OBJECTIVES/GOALS: The Title V Coop developed CRESCO, a physical and virtual space in the libraries of the two cooperating institutions. Adopting a flexible and transformational approach, it offers services to support the development of research and information skills of undergraduate students and faculty who receive clinical-translational research (CTR) training. METHODS/STUDY POPULATION: Since 2016, CRESCO has been staffed by a multidisciplinary team composed of three librarians, a statistician, an instructional designer, and an IT specialist. The physical facilities of the two libraries were remodeled and equipped, and a central portal was created to provide services and access to resources on a 7/24 basis. Online tutorials, workshops, and mentoring services have been offered that address topics in statistics, literature search, plagiarism, and the use of several research software. Services statistics are collected, and a questionnaire is administered to evaluate the workshops. RESULTS/ANTICIPATED RESULTS: The main results include 12 online tutorials created in CTR areas and available in the CRESCO hub portal; 14,660 mentoring/consultations offered in statistics, the use of research-related software, and the search for scientific literature search; and 6 online workshops created in CTR areas, with 463 attendees. When evaluating online workshops, participants considered that their acquired learning was high or extremely high on the following topics: use of Intellectus Statistics (88%, n = 96); selection of statistical tests (81%, n = 92); use of Turnitin (85%, n = 76); literature search (91%, n = 58); and citations and references in Mendeley (90%, n = 67). DISCUSSION/SIGNIFICANCE: These results suggest that the flexible, multidisciplinary, and transformational approach of CRESCO has been successful in helping undergraduate students and faculty develop the skills necessary to conduct CTR projects.

OBJECTIVES/GOALS: Multiple Organ Failure, often precipitated by Acute Lung Injury, is a life-threatening condition that causes death in military and civilian life. Furthermore, Acute Kidney Injury is very common, increasing morbidity and mortality rates. Therefore, understanding the molecular difference between survivors and non-survivors is urgently needed. METHODS/STUDY POPULATION: A 24-hour unilateral pulmonary contusion porcine model (pneumonectomy) of trauma-induced Multiple Organ Failure (MOF) model (n=17) and separate 48-hour polytrauma injury of bilateral pulmonary contusion, traumatic brain injury, and hemorrhage (polytrauma) MOF model (n=26) was developed at Dr. Batchinsky's AREVA laboratory. Serum was assayed at baseline and 3h or 6h post-trauma for amino acid metabolites using the Zip-Chip platform for mass spectrometry. The IDO1 enzyme activity assay kit (ab235936) was used to measure IDO1 enzyme activity in the tissue. Mass Spectrometry Imaging (MSI) was employed to frozen kidney tissues. Tissues were sectioned to 10- micron thickness. For MSI, the DAN matrix was utilized, and MALDI-MSI images were processed and obtained from METASPACE and SCILS software. RESULTS/ANTICIPATED RESULTS: In the pneumonectomy model, 10 survived, 7 died, and in the polytrauma group, 13 survived, and 13 died. In the pneumonectomy model, there was a significant increase in the serum kynurenine/tryptophan (KYN/TRP) ratio in the non-survivors 3h post-injury. A similar pattern was found in the validation group, which showed a significant increase in the KYN/TRP ratio at 6h post-trauma in non-survivors from the polytrauma model. There was a significant increase in IDO1 enzyme activity in non-survivor kidney tissues and a downregulation of tryptophan (TRP) metabolite in the kidney section in the non-survivor group post-trauma. DISCUSSION/SIGNIFICANCE: An increase in the KYN/TRP ratio post-trauma identified the pigs that suffered early mortality. A decrease in TRP metabolite and an increase in IDO1 enzyme activity in the kidney could contribute to an increase in KYN in the non-survivors. As a result, focusing on therapeutics targeting the KYN/TRP to reduce the incidence and severity of MOF is warranted.

