bluuebunny/crossref_metadata_2025 huggingface dataset:
2173 RNA-nanoparticles to enhance and track dendritic cell migration
Authors: Grippin Adam J. , Sayour Elias J. , Wummer Brandon , Monsalve Adam , Wildes Tyler , Dyson Kyle , Dobson Jon , Mitchell Duane A.
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: Despite aggressive chemotherapy, surgical resection, and radiation therapy, glioblastoma remains almost universally fatal. In a pilot, randomized, and blinded clinical trial, we recently demonstrated that administration of RNA-loaded DC vaccines was associated with significantly improved progression-free and overall survival in patients with glioblastoma (Mitchell et al., Nature, 2015). Furthermore, clinical outcomes correlated with DC migration to vaccine-site draining lymph nodes measured by Indium-111 labeling of RNA-loaded DCs and SPECT/CT imaging. Although these studies demonstrated that tracking DC migration may be an important clinical biomarker for response to DC vaccination, the complexity and regulatory requirements associated with nuclear labelling to track DC migration limits widespread application of this technique. We have therefore developed RNA-loaded magnetic nanoparticles (RNA-NPs) to enhance DC migration to LNs and track that migration with a widely available imaging modality (i.e., MRI). METHODS/STUDY POPULATION: Cationic liposomes were loaded with iron oxide nanoparticles with or without cholesterol. The resulting nanoparticles were complexed with RNA and used to transfect DCs ex vivo. RNA-NP-loaded DsRed+ DCs were then injected intradermally into mice and tracked noninvasively with T2-weighted 11T MRI before excision and quantification with flow cytometry. RESULTS/ANTICIPATED RESULTS: In vitro experiments demonstrate that iron oxide loading does not reduce RNA-NP-mediated transfection of DCs. Additionally, replacement of cationic lipids with cholesterol increased RNA-NP transfection of the DC2.4 cell line and enhanced the T cell stimulatory capacity of treated bone marrow-derived dendritic cells (BMDCs). Compared to electroporation, RNA-NPs enhanced DC migration to lymph nodes and reduced T2 MRI intensity in DC-bearing lymph nodes. DISCUSSION/SIGNIFICANCE OF IMPACT: This data suggests that iron oxide-loaded RNA-NPs enable noninvasive cell tracking with MRI and enhance DC migration to lymph nodes. We have further shown that inclusion of cholesterol in RNA-NPs augments the stimulatory capacity of transfected DCs. Future work will consider effects of RNA-NPs on antitumor immune responses and the utility of MRI-detected DC migration as a biomarker of vaccine efficacy.
2385 Role of the antioxidant enzyme catalase in respiratory syncytial virus infection
Authors: Ansar Maria , Chambliss Jeffrey M. , Komaravelli Naryana , Ivanciuc Teodora , Casola Antonella , Garofalo Roberto P.
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: The goal of this study is to further evaluate underlying disease parameters in respiratory syncytial virus (RSV) infection, that is reduction in antioxidant potential, and determining if supplementation of the antioxidant enzyme catalase could be employed as a potential therapeutic. METHODS/STUDY POPULATION: Nasopharyngeal secretions were obtained from patients (<2 years old) verified for RSV infection, and assessed for catalase activity and correlated with disease parameters. In addition, the BALB/c animal model of RSV infection was utilized to directly study the effect of supplemental catalase on RSV-related disease parameters in vivo. The catalase formulation used in these studies is pegylated, and has been tested to provide long-term increased catalase activity in vivo. We are also currently working on designing an in vitro model of catalase supplementation in A549 bronchial epithelial cells. RESULTS/ANTICIPATED RESULTS: Our preliminary data shows that patients with more severe disease (based on hospitalization, oxygen supplementation) have significantly lower levels of catalase activity (p<0.02). Additionally, when pegylated-Catalase (PG-CAT) treatment is utilized in RSV infection of mice, there is significant improvement in several disease parameters. PG-CAT-treated mice show an attenuated body weight loss (p<0.001) and clinical disease (p<0.02), and also have lower levels of key pro-inflammatory cytokines including CXCL1 and TNF-α. PG-CAT treatment also resulted in a minor decrease in viral titer, which is being further evaluated. In addition, PG-CAT treatment resulted in an improvement in airway hyperresponsiveness observed at baseline, we are further characterizing this improvement and also conducting methacholine challenges. Currently, we are working to determine the underlying mechanism through which PG-CAT results in these improvements, and whether it is through changes in immune cell populations, cellular signaling or apoptosis signaling pathways (i.e., caspases). DISCUSSION/SIGNIFICANCE OF IMPACT: RSV is the leading cause of viral pneumonia and bronchiolitis in infants, with no vaccines or effective therapeutics available currently. Our study indicates that catalase activity could be used as a potential correlate for disease severity and be used as an indicator of disease during patient treatment. Additionally, and more importantly supplementation of catalase could be used as a potential therapeutic for treatment of RSV.
