Mercy Research

Some of the most daunting challenges facing health care today are complex (as opposed to complicated), and leadership approaches developed for merely complicated work (emphasizing measurement, efficiency, and standardized practices) have limited effectiveness. The decision-making processes honed by clinicians in medical school and residency, which emphasize teamwork, hypothesis-testing, and rapid adaptation, are better suited to complex problems than the processes typically taught in business and health administration programs, and organizations can benefit from harnessing their clinicians’ skills to address complex operational problems.

The objectives of this study were to investigate associations between co-occurring developmental, psychiatric, behavioral, and medical symptoms and conditions and autism spectrum disorder (ASD) traits, as well as predictors of changes in autistic traits from early childhood to adolescence. Participants from the Study to Explore Early Development (SEED) were identified as having autism spectrum disorder (ASD) (n = 707), another developmental disorder (DD) (n = 995), or as a population comparison group (POP) (n = 898). Caregivers completed the Social Responsiveness Scale-2nd edition (SRS-2) to measure autistic traits and were asked about co-occurring symptoms and conditions when their child was 2-5 years old and 12-16 years old. Children completed the Mullen Scales of Early Learning (MSEL) when they were 2-5 years old. Regression models revealed that in early childhood and adolescence, multiple co-occurring symptoms and conditions were significantly associated with higher SRS-2 scores (e.g., motor, sensory, and sleep problems for children with ASD and DD). Within the ASD and DD groups, but not the POP group, lower MSEL scores at childhood were associated with greater increases in SRS-2 scores between early childhood and adolescence. Findings suggest that motor, sensory, and sleep problems may be important intervention targets for ASD and DD youth with elevated SRS-2 scores and that interventions that target cognitive functioning in childhood may be important to modify trajectories of autistic traits from childhood to adolescence.

Abstract Description Autoantibodies are host-targeting antibodies typically removed through immune tolerance mechanisms. The presence of autoantibodies is commonly associated with autoimmune conditions such as systemic lupus erythematosus and rheumatoid arthritis, however recent large cohort studies have identified healthy individuals possess autoantibodies with ability to regulate immune response. The origin and functions of autoantibodies in individuals without autoimmune disease is not well characterized. Here, we identified autoantibodies directed against intracellular adhesion molecule 1 (ICAM-1), a cell surface glycoprotein important for inflammation and immune cell adhesion that is widely exploited by pathogens for cell entry. Serum from healthy individuals maintained heterogenous levels of anti-ICAM-1 antibodies and ICAM-1 autoantibody levels were associated with age. Individuals with inflammatory conditions, such as severe COVID-19 or autoimmune disease, had significantly less anti-ICAM-1 antibodies compared to healthy controls. Using peptide microarrays, we determined immunodominant epitopes targeted across individuals by ICAM-1 autoantibodies. Finally, we identified that anti-ICAM-1 antibodies could inhibit cellular adhesion of immune cells, disrupting immune system function. The findings of this study elucidate autoantibodies against ICAM-1 could play a role in immunoregulation during inflammation and may provide a future target for managing immune response. Funding Sources Supported by Children’s Mercy Research Partners, Children’s Mercy Research Institute, and Paul Henson Endowment Clinical Scholar Award Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)

BackgroundCell migration and invasion are well‐coordinated in development and disease but remain poorly understood. We previously showed that the neural crest (NC) cell migratory wavefront shares a 45‐gene panel with other cell invasion phenomena. To rapidly and systematically identify critical genes, we performed a high‐throughput siRNA screen and statistical and deep learning analyses to determine changes in NC‐ versus non‐NC‐derived human cell line behaviors.ResultsWe find 14 out of 45 genes significantly reduced c8161 melanoma cell migration; four of the 14 genes altered leader cell motility (BMP4, ITGB1, KCNE3, and RASGRP1). Deep learning identified marked disruptions in cell‐neighbor interactions after BMP4 or RASGRP1 knockdown in c8161 cells. Recombinant proteins added to the culture media revealed five out of the 11 known secreted molecules stimulated c8161 cell migration. BMP4 knockdown severely reduced c8161 in vivo invasion in a chick embryo transplant model. Addition of BMP4 protein to the culture media of BMP4‐siRNA‐treated c8161 cells rescued cell migratory ability.ConclusionHigh‐throughput screening and deep learning distilled a 45‐gene panel to a small subset of genes critical to melanoma and warrant deeper in vivo functional analysis for their role and potential synergies in driving NC cell migration and invasion.

