Objectives/Goals: Community engagement is required to translate scientific discovery into improvements in health. Lived experience is essential knowledge for translational research activities. Community studios facilitate interaction between researchers and community members, but mechanisms of how lived experience integrates into research are under explored. Methods/Study Population: The community studio program at the Center for Community Health Partnership and Research was evaluated through interviews with participating community health consultants (CHCs) and researchers. Fifteen facilitated community studios held since 2023 were included. Study participation was organized by studio: invitations went to all researchers, and then to three CHCs randomly selected from each researcher’s studio. Rapid qualitative analysis methods were used to create analysis templates based on key questions from the interview guide. Interview notes were summarized according to the template and compiled into matrices for study team reflection and discussion. Responses to key questions were articulated during group discussions and iteratively refined. Results/Anticipated Results: Thirteen researchers and 25 CHCs were interviewed from April to June 2025. Eighty-six percent of researchers had a research degree, either a PhD or Master’s; 85% were associate or full professors. None reported formal training in community engaged research. Several types of knowledge gaps were filled including correction of faulty assumptions, awareness of the impacts of SDOH, and ideas for solving operational challenges. CHCs were 80% female. CHCs felt valued during the studio experience, received benefit from hearing the lived experiences of others, and gained new perspectives on their health issue. CHCs expressed a desire to know the impact their participation had on the research, and several said they would have to see it to believe it. Both researchers and CHCs appreciated the expert facilitator. Discussion/Significance of Impact: Everyone learned during studios. Eliciting lived experience filled different knowledge gaps. Sharing provided social benefits and studios functioned like a third space, a merging between the built and social environment. An expert facilitator played key roles that included fostering belonging and translation of lived experience into knowledge.

Objectives/Goals: We aim to enhance risk prediction in kidney transplantation outcomes by improving models of peptide antigen presentation of mismatched HLA molecules. HLA-derived peptides presented by recipient HLA Class II to T-cells can activate an immune response ultimately leading to graft failure. Methods/Study Population: T-cell epitope models for HLA mismatching struggle to predict which peptides are presented because antigen processing by proteases is not well modeled. We model antigen processing of HLA Class II proteins using 3D HLA structures (crystallography data) to create an HLA-specific Antigen Processing Likelihood (APL) model. APL uses conformational stability measurements to predict cleavage sites from proteolysis. We integrated APL into a T-cell epitope prediction tool for HLA-derived peptides called PIRCHE-II that is currently used to risk-stratify risk of kidney allograft failure based on donor and recipient HLA genotypes. To measure risk stratification of APL-informed peptide predictions, we will use a historical kidney transplant cohort from 2000 to 2023. Results/Anticipated Results: We expect the application of APL could reduce false- positive peptide binders that influence risk prediction scores. We anticipate improved peptide prediction accuracy compared to existing tools such as NetMHCIIPan which assumes all possible peptides are equally likely to emerge from antigen processing. NetMHCIIPan is currently used by PIRCHE-II HLA mismatch risk algorithm. Out of 12 donor–recipient transplant pairs, NetMHCIIPan has found an average of 41 peptides per pairing and APL found an average of 62 peptides per pairing. These peptides are unique to each prediction, so a combined prediction could reduce the peptide list. We expect that merging antigen processing (APL) and peptide binding (NetMHCIIPan) models into a unified model would enhance risk stratification for graft failure compared to PIRCHE-II. Discussion/Significance of Impact: More holistic modeling of immune pathways can lead to more realistic numbers of peptides found from mismatched HLA proteins. Understanding how HLA matching contributes to kidney transplant outcomes can better stratify risks for recipients, enabling personalized treatment to induce immune tolerance and ultimately improving outcomes.

