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OBJECTIVES/SPECIFIC AIMS: Patients with locally advanced pancreatic cancer typically have poor outcomes, with a median survival of ~16 months. Novel methods to improve local control are needed. Nab-paclitaxel (abraxane) has shown efficacy in pancreatic cancer and is FDA approved for metastatic disease in combination with gemcitabine. Nab-paclitaxel is also a promising radiosensitizer based on laboratory studies, but it has never been clinically tested with definitive radiotherapy for locally advanced disease. METHODS/STUDY POPULATION: We performed a phase 1 study using a 3+3 dose-escalation strategy to determine the safety and tolerability of dose escalated nab-paclitaxel with fractionated radiotherapy for patients with unresectable or borderline resectable pancreatic cancer. Following induction chemotherapy with 2 cycles of nab-paclitaxel and gemcitabine, patients were treated with weekly nab-paclitaxel and daily radiotherapy to a dose of 52.5 Gy in 25 fractions. Final dose-limiting toxicity (DLT) determination was performed at day 65 after the start of radiotherapy. RESULTS/ANTICIPATED RESULTS: Nine patients received nab-paclitaxel at a dose level of either 100 mg/m2 (n=3) or 125 mg/m2 (n=6). One DLT (grade 3 neuropathy) was observed in a patient who received 125 mg/m2 of nab-paclitaxel. Other grade 3 toxicities included fatigue (11%), anemia (11%), and neutropenia (11%). No grade 4 toxicities were observed. With a median follow-up of 8 months (range 5–28 months), median survival was 19 months and median progression-free survival was 10 months. Following chemoradiation, 3 patients underwent surgical resection, all with negative margins and limited tumor viability. Of the 3 patients, 2 initially had borderline resectable tumors and 1 had an unresectable tumor. Tumor (SMAD-4, Caveolin-1) and peripheral (circulating tumor cells and microvesicles) biomarkers were collected and are being analyzed. DISCUSSION/SIGNIFICANCE OF IMPACT: The combination of fractionated radiation and weekly nab-paclitaxel was safe and well tolerated. This regimen represents a potentially promising therapy for patients with unresectable and borderline resectable pancreatic cancer and warrants further investigation.

OBJECTIVES/SPECIFIC AIMS: The objective of this study is the pharmacology of sublingual Buprenorphine in Hispanics/Latino men and women. Specifically we plan to: (1) Administer sublingual buprenorphine to Hispanic/Latino men and women volunteers, and measure the circulating amounts of the drug in the bloodstream as a function of time; that is, pharmacokinetics of buprenorphine. The goal of the proposed study is to evidence that there are gender and ethnic differences in the pharmacokinetics of sublingual buprenorphine between not only Hispanics/Latinos and non-Hispanics/Latinos (Caucasian), but also within Hispanic/Latino men and women. METHODS/STUDY POPULATION: We are proposing a phase 1 of buprenorphine using 12 healthy volunteers. To test for differences in pharmacokinetics between Hispanic/Latino men and women, 6 Hispanic/Latino men, and 6 Hispanic/Latino women 21 years of age and older will be recruited. The volunteers should be living in Puerto Rico, and must have both parents born in Puerto Rico. Sublingual buprenorphine will be administered using a low dose of 16 mg one time only. Blood samples will be collected from each volunteer at t = 0, 1, 2, 4, 6, 8, 12, and 24 hours after administration. The amount of circulating drug in the bloodstream of the volunteers will be measured using liquid chromatography combined with mass spectrometry. Pharmacokinetic obtained parameters will be maximal plasma concentration, minimal plasma concentration, predose concentration, 24 hour post predose concentration, the time for maximum concentration. The area under the curve will be determined by the trapezoidal rule. Male Versus female data will be compared using 2-tailed t-test. RESULTS/ANTICIPATED RESULTS: We anticipate that: (1) Hispanic/Latino women will have longer circulating times of the drug in the bloodstream and higher maximum concentrations, compared with men. (2) Hispanic/Latino men and women will have higher amounts of the circulating drug, compared with already reported pharmacokinetic data of non-Hispanic Caucasian men. DISCUSSION/SIGNIFICANCE OF IMPACT: Gender differences have been elucidated in the prevalence rates of substance abuse, health service utilization, treatment outcomes, and physiological consequences of drug consumption in the United States. It is known that in general, women progress from drug use to dependence must faster than men; women also suffer more severe physical and emotional consequences than men, yet women seek treatment for drug addiction in lower rates compared with men. Women also show lower pharmacological treatment effectiveness as they are less likely to feel satisfied upon entering a substance abuse treatment and they show higher cravings. Sublingual buprenorphine is a very popular and relatively new medication used primarily for opiate addiction since 2002. Gender differences have been elucidated in the pharmacology of buprenorphine sublingual tablets used for the treatment of opioid addiction. One study showed that women had higher concentrations of circulating parent drug and it is metabolites compared with men. One metabolite in particular norbuprenorphine was found in almost double the plasma concentration in women. Interestingly, gender differences were not pursued at all by the Pharmaceutical Company sponsoring the approval of the sublingual Buprenorphine by the FDA. The cytochrome enzyme CYP 3A4 responsible for the metabolism of Buprenorphine has higher activity in Caucasian/African American women compared with men. However these studies failed to design and recruit significant amount of patients with Hispanic ethnicity to adequately elucidate the gender differences within this ethnic group. Higher plasma concentrations and longer circulation times of a drug may result not only in lower efficacy outcomes but also higher toxicity and undesired effects. Unfortunately, the lack of pharmacological effectiveness and lack of satisfaction in women undergoing drug treatment programs has not been adequately studied to understand the gender difference in pharmacological treatment outcomes between Hispanic/Latino men and women. Due to the under-representation of Hispanic/Latino men but most importantly women in s studying the pharmacology of sublingual Buprenorphine, and considering the well-established gender difference of the principal enzyme (CYP 3A4) responsible for the pharmacology of Buprenorphine, we are proposing a pilot study of the pharmacology of sublingual Buprenorphine in Hispanic/Latino volunteers living in Puerto Rico with equal number of male and female patients. We expect our research to clinically and scientifically elucidate the gender differences of sublingual buprenorphine for opioid addiction in Hispanics/Latinos. The outcome of such research will be the foundation of subsequent clinical studies that aim in updating the current standard of care for Hispanic/Latino men and women that require therapy for opioid addiction.

