Digital Commons Network^™

Stance And Gait Analysis Of Apollo Astronauts On The Moon, Faye Y Chiou-Tan, Conrad Li, Jason P Caffrey, Millard Reschke, Timothy R Macaulay

Faculty, Staff and Students Publications

Introduction/aim: As humans return to the Moon, safe efficient ambulation and fall prevention on the lunar surface are key concerns. The analysis of gait from archived Apollo mission video footage is now possible with pose estimation video analysis software. Thus, this study aims to retrospectively quantify parameters of Apollo astronauts' stance and gait on the Moon.

Methods: Publicly available National Aeronautics and Space Administration (NASA) footage of astronauts ambulating on the Lunar surface was examined using body pose analysis software. Goniometric lower limb joint/torso angles and width of base of stance and gait were derived. Gait cycle stance phase, swing …

Diacylglycerol Kinase Eta As A Novel Target In Nras Mutant Melanoma, Haley P. Wilson, Casey D. Stefanski, Signe Caksa, Glenn L. Mersky, Scott D. Varney, Jelan I. Haj, Dan A. Erkes, Timothy J. Purwin, Vivian Chua, Andrew E. Aplin

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

NRAS mutations occur in 10%-30% of cutaneous melanomas and are associated with high tumor mutational burden. Mutant NRAS signaling drives aberrant cell growth and proliferation, in part, through activation of the RAF-MEK-ERK1/2 kinase pathway; however, targeted therapies to this pathway have limited effectiveness in patients with NRAS mutant melanoma. The role of other targetable signaling pathways in NRAS mutant melanoma is poorly characterized. Here, we demonstrated that one isoform of diacylglycerol kinase, diacylglycerol kinase eta (DGKη), a lipid signaling regulator, was highly expressed in NRAS mutant melanoma patient samples. Knockdown of DGKH in NRAS mutant melanoma cell lines resulted in …

Mif-Cd74 Signaling Drives Immune Modulation In Medulloblastoma, Benjamin Draper, Zhen You, Dean Thompson, Xu Guo, Alaide Morcavallo, Diego Chillon Pino, Carlos Lorenzo Gido Nery, Sumana Shrestha, Chantelle E Bowers, Courtney Himsworth, Alberto Delaidelli, Bethany Remeniuk, Sonia Morlando, Brandon Wade, Freya Gordon, Yara Sanchez-Corrales, Bei Hopkins, Natalie Monteiro, Darren Locke, Miao Liu, Jacob Torrejon Diaz, Kevin Greenslade, Barbara Martins Da Costa, Karen Barker, Colin Kwok, Olumide Ogunbiyi, Anya Fletcher, Stacey Richardson, Carlos Custodia, Rafael Roque, Thomas Jackson, Regan Barfoot, Sergi Castellano, Rebecca M Hill, Olivier Saulnier, Thomas S Jacques, Michael D Taylor, Claudia C Faria, Olivier Ayrault, Poul H Sorensen, John Anderson, Louis Chesler, L Frank Huang, Steven C Clifford, Laura K Donovan

Faculty, Staff and Students Publications

Background: Relapsed medulloblastoma remains a significant therapeutic challenge as it is near universally fatal. The tumor microenvironment of medulloblastoma plays a critical role in tumor progression, influencing tumor growth, immune evasion, and therapeutic resistance. We hypothesized that defining tumor-immune interactions in diagnostic and relapsed medulloblastoma may uncover mechanisms of immune evasion and identify novel therapeutic targets.

Methods: We analyzed paired primary and recurrent RNA-sequencing data from 140 medulloblastoma patients to profile immune cell composition and validate spatial relationships within the TME. To identify key tumor-immune interactions, we developed a novel algorithm to detect receptor-ligand pairs using single-cell RNA-sequencing data. These …

Noncanonical Clock Regulators Control Stress Responses In Digestive Diseases, Dishu Zhou, Roberto E López-Valiente, Samer G Mattar, Dongyin Guan

Faculty, Staff and Students Publications

The digestive system is essential for nutrient absorption, processing, and waste elimination. The expression of many genes and physiological processes within this system exhibits a 24-h rhythmicity. However, modern lifestyle factors, such as jet lag, shift work, and irregular eating patterns, significantly disrupt these rhythms, triggering various stress responses and contributing to numerous digestive disorders. Here, we focus on emerging studies on noncanonical clock regulators involved in stress responses, integrate these novel findings into the established model of the core circadian clock, and highlight recent advances in the development of novel therapeutics targeting these 24-h regulators. In addition, we discuss …