Objectives/Goals: We evaluated the associations of urine uranium with incident chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1.73m2), incident albuminuria (albumin-to-creatinine ratio >30 mg/g), and baseline and follow-up plasma metabolite levels in participants without diabetes across the Great Plains and Southwest. Methods/Study Population: We evaluated participants with available urine uranium estimates, eGFR, uACR, and other variables of interest. In incident case analyses, participants were free of CKD (N=1,845) and albuminuria (1,693) at baseline (2001-2003). We used generalized estimating equations, clustering on family identifier, to estimate risk ratios (RRs) of incident CKD and albuminuria per doubling of urine uranium adjusted for sex, age, eGFR or uACR, study center, educational level, smoking status, BMI, and arsenic exposure. Nontargeted metabolomic profiling was analyzed by gas chromatography-mass spectrometry. In metabolome-wide association analyses, we used adjusted linear mixed models to estimate the association of urine uranium (N=1,223) with relative changes in metabolite concentrations over time. Results/Anticipated Results: Overall, the median (IQR) age was 35.9 (23.7, 46.8) years and 60% participants were female. The number of incident CKD cases was 28 (mean follow-up 5.6 years), and the number of albuminuria cases was 140. The adjusted RR (95% CI) per doubling of urine uranium was 0.90 (0.71, 1.15) for incident CKD and 1.00 (0.92, 1.08) for incident albuminuria. In metabolome-wide analyses, urine uranium was associated with a relative change in 8 unique metabolites and 31 unknown metabolomic features (p-value <0.05), with 5 unique metabolites (threonic acid, N-acetylornithine, isocitric acid, cellobiose, and 6-deoxyglucose) and 7 unknown metabolomic features reaching false discovery rate significance (BH-adjusted p-value <0.05). Discussion/Significance of Impact: Urine uranium was not associated with incident CKD nor with albuminuria. We identified 5 unique metabolites associated with urine uranium. Our findings are relevant for uranium-related kidney disease in people without diabetes, but require additional confirmation due to potential reverse causality and lack of drinking water uranium exposure.

Objectives/Goals: To evaluate the feasibility of developing salivary DNA methylation-based biomarkers for objective diagnosis and stratification of Temporomandibular Disorders (TMD), addressing the critical need for quantitative diagnostic tools to complement current subjective assessments and clinical examinations. Methods/Study Population: This cross-sectional pilot study enrolled 13 TMD patients and 4 pain-free controls from the University of Minnesota TMD Orofacial Pain Clinic. Participants underwent comprehensive DC/TMD diagnostic evaluation and completed validated instruments measuring pain intensity (VAS), psychological status (PHQ-9, PCS), and functional impairment (GCPS). Saliva samples were analyzed using Illumina EPIC BeadChip arrays interrogating ~850,000 CpG sites. Bioinformatic analyses included principal component analysis, identification of differentially methylated sites, and development of composite Methylation Profile Scores for patient stratification Results/Anticipated Results: Principal component analysis showed clear clustering separation between TMD patients and controls. Methylation profile scores demonstrated clear stratification between controls, high-impact, and low-impact TMD subgroups. High-impact TMD participants (n=6) showed significantly elevated clinical severity scores compared to low-impact TMD (n=7): pain intensity (52.0±11.3 vs 25.0±13.8), depression (20.5±7.3 vs 8.4±4.9), and catastrophizing (12.6±8.1 vs 6.4±6.5). Promoter-level analysis identified candidate genes associated with TMD severity phenotypes, supporting the potential for epigenetic biomarkers to enable objective patient stratification and guide precision treatment selection. Discussion/Significance of Impact: Epigenetic biomarkers capturing TMD heterogeneity could transform clinical practice by enabling early-risk stratification, preventing progression to high-impact chronic pain through personalized interventions, and reducing the substantial healthcare burden of this prevalent orofacial pain condition.

