Patient and public involvement (PPI) must be more frequently embedded within clinical research to ensure translational outcomes are patient-led and meet patient needs. Active partnerships with patients and public groups are an important opportunity to hear patient voices, understand patient needs, and inform future research avenues. A hereditary renal cancer (HRC) PPI group was developed with the efforts of patient participants (n = 9), pooled from recruits within the early detection for HRC pilot study, working in collaboration with researchers and healthcare professionals (n = 8). Patient participants had HRC conditions including Von Hippel–Lindau (n = 3) and Hereditary Leiomyomatosis and Renal Cell Carcinoma (n = 5), and public participants included two patient Trustees (n = 2) from VHL UK & Ireland Charity. Discussions among the enthusiastic participants guided the development of a novel patient information sheet for HRC patients. This communication tool was designed to aid patients when informing family members about their diagnoses and the wider implications for relatives, a gap identified by participants within group discussions. While this partnership was tailored for a specific HRC patient and public group, the process implemented can be employed for other hereditary cancer groups and could be transferable within other healthcare settings.

Retrospective case studies are one approach to help identify processes underlying the translation of successful health interventions. This case study investigates the development of RealRisks and Breast Cancer Risk Navigation (BNAV), decision support tools for breast cancer risk assessment, and risk-stratified prevention. Following a recently developed protocol for retrospective translational science case studies, we examined the career trajectory of Dr Katherine Crew as she expanded from basic science to interdisciplinary, patient-oriented research in oncology and began collaboration with Dr Rita Kukafka, a public health informatician focused on communicating risk. Data collection methods included key informant interviews and examination of peer-reviewed publications, funded grants, and news articles associated with the research. Data were analyzed to identify key milestones in the development of RealRisks and BNAV and to elucidate facilitators and barriers to the translational process. Facilitators to translation included funding and infrastructure provided by a Clinical and Translational Science Award (CTSA), the creation of an interdisciplinary team, and broad support from stakeholders including patient advocacy groups. Barriers to translation included limited mid-career support, ongoing costs for technology, and the time required to establish interdisciplinary, team science efforts. The findings reported here can be used to inform ongoing efforts to develop a more robust science of translation.

ABSTRACT IMPACT: Genomic data can be used by policy and decision makers to guide, and assess the impact of, public health responses to the COVID-19 pandemic. OBJECTIVES/GOALS: Our objective is to investigate the transmission and population dynamics of SARS-CoV-2 in New Mexico and other Mountain West states using whole genome sequencing. Understanding how the virus is spreading within and between communities is vital for the design of rational, evidence-based control measures. METHODS/STUDY POPULATION: We obtained an aliquot of 500ul - 1 ml of inactivated viral transport media (VTM) from positive SARS-CoV-2 nasopharyngeal swabs as determined by qPCR from the New Mexico Department of Health, TriCore Reference Laboratory, Idaho Bureau of Laboratories, and Wyoming Public Health Laboratory. We extracted viral RNA from the VTM, and sequenced the genomes using the methodology as described by the widely adopted ARTIC amplicon tiling protocol for SARS-CoV-2. Viral genomes were then sequenced on either an Illumina MiSeq or an Oxford Nanopore Technologies (ONT) GridION. We placed these samples within the context of globally representative sequences made available via the GISAID database. Consensus sequences were aligned and added into this global dataset using the Nextstrain augur pipeline. RESULTS/ANTICIPATED RESULTS: We sequenced over 1,000 SARS-CoV-2 genomes thus far from New Mexico (n=861), Wyoming (n=213) and Idaho (n=44). We used this sequence data to infer the transmission dynamics and spread of the virus, both within states and in context of regional and international spread. We inferred at least 128 separate introductions of the virus into New Mexico and at least 29 introductions into Wyoming. The origins of these introductions are diverse, spread across multiple regions in the US and abroad. We also sequenced samples from an individual who had multiple positive tests over time. Our results suggest that this individual was re-infected with a different strain than that of the initial infection. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our data show that New Mexico and other Mountain West states have continually experienced many introductions of the virus that then seed local outbreaks. By understanding the number of introductions over time, we can assess the impact of travel restrictions on transmission. Our data also supports that some individuals can be re-infected.