An Integrated Framework For Early Detection And Transmissibility Assessment Of Emerging Variants In Wastewater, Xingwen Chen, Tin Phan, Wei Lin Lee, Katie Clark, Steven F Rhode, Samantha Brozak, Bruce Pell, Tsultrim Palden, Mats Leifels, Anna Gitter, Yang Kuang, Stefan Wuertz, Janelle Thompson, Kristina D Mena, Eric J Alm, Fuqing Wu

Faculty, Staff and Student Publications

Tracking the emergence of new viral variants is critical for epidemic preparedness, but remains challenging because variants typically circulate at low prevalence during the early phase of outbreaks. Here, we present an integrated framework that combines sensitive variant detection in wastewater with quantitative assessment of transmissibility through dynamic epidemic modeling. Using the SARS-CoV-2 Omicron variant as a proof of concept, we developed a novel nested allele-specific RT-qPCR assay (NAS-PCR) that achieved a thousand-fold increase in sensitivity compared with allele-specific RT-qPCR (limit of detection: 0.5 copies/μl). NAS-PCR detected Omicron in wastewater samples from the Greater Boston area starting in September 2021, …

Addressing Nonignorable Missing Data And Heterogeneity In Prognostic Biomarker Assessment, Xinran Huang, Ruosha Li, Jing Ning, For The Alzheimer's Disease Neuroimaging Initiative

Faculty, Staff and Student Publications

Covariate-specific and time-dependent area-under-curve (AUC) is often used to evaluate the discriminative performance of biomarkers with time-to-event outcomes, particularly when certain covariates influence biomarkers' accuracy. In biomarker research, despite extensive efforts, missing data remain unavoidable, with nonignorable missingness posing significant challenges. This article focuses on estimating the impact of covariates on time-dependent AUC in the presence of nonignorable missing biomarkers. Assuming a parametric model on the missing probability, we leverage instrumental variables to address the identifiable issue and estimate the unknown parameters. We integrate the inverse probability weighting approach into the score equation of a pseudo partial likelihood for estimation …

Qualitative Beta-2-Adrenoceptor Signaling In The Regulation Of Human Airway Epithelia Mucin And Cytokine Production, Fred Graumuller, Diana Cervantes, Tung O. Chan, Niccolette Schaunaman, Dominic R. Villalba, Burton F. Dickey, Julia K. L. Walker, Hong Wei Chu, Raymond B. Penn

Division of Pulmonary, Allergy, and Critical Care Medicine Faculty Papers

BACKGROUND: Numerous in vivo studies have demonstrated beta-2-adrenoceptor (β2AR) -agonism as permissive in the development of allergic lung inflammation, and have implicated the arrestin-dependent signaling arm of the β2AR in mediating this effect. However, the specific cell type(s) mediating β2AR regulation of allergic lung inflammation remain unestablished.

METHODS: To explore the potential contribution of airway epithelia in this phenomenon, we compared the ability of ractopamine (RP), recently identified as a Gs-biased beta-agonist, to that of the unbiased/balanced beta-agonist albuterol (ALB), on IL-13-stimulated mucin and cytokine production in human airway epithelia cultures in air-liquid interface (HAE).

RESULTS: ALB, which activates both …

Targeted Epigenome Sequencing Of Eosinophils Reveals Cpg Sites And Regulatory Variants Associated With Asthma., Rébecca Dionne-Gagné, Anne-Marie Madore, Anne-Marie Boucher-Lafleur, Tomi Pastinen, Catherine Laprise

Manuscripts, Articles, Book Chapters and Other Papers

Eosinophils are pro-inflammatory cells that play a central role in asthmatic inflammation. However, few studies have examined their methylation profiles in asthma, all relying on microarray-based approaches. Here, an epigenome-wide association study in 183 purified eosinophil samples from the Saguenay-Lac-Saint-Jean asthma family cohort was performed using a custom sequencing panel targeting 4,609,564 CpGs in immune regulatory regions. Two CpG sites in MAEA and SLC9A2 genes, known to be involved in immune function, were significantly associated with asthma, while five additional sites showed suggestive associations. Integration with genotype data (7,829,429 variants) and expression counts (17,513 genes) identified significant quantitative trait loci-mediated …