Objectives/Goals: This research aims to develop a regulatory and clinical framework that integrates pharmacogenomic testing into opioid prescribing in order to optimize analgesic efficacy, minimize toxicity, and reduce the incidence of serious adverse events in chronic pain and palliative care populations. Methods/Study Population: A structured literature review was conducted using PubMed, Google Scholar, and ClinicalTrials.gov (2010–2025) with the terms “CYP2D6,” “COMT,” “OPRM1,” “opioid,” “pharmacogenomics,” and “precision dosing.” Human studies evaluating genotype–response, adverse events, or dosing variability were included. The FDA REMS database and Federal Register were reviewed to determine how pharmacogenomic testing could be integrated into existing Elements to Assure Safe Use. CPIC and PharmGKB guidelines were consulted to confirm gene–drug clinical relevance, while CMS reimbursement data were analyzed to assess coverage feasibility and implementation barriers. Results/Anticipated Results: Clinical trial “Pharmacogenetics and Pharmacokinetics of Oxycodone to Personalize Post-Operative Pain Management” shows that CYP2D6 genotype significantly alters oxycodone metabolism and analgesic response. Poor metabolizers experience reduced pain relief, while ultra-rapid metabolizers face increased toxicity with codeine, tramadol, and oxycodone. COMT variants affect pain sensitivity and morphine dosing, and OPRM1 A118G influences receptor binding and opioid response. Although opioid REMS programs do not include PGx testing, Vanda v. West-Ward (2018) supports integration, while CMS data show higher reimbursement for multigene panels ~74% than single-gene tests ~43%, reinforcing feasibility. Discussion/Significance of Impact: Adverse drug reactions remain a leading cause of preventable mortality. Integrating pharmacogenomic testing into REMS would advance precision opioid prescribing, reduce toxicity, and improve pain management while creating a scalable model for personalized therapeutics.

Objectives/Goals: Improvements in acute stroke treatment, including critical care management, have increased survival rates post-stroke. However, many stroke survivors have significant neurological deficits, and stroke remains a leading cause of long-term disability. We aim to study the chronic progression and long-term sequelae of ischemic stroke pathology. Methods/Study Population: We examined long-term neurobehavioral recovery and progressive neuropathology of young (3 months) and middle-aged (14 months) adult male and female C57Bl/6 mice at 1, 3, and 6 months after a 60-minute transient middle cerebral artery occlusion (MCAO) or sham surgery, as well as histopathological analysis of post-mortem brain samples from patients with a chronic infarct. Behavioral examination included the tail suspension test, the novel object recognition test (NORT), and the fear conditioning test (FCT). Molecular and pathological analyses included bulk transcriptomic screening, immunohistochemistry (IHC), flow cytometry, and atrophy analyses via MRI and microCT scanning. Results/Anticipated Results: In mice, depression-like behavior persisted for 6 months post-stroke (p<0.0001), while cognitive function progressively worsened from 3 to 6 months post-stroke as seen by NORT (6 months, p=0.0063). Memory retention deficits at 6 months were seen in the FCT (p=0.0084). Significant brain atrophy was evident by MicroCT and MRI at 2 and 6 months post-stroke. IHC showed significant demyelination (mouse p=0.0361; human p=0.0001) and increased microglial (p=0.0059) and astrocyte activation. TUNEL co-labeling with a neuronal marker showed neuronal apoptosis in human samples of chronic stroke. Disease-associated microglia (DAM) displayed senescent-like phenotypes. Nanostring showed neuroinflammatory pathway upregulation up to 6 months PS. Human stroke brains had more amyloid plaque (p=0.06). Discussion/Significance of Impact: Cellular senescence and chronic neurodegenerative signatures likely result in poor cognitive function that may progressively worsen after stroke. Studying this neurodegenerative etiology in the long-term post-stroke may offer viable targets for delayed stroke treatment, which would fill a severely unmet need for stroke survivors.

Objectives/Goals: To investigate how distinct KRAS mutations (G12D, G12V, and G12R) drive distinct molecular and phenotypic programs in pancreatic tumorigenesis, linking early lineage and signaling differences to clinical patterns such as stage at diagnosis, nodal status, and survival to ultimately inform allele-specific therapies. Methods/Study Population: We analyzed clinical cohorts (MSK-IMPACT n=1,360; COMPASS n=100) and conducted lineage-tracing studies in mice carrying KRAS-G12D, KRAS-G12V, or KRAS-G12R alleles under inflammatory, genetic, and pharmacologic perturbations. Spatial transcriptomic and proteogenomic profiling of resected PDAC tissues characterized EMT and immune signaling states. Functional studies assessed EGFR–PI3K/AKT–RAC1/VAV1 signaling, including RAC1 inhibition and constitutive AKT activation, to reveal allele-specific susceptibilities. Results/Anticipated Results: KRAS-G12D drove robust lineage plasticity, enhancer remodeling, and early neoplastic progression. KRAS-G12R/V showed limited EMT and increased inflammatory signatures, with impaired EGFR–RAC1/VAV1 activation restricting lineage reversion. Constitutive AKT activation rescued the tumor-initiating defect of KRAS-G12R in vivo, pinpointing a downstream signaling bottleneck, which could be exploited therapeutically. Spatial and transcriptomic profiling of resected human PDAC revealed that KRAS-G12R tumors were more often early-stage, node-negative, and linked to improved survival relative to KRAS-G12D. Discussion/Significance of Impact: Integrating patient and mouse data reveals a mechanistic hierarchy among KRAS alleles that governs lineage fate, signaling reliance, and clinical course, pointing to opportunities for allele-tailored therapeutic strategies in pancreatic cancer.

