculty, Staff and Student Publications

To understand the relative importance of cis and trans effects on regulation, we crossed multi-parent recombinant-inbred lines (RILs) to a common tester and measured allele-specific gene expression in the offspring. Testing the difference of allelic imbalance between two RIL × Tester crosses is a test of cis or trans, depending on the RIL alleles compared. The study design also enables to separation of two sources of trans variation, genetic and environmental, detected via interactions with cis effects. We demonstrate the effectiveness of this approach in a long-read RNA-seq experiment in female abdominal tissue at two time points in Drosophila melanogaster. …

Ubiquitination Of Oncogenic Mutant P53 Via Attenuation Of Ribosome Biogenesis Machinery Effectively Inhibits Pancreatic Tumor Growth, Mudassier Ahmad, Sahir Sultan Alvi, Haider Ahsan, Carlos Perez, Andrew Massey, Vivek K Kashyap, Neeraj Chauhan, Emmanuel Anning, Manish K Tripathi, Dae J Kim, Nirakar Sahoo, Tamer Oraby, Murali M Yallapu, Mohammad Moshahid Khan, Manu M Sebastian, Subhash C Chauhan, Bilal B Hafeez

Faculty, Staff and Student Publications

Dysregulated ribosome biogenesis and p53 mutations are known to play oncogenic roles in various cancers, including pancreatic cancer. In this study, we demonstrated the therapeutic potential of BMH-21, a pharmacologic inhibitor of RNA polymerase I, against pancreatic cancer by uncovering a novel molecular mechanism involving RPA194-mediated ubiquitination of mutant p53 without affecting the ubiquitination of wild-type p53. Our key findings are that (i) BMH-21 selectively induces apoptosis and cell growth inhibition of pancreatic cancer cells with no effect on normal human pancreatic ductal epithelial cells; (ii) BMH-21 degrades RPA194; (iii) BMH-21 inhibits recruitment of both RPA194 and RPA135 on rDNA …

The Next Layer: Augmenting Foundation Models With Structure-Preserving And Attention-Guided Learning For Local Patches To Global Context Awareness In Computational Pathology, Muhammad Waqas, Rukhmini Bandyopadhyay, Eman Showkatian, Amgad Muneer, Anas Zafar, Frank R Alvarez, Maricel Corredor Marin, Wentao Li, David Jaffray, Cara Haymaker, John V Heymach, Natalie Vokes, Luisa M Solis Soto, Jianjun Zhang, Jia Wu

Faculty, Staff and Student Publications

Foundation models have emerged as powerful feature extractors in computational pathology. However, they typically omit mechanisms for leveraging the global spatial structure of tissues and the local contextual relationships among diagnostically relevant regions-key elements for understanding the tumor microenvironment. Multiple instance learning (MIL) remains an essential next step following the foundation model, designing a framework to aggregate patch-level features into slide-level predictions. We present EAGLE-Net, a structure-preserving, attention-guided MIL architecture designed to augment prediction and interpretability. EAGLE-Net integrates multi-scale absolute spatial encoding to capture global tissue architecture, a top-K neighborhood-aware loss to focus attention on local microenvironments, and background suppression …

Tumor Radiosensitization With Gold Nanoparticles: Evolving Strategies To Improve Tumoral Gold Uptake And Catalyze Future Clinical Translation, Prapannajeet Biswal, Geraldine V Vijay, Gabrielle Krouse, Phuoc Minh Quan Mai, Bhoomika Muruvekere Lakshmisha, Sanaz Keshavarz Shahbaz, Mahdieh Yousefi Taba, Aria Sabbagh, Lydia Wt Cheung, Yuri Mackeyev, Khadijeh Koushki, Sunil Krishnan