Treatment Of Haemophilia A Without Inhibitors: Real-World Treatment Patterns And Clinical Outcomes In The Us., Allison P. Wheeler, Lauren Amos Md, Shveta Gupta, Sylvie Bozzi, Gandarvaka Miles, Kalyani Hawaldar, Andrew Wilson, Gillian Hanson, Emily Cibelli, Amanda Wilson, Siddhi Umarje, Anne-Laure Tardy, Jennifer Dumont, Graham Neill, Alix Arnaud

Manuscripts, Articles, Book Chapters and Other Papers

INTRODUCTION: Despite available prophylactic therapies for haemophilia A, breakthrough bleeding and consequent pain and joint damage still occur.

AIM: To provide insights into the unmet treatment needs of people with moderate-to-severe haemophilia A in the US.

METHODS: For this descriptive, observational cohort study, eligible participants diagnosed with moderate-to-severe haemophilia A were enrolled in the PicnicHealth database on or before 3 October 2022. Three patient groups were established to identify: (1) treatment patterns; (2) clinical outcomes by therapy class (standard half-life [SHL] factor VIII [FVIII]; extended half-life FVIII [EHL]; emicizumab); (3) health-related quality of life (HRQoL) using the Patient-Reported Outcomes Measuring …

Functional Heterogeneity In Trophoblast Stem Cells Derived From Recurrent Pregnancy Loss Products Of Conception., Qi Fu, Keisuke Kozai, Xingrao Ke, Joe Varberg, Sheng Xia, Ashley S. Howard, Michael Lydic, Kristin Holoch, Courtney Marsh, Elin Grundberg, Kaela Varberg

Manuscripts, Articles, Book Chapters and Other Papers

Recurrent pregnancy loss (RPL), defined as two or more consecutive miscarriages, affects 1-5% of couples attempting to conceive and most frequently occurs between 6 and 8 weeks of gestation, coinciding with critical stages of placental development. Despite this temporal association, placental contributions to RPL pathogenesis remain poorly understood. We hypothesized that trophoblast lineage development, including extravillous trophoblast (EVT) and syncytiotrophoblast (STB) differentiation, are disrupted in RPL. To test this hypothesis, we established and functionally characterized human trophoblast stem (TS) cell lines derived from products of conception (POC) obtained from consenting idiopathic RPL cases. Four TS cell lines were successfully derived …

2-Aminobutyrate Mediates The Impact Of Air Pollution On Blood Biomarkers Of Alzheimer’S Disease, Anum Saeed, Chris Mckennan, Jane E Clougherty, Peidi Zhou, Sheila Tripathy, Ellen J Kinnee, Jiaxuan Duan, Kevin Kip, Xuemei Zeng, Victor Villemagne, Tharick Pascoal, Mark Mapstone, Eric A Whitsel, Oscar I Lopez, Christie Ballantyne, Thomas K Karikari, Bing Yu, Steven Reis, Annie Cohen

Faculty, Staff and Students Publications

Introduction: We examined the impact of mid-life metabolites on late-life Alzheimer's disease (AD) plasma biomarkers and whether these metabolites mediate air pollution effects.

Methods: In the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) cohort, we applied high-dimensional regression and meditation models, adjusting for observed and latent confounders, with replication in the Atherosclerosis Risk in Communities (ARIC) study. Exposures included mid-life fine particulate matter (PM2.5), black carbon, metals, and metabolites. Outcomes were: late-life plasma p-tau(181, 217, and 231) and amyloid beta 42/40 (Simoa assays).

Results: In the Heart SCORE study, seven lipid- and amnio acid-pathway metabolites measured in mid-life were …

A Smoking-Related Plasma Protein Score And Smoking-Related Cancer Risk And Mortality In The Atherosclerosis Risk In Communities Study, Meng Ru, Christopher Douville, Aghiles Guenoun, Hana Zahed, Christie M Ballantyne, Kenneth R Butler, Josef Coresh, David J Couper, Panagis Galiatsatos, Marc J Gunter, Ron C Hoogeveen, Mattias Johansson, Corinne E Joshu, P Martijn Kolijn, Christina M Lill, Jiayun Lu, Michael T Marrone, Giovanna Masala, David C Muller, Anna E Prizment, Raul Zamora-Ros, Nilanjan Chatterjee, Adrienne Tin, Elizabeth A Platz

Faculty, Staff and Students Publications

Background: Self-reported smoking may not fully capture individualized risk of smoking-related cancer, but circulating proteins may reflect biological consequences of smoking. Thus, we developed a score based on smoking-related proteins and evaluated its association with smoking-related cancer.