Objectives/Goals: Persistent gaps in inclusive research demand new approaches. We propose the Individualized and Differential Benefit (IDB) framework to develop tools that prioritize balance and elevate underrecognized voices within today’s research landscape. Methods/Study Population: The IDB framework ensures research benefits all, including individuals within underserved communities. To apply IDB, three criteria must be met: (1) inclusivity: work must apply to all and exclude none; (2) utility: work must benefit all stakeholders; and (3) differential benefit: work must offer greater advantages to individuals from any group who are most in need. This approach aims to elevate everyone while offering a tool to achieve equity. Results/Anticipated Results: Within the poster, we use two examples to illustrate IDB. In the first example, Health Outcome and Population Engineering, or HOPE, exemplifies how health outcomes are achieved with an individualized approach while population differences are modified. In the second example, Population Conscious Analysis, or PCA, is used to display a nuanced approach to analysis that yields an individual benefit while again yielding the opportunity for population-level differences. Discussion/Significance of Impact: IDB reframes public health research by prioritizing individual-level insights to drive precision, equity, and upstream interventions. It enables tailored strategies, community engagement, and scalable solutions that benefit all, but specifically those most in need.

Objectives/Goals: In peri- and postmenopausal women, to determine 1) whether vasomotor symptoms (VMS) reflect underlying vascular and skeletal muscle dysfunction as well as cardiorespiratory fitness (CRF) and 2) to assess the impact of hormone replacement therapy (HRT) on VMS, vascular and muscular function, and CRF. Methods/Study Population: Peri- and postmenopausal women with 1) no/mild, 2) moderate, or 3) severe VMS will be recruited. Muscle and vascular function as well as CRF will be assessed at baseline and after 3 months in women who initiate VMS-specific therapy (HRT vs. SSRIs). Muscle function will be assessed as quadriceps strength (MVC), size (ultrasound), and contraction kinetics (nerve stimulation). Vascular function will be assessed as brachial flow-mediated dilation and carotid artery measures including intima-media thickness. CRF will be assessed during a graded cardiopulmonary exercise test. VMS will be tracked via ambulatory skin temperature, blood pressure, and heart rate (via wearable device(s)) and patient symptomology diaries completed during the 1st, 6th, and 12th week after treatment initiation. Results/Anticipated Results: We anticipate that 1) increasing VMS severity will be associated smaller muscle size and impaired function, worse vascular function, and lower CRF after correcting for independent variables (e.g., age, time in peri/menopause, BMI, and ethnicity); 2) HRT will result in great improvements in muscle and vascular function and CRF, as well as greater alleviation of VMS, compared to SSRIs initiation. Discussion/Significance of Impact: This research will elucidate potential physiological system correlates and dysfunction that occur during VMS events. This insight into the physiological underpinnings of VMS will inform optimal management strategies that can improve quality of life and cardiovascular health in menopausal women.