OBJECTIVES/GOALS: Our preclinical data demonstrate that the principal effects of nilotinib, a multi-tyrosine kinase inhibitor, in models of neurodegeneration is clearance of misfolded proteins via autophagy. Here we aimed to evaluate the effects of nilotinib on microRNAs in the cerebrospinal fluid of Parkinson’s disease patients. METHODS/STUDY POPULATION: Cerebrospinal fluid (CSF) was collected as part of an open label phase I (NCT02281474) (n = 12, 300 mg nilotinib taken orally once daily for 6 months), and a phase II randomized, double-blind, placebo-controlled study (NCT02954978) (n = 75, randomized 1:1:1 into placebo, 150 mg or 300 mg nilotinib taken orally once daily for 12 months). RNA was isolated from CSF and Indexed sequencing libraries were prepared from total RNA plus miRNA. Next generation whole-genome sequencing (single-end 1x75 bp, 25 million raw reads per sample) was performed to identify miRNAs significantly differentially expressed (fold-change ≥ 2, Benjamini-Hochberg FDR p-value ≤ 0.05 or Empirical Bayes FDR ≤ 0.05) with treatment compared to baseline. RESULTS/ANTICIPATED RESULTS: Next generation whole-genome sequencing of microRNAs in the CSF demonstrated that nilotinib significantly increases microRNAs that specifically regulate expression of autophagy and ubiquitination genes in individuals with Parkinson’s disease. In the open label phase I, samples, 28 microRNAs found to regulate autophagy and ubiquitination genes, were significantly altered with treatment (Benjamini-Hochberg FDR p-value ≤ 0.05). In the phase II randomized, double-blind, placebo-controlled study samples, we verified several of those 28 candidate microRNAs had been significantly deferentially expressed with treatment (Empirical Bayes FDR p-value ≤ 0.05). DISCUSSION/SIGNIFICANCE OF IMPACT: Our data provide robust evidence that nilotinib’s effects on misfolded protein clearance is via autophagy and CSF miRNA sequencing is a valid biomarker of nilotinib’s effects in a definitive phase III study to investigate nilotinib in Parkinson’s and other neurodegenerative diseases. CONFLICT OF INTEREST DESCRIPTION: Charbel Moussa is listed as an inventor on several Georgetown University patents for the use of tyrosine kinase inhibitors as a treatment for neurodegenerative diseases

OBJECTIVES/GOALS: Artificial Intelligence (AI) is gaining popularity in a variety of disciplines. While clinical applications for AI have increased in recent years, the use of AI in pediatric congenital heart disease (CHD) is limited. The goal of this systematic review was to assess how AI is currently used in this patient population and to describe knowledge gaps. METHODS/STUDY POPULATION: A systematic search was performed up to July 2023 using PubMed and Scopus databases and revealed 814 articles. Upon initial screening, 161 duplicates, 76 non-AI articles, and an additional 318 irrelevant articles were removed. A total of 259 full-text articles were reviewed for relevance. Articles that did not include a retrospective or prospective review of human subject data were excluded. Articles that had only results in the adult, prenatal, or non-CHD population were excluded. The remaining 68 articles were included in this review. RESULTS/ANTICIPATED RESULTS: Of the 68 articles in this review, 19 were performed within cardiac surgery, 41 were within cardiology, and the remaining 8 included articles were combined cardiac surgery and cardiology. Upon initial review, 24 used AI for diagnostic purposes, 40 for predicting survival or adverse outcomes, 2 for developing training tools, and 2 for surveillance of CHD trends. We anticipate that upon further review of these 68 articles, there will be a wide variety in the types of AI models that were used. The results will reveal a multitude of challenges and limitations that future studies will need to further address. DISCUSSION/SIGNIFICANCE: While technical innovations in pediatric CHD have dramatically improved survival rates, we have hit a plateau in improving the complications of these patients. AI has created an opportunity to build new diagnostic, predictive, teaching, and surveillance tools for advancing CHD care, but it seems we still have a long way to go.