Methods: This prospective cohort study included 10 563 participants aged 47-70 years in the Atherosclerosis Risk in Communities study. Plasma proteins were measured using the SomaScan Platform (SomaLogic Operating Co, Inc). The score was constructed from proteins associated with current smoking, pack-years, or recent quitting identified by linear regression and elastic net regression. Cox regression was used to estimate adjusted hazard ratios and …

Fructose: Metabolic Signal And Modern Hazard, Richard J Johnson, Miguel A Lanaspa, Dean R Tolan, Marcus D Goncalves, Samir Softic, Kimber L Stanhope, Laura G Sánchez-Lozada, Mark A Herman, Joshua D Rabinowitz

Faculty, Staff and Students Publications

There is much interest in the role of sweeteners such as table sugar (sucrose) and high-fructose corn syrup in obesity and metabolic disease. Both sweeteners consist of glucose and fructose, two six-carbon isomeric sugars. Whereas glucose ingestion may promote obesity through its effects to stimulate insulin secretion, fructose has unique metabolic effects that promote triglyceride synthesis and fat accumulation. These effects arise from fructose's well-known role as a signal of metabolic plenty. Under modern conditions of overnutrition, chronic excess fructose drives features of metabolic syndrome. Emerging evidence further links fructose to cancer and dementia. Here we review the biochemical, molecular …

Risk Factors For The Development Of Food Allergy In Infants And Children: A Systematic Review And Meta-Analysis, Nazmul Islam, Alexandro W L Chu, Falana Sheriff, Farid Foroutan, Gordon H Guyatt, Romina Brignardello-Petersen, Paul Oykhman, Alfonso Iorio, Ariel Izcovich, Katherine M Morrison, Yetiani Roldan Benitez, Rachel J Couban, Dorota Borovsky, Yiming Zhang, Leonardo Ologundudu, Keerthana Pasumarthi, Syed Fahad Farooq, Kyle Tong, Wang-Choi Tang, Haseeb Faisal, Muhammad Faran Khalid, Mohammad Saad Asif, Shannon French, Susan Waserman, R Sharon Chinthrajah, Hugh A Sampson, S Shahzad Mustafa, Jay A Lieberman, Kirsi M Järvinen, Sally Bailey, Philippe Bégin, Scott H Sicherer, Jennifer Gerdts, Melanie Carver, Lynda Mitchell, Kelly Cleary, Matthew J Greenhawt, Julie Wang, Aikaterini Anagnostou, Marcus S Shaker, Anita Chandra-Puri, Patricia C Fulkerson, Robert A Wood, Derek K Chu

Faculty, Staff and Students Publications

Importance: The incidence and risk (predictive) factors for early life food allergy development remain uncertain.

Objective: To estimate the incidence and quantify risk factors for food allergy development.

Data sources: MEDLINE and Embase were systematically searched to January 1, 2025. Data were analyzed from June 1, 2025, to November 25, 2025.

Study selection: Incidence estimates included studies confirming food allergy via food challenge. Risk factor analyses included cohort, case-control, and cross-sectional studies in any language assessing children younger than 6 years using multivariable analyses.

Data extraction and synthesis: Paired reviewers independently extracted data. Random-effects meta-analyses pooled incidence and adjusted odds …

Plasma Proteins Associated With Psychosocial Factors And Heart Disease: The Jackson Heart Study, Sara N O'Brien, Madeline G Gillman, Michael D Green, Daniel E Cruz, James S Floyd, Susan Hankinson, Daniel H Katz, Xiaojuan Liu, Michelle C Odden, Bruce M Psaty, Alexander P Reiner, Jerome I Rotter, Stephen S Rich, Robert E Gerszten, Amil Shah, Mario Sims, Usman A Tahir, Lesley F Tinker, Alexis C Wood, Bing Yu, Anthony S Zannas, Laura M Raffield, Láshauntá M Glover

Faculty, Staff and Students Publications

Background: Knowledge of proteomic mechanisms explaining the link between psychosocial stress and cardiovascular disease is limited. This study aimed to (1) identify plasma proteins associated with psychosocial factors and (2) assess associational pathways between psychosocial factors, identified proteins, and incident cardiovascular disease events in a discovery cohort, JHS (Jackson Heart Study), and 2 replication cohorts, the CHS (Cardiovascular Health Study), and the MESA (Multi-Ethnic Study of Atherosclerosis).