ABSTRACTObjectiveTo describe the utilization patterns and outcomes of pediatric patients supported with oxygenators during their ventricular assist device (VAD) course.DesignMulti-center, retrospective cohort study using data from the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) registry.SettingData query from the ACTION registry, which collects clinical data on pediatric patients with end-stage heart disease, reported cases of combined oxygenator-VAD use.PatientsSixty-one pediatric patients (27 female) from 21 contributing ACTION centers were supported on oxygenators during their VAD course between 2013-2024. The median age was 272 days (IQR 68-1334), and the median weight was 7.9kg (IQR 4.4-12). The majority had congenital heart disease (CHD), with 66% having single-ventricle pathology.InterventionsNone.Measurement and Main ResultsThe study population demonstrated high illness severity at the time of VAD implant, with 97% requiring inotropic support, 79% requiring mechanical ventilation, and 46% on ECMO. The total median duration of VAD support was 45 days (IQR 16-163). Of the 61 patients, 44% achieved transplant or recovery. The mortality rate was high at 52%, and was associated with younger age, smaller size, CHD and pre-implant use of neuromuscular blocking agents. Adverse events included infection (36%), major bleeding (36%), central nervous system injuries (21%), and dialysis (20%). None demonstrated clinically significant association with oxygenator support timing, but mortality was associated with higher adverse events rates, particularly pulmonary hemorrhage, dialysis, and infections (especially mediastinitis).ConclusionPediatric patients requiring oxygenators during VAD therapy exhibit high illness severity and frequent adverse events. Mortality is high and associated with younger age, smaller size, CHD, pre-implant use of neuromuscular blocking agents as well frequency of on-device adverse events, particularly pulmonary hemorrhage, dialysis, and infections. Oxygenator support likely reflects disease severity rather than directly contributing to mortality. Further investigation is needed to optimize patient selection and management strategies.Research In ContextOver the past two decades, pediatric VAD utilization has increased. Support from collaborative networks like ACTION has enabled investigation of nuanced strategies, such as temporary oxygenator use, providing a platform to evaluate feasibility, safety, and patient-specific considerations across diverse populations.In adult populations, oxygenator use alongside VADs has been employed for respiratory failure, ARDS, RV support, and as a bridge to lung transplant or transition from ECMO. However, these strategies have not been systematically studied in pediatric cohorts until now.This study presents the most comprehensive review of pediatric (or adult) oxygenator-VAD support to date, characterizing patient populations, utilization patterns, and associated outcomes. It provides foundational data for guiding future research into management strategies in this high-risk group.At the BedsidePediatric patients requiring oxygenator support during VAD therapy were typically younger, smaller, and had complex congenital heart disease, particularly single-ventricle physiology. These characteristics were associated with higher mortality and reflect a population with profound critical illness at baseline.This cohort experienced high rates of adverse events, including major bleeding, infections, dialysis, and neurologic injury. While oxygenator timing was not independently associated with outcomes, mortality exceeded 50% and was linked to complications such as dialysis, pulmonary hemorrhage, and infections.Clinicians should view oxygenator-VAD support as a surrogate marker for extreme illness severity rather than a direct contributor to poor outcome. This study highlights the need for tailored management strategies and informs clinician and family decision-making in this high-risk population.

Abstract Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma (DIPG), are the most aggressive pediatric brain tumors with a median survival of less than one year. Over 85% of DMGs harbor the H3K27M mutation in histone genes H3F3A (H3.3) and H3C2 (H3.1), which inhibits EZH2, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), leading to global loss of H3K27 trimethylation (H3K27me3). This epigenetic disruption drives oncogenesis by reprogramming gene expression and activating oncogenic pathways. Current treatments, including chemotherapy and radiotherapy (IR), offer marginal benefits, with 95% of patients dying within 1.5 years of diagnosis. ONC201 has shown clinical benefits in H3K27M-mutant DMGs, extending median survival to 21.7 months by disrupting metabolic and epigenetic pathways and reversing H3K27me3 loss. Novel therapeutic strategies targeting H3K27M oncohistone are urgently needed. We performed high-throughput screening (HTS) of 1, 520 FDA-approved compounds to identify drugs that selectively target H3K27M-mutant primary DMG cell lines, but not CRISPR-corrected H3K27M-KO lines, derived from distinct neuroanatomical location: the thalamus (BT-245) and the pons (DIPGXIIIP). From this screening, we identified 86 promising drugs, further narrowed down to five lead compounds: floxuridine, gemcitabine, cytarabine, pyrimethamine, and cladribine (HTS-identified lead candidates, HTS-ILCs). These HTS-ILCs exhibited potent cytotoxicity against other patient-derived H3K27M-mutant DMG lines (DIPG007, SF8628) and murine PPK cells (DNp53/PDGFRA/H3.3K27M) from genetically engineered mouse models (GEMMs). HTS-ILCs were further tested for radiosensitizing potential, with floxuridine, gemcitabine, cytarabine, and pyrimethamine showing enhanced efficacy when combined with IR. Western blot analysis confirmed H3K27me3 restoration, indicating epigenetic modulation and reduced DMG growth. Combining IR, HTS-ILCs, and ONCs (201/206/212) showed synergistic effects and reversed epigenetic dysregulation. Gemcitabine exhibited strong anti-invasive properties, followed by floxuridine against H3K27M mutant DIPGXIIIP and SF8628 cells. Conditioned medium from HTS-ILCs-treated PPK cells showed enhanced HMGB1 secretion, suggesting activation of an immune-stimulatory response. Ongoing in vivo testing includes orthotopic implantation of PPK cells in immune-competent murine models and IUE-generated GEMMs of H3K27M DMGs. Spatial transcriptomics and phosphoproteomic microarray analysis are being used to elucidate the molecular mechanisms. Our findings suggest that combining HTS-ILCs with IR, alone or with ONC therapies, offers a promising strategy for treating H3K27M-mutant gliomas, potentially leading to more effective, personalized therapies for children with DMGs. Citation Format: Syed M. Faisal, Monika Yadav, Garrett R. Gibson, Adora T. Klinestiver, Ryan Sorenson, Anuradha Roy, Carl Koschmann, Scott J. Weir, Stefan H. Bossmann, Viveka N. Yadav. High-throughput identification of radiosensitizers and synergistic drug combinations with potent therapeutic efficacy against diffuse midline glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3153.