Faculty, Staff and Student Publications

Radiation therapy is integral to the treatment regimens of over 50% of cancer patients. However, it is not biologically targeted to just the tumor, leading to adverse effects in peritumoral normal tissue. Selective uptake of gold nanoparticles (AuNPs) by tumors realizes tumor-specific radiosensitization via increased secondary electron release from high atomic number gold atoms. Here, we review AuNP-mediated radiosensitization and outline strategies to optimize tumor-targeted AuNP delivery. Modifying the physicochemical characteristics of AuNPs, including size, shape, charge, and surface chemistry, can increase their ability to evade the reticuloendothelial system (RES) and penetrate the dense tumor stromal architecture, thereby promoting tumor …

Exploring Sex Differences In Stroke Outcomes: A Comprehensive Analysis From The Span 1 Trial, Anjali Chauhan, Eunyoung Angela Lee, Rakesh B Patel, Mariia Kumskova, Enrique C Leira, Anil Chauhan, Yanrong Shi, Suyi Cao, Raymond C Koehler, Krishnan M Dhandapani, Mohammad Badruzzaman Khan, Pradip K Kamat, Ali Arbab, David C Hess, Alison L Herman, Ligia Boisserand, Lauren H Sansing, Andreia Morais, Xuyan Jin, Sanem Aykan, Takahiko Imai, Cenk Ayata, Karisma A Nagarkatti, Jessica Lamb, Márcio A Diniz, Patrick D Lyden, Jaroslaw Aronowski, Louise D Mccullough

Faculty, Staff and Student Publications

Background: Stroke is a sexually dimorphic disease, with different risk factors, incidence, outcomes, and treatment responses in men and women. While sex differences have been documented in preclinical studies, these findings often come from single-site studies with small sample sizes and require validation across diverse research settings.

Methods: We used data from the SPAN (Stroke Preclinical Assessment Network), a randomized, placebo-controlled, blinded, multilaboratory trial, to determine if sex differences in neurological outcomes are present in preclinical stroke models. We analyzed data from 665 stroke animals treated with saline, including young mice, diet-induced obese mice, aging mice, young rats, and spontaneously …

Cd8+ T Cells In The Tumor Microenvironment Modulate The Response To Endocrine Therapy In Breast Cancer, Fabiana Napolitano, Yunguan Wang, Dhivya R Sudhan, Paula I Gonzalez-Ericsson, Luigi Formisano, Nisha Unni, Shahbano Shakeel, James Z Zhu, Khushi Ahuja, Lei Guo, María Rosario Chica-Parrado, Yuki Matsunaga, Pamela Luna, Chang-Ching A Lin, Yasuaki Uemoto, Kyung-Min Lee, Hongli Ma, Nathaniel J Evans, Alberto Servetto, Saurabh Mendiratta, Spencer D Barnes, Roberto Bianco, Yisheng V Fang, Lin Xu, Jeon Lee, Tao Wang, Justin M Balko, Gordon B Mills, Marilyne Labrie, Ariella B Hanker, Carlos L Arteaga

Faculty, Staff and Student Publications

The role of the tumor immune microenvironment (TIME) in modulating responses to antiestrogen therapy in hormone receptor-positive (HR+) breast cancers remains unclear. We analyzed pre- and on-treatment biopsies from patients with HR+ breast cancer treated with letrozole to induce estrogen deprivation (ED). Stromal tumor-infiltrating lymphocytes, assessed by H&E staining, and immune-related gene sets, including IFN-γ signaling genes, measured by RNA-Seq, were increased in ED-resistant tumors. Cyclic immunofluorescence and spatial transcriptomics revealed an abundance of CD8+ T cells and enhanced antigen processing and immune gene signatures in ED-resistant tumors. In this group, the expression of CXCL9, CXCL10, and CXCL11 - chemokine …

Osimertinib Activates A Tgf-Β2-Dependent Secretory Program That Drives Lung Adenocarcinoma Progression, Madhurima Ghosh, Chao Wu, Abhishek Kumar, Monique Nilsson, John V Heymach, Weina Zhao, Jiang Yu, Xin Liu, Na Ding, Shike Wang, Guan-Yu Xiao, Angelo Chen, Kate Grimley, William K Russell, Chad J Creighton, Xiaochao Tan, Jonathan M Kurie