Objectives/Goals: Our goal is to determine whether insufficient Pumilio2 (Pum2) leads to neurological disorders. We identified predominantly young patients with mutations in PUM2 who suffer from developmental delays, motor incoordination, seizures, and so on. We will utilize Pum2 null mice to identify behavioral issues and neural degeneration. Methods/Study Population: We conducted several neurobehavioral assays with the Pum2 mutant mice (an estimated 40 mice) throughout their development. These assays measure learning and memory, motor coordination, spatial recognition, hyperactivity, and social cues. In addition to these experiments, we conducted immunofluorescence and Nissl staining to characterize brain morphology and Purkinje cells. Additionally, we collected patient-derived fibroblasts for qPCR and Western blot to measure the mRNA and protein levels of PUM2 in the different variants. Using both eCLIP and RNA sequencing, we will determine and rank targets bound by Pum2 in the murine brain. Results/Anticipated Results: At 12 weeks, we discovered Pum2 mutant mice exhibit neurological phenotypes that worsen with age development, such as motor incoordination, muscle atrophy, hyperactivity, impulsiveness, and compulsiveness. We observed a decrease in dendritic density in the Purkinje cells at 10 weeks of age, but no neural degeneration. However, we observed a reduction in dendritic density and aggressive Purkinje cell degeneration much later in adulthood. We obtained patient-derived fibroblasts to conduct Western and qPCR. We found that the missense mutations lead to a decrease in PUM2 protein and mRNA levels. These findings exhibit phenotypes similar to those observed in PUM2 patients, suggesting that insufficient levels of PUM2 lead to neurodevelopmental disorders and ataxia. Discussion/Significance of Impact: Pumilio2 is an RNA-binding protein from the PUF family that either promotes mRNA degradation or inhibits translation. It controls dendritic development and synaptic activity. PUM2 may be a novel ataxia gene that manifests neurodevelopmental problems.

Objectives/Goals: The Research Coordinator Plus (RC+) program was developed to provide comprehensive and accessible professional development at an academic institution to support high-quality human subjects research. The program supplements existing research training programs, is free, self-paced, and combines general knowledge with institution-specific practical applications. Methods/Study Population: RC+ is a professional development program created by the Center for Clinical and Translational Science (CCTS) for non-faculty staff involved in human subjects’ research. It covers regulatory, project management, and financial aspects across the research lifecycle, relevant to both biomedical and social/behavioral research. The program focuses on institutional policies and procedures, led by CCTS staff with stakeholder input. Follow-up surveys assess expectations and gather feedback on program content. The content was informed by best practices, the Joint Task Force for Clinical Competencies, workforce development programs at other CTSA-funded institutions, and input from our CCTS staff and a research advisory board. Results/Anticipated Results: RC+ is in its 4th year and enrollment has exceeded expectations. The program has built in flexibilities to allow greater access to professional development. It is free to attend with year-round enrollment and self-paced completion. Content is delivered by different modalities, including online, on-demand, and live and recorded virtual programs. To date, 279 individuals have registered, with 13 completing all requirements. 71 have left UIC without finishing. Self-reported research roles include research coordinator, grants manager, PI, and university administrator. Survey response to date has been low, with 60% indicated they had learned something new and would recommend the program to others, and 65% of respondents indicated they are satisfied or extremely satisfied with the program overall. Discussion/Significance of Impact: We successfully created a free program with minimal operating budget, flexible start dates, and accessible programming. RC+ is a model for institutions wishing to provide training for their research staff that integrates key considerations for human research protections, research integrity, project management, and implementation.

Objectives/Goals: The Mayo Clinic Comprehensive Cancer Center’s Community Outreach and Engagement program and the Center for Clinical and Translational Science’s Community Engagement Research program developed a shared service to foster and catalyze community engagement in research. We describe the development, operations, and management of this shared service. Methods/Study Population: Community Outreach and Engagement in Research Services (COERS) is a shared service for all 19 Mayo Clinic sites across five US states. COERS is supported by 31 staff, located across all Mayo Clinic sites. The staff offers consultative services assisting investigators in engaging communities to increase robust participation in research and develop trusting research relationships with over 200 collaborative community partners. Consultative services include facilitating research through resource connections; development of community partner engagement plans; development of community outreach and engagement strategies; development of community-based recruitment and retention strategies; assigning Community Scientists to study teams; and facilitating Community Engagement Studios. Results/Anticipated Results: Since 2021, COERS has engaged over 100,000 community members across all Mayo Clinic sites in outreach, health education, and research awareness activities with the goals of addressing disease burden in communities; improving trust and participation in research; and engaging communities as collaborators and advisors in research design. There have been over 250 consultations with investigators. COERS developed a Community Research Registry to enhance participation in research with over 2000 participants enrolled. Forty Community Scientists were trained, and 20 were matched to study teams. Over 75 Community Engagement Studios were conducted with a total of 180 community experts. COERS provided $260K to 12 community organizations to develop evidence-based interventions to improve community health. Discussion/Significance of Impact: COERS creates a platform that expands Mayo Clinic’s capacity to foster trust, engagement, and translate discoveries into meaningful community health outcomes. This approach has strengthened the relevance and impact of Mayo Clinic research and laid a foundation for continued progress in improving health outcomes through community-engaged science