ABSTRACT IMPACT: This study highlights the importance of creatine in developmental myelination and remyelination to investigate whether creatine provides a therapeutic value during a central nervous system (CNS) demyelinating insult with a potential value in patients with Multiple Sclerosis. OBJECTIVES/GOALS: Creatine is vital for ATP buffering in the brain. Interestingly, the cells that generate myelin express the main enzyme for creatine synthesis, Gamt. Patients with Gamt mutations display intellectual delays and impaired myelination. Therefore, we hypothesize that creatine is essential for developmental myelination and improves remyelination. METHODS/STUDY POPULATION: To investigate these hypotheses, we developed a new transgenic mouse model with LoxP sites flanking exons 2-6 of the guanidinoacetate methyltransferase (Gamt) gene where excision leads to expression of a green fluorescent tag allowing us to track the cells normally expressing Gamt. We used immunohistochemistry techniques to look at the corpus callosum, the main white matter tract in the brain, and evaluate the number of oligodendrocytes (OL), glial cells responsible for generating myelin. We also used the cuprizone model of toxic demyelination to investigate whether dietary creatine and cyclocreatine, a planar analog of creatine that more efficiently crosses the blood-brain barrier, can enhance remyelination. RESULTS/ANTICIPATED RESULTS: In this mouse model, we show a 95% (+/-0.47%, n=3) co-localization of Gamt within mature OL during postnatal (P) day P14 with no co-localization in neurons or other glial cells. This suggests that mature OL are the main cells making creatine in the CNS. Next, we show that knocking out Gamt leads to a significant reduction in OL in the developing corpus callosum, at P14 and P21 (P14: 0.007, n=3; P21: 0.04, n=3). We also show that creatine supplementation causes a trending increase in mature OL density in the corpus callosum following cuprizone demyelination (2% creatine; p=0.052; n=4). Interestingly, cyclocreatine supplementation significantly increased mature OL density in the corpus callosum following cuprizone demyelination (0.1% cyclocreatine; p=0.034; n=4). DISCUSSION/SIGNIFICANCE OF FINDINGS: These studies highlight the important role creatine plays in developmental myelination and remyelination to investigate whether creatine and cyclocreatine provide a therapeutic value during a CNS demyelinating insult. This work investigates a potential therapeutic value of creatine to patients with Multiple Sclerosis.

OBJECTIVES/SPECIFIC AIMS: Black patients with hepatocellular carcinoma (HCC) receive fewer curative therapies and have higher mortality than other groups. Reducing this disparity will require an in-depth understanding of patient comorbidities, tumor characteristics, and social determinants of health. Our objectives are to a) perform a multi-center retrospective cohort study of black and white patients diagnosed with HCC in the Indianapolis area. b) prospectively enroll black and white patients with HCC to collect clinical characteristics as well as data on the social determinants of health. METHODS/STUDY POPULATION: A retrospective chart review of patients with a diagnosis of HCC from 2010-2017 from five area Indianapolis hospitals will be performed. Demographics, comorbidities, liver disease severity, and tumor characteristics will be collected using the Indiana Network for Patient Care database and compared between black and white patients. Concomitantly, a prospective cohort of black and white patients will be enrolled and surveyed to collect data on socioeconomic status and income adequacy, literacy, functional status, substance abuse history, social support, activation, and adherence. The primary outcomes are the receipt of curative therapies for HCC including liver transplantation, resection or ablation. The secondary outcome is mortality. Multivariable logistic regression models will be used to explore disparities seen in the primary and secondary outcomes. RESULTS/ANTICIPATED RESULTS: These preliminary results include Indiana University Hospital (IUH) findings; a multicenter analysis is underway. The IUH cohort included 1,032 (86%) white and 164 (14%) black patients. Black and white patients had similar Model for End-Stage Liver Disease and Child-Pugh scores. There was a trend toward larger tumor size (5.3 cm vs. 4.7 cm; P = 0.05) in black patients; however, Barcelona Clinic Liver Cancer staging and Milan criteria were similar. Black patients were less likely to undergo liver transplantation than white patients—a disparity that was not attenuated (odds ratio [OR], 0.43; 95% confidence interval [CI]: 0.21-0.90) on multivariable analysis. Substance abuse was more frequently cited as the reason black patients within Milan criteria failed to undergo transplantation than white patients. Survival was similar between the two groups. DISCUSSION/SIGNIFICANCE OF IMPACT: Racial differences in patient and tumor characteristics were small in our single center analysis and did not explain the disparity in liver transplantation. This analysis however only reflects 25% of patients diagnosed with HCC in the Indianapolis metropolitan, highlighting the need for a multicenter study. Higher rates of substance abuse in black patients within Milan criteria who failed to undergo transplantation suggest social factors contribute to this disparity and highlight the need for a prospective study that can explore these and other social factors.