Objectives/Goals: We assessed the feasibility of using a large language model (LLM) to create lay language descriptions of study protocols for recruitment, which has the potential to improve accessibility and transparency of clinical studies and enable participants to make informed decisions. Methods/Study Population: All studies from a clinical research recruitment platform were included, which features human-written lay descriptions and titles for study recruitment. Corresponding protocol summaries in the IRB system were extracted and translated into lay language using a LLM (gpt-35-turbo-0613). A subset was used to develop prompt variations through an iterative process. Prompt strategies evaluated include chain-of-thought and few-shot prompting techniques. LLM-generated and human-written descriptions were compared for readability using Flesch–Kincaid and Simple Measure of Gobbledygook (SMOG) reading grade levels and information completeness using Word Movers’ Distance (WMD). Results/Anticipated Results: A total of 55 study descriptions were included – 10 were used to develop prompts and 45 were used for evaluation. The final LLM instructions included multistep prompts. The LLM was first instructed to produce a two- to three-sentence long description without using scientific jargon and included two pairs of examples. The LLM was then asked to shorten the description and finally to provide an engaging title. LLM-generated and human-written summaries were similar in length (median (IQR) 328 (278.5–360.5) vs. 342 (203–532.5) characters, respectively). LLM-generated summaries had lower Flesch-Kincaid grade level (5.15 vs. 8.28, p Discussion/Significance of Impact: An LLM can be used to generate lay language summaries that are readable at a lower grade level while maintaining semantic similarity. This approach can be used to improve the drafting of summaries for recruitment, thereby improving accessibility to potential participants. Future work includes human evaluation and implementation into practice.

Objectives/Goals: Sexual minority populations report a disproportionately high prevalence of alcohol use, often attributed to coping with bi/homonegativity and systemic inequities across various social domains. This study aims to explore alcohol use patterns and associated neighborhood and individual factors among sexual minority populations (SMPs) using data from the NIH All of US dataset. Methods/Study Population: Alcohol use was assessed using the AUDIT-C (Alcohol Use Disorders Identification Test—Consumption) scale across a sample of 9,454 gay, 15,284 bisexual, 5,267 lesbian, and 349,748 straight participants. The AUDIT-C measured hazardous alcohol use, and logistic regression models were employed to examine its association with neighborhood-level factors (e.g., socioeconomic status, alcohol outlet density) and individual-level factors (e.g., age, race/ethnicity, income, and education) among SMPs. Interaction terms assessed how these relationships varied by sexual orientation. Sensitivity analyses were conducted to assess the robustness of the findings, including stratified analyses by gender identity and the exclusion of extreme outliers in alcohol use reporting. Results/Anticipated Results: Our analyses revealed that gay participants had the highest AUDIT-C scores (mean  =  3.60, SD  =  2.27), followed by bisexual (mean  =  3.35, SD  =  2.21), other SMPs (mean  =  3.18, SD  =  2.19), lesbian (mean  =  3.04, SD  =  2.08), and straight individuals (mean  =  3.05, SD  =  2.06). Alcohol use was positively associated with neighborhood disorder (β  =  0.12, 95% CI  =  0.07, 0.17), housing insecurity (β  =  0.14, 95% CI  =  0.03, 0.25), and male gender (β  =  0.98, 95% CI  =  0.96, 1.00). In contrast, neighborhood density (β  =  -0.11, 95% CI  =  -0.15, -0.07), food insecurity (β  =  -0.14, 95% CI  =  -0.20, -0.08), being Black, and identifying as bisexual were negatively associated with alcohol use. Sensitivity analyses determined no significant differences among specfic supgroups. Discussion/Significance of Impact: This study highlights important differences in alcohol use across SMPs and emphasizes the influence of neighborhood-level stressors (e.g., disorder and housing insecurity). These findings underscore the need for addressing social and environmental determinants of alcohol use in SMPs to mitigate the negative impacts of alcohol consumption.