Methods: JHS participants from exam 1 (2000-2004) with SomaScan 1.3k platform proteomics data were included (n=2143, mean age=55.3). Depressive symptoms and perceived stress scores were measured via the 20-item Center for Epidemiological Studies …

Severe, Non-Apneic Respiratory Dysfunction And Hypoxia Following Generalized Convulsive Seizures, Haley E Pysick, Rup K Sainju, Roshni Nair, Deidre N Dragon, Eduardo Bravo, Laura Vilella, Xiaojin Li, Samden D Lhatoo, George B Richerson, Brian K Gehlbach

Faculty, Staff and Student Publications

Objective: Sudden unexpected death in epilepsy (SUDEP) is a devastating consequence of some generalized convulsive seizures (GCS). Recent work has focused on seizure related apnea as a biomarker of SUDEP risk, frequently without characterizing the adequacy of non-apneic ventilation or identifying other dysfunctional breathing patterns. We hypothesized that GCS frequently induce immediate, severe, non-apneic respiratory dysfunction that can induce critical hypoxia and bradycardia and sought to characterize breathing patterns after GCS.

Methods: Adult patients admitted to an epilepsy monitoring unit were studied. The effects of GCS on breathing and heart rate were analyzed using nasal pressure transducers, chest and abdominal …

Multidisciplinary Approach To Complex Lower Extremity Limb Salvage In Pyogenic Arthritis, Pyoderma Gangrenosum, And Acne (Papa) Syndrome: A Case Report, Michael M Talanker, Anthony V Basta, Tien Do, Robert Tung, Addison Allen, Morgan Martin, Bryan L Ruygrok, Patrick J Kellam, Jeffrey G Trost, Mohin A Bhadkamkar

Faculty, Staff and Student Publications

Limb salvage using free tissue transfer in patients with rare autoinflammatory syndromes is poorly described, and the safety of microvascular reconstruction in this population remains uncertain. Hereditary pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is characterized by dysregulated inflammation, pathergy, and impaired wound healing, raising concern for flap compromise and postoperative complications. We report a rare case of lower extremity free tissue transfer in a patient with PAPA syndrome. A 66-year-old woman with rheumatoid arthritis and PAPA syndrome presented with rapid wound breakdown, violaceous ulceration, exposed hardware, and periprosthetic joint infection following left total knee arthroplasty (TKA). Examination revealed …

Long Covid Persistence And Surveillance Gaps Across 58 Us Hospitals, Jiazi Tian, Alaleh Azhir, Matthew Decaro, Ngan Chau, Jonas Hügel, Michele Morris, Jingya Cheng, Pedram Fard, Ingrid V Bassett, Douglas S Bell, Elmer V Bernstam, Shyam Visweswaran, Jeffrey G Klann, Shawn N Murphy, Hossein Estiri

Faculty, Staff and Student Publications

Importance: Surveillance of postacute sequelae of SARS-CoV-2 infection (PASC) depends on diagnostic coding systems that capture fewer than one-half of affected individuals, rendering millions invisible to health systems and policymakers.

Objective: To quantify the gap between true PASC burden and diagnostic code-based estimates, determine the proportion representing chronic disease, and characterize organ system heterogeneity and temporal trends across diverse populations.