OBJECTIVES/GOALS: Characterizing and analyzing research studies presents several challenges given the various ways studies may be labeled or organized. The Medical Subject Headings (MeSH) thesaurus is a hierarchical vocabulary that can index and organize research foci using common business intelligence tools to enable rapid exploration of research portfolios. METHODS/STUDY POPULATION: Metadata from ClinicalTrials.gov on 455,437 trials were downloaded and all MeSH terms associated with trials in the condition_browse section were loaded into a database. The corresponding MeSH trees for each term were then identified and mapped to their ancestor terms within the tree. Trials were then indexed based on top four hierarchical levels for each associated MeSH term. Trials performed at the University of Miami (UM) were identified based on locations associated with the trial as well as matching National Clinical Trial (NCT) numbers identified from internal research administration systems. Business intelligence software (Microsoft PowerBI) was applied to the corresponding dataset to enable end user exploration and analysis of the trials within ClinicalTrials.gov. RESULTS/ANTICIPATED RESULTS: A total of 3,271 studies associated with UM were identified, of which, 3,054 (93.3%) had at least one condition MeSH term linked. A total of 7,711 MeSH terms were associated with the trials overall, representing 1,112 unique MeSH terms; the most common terms were carcinoma (164), lymphoma (155), HIV Infections (139), neoplasms (136), and leukemia (122). Utilizing MeSH hierarchy, trials were characterized were categorized into 36 different trees. The most common top tree nodes were neoplasms (1,181), followed by pathological conditions/signs and symptoms (913), immune system diseases (574), nervous system diseases (513), and digestive system diseases (483). Within trees, a total of 184, 681, and 1057 different MeSH terms were specified at the second, third, and fourth nodes in the hierarchy respectively. DISCUSSION/SIGNIFICANCE: Utilizing existing metadata from trials posted on ClinicalTrials.gov and MeSH tree structures can enable organizations to readily explore the foci of clinical trials research. High rates of MeSH term association to research study conditions are necessary to ensure adequate representation of research foci.

OBJECTIVES/GOALS: Diversity and interdisciplinarity are required for successful and transformational CTR. The Title V Coop developed a training curriculum for underrepresented in CTR health professions faculty and students, successfully integrating them in CTR teams. The curriculum exposed students to theory and then a practicum. METHODS/STUDY POPULATION: The curriculum and practicum included basic aspects of training in research including responsible conduct of research and the design of a proposal. The practicum focused on the organizing of a research team identified as a Clinical and Translational Mentoring Team (CTMT) and the implementation of the proposed project. Emphasis was placed on the importance of the mentor-mentee relationship, including peer mentoring. Participants were recruited from across all post-secondary institutions in Puerto Rico emphasizing the participation of faculty(UgF) and students (UgS) from undergraduate programs in health professions and the participation of graduate students GS) as peer mentors. Research mentors for each of the CTMTs were selected from faculty members that are established researchers. RESULTS/ANTICIPATED RESULTS: Twenty-seven (27) proposals from the CTMTs were approved. A total of one hundred and eight (108) participants were or are still engaged in the proposed research. Thirty-four faculty (34) members participated as mentors and three (3) peer reviewed publications have been done. Health professions and science fields represented by the participants include: Nursing, radiology technician, audiologist, medical students, basic science in biology or chemistry, public health and industrial microbiology among others. We will showcase the diversity in research topics and teams composition and their accomplishments. DISCUSSION/SIGNIFICANCE: The Title V Coop has been successful in integrating individuals from academic programs underrepresented in research into interdisciplinary and interprofessional research teams, launching a model for diversity and interdisciplinarity and representation of health professionals at all levels of research.