Faculty, Staff and Student Publications

EGFR-mutant lung adenocarcinomas (LUADs) that are vulnerable to the EGFR antagonist osimertinib (Osi) eventually relapse, owing in part to the emergence of drug-tolerant persister (DTP) cells that arise through epigenetic mechanisms. Intratumoral DTP cells can herald a worse clinical outcome, but the way in which DTP cells influence LUAD progression remains unclear. Osi-resistant (OR) cells exhibit typical DTP cell features, including a propensity to undergo senescence and epithelial-mesenchymal transition (EMT), which can activate heightened secretory states. Therefore, we postulated that OR cells influence LUAD progression through paracrine mechanisms. To test this hypothesis, we utilized congenic pairs of EGFR-mutant LUAD cell …

Dispersion-Enhanced Nitrogen-Centered Photocatalysis Of The Direct Hydrogen Atom Transfer, Jiasong Zhang, Kaitong Zhuang, Ramon Trevino, Babu Raj Dhungana, Huiying Sun, Shuyu Yin, Yuting Li, Jacob A Sanchez, Xiaoyu Xia, Ramy Elerian, Yao Sun, Seth O Fremin, Chao Huang, Min He, Maosheng Cheng, Oleg V Larionov, Shengfei Jin

Faculty, Staff and Student Publications

The development of structurally distinct and modular photocatalysts for direct hydrogen atom transfer (HAT) has emerged as a key frontier in radical-mediated C-H functionalization of strong carbon-hydrogen bonds. Despite the largely untapped potential across the fields of organic synthesis, medicinal chemistry, and materials science, few classes of direct HAT photocatalysts are currently known, and the approaches to enhancing their photocatalytic activity remain underdeveloped. We report herein the development of nitrogen-centered direct HAT photocatalysts based on the acridine framework, which leverage a C9-ortho-biaryl substituent for enhancing the photocatalytic activity through stabilizing dispersion interactions with the substrate as the key steering effect. …

Mapping The Causal Chain From Genetic Risk Variants To Lipid Dysmetabolism In Parkinson’S Disease, Ruth B De-Paula, Jonggeol Kim, Herve Rhinn, Hiba Saade, Fatima Chavez, Téah Segura, Maria Valeria Lozano, Michelle Etoundi, Karla Silos, Naomi Kass, Viktoriya Korchina, Harshavardhan Doddapaneni, Eric Venner, Joseph C Masdeu, Valory Pavlik, Melissa M Yu, Chi-Ying R Lin, Joseph Jankovic, Aron S Buchman, Donna Muzny, Richard A Gibbs, Sarah H Elsea, Asa Abeliovich, Peter Lansbury, Nora Vanegas-Arroyave, Chad A Shaw, Joshua M Shulman

Faculty, Staff and Students Publications

The molecular pathways linking genetic variants to Parkinson's disease (PD) onset and progression remain incompletely defined; however, risk alleles in multiple genes, including GBA1, strongly implicate lipid metabolism. To systematically identify causal biomarker signatures, we analyzed comprehensive metabolome profiles from blood plasma in 149 PD patients and 150 controls, along with complementary genetic, RNA-sequencing, and metabolic data from other available clinical and pathologic cohorts. Using colocalization and summary-data-based Mendelian randomization, we tested whether expression and metabolic quantitative trait loci mediate the association between implicated genetic variants and PD risk. We further integrated differential metabolomics and proteomics from blood and brain …

Cleavage And Polyadenylation Specificity Factor Subunit 5 Regulates Pulmonary Artery Smooth Muscle Expansion And Hypoxic Response, Scott D Collum, Lisha Zhu, Tingting W Mills, Rene Girard, Jamie Tran, Tinne C J Mertens, Cory Wilson, Nancy Wareing, Erik E Suarez, Howard J Huang, Rahat Hussain, Bindu Akkanti, Wenjin J Zheng, Hari K Yalamanchili, Bela Patel, Eric J Wagner, Sandeep Agarwal, Harry Karmouty-Quintana