OBJECTIVES/SPECIFIC AIMS: We previously demonstrated that products released by cultured B cells from patients with Multiple Sclerosis (MS) are cytotoxic to neurons and oligodendrocytes, while minimal toxicity was observed in response to B cell secretory products from age- and sex-matched normal controls. The goal of this proposal is to identify the range of brain cells susceptible to MS B cell-mediated cytotoxicity, to define the cytotoxic factor(s) released by MS B cells, and to determine whether particular subset(s) of MS B cells harbor the greatest pathogenic potential. METHODS/STUDY POPULATION: The toxicity of B cell products will be demonstrated by incubating primary rat cultures of neurons, oligodendrocytes, and oligodendrocyte progenitor cells (OPCs) with B cell supernatants. B cells will be isolated from the peripheral circulation of untreated relapse-remitting MS (RRMS) patients and age- and sex-matched normal controls. The identification of specific toxic factor(s) in MS B cell supernatants will be achieved through a combination of exosome-depletion/enrichment of conditioned media, proteomics, next generation sequencing, and lipidomics. Determining pathogenic B cell subsets will be achieved by cell sorting into memory and naïve B cell subsets prior to collection of supernatants. RESULTS/ANTICIPATED RESULTS: We hypothesize that the toxicity of MS B cell products is mediated, at least in part, by extracellular vesicles, such as exosomes. We expect depletion of these exosomes from the B cell conditioned media or inhibition of their biogenesis will mitigate the observed toxicity. Furthermore, differences in B cell-derived exosomal content, such as proteins, (mi)RNAs, or lipids, likely explain the differences in observed toxicity. Lastly, we hypothesize that memory B cells, which are enriched in the CNS of MS patients and demonstrate a more pro-inflammatory profile than naïve B cells, are responsible for the toxicity observed in supernatants of total B cells. DISCUSSION/SIGNIFICANCE OF IMPACT: MS is the most prevalent chronic inflammatory disease of the CNS, affecting more than 2 million people worldwide. Although over a dozen disease-modifying therapies are approved for the treatment of RRMS, none are meaningfully effective at limiting disease progression. This proposal will provide new insight into immune-CNS interactions in progressive MS and provide much-needed novel targets for therapeutic intervention, either via blocking identified toxic molecule(s) or by selectively depleting pathogenic B cell subsets.

OBJECTIVES/GOALS: To examine the prevalence of new indications for existing drugs conducted by non-originator companies from 2015 to 2021 and determine how many could qualify for 505(b)(2) under the Food, Drug, and Cosmetics Act. METHODS/STUDY POPULATION: A search within Clinicaltrials.gov was conducted to identify phase 3 drug interventional studies completed from 2015 to 2021. Results were categorized by funding source and industry sponsored studies were further separated into originator- and non-originator companies using dailymed.com. An in-depth review of 2018 was conducted to understand the nature of the studies including indication, dosage form, and route of administration. RESULTS/ANTICIPATED RESULTS: According to clinicaltrials.gov, a total of 7148 phase 3 studies were conducted between 2015 and 2021. Most of these studies were funded by industry (4447, 66.21%), followed by other (2428, 33.97%), NIH (266, 3.72%), and government (62, 0.87%). In-depth examination of the studies completed in 2018 (n=1077) revealed similar pattern in that most were funded by industry (674, 62.58%) followed by other (356, 33.05%), NIH (43, 3.99%), and government (10, 0.93%). Some studies were funded by more than one type. Of the industry-sponsored studies, 623 were funded by originator companies and 51 by non-originator companies. A total of 49/674 of the industry sponsored studies were for new indications, with 42 studies conducted by originator companies and 7 conducted by non-originator companies. DISCUSSION/SIGNIFICANCE: The 505(b)(2) is a way for manufacturers to add new indications to drugs by non-originator companies. In 2018, 49/674 studies were conducted to pursue new indications with few, 7/49, conducted by non-originator companies. The product development landscape reveals few opportunities for entities pursuing the 505(b)(2) pathway for new indications.

ABSTRACT IMPACT: Our work will provide valuable information about the associations between physical symptoms and PTSD in patients from a Spanish-speaking, evidence-based clinic. OBJECTIVES/GOALS: In this reserach study, we want to describe physical symptoms of patients with a preliminary PTSD diagnosis. We also want to explain associations between physical symptoms, and the presence, or absence of PTSD, and to evaluate findings in terms of prevention services, referrals, and alternatives for augmenting treatment-adherence. METHODS/STUDY POPULATION: This was a descriptive, secondary database analysis of the Center for the Study of Fear and Anxiety (by its Spanish acronym, CETMA). The database included information of the initial evaluation between 2012 and 2019. We aimed to describe sociodemographic and medical variables, and evaluate associations, in terms of the presence or absence of PTSD. RESULTS/ANTICIPATED RESULTS: Patients with PTSD were mostly women, single, with a completed bachelor’s degree. The majority had at least one neurological, or musculoskeletal condition. Respiratory conditions were the least represented. We found significant associations between musculoskeletal, neurological, and ear/nose/throat conditions, in terms of PTSD diagnosis. DISCUSSION/SIGNIFICANCE OF FINDINGS: Puerto Rico recently experienced two hurricanes, several earthquakes, and the pandemic. Findings provide data about the interface between mental and physical symptoms of patients with PTSD. We recommend a randomized population study with mental and physical variables, for understanding possible effects of cumulative stress in Puerto Ricans.