Objectives/Goals: To develop and implement a centralized Smartsheet-based portfolio to streamline data collection, coordination, and reporting of NJ ACTS Workforce Development programs, improving efficiency, transparency, and alignment with CTSA translational science goals. Methods/Study Population: NJ ACTS Workforce Development programs, including digital badges, seminars, workshops, and internships, were mapped into a unified Smartsheet platform. Program participation, training metrics, and milestone data were integrated through automated workflows and real-time dashboards, enabling seamless tracking and analysis. Data collection templates and standardized reporting tools were co-designed with program managers to ensure consistency across domains. Continuous user feedback informed iterative refinements to improve usability and data integrity. Results/Anticipated Results: Early results of the Smartsheet portfolio have reduced administrative workload, standardized reporting, and enhanced transparency across programs. Real-time dashboards now track learner progress, completion rates, and cross-program engagement. Early adoption indicates improved collaboration among stakeholders and stronger alignment with CTSA goals and performance metrics. Anticipated outcomes include sustained efficiency gains, improved accountability, and scalable use across institutional partners. Discussion/Significance of Impact: A centralized Smartsheet platform supports coordinated management of training initiatives, enabling data-driven decision-making, continuous improvement, and replicable models for translational workforce development across the CTSA consortium.

Objectives/Goals: Clinical studies with triple-negative breast cancer (TNBC) are encouraging for immunotherapy combined with chemotherapy. Additional clinical advances may be accelerated by leveraging preclinical TNBC models including syngeneic mammary tumor cell lines. Here, we report two lines exhibit differential immunotherapy responses in vivo. Methods/Study Population: Spontaneous mammary tumors from C57BL/6J MMTV-Cre Trp53fl/+ animals were passaged serially in cell culture and in vivo in the mammary fat pad of fully wildtype animals. The resulting lines, MM001i and MM008i, lost Trp53 and formed 1000 mm3 [https://www.biorxiv.org/content/10.1101/2025.09.18.677171v1#ref-3] tumors in the mammary fat pad within 21–28 days. Tumors from each group were analyzed for their response to αPd-1 and αCtla-4 immunotherapy, infiltrating immune populations, and transcriptional profiles. Results/Anticipated Results: Despite originating from the same genetic background, these lines exhibit differential responses to immunotherapy. For αPd-1 therapy, MM001i is poorly responsive and MM008i is strongly responsive with near-complete tumor regression. In comparison, both MM001i and MM008i respond rapidly to αCtla-4 therapy. Both models express unique tumor antigens as evidenced by immunity to subsequent engraftments. Primary MM008i tumors exhibit greater T-cell infiltration, and CD8-positive T lymphocytes are required for αPd-1 responses. Cancer epithelial cells within MM008i tumors demonstrate a greater abundance of Pd-l1 expressing cells, correlating with observations in human TNBC where PD-L1 expression is a biomarker for αPD-1 response. Discussion/Significance of Impact: These TNBC models are promising for further mechanistic studies and testing future single and combinatorial therapies.