Faculty, Staff and Student Publications

Pulmonary hypertension (PH) is a fatal condition that affects individuals with systemic sclerosis (SSc), a multiorgan fibrotic disease with limited treatment options. A central feature of PH is vascular remodeling, defined by the narrowing of the arteriole lumen due to cell proliferation and extracellular matrix deposition. Herein, we identify a central mechanism that can regulate multiple transcripts important for vascular remodeling. The highlight of our study is the demonstration that reduced pulmonary artery smooth muscle (PASMC) Nudt21, which codes for the RNA binding protein Cleavage and Polyadenylation Specificity Factor Subunit 5 (CPSF5) The, known to regulate alternative polyadenylation, results …

Insomnia In Stimulant Use Disorders: Prevalence And Associations With Negative Affect, Isabella G Bourtin, Constanza De Dios, Jessica Vincent, Joy M Schmitz, Scott D Lane, Heather E Webber

Faculty, Staff and Student Publications

Research suggests that sleep disturbances are common among people who use psychostimulants, including cocaine use and methamphetamine use. These sleep disturbances hinder recovery, heighten relapse risk, and worsen physical and mental health outcomes. This study aimed to estimate the prevalence and severity of insomnia among individuals who use cocaine and methamphetamine and to explore potential psychological factors that are associated with more severe insomnia. The sample included participants who completed in-person screening assessments for ongoing studies at an outpatient research clinic. As a part of this screening, participants completed the Insomnia Severity Index (ISI) and validated assessments of psychological domains …

Transcriptomics And Metabolomics Analysis Reveal Cell Subpopulations Of Trophoblast Cells Associated With Preeclampsia, Xiaojun Zhu, Ying Jiang, Lilin Wang, Peiyue Jiang, Zixing Zhong, Hetong Li, Caihong Zheng, Lujiao Chen, Juan Wei, Xishi Lin, Peng Ding, Zehua Dong, Xiaosheng Wang, Qiong Luo

Faculty, Staff and Student Publications

Placental abnormalities are central to preeclampsia (PE), yet the cellular and molecular mechanisms underlying this dysfunction remain unclear. We applied a multi-layered, integrative approach to investigate placental tissue from patients with PE and matched controls. Single-cell RNA sequencing (scRNA-seq; GSE173193) and bulk RNA sequencing (bulk RNA-seq; GSE203507) datasets were obtained from the Gene Expression Omnibus. The scRNA-seq dataset included two PE and two control samples, whereas the bulk RNA-seq dataset focused on eight early-onset PE and five uncomplicated term births. Trophoblast subpopulations were identified via scRNA-seq, and pseudotime analysis was used to trace differentiation trajectories. Differential expression and pathway enrichment …

A Murine Model Of Cardiovascular-Kidney-Metabolic Syndrome Demonstrates Compromised Limb Function In The Ischemic Hind Limb, Saran Lotfollahzadeh, Herreet Paul, Joshua Bonifacio, Ricardo Almiron, Isaac Hockestra, Kylla Przekop, Trent Yamamoto, Maria Carmen Piqueras, Wenqing Yin, Kashvi Sethuraman, Asha Jose, Marina Malikova, Jeffrey J Siracuse, Mostafa Belghasem, Howard Cabral, Nazish Sayed, Vipul C Chitalia

Faculty and Staff Publications

Key Points:

1. Cardiovascular-kidney-metabolic (CKM) is a global public health problem; however, its mediators remain poorly known, in part due to the lack of a reliable animal model.

2. A combination of high fat and adenine diet recapitulate some of the CKD and metabolic phenotypes of CKM.

3. This model also demonstrates myocardial fibrosis and peripheral artery disease with sex-based differences and can be leveraged to probe mechanisms of CKM.