OBJECTIVES/GOALS: Our long term goal is to identify the socioeconomic and cancer-specific determinants in patients with prostate cancer undergoing prostatectomy that impact their ability to maintain a healthy weight. This study explores the association between participants’health determinants and their indicated degree of self-efficacy and quality of life (QoL). METHODS/STUDY POPULATION: Study population includes participants of the WARRIOR trial (n=40), which included overweight men scheduled radical prostatectomy from the University of Kansas Medical Center. In addition to baseline demographics, the study team will administer a questionnaire based on a socioeconomic position and health-related QoL framework. This questionnaire will assess participants' socioeconomic, cancer-specific, and psychological circumstances at time of surgery and present day. Univariate analyses will be conducted on all variables with bivariate analyses between socioeconomic and clinical items to the outcome of composite self-efficacy scoring. RESULTS/ANTICIPATED RESULTS: We anticipate that participants in the intervention will report higher self-efficacy and emotional/social support than participants in the control group, participants with social vulnerability (lower income, marginalized race/ethnicity, etc) will report decreased self efficacy and poorer QoL compared with participants who are not socially vulnerable, and that participants who previously indicated social vulnerability will report more emotional barriers to weight loss, and lesser weight loss satisfaction, self-esteem, and QoL. DISCUSSION/SIGNIFICANCE: Lifestyle interventions have helped prostate cancer patients lose weight before surgery, but many regain weight. Exploring perceptions of self efficacy as well as learning more about what structural and systemic barriers affect self efficacy is important to inform how to improve our approach for sustained weight loss and health behavior changes.

OBJECTIVES/SPECIFIC AIMS: Engaging patients and consumers in research is a complex process where innovative strategies are needed to effectively translate scientific discoveries into improvements in the public’s health (Wilkins et. al., 2013; Terry et. al., 2013). The Clinical Translational Science Awards (CTSA)—supported by the National Institute of Health (NIH) under the auspices of the National Center for Advancing Translational Sciences (NCATS)—aim to provide resources and support needed to strengthen our nation’s clinical and translational research (CTR) enterprise. In 2008, Stanford University was awarded a CTSA from the NIH, establishing Spectrum (Stanford Center for Clinical and Translational Research and Education) and its Community Engagement (CE) Program aimed at building long-standing community-academic research partnerships for translational research in the local area surrounding Stanford University. To date, the CE Pilot Program has funded 38 pilot projects from the 2009-2017 calendar year. The purpose of this study was to understand, through a unique pilot program, the barriers, challenges, and facilitators to community-engaged research targeting health disparities as well as community-academic partnerships. METHODS/STUDY POPULATION: Investigators conducted a qualitative study of the community engagement pilot program. Previous pilot awardees were recruited via email and phone to participate in a one-hour focus group to discuss their pilot project experience—describing any barriers, challenges, and facilitators to implementing their pilot project. RESULTS/ANTICIPATED RESULTS: The focus group revealed that community engage research through the pilot program was not only appreciated by faculty, but projects were successful, and partnerships developed were sustained after funding. Specifically, the pilot program has seen success in both traditional and capacity building metrics: the initial investment of $652,250.00 to fund 38 projects has led to over $11 million dollars in additional grant funding. In addition, pilot funding has led to peer-reviewed publications, data resources for theses and dissertations, local and national presentations/news articles, programmatic innovation, and community-level impact. Challenges and barriers were mainly related to timing, grant constraints, and university administrative processes. DISCUSSION/SIGNIFICANCE OF IMPACT: The Community Engagement Pilot Program demonstrates an innovative collaborative approach to support community-academic partnerships. This assessment highlights the value and importance of pilot program to increase community engaged research targeting health disparities. Challenges are mainly administrative in nature: pilot awardees mentioned difficulties working on university quarterly timelines, challenges of subcontracting or sharing money with community partners, onerous NIH prior approval process, and limitations to carryover funding. However, pilot grants administered through the program strengthen the capacity to develop larger scale community-based research initiatives.