Design, setting, and participants: This retrospective cohort study used electronic health record data from 58 hospitals and affiliated clinics in 4 US regions, from 2017 to 2025. Adults (aged ≥18 years) with laboratory-confirmed SARS-CoV-2 infection or a COVID-19 diagnosis code …

Ucva Ontology: Standardizing Local Context Factors To Support The Analysis Of Unwarranted Clinical Variation, Apollo Mcowiti, Xubing Hao, Rebecca Z Lin, Laila Rasmy-Bekhet, Cui Tao, Susan Fenton

Faculty, Staff and Student Publications

Objectives: Unwarranted clinical variation (UCV), defined as care provided to a patient that is not proportional to the patient's needs, clinical characteristics, or preferences, results in negative patient outcomes. UCV detection is performed to compare healthcare outcomes across regions or organizations and reduce UCV incidences. However, the lack of standardized UCV concepts and the local context factors hinder the interoperability of UCV analyses between organizations. Currently, UCV analysis relies on centralized analysis, posing challenges due to the proprietary nature of an organization's healthcare and operational data. Standardizing analysis factors enables interoperable analyses by establishing a common context between organizations. This …

Computational Modeling Meets 3d Bioprinting: Emerging Synergies In Cardiovascular Disease Modeling, Tanmay Mukherjee, Mehdi Salar Amoli, Sarah Rezapourdamanab, Lama Rita El Shammas, Martin L Tomov, Emilio A Mendiola, Vahid Serpooshan, Reza Avazmohammadi

Faculty, Staff and Student Publications

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide, underscoring the need for improved strategies in diagnosis, treatment, and disease modeling. Traditional in vitro models often fall short in replicating human CV physiology, prompting efforts to advance cardiac tissue engineering and computational modeling. Among these, three-dimensional (3D) bioprinting has emerged as a transformative tool, enabling the creation of biomimetic CV constructs that more faithfully replicate native tissue structure and function. However, challenges persist in achieving appropriate mechanical properties and long-term performance of engineered CV constructs. Computational modeling offers powerful solutions to assist with these challenges, providing predictive insights into …

Estrogen As A Therapeutic Agent: Targeting Endotheliopathy And Coagulopathy In Trauma, Niruktha Raghavan, Mira Patel, Bryan A Cotton, Julia Coleman, Donald Jenkins

Faculty, Staff and Student Publications

Background: Traumatic injury remains a leading cause of death, often due to uncontrolled hemorrhage and trauma-induced coagulopathy (TIC). TIC is critically triggered by the endotheliopathy of trauma, involving endothelial cell injury and glycocalyx degradation. Despite conventional advances, the stable casualty rate underscores the urgent need for new precision resuscitation strategies that acknowledge factors like biological sex.

Design: The central hypothesis is that estrogen confers a survival advantage in hormonally active females through a dual action: endothelial cell stabilization (halting glycocalyx shedding) and its inherent procoagulant effect. The analysis assesses the therapeutic potential of both exogenous estrogen and female-derived blood products …

Promises, Pitfalls, And Paths Forward For The Pediatric Research Equity Act., Alexa L. Pagano, Danielle J. Green, Jennifer Goldman, Anjali Deshmukh

Manuscripts, Articles, Book Chapters and Other Papers

IMPORTANCE: Since its enactment in 2003, the Pediatric Research Equity Act (PREA) has significantly increased the number of pediatric drug studies performed and expanded pediatric drug labeling. Despite these advancements, many drugs used in children still lack pediatric-specific US Food and Drug Administration (FDA) labeling, even when pediatric studies are required by law. Recent legislative changes strengthened the FDA's enforcement authority over PREA. As these changes are implemented, persistent gaps in pediatric drug development warrant examination. Addressing these gaps may help ensure that children are systematically included in clinical research and that medications used in children are supported by rigorous …

High-Penetrance Rare Variants Underlying Familial Lung Cancer Risk: Insights From Genetic Epidemiology Of Lung Cancer Consortium, Yanhong Liu, Yafang Li, Jinyoung Byun, Vikram R Shaw, Claudio Pikielny, Bo Peng, Chao Cheng, Spiridon Tsavachidis, Xiangjun Xiao, Dakai Zhu, Younghun Han, Ivan P Gorlov, Olga Y Gorlova, Michael Cole, Colette R Gaba, Erin L Crawford, Kristen Purrington, Ellen L Goode, Ping Yang, James Mckay, John K Field, Geoffrey Liu, Rayjean J Hung, Jun Xia, Jiyeon Choi, Matthew B Schabath, Jaclyn Lopiccolo, David C Christiani, Joan Bailey-Wilson, Ann G Schwartz, James C Willey, Diptasri Mandal, Susan M Pinney, Christopher I Amos

Faculty, Staff and Students Publications

Introduction: Rare, deleterious germline variants are key contributors to inherited lung cancer (LC) risk. The Genetic Epidemiology of LC Consortium (GELCC) has curated valuable high-risk LC families and is uniquely positioned to uncover rare, high-penetrance variants underlying familial LC (FLC).