2153 The plasma contact system and its role in common variable immunodeficiency (CVID): An explorative study
Authors: Smith Tukisa , Ponda Manish , Breslow Jan , Cunningham-Rundles Charlotte
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: Assess the presence of contact activation at baseline in sera from common variable immunodeficiency (CVID) patients with and without inflammatory complications compared with healthy controls. METHODS/STUDY POPULATION: CVID patients were recruited in the outpatient setting and the measurement of cleaved plasma HK (cHK) levels was determined by Western blot analysis, under reducing conditions, with quantitation of total and cHK bands using an Odyssey imaging system (Licor). One-way ANOVA test for differences among the 3 studied groups will be applied. Biomarkers C3, C4, C1 inhibitor levels and hs-CRP were also measured. RESULTS/ANTICIPATED RESULTS: Participant enrollment continues and to date, 9 CVID patients were studied, 7 with and 2 without inflammatory complications. Repeated determinations of cleaved HK% (cHK%) revealed an average of 1.20% (range: 0.46%–2.66%) in CVID patients with inflammatory complications and those without complications averaged 1.07% (range: 0.79%–1.35%). Healthy controls had an average cHK of 1.15% (range: 0.60%–2.10%). DISCUSSION/SIGNIFICANCE OF IMPACT: Cleaved kininogen detected in the sera of CVID patients was found at similar levels compared with healthy controls (cHK<5%). Findings suggest that systemic activation of the contact system might be absent in CVID, however, future considerations include developing detection methods for local tissue activation.
2303 Trauma-related acute respiratory distress syndrome (ARDS) in India: Current incidence and management strategies
Authors: Adžemović Tessa , Park Pauline
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: Aim 1: To determine the true incidence of trauma-related acute respiratory distress syndrome (ARDS) in India. We propose to perform a prospective observational study to determine the incidence of ARDS in India. Aim 2: To perform a preliminary assessment of risk factors for ARDS in the Indian trauma population. We will leverage these findings against the global ARDS data to provide a foundation for further interventional studies. Aim 3: To evaluate the current management strategies and patient outcomes from ARDS in trauma subjects admitted to the Jai Prakash Narayan Apex Trauma Center (JPNATC). These findings will identify areas in need of practice-based performance improvement in ARDS therapies in India. METHODS/STUDY POPULATION: This application proposes an observational study of trauma patients with ARDS, a population that continues to have substantial in-hospital mortality. The approximate number of ICU-admitted trauma cases for the study period is 1700. Specific data elements to be collected include patient demographics, comorbidities, mechanism of injury, Injury Severity Score, risk factors for ARDS, sequential organ failure and assessment scores, vital signs, laboratory values, and evidence-based treatments received, including mechanical ventilation and adjunctive therapies. Outcome data will include discharge location, ICU and hospital length of stay and all-cause mortality. Selection of Subjects: We will include all patients admitted to the JPNATC Trauma and Neurosurgical ICUs intubated and mechanically ventilated and meeting the definition of Berlin definition of ARDS8. We will collect data for a total of 12 months. RESULTS/ANTICIPATED RESULTS: Due to gaps in reporting, the incidence, mortality, and practice-based management algorithms applied in trauma patients suffering from ARDS in India is unknown. We hypothesize that the overall incidence of trauma-related ARDS is higher, and the fraction of patients managed with evidence-based therapies is lower than global reported averages. DISCUSSION/SIGNIFICANCE OF IMPACT: Although the true incidence of ARDS in trauma subjects in India is currently unknown, we suspect that it is much higher than reported. Such data are important in identification of resource allocation including ICU bed and mechanical ventilator availability, particularly in a resource-limited environment. This proposal will aid in the development of research infrastructure at JPNATC, contribute to capacity building, and the establishment of a Clinical Research unit at the Apex Institute. Finally, a provision to develop a consortium and trauma quality improvement program among the existing trauma centers in New Delhi to disseminate important research findings and guidance to the rest of India is a future benefit of the study.