OBJECTIVES/GOALS: Despite expanded interest in translational research, barriers in funding, infrastructure, staffing, training opportunities, and interdisciplinary collaboration still remain. Our goal was to interview basic science researchers to identify research barriers and potential areas for improvement. METHODS/STUDY POPULATION: After receiving an IRB determination for a quality improvement study, 15 New Jersey-based principal investigators (PIs) from various departments and at various stages of their careers were virtually interviewed one-on-one by a trained medical student and asked a series of standardized questions about their subjective experiences with their institutions’ research processes, training and mentoring, interdisciplinary collaboration, and intellectual property. The interview was then transcribed to complete an anonymous, standardized REDCap form. Qualitative data analysis was performed to identify common themes, barriers, and gaps in conducting translational research as reported by the PIs. RESULTS/ANTICIPATED RESULTS: Of the 15 PIs, 4 (27%) were assistant professors, 6 (40%) associate professors, and 5 (33%) professors. 5 (33%) joined the institution less than 5 years ago. The most common barrier was translational research funding. Time needed to navigate administrative and regulatory processes and access to clinical collaborators were other common barriers. One PI noted leaving the institution due to difficulty accessing clinicians and patient samples. PIs with extensive training or who reported successfully conducting translational research noted fewer barriers. Suggested solutions included programs and grants to link basic scientists with clinicians, a streamlined IRB process, and better staffing to support research. DISCUSSION/SIGNIFICANCE: The findings suggest a need to increase grant funding for translational research. Improving support staffing and minimizing administrative barriers would also be helpful. Improving the dissemination of available resources, grants, and guidance on administrative processes may further decrease barriers.

OBJECTIVES/GOALS: Many economic evaluations rely on clinical trial data that may not represent real world populations and intervention effectiveness. We compare risk and cost-effectiveness for the Diabetes Prevention Program (DPP) clinical trial cohort and a real world population eligible for the national DPP to assess the impact of using real world data. METHODS/STUDY POPULATION: To produce real world (US population) representative results, we identified National Health and Nutrition Examination Survey (NHANES) subjects eligible for the national DPP and adjusted projections using survey weights. We used clinical predictive models to estimate individual diabetes risk, and microsimulation to estimate lifetime costs, benefits, and net monetary benefits (NMB) for lifestyle intervention and metformin. We compared results across the DPP clinical trial and NHANES populations. RESULTS/ANTICIPATED RESULTS: Three-year risk of diabetes onset for the DPP trial population (mean of 19.7%, median of 10.3%) exceeded corresponding risk for the NHANES population (mean of 14.6%, median of 4.8%). The proportion of individuals with a three-year diabetes risk < 10% for the DPP trial population (49%) was less than the corresponding proportion for NHANES (67%). Mean NMB for metformin for the DPP trial population ($9,749) exceeded the corresponding value for NHANES ($5,391). The proportion of subjects with negative NMB was 49% for the DPP trial population and 67% for NHANES. Lifestyle intervention had a mean NMB of $34,889 for the DPP trial population and $28,652 for NHANES. Only 20% of the NHANES population eligible for national DPP met inclusion/exclusion criteria for the DPP trial. DISCUSSION/SIGNIFICANCE: Real world populations eligible for the national DPP include a greater proportion of low-risk individuals, and for these people, prevention programs may confer smaller benefits. Technology assessments based on clinical trial data should be revised using real world population and treatment effect data.