Objectives/Goals: This project provides a framework for collaborative design of a health technology intervention. We aim to provide guidance for those seeking to incorporate community-informed insights into their intervention development, particularly within the context of a large randomized controlled trial. Methods/Study Population: As part of the patient engagement arm of the Championing Hypertension Remote Monitoring for Equity and Dissemination study, we designed patient-facing intervention components for a home hypertension monitoring system. In the design process, we convened patient consultants via regular meetings, one-on-one interviews, and focus groups, and then subsequently analyzed meeting recordings, audio transcripts, and stakeholder notes. All design sessions were offered in either English or Spanish, and sixteen participants were involved. An inductive thematic analysis is being performed utilizing two coders, and Dedoose has been used to organize and refine the data. Results/Anticipated Results: The randomized trial will begin late 2024, with overall design findings incorporated into the intervention. A more detailed qualitative analysis will map these design findings to overarching theory from the Technology Acceptance Model. These qualitative themes will provide a model of patient involvement in study design in a large randomized controlled trial, potentially guiding future improvements in technology-based healthcare delivery interventions. Discussion/Significance of Impact: As technology becomes integral to healthcare, involving patients in intervention design and rollout can improve efficacy and utilization. By offering a framework for patient involvement in intervention design, we aim to create a replicable model to enhance the translation of research into practice.

OBJECTIVES/GOALS: People living with HIV, despite antiretroviral therapy (ART), have increased burden of inflammatory and aging-related comorbidities such as periodontitis. Oral microbiota have been linked to periodontitis, but not in the context of HIV. We aim to compare relationships between the oral microbiome and periodontal disease in HIV+ vs healthy controls. METHODS/STUDY POPULATION: In an ongoing cohort study we have been recruiting pre- and post-menopausal women with HIV+ on ART for ≥6 months and HIV- controls matched by menopausal status (target n = 30 per arm; currently HIV+: n = 30 post- and 9 pre-M; HIV-: n = 15 post- and 6 pre-M). Patients age <18 or on antibiotics within 3 mos., except prophylaxis, are excluded. Patients provide saliva, then subgingival plaque collection during a dental examination through scaling from six index teeth. Standard CDC/AAP classifications of periodontitis are used. We will perform 16S rRNA and ITS sequencing to profile bacterial and fungal communities in saliva and plaque. Linear mixed effect regression and differential abundance analyses will be used to identify microbial and mycobial oral signatures of periodontal disease severity in HIV+ and HIV- populations. RESULTS/ANTICIPATED RESULTS: We found a markedly high prevalence of severe periodontal disease in HIV+ women despite ART (59%, compared to 11% in HIV- controls). In post-menopausal women with HIV, saliva bacterial α- and β-diversity in the saliva differed significantly with periodontal disease severity. Fungal α-diversity was also significantly lower in plaque from teeth with severe loss of tissue attachment (CAL ≥4 mm). We identified bacterial and fungal taxa significantly enriched in post-menopausal HIV+ women with severe compared to no or mild periodontitis. We hypothesize, similarly, associations between the oral microbiome and periodontitis in HIV- controls. However, we expect overall diversity metrics to be significantly altered in HIV+ compared to HIV- patients, indicating long-term dysbiosis despite treatment with ART. DISCUSSION/SIGNIFICANCE OF IMPACT: Contrasting associations between the oral microbiome and periodontal disease with respect to HIV will provide evidence for the role of microbiota in accelerated aging phenotype caused by HIV. Our results would also provide rationale for interventions targeting co-morbidities in people living with HIV to account for both inflammation and dysbiosis.