Objectives/Goals: Both mandibular advancement device (MAD) and hypoglossal nerve stimulation surgery (HGNS) are accepted options for positive airway pressure (PAP) intolerant OSA, yet decisions rely more on preference than evidence. We ask whether MAD is an effective alternative to HGNS for adults with moderate-to-severe OSA who have failed PAP. Methods/Study Population: In this single institution, nonrandomized clinical trial in adults with moderate-to-severe OSA (3% AHI 15-65) who failed, declined, or are intolerant to PAP were assessed for eligibility starting June 2025. Patients with BMI>40, prior MAD failure, or chronic nasal obstruction were excluded. PAP-intolerant patients from the WashU Sleep Center and ENT clinics were offered MAD (N = 30) and compared with propensity score-matched patients scheduled for HGNS at the same center (N = 30). Follow-up data will be collected 4 weeks after treatment (MAD) or post-titration (HGNS). Planned analyses will control for baseline differences and other factors associated with outcomes. Results/Anticipated Results: We will capture the change in baseline and post-intervention patient-reported outcome measures (PROMs) and sleep metrics to compare treatment efficacy. PROMs include: the Pittsburgh Sleep Quality Index (primary outcome), Epworth Sleepiness Scale, and SNORE-25 for OSA-related quality of life. Sleep metrics include AHI, oxygen desaturation Index, and modified Sher criteria. Data on adherence, tolerability, treatment satisfaction, and adverse events will also be collected. To date, we have enrolled 19 of 60 participants. Discussion/Significance of Impact: This study will estimate the magnitude of the difference in the change in PROMs and sleep study outcomes between MAD and HGNS. Findings may guide post-PAP treatment selection, inform payer coverage for MAD therapy, and provide data for a follow-up RCT.

Objectives/Goals: Although parental ethnic-racial socialization (ERS) supports positive mental health outcomes, existing literature often treats Black identity as monolithic and rarely considers variation across ethnic backgrounds. This study examines differences in ERS messages shared by African American and Somali families. Methods/Study Population: Three dyadic focus groups were conducted between June and August 2025, including a total of 15 (8 Somali and 7 African American) parents and 14 (7 Somali and 7 African American) youth (N=29). Parents and youth participated in separate, semi-structured discussions guided by a parallel script covering five domains: identity and family, racial socialization messaging, context and frequency of conversations, the perceived usefulness of messages, and responses to racialized experiences. Sessions, which lasted 60 to 90 minutes, were audio-recorded, transcribed verbatim, and analyzed in NVivo using a collaboratively developed codebook. Descriptive counts of message endorsement were also calculated to identify patterns in messaging across dyads. Results/Anticipated Results: Participants shared a complex understanding of race and racism, often acknowledging that race “shouldn’t matter, but does,” and describing discrimination as a normalized part of daily life. Parents emphasized that racist moments require a response, while youth described a range of reactions, including anticipation, humor, resistance, and disengagement, often adapting strategies to specific contexts. Across dyads, anticipation emerged as a dominant coping mechanism, with youth preparing mentally and emotionally for potential racial bias. Social media and humor were commonly used for processing experiences, while parents often encouraged measured resistance or dialog over avoidance or physical confrontation. Discussion/Significance of Impact: This study, by examining differences in racial socialization messages across Black ethnic subgroups, can easily identify novel intervention routes that may have been overlooked. Existing racial socialization mental health programs can be expanded and adapted to incorporate the unique messaging or values identified by these different groups.

Objectives/Goals: To determine how loss of sympathetic nerves and β2-adrenergic receptor (Adrb2) signaling remodels the leukemic bone marrow niche, alters immune responses against leukemia, and influences acute myeloid leukemia (AML) progression. Methods/Study Population: AML was modeled using MLL-AF9-driven murine leukemia and human AML xenografts (MOLM-13 and patient-derived samples) in NOD scid gamma (NSG) mice. Sympathetic signaling was disrupted chemically with 6-hydroxydopamine or genetically using Adrb2 knockout mice. Leukemic burden, survival, and immune composition were analyzed by flow cytometry and imaging. Public RNA-seq and clinical datasets were used to assess ADRB2 expression and its prognostic value in AML patients. Results/Anticipated Results: AML induces sympathetic neuropathy in both mouse and human bone marrow. Denervation or Adrb2 loss accelerated AML and reduced survival in immune-competent mice, correlating with decreased CD8+ T cell activity. In contrast, denervation reduced leukemia burden in immunodeficient NSG mice, and β2-adrenergic agonist treatment enhanced AML proliferation in vitro. High ADRB2 expression in AML patients predicted worse survival, particularly in M5/MLL-rearranged subtypes. Discussion/Significance of Impact: Sympathetic signaling exerts dual roles in AML, supporting immune surveillance but directly acting on leukemic cells to promote AML progression. These findings identify β2-adrenergic signaling as a potential therapeutic target, especially in immunodeficient or chemotherapy-treated AML patients.