OBJECTIVES/GOALS: Preeclampsia increases cardiovascular (CV) risk, likely via persistent endothelial dysfunction and angiotensin II type 1 receptor autoantibodies (AT1R-Ab). We aim to assess coronary endothelial function (CEF) and AT1R-Ab levels in postpartum preeclampsia with a hypothesis this mediates CV risk. METHODS/STUDY POPULATION: We prospectively enrolled age and CV risk factor matched postpartum women. Coronary MRI was performed at rest and with isometric handgrip stress, an endothelial dependent stressor. CEF was quantified as % stress-induced change in coronary cross-sectional area (%CSA) and in coronary blood flow (%CBF). AT1R-Ab was measured using a novel antigen capture enzyme-linked immunosorbent assay. RESULTS/ANTICIPATED RESULTS: Women with and without preeclampsia were similar in age (mean 32.7+5.0 years), BMI (mean 28.0+6.3 kg/m2) and race/ethnicity (58% White, 35% Black and 4% Hispanic). %CSA was lower with (-2.1+13.6) vs without preeclampsia (8.8+17.1), p=0.023. %CBF was also lower with (11.3 [-11.8, 25.2]) vs without preeclampsia (25.7 [-0.7, 62.9]), p=0.039. AT1R-Ab was higher among women with preeclampsia (p=0.029) and was inversely associated with %CBF (beta coefficient -4.6 [-8.9, -0.3], p=0.037) but not with %CSA. DISCUSSION/SIGNIFICANCE: Women with preeclampsia have elevated AT1R-Ab and impaired CEF demonstrated by insufficient coronary reserve with exercise. Coronary endothelial dysfunction and dysregulation of the renin-angiotensin pathway likely contribute to long-term CV risk and should be considered for targeted risk reduction.

OBJECTIVES/GOALS: Guided by the health belief model and social identity theory, we aim to identify socio-cultural and psychological factors that influence rural tobacco users a) participation in research and b) quitting tobacco use. We also explore how citizen scientists are perceived as disseminators of messages. METHODS/STUDY POPULATION: In Phase I of this multi-stage project, we are conducting in-depth interviews with approximately 30 tobacco users. Interviews are on-going, and have been conducted with 16 participants thus far from four rural counties in Florida. The interview consists of semi-structured questions and multiple validated questionnaires. Specifically, we ask a series of questions about participants’ barriers to participating in research, tobacco use history, and internet use and message preferences. Additionally, we include questionnaires on participants’ substance use, nicotine dependence, motivation to quit, and willingness to participate in research studies. RESULTS/ANTICIPATED RESULTS: Initial findings suggest that rural tobacco users have an overall positive perception of research, and many choose to participate in research for altruistic reasons (i.e. they want to help others). Further, participants noted described feeling stigmatized due to their tobacco use. Although most began smoking to fit in with their community, many now feel on the outs. Participants also reported logistical barriers to participating in research, including lack of transportation. DISCUSSION/SIGNIFICANCE OF IMPACT: Findings can inform the development of recruitment materials to resonate with rural adults, including by emphasizing the collective potential to help by participating. This interdisciplinary highlights areas for collaboration to enhance the reach of health education and public health messages.

OBJECTIVES/GOALS: To evaluate the clinical trial designs of stimulant medications approved for the treatment of adult Attention-Deficit/Hyperactivity Disorder (ADHD) and identify discrepancies between safety and efficacy outcome measure criteria. METHODS/STUDY POPULATION: There are 24 stimulants currently approved and marketed for the treatment of adult ADHD: 12 amphetamine (AMP)-based and 12 methylphenidate (MPH)-based formulations. A mixed methods review of clinical trials that have evaluated the safety and efficacy of these drugs will be performed using qualitative and quantitative data, including inclusion and exclusion criteria, primary and secondary outcome measures, manufacturer recommendations, and package inserts, as well as FDA recommendations for industry. After compiling a list of clinical trials for each of the 24 drugs, this information will be analyzed for themes and trends in the assessment of safety and efficacy with particular attention paid to differing criteria between individual drugs and/or the two subclasses of prescription stimulants. RESULTS/ANTICIPATED RESULTS: The FDA has published recommendations for ADHD medication clinical trial design, including suggested outcome measures utilizing validated assessment tools. However, the FDA notes that these assessments may be altered to fit study populations and indicate that other primary and secondary endpoint measures may be acceptable. As such, efficacy assessments for these drugs may vary greatly, and the specific criterion selected for each drug’s study population and outcome measures may suggest more specific indications and usage conditions for optimal efficacy. DISCUSSION/SIGNIFICANCE: Regulatory officials consider AMP- and MPH-based stimulants equivalent therapeutic options for the treatment of ADHD. A study of clinical trial criteria reveals that differing mechanisms have been used to evaluate safety and efficacy. This discrepancy may have implications that affect clinical decision-making and patient experiences.