ABSTRACT IMPACT: Lipidomics is emerging as a powerful strategy to identify biomarkers for Major Depressive Disorder, as well as therapeutic targets in lipid metabolic pathways. OBJECTIVES/GOALS: Lipidomics is increasingly recognized in precision psychiatry for global lipid perturbations in patients suffering from Major Depressive Disorder (MDD). We will test the hypothesis that lipid metabolism dysregulation is associated with familial risk of depression. METHODS/STUDY POPULATION: Patients with MDD (G1), children (G2), and grandchildren (G3) have been part of a longitudinal study since 1982. If a parent G2 and grandparent G1 have MDD, G3 is considered a high risk of depression. Biospecimens (saliva and serum) were collected for full exome sequencing and RNA analysis. Samples will also be extracted for lipid content and lipids will be identified by mass spectrometry. A panel of nearly 600 lipid species can reliably be identified and quantified using liquid chromatography paired with tandem mass spectrometry (LC-MS/MS). Dysregulated lipids will be correlated with familial risk of depression in samples of G3. RESULTS/ANTICIPATED RESULTS: We hypothesize that dysregulation of lipids and lipid metabolism will be apparent in biospecimens from the high risk compared to the low risk of depression. Also, alterations in RNA transcriptomics of genes involved in lipid metabolic networks are associated with familial risk of depression. Several differential lipid species were previously identified to be associated with MDD. Reduced phosphatidylcholine(PC), phosphatidylethanolamine(PE), phosphatidylinositol(PI), and increased LysoPC, LysoPE, ceramide, triacylglycerol, and diacylglycerol levels have been correlated to MDD. However, these results need to be replicated in independent studies using lipidomics analysis. DISCUSSION/SIGNIFICANCE OF FINDINGS: It is highly likely that completely novel cellular targets will emerge from these studies by uncovering the convergence of lipidomics and genetic variance of lipid metabolic enzymes as biomarkers for predisposition to MDD as well as potential targets for therapeutic development for MDD.

Over the last year, COVID-19 has emerged as a highly transmissible and lethal infection. As we address this global pandemic, its disproportionate impact on Black, Indigenous, and Latinx communities has served to further magnify the health inequities in access and treatment that persist in our communities. These sobering realities should serve as the impetus for reexamination of the root causes of inequities in our health system. An increased commitment to strategic partnerships between academic and nonacademic health systems, industry, local communities, and policy-makers may serve as the foundation. Here, we examine the impact of the recent COVID-19 pandemic on health care inequities and propose a strategic roadmap for integration of clinical and translational research into our understanding of health inequities.

Revisions to the Common Rule and NIH policy require the use of a single Institutional Review Board (sIRB) for the review of most federally funded, multisite research, with the intent of streamlining the review process. However, since initial implementation in 2018, many IRBs and institutions continue to struggle with the logistics of implementing this requirement. In this paper, we report the findings of a workshop held in 2022 to examine why sIRB review remains problematic and propose possible solutions. Workshop participants identified several issues as major barriers, including new responsibilities for study teams, persistent duplicative review processes, the lack of harmonization of policies and practices across institutions, the absence of additional guidance from federal agencies, and the need for greater flexibility in policy requirements. Addressing these problems will require providing additional resources and training to research teams, the commitment of institutional leaders to harmonize practice, and policymakers to critically evaluate the requirement and provide flexibility in applicability.