Methods: We performed whole-genome and exome sequencing on germline DNA from 120 high-risk LC families (177 FLC cases, 309 unaffected relatives). We prioritized rare (allele frequency < 1% in the genome aggregation database), potentially deleterious variants present in two or more FLC cases. These variants were then validated in 10,085 sporadic LC (SLC) cases and 612,970 controls.

Results: We identified 118 candidate variants, 28 of which were validated in SLC with strong statistical support. We discovered a novel pathogenic axis of three truncating variants in GALNT6, MUC4, and ERBB3 genes, which …

Phenotypic Diversity And Outcomes In Pediatric Nmda Receptor Encephalitis: A 15-Year Retrospective Study From The Largest Children's Hospital In The United States, Alexander J Sandweiss, Timothy Erickson, Yike Jiang, Varun Kannan, Jonathan M Yarimi, Kristen S Fisher, Nikita Shukla, Tim Lotze, Eyal Muscal, Kristy O Murray

Faculty, Staff and Students Publications

Anti‐NMDAR encephalitis (NMDARE) is an autoantibody‐mediated disorder characterized by seizures, movement disorders, neurocognitive deficits, and psychosis, but the complete phenotypic heterogeneity, and outcomes are incompletely understood in children. This single‐center retrospective analysis of NMDARE at the largest pediatric hospital in the United States between 2009 and 2024 screened 115 patients diagnosed with NMDARE. 103 had sufficient clinical data available for analyses. Two‐thirds were Hispanic, disproportionate to the Houston metro area demographics, and Hispanic patients had a higher CSF white cell count and antibody titer. Approximately one‐half of the patients with idiopathic NMDARE presented with a focal cortical phenotype that localized …

Interplay Between Genetic Ancestry, Self-Reported Race And Ethnicity, And Clinical Factors In Pediatric Acute Lymphoblastic Leukemia: A Redial Consortium Report, Pragati Kore, Jennifer M Geris, Maria Leon-Camarena, Maria I Castellanos, Olga A Taylor, Veronica Garcia-Morales, Austin L Brown, Pagna Sok, Jeremy M Schraw, Van Huynh, Kathleen F Ludwig, Laura J Klesse, Sandi L Pruitt, Amy E Hughes, Kevin Tien, Kenneth M Heym, Timothy Griffin, Rodrigo Erana, Juan Carlos Bernini, Maria M Gramatges, Elizabeth G Atkinson, Philip J Lupo, Michael E Scheurer, Karen R Rabin

Faculty, Staff and Students Publications

Background: Pediatric acute lymphoblastic leukemia (ALL) is the most common cancer in children, and its incidence and outcomes vary by race and ethnicity.

Methods: The Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium has assembled a cohort of patients < 25 years at diagnosis to examine genetic and neighborhood-level factors influencing ALL. As the cohort is ongoing, for this report, we examined sociodemographic and cytogenetic factors that might be associated with ALL outcome disparities.

Results: Among 2,512 patients diagnosed between 2005 and 2020, we observed distinct patterns of genetic ancestry and residential characteristics across self-reported race and ethnicity. Latino children, who comprised 55.3% of the cohort, had a mean Amerindigenous ancestry proportion of 50.9%, whereas non-Latino White children exhibited a predominantly European ancestry (mean = 78%). Neighborhood-level analysis revealed significant socioeconomic and geographic differences by …

Adaptive Evolution Of Gene Regulatory Networks In Mammalian Neocortex, Zhuo Li, Linda J Richards, Et Al.

2020-Current year OA Pubs

Mammals have evolved a more complex brain, exemplified by the transformation of the single-layer dorsal cortex of excitatory projection neurons (ExNs) in ancestors into a multilayered cerebral neocortex

Sustainment Of Hydroxyurea Adherence In Patients With Sickle Cell Disease, Andrew M Heitzer, Zachary Wooten, Guangjin Luo, Marsha Treadwell, Allison A King, Victor R Gordeuk, Nirmish Shah, Christina M Abrams, Sarah Mccuskee, Siera Gollan, Jennifer Longoria, Jane S Hankins, Sickle Cell Disease Implementation Consortium

2020-Current year OA Pubs

IMPORTANCE: Despite established treatment guidelines and strong therapeutic benefit, hydroxyurea remains underused among patients with sickle cell disease.