OBJECTIVES/GOALS: There is universal recognition of the importance of team science and team leadership. We have developed a semi-quantitative translational science specific team leadership competency assessment tool and have begun implementation studies to assess the impact of personalized feedback on the team science leadership skills of KL2 Clinical Scholars. METHODS/STUDY POPULATION: To create the instrument, we employed a modified Delphi approach by conducting a thorough literature review on Leadership to concretize the relevant constructs, then used these extracted constructs as a springboard for the Rockefeller Team Science Educators (TSE’s) to discuss and refine the leadership domain areas, collectively create domain-specific survey items. Further discussion helped refined the number, grouping, and wording. Scholars also contributed feedback in item development. We piloted the Leadership Survey by having all of the Rockefeller TSEs rate Clinical Scholars, and having each Scholar rate themselves. Each item was answered using a six-point Likert scale where a low score indicated poor expression and a high score represented excellent expression of the specific leadership attribute. RESULTS/ANTICIPATED RESULTS: Incorporation into a REDCap data base made consenting and rating process by TSE’s and the Scholars straightforward. The a priori domains (Foundational Leadership Competencies, Professionalism, Team Building and Team Sustainability, Appropriate Resource Use and Study Execution, and Regulatory Accountability) had high internal validity and good internal factor structure. The congruence between TSE and Scholar self-ratings were uniformly high, and discordance was often a function of “confidence” and “modesty” on the part of the scholar, rather than deficiency. Supporting comments were informative about performance barriers and mechanisms for improvement. Return of results allowed for the exploration of training gaps. Scholars were surveyed to gauge their reaction to the formal feedback. DISCUSSION/SIGNIFICANCE OF IMPACT: This quantification of team science leadership constructs has allowed for A)- the articulation of constructs essential for successful Translational Scientists to acquire during their training, B)- identification of gaps in that training and skill set, and C)- mechanisms for bolstering any identified gaps in these essential leadership constructs. CONFLICT OF INTEREST DESCRIPTION: None

OBJECTIVES/GOALS: Glioblastoma (GBM) is the most malignant brain tumor in adults and remains incurable with an average survival of 15 months after diagnosis. There is great need for treatment options without side effects that are devastating to the quality of life for patients. GBM tumors can circumvent cellular damage by upregulating antioxidant production. METHODS/STUDY POPULATION: Highly aggressive tumors tend to exhibit increased oxidative metabolism, and thus rely on a mechanism to eliminate reactive oxygen species (ROS) in order for cells to evade autophagy and cell death. We propose that recurrent GBM cells achieve this is by promoting methionine metabolism, upregulating glutathione production and preventing ROS accumulation. We investigated the expression of AHCY and MAT2A, two key enzymes in the methionine pathway, at the gene and protein level in both GBM and non-GBM tissues. We probed for markers of cell death following pharmacological inhibition and siRNA knockdown, and performed metabolite-mediated rescue experiments. Finally, we evaluated changes in cellular respiration using the Seahorse XFe96 real-time mitochondrial stress test following inhibitor treatment. RESULTS/ANTICIPATED RESULTS: The selective AHCY inhibitor markedly reduced cell viability in different cancer cell types, but significantly reduced cell viability in recurrent GBM cells compared to newly diagnosed GBM (p=.009; MD: -0.828, 95% CI -1.350 to -0.306) and normal astrocytes (p=.073; MD: -0.609, 95% CI -1.305 to 0.085). AHCY and MAT2a protein expression appeared to be higher in GBM cells compared to normal astrocytes, medulloblastoma cells and other cancer cell lines. Genetic knockdown of AHCY and MAT2A demonstrated reduced cell viability, increased Caspase, SOD2, LC3-II and Transferrin receptor expression. Acute treatment with the AHCY inhibitor induced cell death, markedly reduced oxygen consumption rate and ablated spare respiratory capacity in recurrent GBM cells compared to newly diagnosed GBM cells. DISCUSSION/SIGNIFICANCE: Oxidative damage was induced following interference with key methionine pathway enzymes by pharmacological inhibition, while a similar concentration of drug largely preserved normal astrocyte viability. These results point to a novel targetable mechanism of disease progression and expand the realm of treatment options for recurrent GBM.