Background: Cardiovascular-kidney-metabolic (CKM) syndrome is a public health problem in the United States and results in premature cardiovascular disease at a relatively preserved GFR. The molecular mediators of CKM are poorly understood, partly …

Pair-Feeding Study Designs Can Create Biases And Inflate Type I Error Rates: A Simulation Study, Wasiuddin Najam, Daniel E Kpormegbey, Deependra K Thapa, Bret Rust, Lilian Golzarri-Arroyo, Lance H Baumgard, Louis Wai-Tong Fan, Joseph G Ibrahim, Edith J Mayorga, David B Allison

Children’s Nutrition Research Center Staff Publications

Objective: Pair-feeding is a study design element where one group's food intake is provided to another group to assess whether a treatment effect is independent of food intake. Investigators often assume equivalent food intake across experimental conditions and exclude it from the statistical analysis. However, the impact of this practice on type I error (T1Er) rates has not been quantified.

Methods: We conducted a Monte Carlo simulation in which animals were assigned baseline weights and food intakes, then randomized to non-pair-fed or pair-fed groups. Daily food intake for both groups was initially drawn from the baseline food intake distribution. For …

Catatonia And Elevated Mortality: A Population-Wide Cohort Study With Healthy, Sibling, And Schizophrenia Spectrum Controls, Chih-Wei Hsu, Yang-Chieh Brian Chen, Marco Solmi, Chih-Sung Liang, Mu-Hong Chen, Yao-Hsu Yang, Liang-Jen Wang, Edward Chia-Cheng Lai

Children’s Nutrition Research Center Staff Publications

Aim: To determine whether catatonia is associated with increased long-term all-cause and cause-specific mortality.

Methods: Using Taiwan's National Health Insurance Database (2000-2022), we assembled a population-based cohort of all adults (≥18 years) with catatonia and matched each to four controls without catatonia on sex and birthdate. Mortality was compared between (1) individuals with catatonia and their unaffected siblings and (2) individuals with schizophrenia spectrum disorders with catatonia and those with schizophrenia spectrum disorders without catatonia. The primary outcome was all-cause mortality; secondary outcomes were natural- and unnatural-cause deaths. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated with …

Does Hla-B27 Status Influence Ixekizumab Efficacy In Axial Spondyloarthritis? Results From The Coast-V, Coast-W, And Coast-X Trials, John D Reveille, Martin Rudwaleit, Proton Rahman, Jose A Maldonado-Cocco, Marina Magrey, Rebecca Bolce, Khai Jing Ng, Theresa Hunter Gibble, Jeffrey Lisse, So Young Park, Andris Kronbergs, Victoria Navarro-Compán

The Brown Foundation: Institute of Molecular Medicine

Introduction: The human leukocyte antigen (HLA)-B27 is associated with axial spondyloarthritis (axSpA) and is a predictor of response to tumor necrosis factor inhibitors. However, limited data are available on HLA-B27 and interleukin-17 inhibitors. We evaluated the influence of HLA-B27 status on ixekizumab response through 52 weeks in patients with axSpA.

Methods: Data were analyzed from three randomized placebo-controlled trials: COAST-V (NCT02696785), COAST-W (NCT02696798), and COAST-X (NCT02757352). Patients fulfilled the Assessment of SpondyloArthritis international Society (ASAS) criteria for radiographic (r)-axSpA or non-radiographic (nr)-axSpA. Patients were randomized to receive 80 mg ixekizumab every 2 weeks, 80 …

Scper: A Rigorous Computational Approach To Determine Cellular Subtypes In Tumors Aligned With Cancer Phenotypes From Total Rna Sequencing, Bingrui Li, Xiaobo Zhou, Raghu Kalluri

Faculty, Staff and Student Publications

Single-cell RNA sequencing (scRNA-seq) is a powerful technique for understanding cellular diversity, but processing large patient cohorts to identify phenotype-associated cell populations remains challenging. Here, scPER (Estimating cell Proportions using single-cell RNA-seq Reference), a rigorous approach combining adversarial autoencoder and extreme gradient boosting to estimate tumor microenvironment cell compositions and identify phenotype-associated subclusters for bulk RNA-seq samples. Integrating scRNA-seq datasets from diverse studies, scPER constructed comprehensive reference panels and disentangled confounders from true signals. scPER achieved superior accuracy in cellular proportion estimation compared to CIBERSORTx, BayesPrism, Scaden, MuSiC, SCDC, DeSide and ReCIDE. It showed high accuracy in predicting metastatic melanoma …