2261 Tumor suppressor RARRES1 regulates cell survival by modulating mitochondrial energetics
Authors: Maimouni Sara , Lee Mi-Hye , Sung You-Me , Ouaari Chokri , Byers Stephen
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: One of the driving mechanisms of cancer progression is the reprogramming of metabolic pathways in intermediary metabolism. Cancers increase their energy expenditure by increasing ATP production for utilization in anabolic pathways to increase production of proteins, nucleic acids and lipids. The Warburg effect, where cancer cells predominantly use aerobic glycolysis rather than oxidative phosphorylation to produce ATP, was long thought to be the main initiating pathway in increasing tumor burden. However, compelling new evidence shows that there exists metabolic heterogeneity among and within tumors. Mitochondrial respiration often plays a major role in tumor progression, as many different cancers contain a subpopulation of slow-cycling tumor-initiating cells that are multidrug-resistant and dependent on oxidative phosphorylation. These cells represent a target for cancer therapy. In this study, we identification a novel endogenous regulator of mitochondrial respiration, retinoic acid receptor responder 1 (RARRES1). METHODS/STUDY POPULATION: We assessed the metabolic phenotype of RARRES1-depleted normal epithelial cells through metabolomics, a flux analyzer and blotting for phosphorylation of AMP kinase, a major regulator of energy homeostasis. We further examined mitochondrial energetics by staining the mitochondria with TMRM and Mito-Tracker. We then analyzed the apoptotic phenotype of epithelial cells with depletion of RARRES1 with fluorescence-activated cell sorting analysis of annexin V-staining. RESULTS/ANTICIPATED RESULTS: Remarkably, fluorescence-activated cell sorting analysis of annexin V-stained epithelial cells with depletion of RARRES1 were resistant to all studied modes of cell death, implying an effect on a fundamental cell process. By using proteomics, metabolomics, cellular and molecular analyses, our data show that RARRES1 regulates mitochondrial membrane potential and subsequently alters 1-carbon metabolism by modulating the function of the mitochondrial voltage-dependent anion channel. We believe this is the first example of a tumor suppressor protein that functions to directly regulate mitochondrial energetics. Using an extracellular flux analyzer, our data also show that depletion of RARRES1 causes an increase in mitochondrial respiration and ATP production, thus enhancing biosynthetic pathways that drive the pathogenicity and survival of cancer. The metabolic and anti-apoptotic phenotype of RARRES1-depleted cells was reversed by treatment of metformin, a mitochondrial inhibitor. DISCUSSION/SIGNIFICANCE OF IMPACT: These data lay the foundation for metabo-therapy of the many tumor types that exhibit RARRES1 depletion and may have the added benefit of targeting drug-resistant tumor-initiating cells.
2213 Tumor suppressors p53 and ARF control oncogenic potential of triple-negative breast cancer cells by regulating RNA editing enzyme ADAR1
Authors: Kung Che-Pei , Bross Emily A. , Kuzmicki Catherine E. , Benjamin Michael , Maggi Leonard B. , Weber Jason D.
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: Triple-negative breast cancer (TNBC) accounts for one-fifth of the breast cancer patient population. The heterogeneous nature of TNBC and lack of options for targeted therapy make its treatment a constant adventure. The deficiency of tumor suppressors p53 and ARF is one of the known genetic signatures enriched in TNBC. Crucial questions remain about how TNBC is regulated by these genetic alterations. METHODS/STUDY POPULATION: In order to address this issue, we established p53/ARF-defective murine embryonic fibroblast and mammary epithelial cell to study the molecular and phenotypic consequences. Moreover, transgenic mice were generated to investigate the effect of p53/ARF deficiency on mammary tumor development in vivo. RESULTS/ANTICIPATED RESULTS: Increased proliferation and transformation capability were observed in p53/ARF-defective cells, and an aggressive form of mammary tumor was also seen in p53−/−ARF−/− mice. Gene expression profiling and knock-down experiments using shRNAs were conducted to identify inflammatory marker ISG15 and RNA-editing enzyme ADAR1 as potential culprits for the elevated oncogenic potential. Interestingly, we found that the overexpression of ISG15 and ADAR1 is also prevalent in human TNBC cell lines. Reducing ADAR1 expression abrogated the oncogenic potential of human TNBC cell lines, while non-TNBC cells are less susceptible. DISCUSSION/SIGNIFICANCE OF IMPACT: These results indicate critical roles played by the tumor suppressors p53 and ARF in the pathogenesis of TNBC, likely through regulating ADAR1-mediated RNA modifications. Further understanding of this pathway promises to shed light on genetics-driven vulnerabilities of TNBC and inform development of more effective therapeutic strategies.
2165 Vesicular secretion of suppressor of cytokine signaling 3 by alveolar macrophages is dysregulated in NSCLC patients and its provision inhibits epithelial cell transformation and tumor cell function
Authors: Speth Jennifer , Penke Loka R. , Bazzill Joseph , Arenberg Douglas A. , Moon James J. , Keshamouni Venkateshwar G. , Lama Vibha N. , Peters-Golden Marc
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: Insufficient endogenous expression of suppressor of cytokine signaling 3 (SOCS3) with subsequent over-activation of its target, the transcription factor STAT3, has been associated with tumorigenesis and cancer development in the lung and other organs. We have observed that a “backup” source of SOCS3 in the lung, namely that secreted in microvesicles (MVs) by alveolar macrophages, is reduced in the bronchoalveolar lavage fluid (BALF) of KRAS mutant mice harboring lung tumors. Here we sought to evaluate levels of SOCS3 in BALF of a cohort of non-small cell lung cancer (NSCLC) patients and to test the effects of vesicular SOCS3 administration on tumor cell transformation and function as potential therapeutic strategy. METHODS/STUDY POPULATION: In total, 22 BALF samples were obtained from healthy volunteers (n=11) as well as patients undergoing diagnostic bronchoscopies for suspected lung cancer (n=11). SOCS3 levels in the BALF were determined by ELISA after brief sonication to disrupt vesicles. In vitro experiments utilized the human adenocarcinoma cell line (A549) or human G12V mutant KRAS-expressing rat lung epithelial cells (RLE-G12V). Proliferation, Fas ligand (FasL)-induced apoptosis, and chemical transformation with N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) or cigarette smoke extract (CSE) were assessed by CyQuant assay, annexin V staining, and soft agar assay, respectively. For SOCS3 rescue, epithelial cells were treated with natural alveolar macrophages-derived MVs (isolated via ultracentrifugation) or synthetic unilamellar liposomes containing human recombinant SOCS3 for at least 1 hour before assay. RESULTS/ANTICIPATED RESULTS: SOCS3 levels were significantly reduced in BALF samples of patients determined to have NSCLC as compared with healthy volunteers (186.6±26.74 vs. 395.6±74.31 pg/mL, p=0.015, n=11). Addition of exogenous SOCS3-containing liposomes had the capacity to significantly inhibit MNNG and cigarette smoke extract-induced transformation and colony formation in soft agar. Exogenous SOCS3 provided in liposomes or in natural MVs significantly induced apoptosis (both in the presence and absence of FasL) and inhibited basal proliferation of A549 cells. DISCUSSION/SIGNIFICANCE OF IMPACT: These data identified a novel dysregulation of immune surveillance in the form of decreased SOCS3 secretion in the tumor-bearing lung that may contribute to tumorigenesis via sustained STAT3 activation. Future studies will focus on the mechanism underlying this defect and whether rescuing SOCS3 secretion can inhibit cancer progression in vivo.