Objectives/Goals: Evaluate the feasibility, acceptability, and effectiveness of a community-based diabetes management program. Assess participant knowledge, confidence, and skills as initial outcomes, and iteratively refine the pilot program across three phases using participant, facilitator, and observer feedback. Methods/Study Population: The pilot program included cohorts of English and Spanish speaking adults diagnosed with or at high risk for type 2 diabetes. The 5-week training addressed diabetes education, self-management skills, health literacy, and SMART goal setting. Participants completed pre-training, weekly post-session, post-training, and 1-month follow-up surveys to assess knowledge, confidence, satisfaction, and application of skills. Training facilitators and observers from our community engagement team completed weekly post-session surveys to understand strengths, weaknesses, and points of improvement. Feedback from participants, facilitators, and observers were used to iteratively refine the training between phases. Results/Anticipated Results: Findings indicated comparative increases in participant knowledge, confidence, and skill application related to diabetes self-management between English and Spanish cohorts. One-month follow-up data suggested knowledge retention, progress toward SMART goals, and health improvements through application of self-management strategies. Improvements in participant knowledge, confidence, skill application, engagement, and satisfaction were demonstrated across refinement phases. Feedback from participants, facilitators, and observers guided iterative refinements to the training, including materials, format, and delivery across refinement phases, thus ensuring the training was tailored to the community, clear, and accessible. Discussion/Significance of Impact: The pilot demonstrates the feasibility, acceptability, and promising initial outcomes of a bilingual, community-based diabetes management program with potential public health significance. Iterative feedback informed refinements and improved implementation, supporting adaptation of this model for broader community health applications.

Objectives/Goals: This work seeks to elucidate the upstream and downstream circuitry of the Keap1–Nrf2 axis in natural killer (NK) cells. We aim to define how the Keap1–Nrf2 axis sets a redox license to calibrate NK function and metabolic fitness, and in turn, to translate these findings into new strategies for metabolically enhancing NK and CAR-NK-based immunotherapy. Methods/Study Population: Keap1 and Nrf2 were investigated primarily in murine models, by using NK-specific knockouts of each gene (Ncr1Cre-Nrf2fl/fl and Ncr1Cre-Keap1fl/fl) in C57BL/6 mice. Flow cytometry was used to profile knockout versus wild-type differences in lymphocyte populations and subpopulations, including receptor repertoire, maturation, and effector function. In vitro and ex vivo experiments were performed by sorting cells from the spleens of knockout mice and their wild-type littermates. Human NK cells from healthy donors were analyzed with collaborators to validate the importance of the axis for human patients. Results/Anticipated Results: Transcriptomics analysis of NK cells during murine cytomegalovirus (MCMV) infection revealed reciprocal regulation of Nrf2 and Keap1, with Nrf2 transcripts downregulated and Keap1 upregulated at day 4 post-infection, highlighting the potential contribution of this pathway to NK cell responses during viral challenge. We demonstrate that both insufficient and excessive ROS buffering impair host survival in response to MCMV and acute myeloid leukemia (AML) and compromise control of tumor metastasis in melanoma models. Importantly, both knockout models also exhibited defects in NK cell expansion, maturation, and cytotoxicity. Ongoing studies map the metabolic, epigenetic and transcriptional programs downstream of this pathway in both murine and human NK cells. Discussion/Significance of Impact: As immunotherapies are developed and optimized, a rigorous understanding of the mechanisms through which immune cells kill pathogens is critical. Collectively, our work thus far identifies the Keap1–Nrf2 axis as a critical regulator of NK cell fitness that can be used to promote cell therapeutic development.