Genetic Architecture Of N-Terminal Pro-B-Type Natriuretic Peptide In A Multiancestry Study Population, Naman S Shetty, Akhil Pampana, Mokshad Gaonkar, Amrita Nayak, Harshvir S Bal, Nirav Patel, Nehal Vekariya, J Gustav Smith, Alanna C Morrison, Bing Yu, Bruce M Psaty, Eric Boerwinkle, James S Floyd, Jerome I Rotter, Kent D Taylor, Leslie A Lange, Marguerite R Irvin, Mary Cushman, Stephen S Rich, Ramachandran S Vasan, Thomas J Wang, Xiuqing Guo, Peng Li, Garima Arora, Pankaj Arora

Faculty, Staff and Student Publications

Background: NPs (natriuretic peptides) are bioactive hormones crucial for regulating blood pressure, glucose homeostasis, and lipid metabolism. Despite the high heritability of circulating NP levels, the genetic determinants of NP regulation, particularly across ancestries and sexes, remain poorly understood. The objective of the current study was to identify genetic variants associated with NT-proBNP (N-terminal pro-B-type NP) levels in a multiancestry study population.

Methods: Whole genome sequencing and array-based data from 81 213 individuals without heart failure were analyzed from the Trans-Omics for Precision Medicine cohorts, UK Biobank, All of Us Research Program, and REGARDS (Reasons for Geographic and Racial Differences …

Cellstaar: Incorporating Single-Cell-Sequencing-Based Functional Data To Boost Power In Rare Variant Association Testing Of Noncoding Regions, Eric Van Buren, Yi Zhang, Xihao Li, Margaret Sunitha Selvaraj, Zilin Li, Hufeng Zhou, Nicholette D Palmer, Donna K Arnett, John Blangero, Eric Boerwinkle, Brian E Cade, Jenna C Carlson, April P Carson, Yii-Der Ida Chen, Joanne Curran, Ravindranath Duggirala, Myriam Fornage, Nora Franceschini, Misa Graff, Charles Gu, Xiuqing Guo, Jiang He, Nancy Heard-Cosa, Lifang Hou, Yi-Jen Hung, Rita R Kalyani, Sharon L R Kardia, Eimear Kenny, Charles Kooperberg, Brian G Kral, Leslie Lange, Dan Levy, Changwei Li, Simin Liu, Donald Lloyd-Jones, Ruth J F Loos, Ani W Manichaikul, Lisa Warsinger Martin, Rasika Mathias, Ryan L Minster, Braxton D Mitchell, Josyf C Mychaleckyj, Take Naseri, Kari North, Jeff O'Connell, James A Perry, Patricia A Peyser, Bruce M Psaty, Laura M Raffield, Ramachandran S Vasan, Susan Redline, Alex P Reiner, Stephen S Rich, Jennifer A Smith, Brian Spitzer, Hua Tang, Kent D Taylor, Russell Tracy, Satupa'itea Viali, Lisa Yanek, Wei Zhao, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Jerome I Rotter, Gina M Peloso, Pradeep Natarajan, Xihong Lin

Faculty, Staff and Student Publications

Understanding how rare genetic variants influence complex traits remains a major challenge, particularly when these variants lie in noncoding regions of the genome. The effects of variants within candidate cis-regulatory elements (cCREs) often depend on the cell type, making interpretation difficult. Here we introduce cellSTAAR, which integrates whole-genome sequencing data with single-cell assay for transposase-accessible chromatin using sequencing data to capture variability in chromatin accessibility across cell types via the construction of cell-type-specific functional annotations and regulatory elements. To reflect the uncertainty in cCRE-gene linking, cellSTAAR uses a comprehensive strategy to link cCREs to their target genes. We applied cellSTAAR …