2003 Mixed meal effects of neprilysin inhibition
Authors: Wilson Jessica R. , Rader Daniel , Townsend Raymond , Rickels Michael
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: Test the hypothesis that neprilysin inhibition with sacubitril/valsartan will increase endogenous intact GLP-1 after a mixed meal compared with valsartan. METHODS/STUDY POPULATION: Adults 18–80 years with pre-diabetes or type 2 diabetes and elevated blood pressure. RESULTS/ANTICIPATED RESULTS: We anticipate higher intact GLP-1 area under the cure after the meal when subjects receive sacubitril/valsartan compared with valsartan. DISCUSSION/SIGNIFICANCE OF IMPACT: Neprilysin inhibition may be a target for anti-diabetes therapy by decreasing degradation of GLP-1.
2137 Percentage of viable tumor Versus radiation treatment effect in surgical specimens is not associated with outcomes in recurrent glioblastoma
Authors: Schwab Robert D. , Bagley Stephen , Binder Zev , Lustig Robert , O’Rourke Donald , Brem Steven , Desai Arati S. , Nasrallah MacLean
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: In patients with recurrent glioblastoma (GBM) who undergo a second surgery following standard chemoradiotherapy, histopathologic examination of the resected tissue often reveals a combination of viable tumor and treatment-related inflammatory changes. However, it remains unclear whether the degree of viable tumor Versus “treatment effect” in these specimens impacts prognosis. We sought to determine whether the percentage of viable tumor Versus “treatment effect” in recurrent GBM surgical samples, as assessed by a trained neuropathologist and quantified on a continuous scale, is associated with overall survival. METHODS/STUDY POPULATION: We reviewed the records of 47 patients with histopathologically confirmed GBM who underwent surgical resection as the first therapeutic modality for suspected radiographic progression following standard radiation therapy and temozolomide. The percentage of viable tumor Versus “treatment effect” in each specimen was estimated by one neuropathologist who was blinded to patient outcomes. RESULTS/ANTICIPATED RESULTS: After adjusting for other known prognostic factors in a multivariate Cox proportional hazards model, there was no association between the degree of viable tumor and overall survival (HR 0.83; 95% CI, 0.20–3.4; p=0.20). DISCUSSION/SIGNIFICANCE OF IMPACT: These results suggest that, in patients who undergo resection for recurrent GBM following standard first-line chemoradiotherapy, histopathologic quantification of the degree of viable tumor Versus “treatment effect” present in the surgical specimen has limited prognostic influence and clinical utility.
2016 Plasma microRNA markers of upper limb recovery following human stroke
Authors: Edwardson Matthew A , Zhong Xiaogang , Cheema Amrita , Dromerick Alexander
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: MicroRNAs are small, non-coding RNAs that control gene expression by inhibiting protein translation. Preclinical studies in rodent stroke models suggest that changes in microRNA expression contribute to neural repair mechanisms. To our knowledge, no one has previously assessed microRNA changes during the recovery phase of human stroke. Our goal was to determine whether patients with significant upper limb recovery following stroke have alteration of neural repair-related microRNA expression when compared to those with poor recovery. METHODS/STUDY POPULATION: Plasma was collected at 19 days post-stroke from 27 participants with mild-moderate upper extremity impairment enrolled in the Critical Periods After Stroke Study. MicroRNA expression was assessed using TaqMan microRNA assays (Thermo Fisher Scientific). Good recovery was defined as ≥6 point change in the Action Research Arm Test (ARAT) score from baseline to 6 months. Bioinformatics analysis compared the plasma microRNA expression profiles of participants with good Versus poor recovery. Candidate biomarkers were identified after correcting for multiple comparisons using a false discovery rate <0.05. RESULTS/ANTICIPATED RESULTS: Eleven microRNAs had significantly altered expression in the good (n=22) Versus poor (n=5) recovery groups, with 2 showing increased expression—miR-371-3p and miR-520g, and 9 showing decreased expression—miR-449b, miR-519b, miR-581, miR-616, miR-892b, miR-941, miR-1179, miR-1292, and miR1296. Three of these could be implicated in neural repair mechanisms. Elevated miR-371-3p levels increase the likelihood that pluripotent stem cells will differentiate into neural progenitors. MiR-892b decreases levels of amyloid precursor protein, which has been implicated as a regulator of synapse formation. Finally miR-941, the only known human-specific microRNA, downregulates the CSPα protein which is involved in neurotransmitter release. DISCUSSION/SIGNIFICANCE OF IMPACT: This preliminary study suggests that circulating microRNAs in the plasma may help serve as biomarkers of neural repair and aid in understanding human neural repair mechanisms. If validated in larger studies with appropriate controls, these markers could aid in timing rehabilitation therapy or designing recovery-based therapeutics.