OBJECTIVE: To assess the change in self-reported hydroxyurea use (ie, taking the medication at all) and adherence (ie, the number of days taken per week) over time and to examine factors associated with the trajectory of hydroxyurea use and adherence.

DESIGN, SETTING, AND PARTICIPANTS: Data were collected through the Sickle Cell Disease Implementation Consortium, a longitudinal, multicenter, observational cohort study that recruited patients from 8 centers across the US. Data collection occurred from 2017 to 2022, and analyses were performed from January …

A Covalent Allosteric Molecular Glue Suppresses Nrf2-Dependent Cancer Growth, Nilotpal Roy, Ilah Bok, Harit Panda, Dhaval P Bhatt, Emily M Wilkerson, Soma Saeidi, Paul Zolkind, Michael B Major, Et Al.

2020-Current year OA Pubs

UNLABELLED: The NRF2 transcription factor is constitutively active in cancer, in which it functions to maintain oxidative homeostasis and reprogram cellular metabolism. NRF2-active tumors exhibit NRF2 dependency and resistance to chemotherapy/radiotherapy (RT). In this study, we characterize VVD-065, a first-in-class NRF2 inhibitor that acts via an unprecedented allosteric molecular glue mechanism. In the absence of stress or mutation, NRF2 is rapidly degraded by the Kelch-like ECH-associated protein 1 (KEAP1)-cullin3 (CUL3) ubiquitin-ligase complex. VVD-065 specifically and covalently engages Cys151 on KEAP1, which in turn promotes KEAP1-CUL3 complex formation, leading to enhancement of NRF2 degradation. Previously reported Cys151-directed compounds decrease KEAP1-CUL3 interactions …

From Low Field To High Value: Robust Cortical Mapping From Low-Field Mri, Karthik Gopinath, Timothy Coalson, Matthew F Glasser, David Van Essen, Et Al.

2020-Current year OA Pubs

Three-dimensional reconstruction of cortical surfaces from MRI for subsequent morphometric analysis is fundamental for understanding brain structure. While high-field Magnetic Resonance Imaging (HF-MRI) is the standard in research and clinical settings, its relatively limited availability hinders widespread use. Low-field MRI (LF-MRI), particularly portable systems, offers a cost-effective and accessible alternative. However, existing cortical surface analysis tools, such as FreeSurfer, are optimized for high-resolution HF-MRI and struggle with the lower signal-to-noise ratio (SNR) and resolution of LF-MRI. In this work, we present a machine learning method for 3D reconstruction and analysis of portable LF-MRI scans over a range of contrasts and …

Inherited Tbx4 Frameshifting Variants Predicted To Escape Nonsense Mediated Decay In Two Families With Variable Phenotypes, Including Lethal Lung Developmental Disorders, Shruti A Pande, Hiuling Chan Joiner, Przemyslaw Szafranski, Tomasz Gambin, Michelle Wright, Qian Wang, Maiah Walters, Jan M Friedman, Jessica Saunders, Nicholas Avdimiretz, Cornelius F Boerkoel, Nahir Cortes-Santiago, Gail Deutsch, Pawel Stankiewicz

Faculty, Staff and Students Publications

Background: Pathogenic variants involving the transcription factor TBX4 gene have been associated with various skeletal and pulmonary abnormalities, including lethal lung developmental disorders (LLDD).

Methods: Whole-genome sequencing (WGS) with AI-powered platform for variant detection and interpretation followed by Sanger sequencing targeted variant segregation analysis were used. Reverse transcription quantitative PCR (RT-qPCR) and immunohistochemistry (IHC) studies were performed to assess gene and protein expression levels, respectively.

Results: We describe two unrelated families with intrafamilial variability in the TBX4 phenotypic expressivity, including LLDDs. WGS analyses revealed two frameshift variants, c.1019del; p.(Arg340GlnfsTer40) in the penultimate exon and c.1167dup; p.(Arg390GlnfsTer30) in the last exon …