Volumetric Buccal Bone Alterations At Immediate Implant Sites With Or Without Soft Tissue Augmentation: A 6-Month Assessment, Mary Jung, Duong Tran, Chi-Ching Chang, Sung K Kim, Yosuke Tsukiboshi, Seiko Min, Srinivas Ayilavarapu, Chun-Teh Lee

Faculty, Staff and Student Publications

Background: This study is part of a randomized controlled trial investigating the impact of soft tissue augmentation (STA) using subepithelial connective tissue graft (SCTG) (immediate implant with subepithelial connective tissue graft [ICT] group) or acellular dermal matrix (ADM) (immediate implant with acellular dermal matrix [IAD] group) versus no STA (control) on the clinical outcomes following immediate implant placement (IIP). This study aimed to investigate volumetric buccal bone dimensional changes at immediate implant sites 6 months after the surgery.

Methods: Forty-five patients requiring extraction of a maxillary anterior tooth or premolar and randomly assigned to one of the three groups were …

Utilization Of Intensive Care Interventions In Critically Ill Patients With Candidemia Versus Bacteremia: A Multicenter Retrospective Cohort Study, Mary North Jones, Masayuki Nigo, Stefano Casarin, James Kurian, Aarjav Sanghvi, Enshuo Hsu, Stephen L Jones, Ashton Connor, David B Corry, Cesar A Arias, Max W Adelman

Faculty, Staff and Students Publications

Objectives: Candida species are one of the most common causes of ICU-onset bloodstream infection (BSI). Yet, there is no robust guidance on when to initiate empiric antifungals for ICU patients suspected of BSI. We compared patients with ICU-onset candidemia vs. ICU-onset bacteremia to determine which patients may benefit from empiric antifungals.

Design: We compared characteristics between patients with bacteremia vs. candidemia at time of culture. We determined risk factors for death and constructed a multivariable regression to determine if candidemia is an independent risk factor for death.

Setting/patients: We included ICU patients from a hospital system in Houston, Texas (n …

Inferring High-Fat Dietary Patterns From Electronic Health Record Data Using Machine Learning, Ya-Yun Yeh, Hsin-Yueh Lin, Jingchuan Guo, Ramon C Sun, Sizun Jiang, Jiang Bian, Hao Dai

Faculty, Staff and Student Publications

Objectives: Electronic health records (EHRs) rarely capture dietary detail, limiting diet-disease research. We aimed to develop machine learning (ML) computable phenotypes to identify high-fat diet (HFD) using variables typically available in EHRs.

Materials and methods: We used National Health and Nutrition Examination Survey (NHANES) 1999-2020 data, where 24-h dietary recall served as ground truth. Dietary fat intake was summarized into a score (0-30) based on percent energy from fat, carbohydrate, and protein; lower scores indicated HFD. We defined HFD at cutoffs of 10, 15, and 20, and trained ML models (Extreme Gradient Boosting, logistic regression, random forest) using EHR-compatible variables …

Hootation: A Gui And Api Library For Ontology Validation And Verbalization., Muhammad Amith, Xubing Hao, Warren Manuel, Manqi Li, Shun Rao, Kirk Roberts, Hua Xu, Yang Gong, Frank Manion, Cui Tao, Licong Cui

Faculty, Staff and Student Publications

Ontology verbalization refers to the process of translating formal axioms into natural language expressions. The primary objective is to facilitate the review and validation of ontology content by subject matter experts without requiring extensive technical expertise. While previous approaches based on templates or controlled grammar have been effective, they often face limitations in scalability, fluency, and adaptability. To address these issues, we developed Hootation, an open-source software system that supports ontology verbalization through both a graphical user interface and an API library. The tool implements rule-based translation of OWL2 axioms and further incorporates optional Large Language Model (LLM) components for …