2280 Subjective, physiological activation and habituation, and response to written trauma narrative exposure
Authors: Howell Mary K. , Myers Jennifer R. , Mellman Thomas A.
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: Emotional processing theory and some observations suggest that activation of subjective and physiological distress during therapeutic exposure and habituation across exposure sessions are key to improvement. This study sought to determine whether initial subjective and physiological activation and between-session habituation would predict PTSD symptom reduction after a series of written trauma narrative exposure sessions. METHODS/STUDY POPULATION: In total, 29 urban-residing African-American participants with PTSD participated in four 30-minute writing sessions. Writing sessions 1 and 2 were 12 hours apart and session 3 and 4 were performed 1 week later, also 12 hours apart. PTSD symptoms were measured at baseline, after session 2, and 1 week after all 4 writing sessions with the Clinician Administered PTSD Scale. During each session, Subjective Units of Distress Scores (SUDS) were assessed 4 times and heart rate was measured continuously. RESULTS/ANTICIPATED RESULTS: Participants exhibited PTSD symptom improvement and habituation of subjective distress, but not physiological arousal, across writing sessions. First session baseline-corrected SUDS maximum and SUDS decrease from the initial to the final writing session were both positively associated with symptom improvement. DISCUSSION/SIGNIFICANCE OF IMPACT: Increased subjective, but not physiological, distress in the first exposure session and diminished subjective distress across sessions may be a helpful marker of emotional processing for clinicians and predictor of symptom improvement after written trauma narrative exposure.
2477 Targeting pulsatile load to increase exercise capacity and quality of life after TAVR for severe aortic stenosis
Authors: Kumar Anupam , Chirinos Julio
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: The objective of the study is to test the effect of oral inorganic nitrate on the primary outcomes of exercise capacity and quality of life in patients who have undergone TAVR for severe aortic stenosis. We will also test the effect of the study drug on various physiology endpoints, including systemic vasodilator response to exercise, LV diastolic function and myocardial strain, late systolic LV load and pulsatile arterial wave reflections. METHODS/STUDY POPULATION: This is a randomized double-blind crossover clinical trial, in which 24 subjects who underwent TAVR for severe AS 3 or more months before enrollment will receive the following 2 interventions, in randomized order: (1) Potassium nitrate (KNO3), at a dose of 12–18 mmol/day by mouth for ~4 weeks, or (2) Potassium chloride (KCl), at a dose of 12–18 mmol/day by mouth for ~4 weeks. A 1-week washout period will be introduced between the 2 interventions. RESULTS/ANTICIPATED RESULTS: We hypothesize that sustained oral administration of potassium nitrate will lead to improvement of exercise capacity and quality of life in this population.DISCUSSION/SIGNIFICANCE OF IMPACT: His study will have a significant impact on assessment and management of patients after TAVR. We will gain a better understanding of physiologic abnormalities leading to exercise intolerance after TAVR. In addition, there are currently no proven therapies that improve exercise capacity in this population.
2244 The effects of gravidity and parity on risk of cognitive impairment and amyloid plaque deposition
Authors: DiBiase Rebecca , Wu Aozhou , Knopman David , Walker Keenan , Mosley Thomas , Lutsey Pamela L. , Gottesman Rebecca
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: Our study seeks to answer the following questions: (1) To determine whether higher numbers of gravidity and parity are associated with a decreased risk of mild cognitive impairment or dementia; (2) To determine whether higher numbers of gravidity and parity are associated with a decreased risk of amyloid deposition by PET MRI. METHODS/STUDY POPULATION: Our study population includes all female study participants in the Atherosclerosis Risk in Communities (ARIC) study who did not have a diagnosis of dementia before enrollment. Participants were also required to have been evaluated for cognitive impairment in the ARIC-NCS ancillary study, or to have received an MRI PET scan of their brain as part of the ARIC-PET ancillary study. Baseline information on the gravidity and parity of all the women was recorded at initial enrollment. We use statistical analyses and epidemiological measures to explore our study questions. For our first question, we use logistic regression to evaluate the association of gravidity and parity as two separate ordinal variables using adjudicated mild cognitive impairment (MCI) and dementia. For our second question, we use logistic regression to evaluate the association of gravidity and parity (again as ordinal variables) with amyloid positivity. We use STATA for our statistical analyses. RESULTS/ANTICIPATED RESULTS: We hypothesize that increased gravidity and parity will have either no effect or a protective effect against MCI, dementia, and amyloid deposition. Our preliminary analyses show that older age of a woman at first pregnancy and at first live birth are both positively correlated with increased incidence of cognitive impairment. No relationship was found between these surrogates of lifetime estrogen exposure and cerebral amyloid deposition. DISCUSSION/SIGNIFICANCE OF IMPACT: Multiple basic science and clinical research studies have shown that estrogen exposure has an effect on cognitive function, likely through a complex interplay of multiple physiologic systems. Our study expands the research in this area by using a large, established epidemiologic cohort to examine gravidity and parity as important factors in lifetime estrogen exposure as they relate to cognitive impairment and amyloid plaque deposition.