OBJECTIVES/GOALS: Treatment options for glioblastoma (GBM) are limited. Prognosis remains dismal, with an 18 month on average survival rate following diagnosis due to treatment resistance and disease recurrence. The goal of this project is to investigate hallmarks of cancer progression that contribute to temozolomide (TMZ) resistance, a first tine treatment for GBM. METHODS/STUDY POPULATION: Two signaling pathways were investigated in TMZ-sensitive and -resistant GBM cell lines and in primary and recurrent patient-derived xenograft (PDX) tumor cells by genetically and pharmacologically inhibiting methionine adenosyltransferase 2A (MAT2A) and adenosylhomocysteinase (AHCY). Cell growth and survival were assessed by measuring protein expression of proliferation, oxidative stress and cell cycle arrest markers. EPIC array analysis and targeted bisulfite sequencing were conducted to identify changes in genome-wide and specific CpG island methylation. The Seahorse XF Analyzer measured mitochondrial respiratory capacity and oxidative metabolism. Induced pluripotent stem cell organoids were co-cultured with PDX tumor cells to determine if treatments mitigate tumor cell invasiveness. RESULTS/ANTICIPATED RESULTS: Compared to parental cells (PC), MAT2A gene expression was increased by 1.7-fold in acquired resistant and de novo resistant GBM cells (RC) [(transcript per million): PC, 7386 ± 0.012; RC, 12925 ± 0.023; n=2; p=2.10e-8]. Compared to TMZ-sensitive cells (TS), TMZ-resistant cells (TR) demonstrated a 56% increase in baseline oxygen consumption rate [(pmol/min): TS, 179 ± 6.7; TR, 279 ± 13; n=18; p=.0012] and 64% increase in maximal respiratory capacity [(pmol/min): TS, 403 ± 29; TR, 659 ± 35; n=6; p DISCUSSION/SIGNIFICANCE: MAT2A and AHCY contribute to TMZ resistance and recurrence by dysregulating methylation programs and upregulating antioxidant programs, respectively. These findings provide a foundation for developing novel combinatory therapeutic strategies and inform clinical studies intended to increase remission and reduce recurrence for GBM patients.

Objectives/Goals: This project will enrich our understanding of basal breast carcinogenesis, highlighting the distinct biological differences in breast cancer risk between non-Hispanic Black (NHB) or non-Hispanic White (NHW) women, but also has the potential to provide real-world solutions thereby contributing to reducing health disparities in breast cancer outcomes Methods/Study Population: In the biological investigation, I am utilizing a unique cohort of normal breast tissues from Mayo Clinic patients who underwent breast reduction surgery that have self-identified as NHB or NHW premenopausal women. From these tissues, we are able to subculture human mammary epithelial cells, which we will use for our consequent experiments. For the qualitative study, I aim to recruit up to 40–50 eligible NHB women identified at increased risk for breast cancer and conduct semi-structured qualitative interviews informed by the National Institute on Minority Health and Health Disparities Research Framework. Results/Anticipated Results: Gene expression profiling on our cohort of 15 NHB and 40 NHW premenopausal women identified a gene expression signature in NHB women indicative of elevated Hedgehog signaling, a key factor in triple-negative breast cancer (TNBC) development and progression. I hypothesize that persistent activation of Hedgehog signaling within NHB women instigates the proliferation and transformation of basal stem cells within the breast, thus fueling TNBC development. Understanding the perceptions and experiences of NHB women that are identified as being at an increased risk for BC will aid in the identification of barriers and facilitators to their risk reduction care and in turn provide implementation strategies that could contribute to alleviating the racial disparity seen in TNBC morbidity, mortality, and preventative care. Discussion/Significance of Impact: The significance of this project lies in its dual approach, uncovering basal breast cancer mechanisms in a high-risk group using normal breast tissue and evaluating the perspectives from NHB women to enhance the practical relevance of our findings.