Therapeutic Potential Of C1-Inhibitor In Vascular Diseases And Beyond, Linda Sundler Björkman, Harish Eswaran, Steven P Grover

Faculty, Staff and Student Publications

C1INH (C1-inhibitor) is a multifunctional SERPIN (serine protease inhibitor) that functions as a major negative regulator of the complement, coagulation, and kallikrein-kinin systems. C1INH products were originally developed for the treatment of hereditary angioedema associated with C1INH deficiency. A growing body of literature indicates that C1INH products may find utility in the management of several other disease states. In this review, we detail the key biological activities of C1INH and consider the pathophysiological role of C1INH targets in many conditions. The therapeutic potential of exogenous C1INH is highlighted in the settings of thromboembolism, ischemia-reperfusion injury, sepsis, transplantation, and coronavirus disease …

Markvcid2 Consortium For Clinical Validation Of Biomarkers Of Cerebral Small Vessel Disease: Validation Framework And Baseline Characteristics, Steven M Greenberg, Marylin S Albert, Hongyu An, Konstantinos Arfanakis, Arnold M Evia, Arvind Caprihan, Andria L Ford, Myriam Fornage, Gregory S Day, Jason D Hinman, Gregory A Jicha, Amir H Kashani, Joel H Kramer, Christian Lachner, Jin-Moo Lee, Peiying Liu, Hanzhang Lu, Pauline Maillard, Ronald C Petersen, Bruce M Psaty, John M Ringman, Gary A Rosenberg, Claudia L Satizabal, Sean I Savitz, Julie A Schneider, Sudha Seshadri, Prashanthi Vemuri, Danny J J Wang, Donna M Wilcock, B Gwen Windham, Rong Zhang, Carissa Tuozzo, Herpreet Singh, Sue Moy, Vilma Okey-Ewurum, Courtney B Page, Hillary Mulder, Pia Kivisäkk, Deborah Blacker, Lidiya Mazina, Karl G Helmer, Kristin Schwab, Lisa M Wruck, Roderick A Corriveau

Faculty, Staff and Student Publications

Objective: To establish a framework for validating candidate biomarkers of cerebral small vessel diseases (SVD) associated with cognitive impairment and characterize individuals enrolled by the MarkVCID2 consortium under this framework.

Methods: Participants age 60 to 90 years were enrolled across 17 MarkVCID2 sites. Recruitment was targeted to enrich in cognitive symptoms (mild dementia, mild cognitive impairment, subjective cognitive decline), defined risk factors (diabetes mellitus, advanced hypertension), and Black/African American, White, and Hispanic/Latino subgroups. Enrolled participants underwent baseline visits that included cognitive testing, multimodal magnetic resonance imaging (MRI), and biofluid collection. Provisional risk for SVD-related cognitive decline was estimated primarily by …

Uterine Tachysystole And Associated Outcomes: A Systematic Review And Meta-Analysis, Fabrizio Zullo, Benedetta Licitra, Nandini Raghuraman, Alison G Cahill, Aaron W Roberts, Stephanie Roth, Daniele Di Mascio, Antonella Giancotti, Giuseppe Rizzo, Kristen A Cagino, Hector Mendez-Figueroa, Anthony C Sciscione, Suneet P Chauhan

Faculty, Staff and Student Publications

Objective: To determine whether uterine tachysystole is associated with adverse neonatal and maternal outcomes.

Data sources: A search strategy for PubMed (National Library of Medicine) was created, and the medical librarian translated the search for every database. The search strategy was peer reviewed by another medical librarian following the Peer Review of Electronic Search Strategies checklist. The databases included in this search were PubMed, Embase.com, Cochrane CENTRAL, CINAHL Ultimate, and Scopus; a combination of key words and subject headings was used.

Methods of study selection: Trials of nulliparous or multiparous parturients exposed to uterine tachysystole were included. Included studies compared …

Fireproof: Intricacies Of Microglial Biology, Wei Cao

Faculty, Staff and Student Publications

No abstract provided.