2432 The relationship between cognitive functioning and abnormal eating behavior in behavioral variant frontotemporal dementia
Authors: Kamath Vidyulata , Chaney Grace-Anna , Onyike Chiadi
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: Abnormal eating behavior is a core and distinguishing diagnostic feature of behavioral variant frontotemporal dementia (bvFTD) that differentiates it from other neurodegenerative disorders and late-life psychiatric conditions. Though it has been proposed that hyperphagia in bvFTD results from cognitive dysfunction, the observation of altered sweet preferences and food foraging indicate that bvFTD is accompanied by fundamental dietary changes associated with hypothalamic and insular atrophy. In the current study, we examined how cognitive dysfunction contributes to abnormal feeding behavior in bvFTD. METHODS/STUDY POPULATION: We analyzed first-visit eating and neuropsychological data from the National Alzheimer’s Coordinating Center database (7 centers; September 2017 data freeze) in a subset of bvFTD patients with clinician-rated characterization of disturbed feeding severity. Group differences in cognitive domains of attention, processing speed, language, memory, and executive functioning were examined between patients with abnormal eating behavior (n=59) and a demographically-matched sample of patients with normal feeding behavior (n=60). Group differences in informant-reported empathy, behavioral inhibition, and depressive symptoms were also examined. RESULTS/ANTICIPATED RESULTS: Cognitive profiles in bvFTD patients did not vary as a function of disturbed feeding behavior. In a subset of cases pathologically-confirmed at autopsy, processing speed was better in cases with abnormal feeding behavior. No significant group differences were found for behavioral indices. DISCUSSION/SIGNIFICANCE OF IMPACT: These findings suggest that cognitive dysfunction is not the sole driver of abnormal eating behavior in bvFTD. Future studies with comprehensive characterization of feeding behavior, cognition and physiological/neuroimaging indices are warranted.
2199 Critical and creative thinking course: Fundamental for a junior researcher
Authors: de Laurido Lourdes E. Soto , Norman Marie K. , Rubio Doris
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: Explain the difference between creative and critical thinking. Practice and enhance the critical thinking skills. Display innovative thinking through creative solutions and insights. Critically evaluate evidence in research. Think imaginatively, actively seeking out new points of view. METHODS/STUDY POPULATION: Offer an online course in Critical and Creative Thinking to junior researchers to improve their capacity to think and transforms their ideas in research questions and aims that bring new option to the field of clinical and translational research. Evaluate their improvement through evaluation forms and exercises that show their process to think imaginatively. RESULTS/ANTICIPATED RESULTS: The Scholars will understood the importance of critical and creative thinking in their careers, believed they could apply the insights and knowledge from the course in their grant and paper writing, recognized that they don’t always consider if they are being critical or creative in their thinking and actions. DISCUSSION/SIGNIFICANCE OF IMPACT: The course helped the participants to improve their capacity to think and saw a need to develop a more systematic thought processes in their life and work. The junior research will understand the difference between opinion, reasoned, judgment and fact and they will be able to judge the credibility of an information source using criteria such as authorship, currency and potential bias that can improve their grant submission and scientific writing skills.
2242 Evaluation of a clinical investigation curriculum: Post-graduate outcomes
Authors: Shakib Julie H. , Sweeney Carol , Cullum Jodi , Rocha Ruben , Letsou Anthea
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: Many CTSA programs have implemented curricula leading to clinical investigation master’s degrees. Evaluation of long-term outcomes for graduates can support curriculum improvement. METHODS/STUDY POPULATION: We evaluated graduates 1–3 years post completion of an MS in Clinical Investigation at the University of Utah. We administered the 12-item Clinical Research Appraisal Inventory (CRAI-12) describing confidence in ability to perform research tasks; we derived 6 CRAI sub-scales. Additional questionnaire items assessed current engagement in research, including percent of effort devoted to research and level of involvement in research projects using specific research methods. RESULTS/ANTICIPATED RESULTS: Graduates reported high confidence for the CRAI domain of reporting, interpreting, and presenting (on a scale of 0–20, mean 17.9±SD 1.9) and the domain of conceptualizing and collaborating (16.5±2.2) on research projects; confidence was somewhat lower in the domains of planning (14.6±3.3) and funding (14.9±2.8) projects. Graduates’ estimated current professional effort devoted to research had a median of 32%, interquartile range (IQR) 20%–70%; among graduates with clinical responsibilities, median effort devoted to research was 23%, IQR 15%–45%. In total, 74% of graduates reported moderate or high involvement in research using existing large databases, 46% reported moderate or high involvement in comparative effectiveness research, and 54% reported moderate or high involvement in quality improvement. DISCUSSION/SIGNIFICANCE OF IMPACT: A majority of clinical investigation graduates remain engaged in research but most are able to devote less than one-third of professional effort to research. Evaluation of clinical investigation graduates who have moved into their research careers can inform program directors about domains of research expertise and methodological areas that may merit additional emphasis in the curriculum.
2518 InCHOIR learning lab: A TL1 and workforce development initiative at Mount Sinai
Authors: Benn Emma K. T. , Gabrilove Janice L. , Fattah Layla , Bagiella Emilia
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: Science and clinical practice are widely regarded as being complementary and synergistic. In an effort to enhance the team science, translational research capacity of the TL1 scholars at Icahn School of Medicine at Mount Sinai (ISMMS), the InCHOIR learning lab aims to provide an accessible, workforce-wide lecture series on the fundamental methods and concepts of randomized clinical trials. METHODS/STUDY POPULATION: The InCHOIR learning lab is a monthly 1 hour lecture series delivered by a range of expert clinical and translational researchers, followed by a 1 hour “Meet the Expert” session. The InCHOIR lecture series has covered a wide range of topics including, but not limited to: Decision Models; Race and Causal Inference; Innovative Strategies for Assessing Environmental Health across the Life Course; Statistics for Geneticists and Genetics for Statisticians; and From the Lab to Translation to Policy—The Neuroscience of Addiction. The “Meet the Expert” session offers TL1 predoctoral and postdoctoral scholars and KL2 scholars the opportunity to have intimate, informal discussions with experts about their career trajectories. RESULTS/ANTICIPATED RESULTS: Feedback from participants has been overwhelmingly positive. Participants have gained important insights into key topics relevant to early stage researchers. The “Meet the Expert” sessions have yielded honest and important conversations about crucial topics ranging from finding effective mentors to essential strategies for establishing a work-life balance, to overcoming adversity as underrepresented minorities and women in translational research. DISCUSSION/SIGNIFICANCE OF IMPACT: Attendance at the InCHOIR learning lab is increasing month on month, indicating the perceived need for this learning not just from early stage researchers, but also from students, senior faculty, and research staff more generally. The InChoir series provides added value through the creation of a video library, fostering new collaborations and contributing to the Icahn School of Medicine at Mount Sinai and Graduate Medical Education landscape. Priorities for the program are to increase internal visibility, in order to continue to grow attendance by MSHS students, research staff, nurses, postdoctoral fellows and residents. The program is also exploring how to engage external participation from regional CTSAs and from community advocates actively involved in community-academic research partnerships.
2017 Sowing the “CEED”s of a more diverse biomedical workforce
Authors: Mayowski Colleen A. , Abebe Kaleab Z. , Morone Natalia E. , Rubio Doris M. , Kapoor Wishwa N.
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: The need to diversify the biomedical research workforce is well documented. The Career Education and Enhancement for Health Care Research Diversity (CEED) program at the University of Pittsburgh Institute for Clinical Research Education (ICRE) promotes success and helps seal the “leaky pipeline” for under-represented background (URB) biomedical researchers with a purposefully designed program consisting of a monthly seminar series, multilevel mentoring, targeted coursework, and networking. METHODS/STUDY POPULATION: Over 10 program years, we collected survey data on characteristics of CEED Scholars, such as race, ethnicity, and current position. We created a matched set of URB trainees not enrolled in CEED during that time using propensity score matching in a 1:1 ratio. RESULTS/ANTICIPATED RESULTS: Since 2007, CEED has graduated 45 Scholars. Seventy-six percent have been women, 78% have been non-White, and 33% have been Hispanic/Latino. Scholars include 20 M.D.s and 25 Ph.D.s. Twenty-eight CEED Scholars were matched to non-CEED URB students. Compared with matched URB students, CEED graduates had a higher mean number of peer-reviewed publications (9.25 vs. 5.89; p<0.0001) were more likely to hold an assistant professor position (54% vs. 14%; p=0.004) and be in the tenure stream (32% vs. 7%; p=0.04), respectively. There were no differences in Career Development Awards (p=0.42) or Research Project Grants (p=0.24). DISCUSSION/SIGNIFICANCE OF IMPACT: Programs that support URB researchers can help expand and diversify the biomedical research workforce. CEED has been successful despite the challenges of a small demographic pool. Further efforts are needed to assist URB researchers to obtain grant awards.
2007 The clinical research operations program: Educating clinical research staff
Authors: Tsao Peg , Haight Veronica , Dunn Ashley , Jackson Lisa , Goodman Steven
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: The Clinical Research Operations Program is a free educational program designed to educate clinical research personnel on the conduct of clinical research (CR). The participant completes 16 required core sessions (24 h), 4 elective sessions (4 h), and passes the final exam to receive a certification in CR operations at Stanford. Sessions focus on the 9 domains of CR (established by the Joint Task Force for Clinical Trial Competency), such as Ethical & Participant Safety Considerations, Clinical Study Operations, & Data Management/Informatics. METHODS/STUDY POPULATION: Sessions are taught by volunteer lecturers. Participants may also attend the sessions without pursuing the certification. The program objective is to provide easy-access education in CR in order to increase regulatory compliance, staff retention, and improve CR at Stanford. The program targets CR coordinators, however, staff, postdocs, fellows, and faculty also participate. RESULTS/ANTICIPATED RESULTS: Since the program’s launch in January 2017, 119 individuals have enrolled in the certification program. The most represented group is the Department of Medicine. Sessions consistently reach their maximum with a waiting list. Each core session requires that the participant complete an evaluation (Likert scale, 1–5) of the registration process (4.5/5), the class environment (4.6/5), the presented content (4.5/5), and the instructor (4.6/5). Data from these evaluations are positive to date and is used to continually refine the program. DISCUSSION/SIGNIFICANCE OF IMPACT: N/A.
2100 TL1 team approach to social and genetic determinants of nocturnal blood pressure
Authors: Dumeny Leanne , Chu Hsiao  , Cavallari Larisa H. , Mulligan Connie J. , McCormack Wayne T.
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: The TL1 Team approach aims to train translational investigators capable of tackling complex and multifaceted diseases, such as hypertension, by beginning multidisciplinary, team-based training early in their graduate programs. METHODS/STUDY POPULATION: Leanne Dumeny is a graduate student in Genetics and Genomics studying how pharmacogenomics can be applied to improve clinical care and cardiovascular outcomes. Chu Hsiao is a graduate student in Anthropology studying how sociocultural experiences become biologically embodied. Both are in the Ph.D. phase of M.D.-Ph.D. training. Joining the seemingly disparate but complementary fields of anthropology and genomics facilitates understanding of the intersection between socially driven experiences and genetics on nocturnal blood pressure. Understanding both social determinants, such as racial discrimination, and biological determinants, such as genetics, is important because an interplay of gene-environment interactions influences many complex diseases. Rarely can 1 individual, or 1 discipline, tackle all the perspectives necessary to answer these types of complex questions. The TL1 Team curriculum teaches students to navigate the spectrum of translational research as a team, reflect on disciplinary limitations, and embrace collaborative research. RESULTS/ANTICIPATED RESULTS: This team project will investigate the relationship between racial discrimination and genetics using a large epidemiological cohort of African Americans in Mississippi. The data request application is currently under review. By the project’s end, the team anticipates their investigation will reveal novel associations between racial discrimination, genetic polymorphisms, and nocturnal blood pressure measurements. The investigators will have gained experience obtaining and analyzing large external data sets, working in diverse team settings, collaborating across state-lines, and publishing articles. Through this team approach, the students will also understand the barriers to working in multidisciplinary groups, and develop a foundation for approaching future collaborations. DISCUSSION/SIGNIFICANCE OF IMPACT: By joining anthropology with genomics, it becomes possible to understand the intersection between socially driven experiences of racial discrimination and genetics on nocturnal blood pressure. The successful training of this first cohort of team-applicants to the TL1 funding mechanism can impact how graduate education will be structured and could reframe graduate education to emphasize a team-based approach.
2388 Utilizing a reviewer database to facilitate integration of an investigator-focused translational research and career development program across the state of Indiana
Authors: Coffee R. L. , Driscol Julie , Saydyk Tammy J. , Shekhar Anantha , Denne Scott C. , Hunt Joe D.
Published: November 2018

OBJECTIVES/SPECIFIC AIMS: The Indiana CTSI is investigating innovative approaches to integrate resources that will enrich scientific investigators. Our goals are to enhance the availability and communication among CTSI resources, for example internal funding, and to expand existing mentorship. METHODS/STUDY POPULATION: Developed a reviewer database that serves to streamline reviewer identification, decrease reviewer fatigue, and promote collaboration among disciplines. We started with a pool of NIH-funded investigators from across the Indiana CTSI core institutions and merged this list with previous CTSI reviewers and internal funding awardees. To expand this list, names and expertise from new faculty hires were added. RESULTS/ANTICIPATED RESULTS: Though this tool is relatively new, we have already observed an increase in junior faculty awareness and engagement with the CTSI. This database allows for increased opportunities of junior faculty to serve as reviewers and to refine grant writing skills and provides a platform for networking and collaborating across disciplines. It also allows for increased integration of programs with a shared reviewer database and promotes grant review standardization. DISCUSSION/SIGNIFICANCE OF IMPACT: Our database utilization seeks to decrease the time for junior faculty to obtain their first extramural grant, to enhance promotion and tenure packages, strengthen integration among CTSI programs, increase interactions between clinical and basic science investigators, and promote team science.