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Engraftment and gene expression of an HIV resistant immune system in a Phase I trial of an HIV stem cell gene therapy strategy Joseph Anderson, Kyle Hendrix, Julie Beegle, Jan A. Nolta and Mehrdad Abedi OBJECTIVES/SPECIFIC AIMS: To date, only 1 documented case of an individual cured of HIV has been reported. He received an allogeneic bone marrow transplant with cells harboring an HIV-resistant genotype. To mimic this result, we have initiated a Phase I to evaluate the safety of an autologous stem cell gene therapy bone marrow transplant in HIV-related lymphoma patients. METHODS/STUDY POPULATION: The first cohort of patients will receive a 1:1 ratio of unmanipulated CD34 hematopoietic stem cells (HSC) and lentivector modified CD34 HSC expressing a combination of HIV-resistant genes and a selectable marker for cell sorting prior to transplantation. Safety of the HIV-resistant stem cells will be assessed by evaluating engraftment, expression of the anti-HIV genes, and the stability and sequence of the vector. RESULTS/ANTICIPATED RESULTS: One patient has been enrolled and transplanted with the HIV-resistant stem cells. After 1 and 2 months posttransplant, patient blood samples were received, processed for genomic DNA, analyzed by quantitative PCR (qPCR), and displayed successful engraftment of 16 and 12 vector copies per 100 cells, respectively. Expression of all anti-HIV genes was confirmed by qPCR. PCR on genomic DNA confirmed the correct sizes and sequences of the integrated vector and confirmed the successful engraftment of our gene modified cells. Currently, we are enrolling more patients into the trial. DISCUSSION/SIGNIFICANCE OF IMPACT: If successful, this therapy has the potential to change HIV treatment. OBJECTIVES/SPECIFIC AIMS: Patients with locally advanced pancreatic cancer typically have poor outcomes, with a median survival of~16 months. Novel methods to improve local control are needed. Nab-paclitaxel (abraxane) has shown efficacy in pancreatic cancer and is FDA approved for metastatic disease in combination with gemcitabine. Nab-paclitaxel is also a promising radiosensitizer based on laboratory studies, but it has never been clinically tested with definitive radiotherapy for locally advanced disease. METHODS/STUDY POPULATION: We performed a phase 1 study using a 3 + 3 dose-escalation strategy to determine the safety and tolerability of dose escalated nab-paclitaxel with fractionated radiotherapy for patients with unresectable or borderline resectable pancreatic cancer. Following induction chemotherapy with 2 cycles of nab-paclitaxel and gemcitabine, patients were treated with weekly nabpaclitaxel and daily radiotherapy to a dose of 52.5 Gy in 25 fractions. Final doselimiting toxicity (DLT) determination was performed at day 65 after the start of radiotherapy. RESULTS/ANTICIPATED RESULTS: Nine patients received nabpaclitaxel at a dose level of either 100 mg/m 2 (n = 3) or 125 mg/m 2 (n = 6). One DLT (grade 3 neuropathy) was observed in a patient who received 125 mg/m 2 of nab-paclitaxel. Other grade 3 toxicities included fatigue (11%), anemia (11%), and neutropenia (11%). No grade 4 toxicities were observed. With a median follow-up of 8 months (range 5-28 months), median survival was 19 months and median progression-free survival was 10 months. Following chemoradiation, 3 patients underwent surgical resection, all with negative margins and limited tumor viability. Of the 3 patients, 2 initially had borderline resectable tumors and 1 had an unresectable tumor. Tumor (SMAD-4, Caveolin-1) and peripheral (circulating tumor cells and microvesicles) biomarkers were collected and are being analyzed. DISCUSSION/SIGNIFICANCE OF IMPACT: The combination 32 cambridge.org/jcts of fractionated radiation and weekly nab-paclitaxel was safe and well tolerated. This regimen represents a potentially promising therapy for patients with unresectable and borderline resectable pancreatic cancer and warrants further investigation.

Characterizing vigilant thoughts and behaviors that disrupt sleep in veterans and utilization of cognitive techniques
Mary Katherine Howell and Thomas Mellman Georgetown -Howard Universities, Washington, DC, USA OBJECTIVES/SPECIFIC AIMS: Sleep disturbance is a common problem following military deployment. Insomnia is associated with other adverse psychiatric and medical health outcomes. There are specialized cognitive behavioral therapies that can effectively treat insomnia; however, these tend to emphasize dysfunctional beliefs about sleep rather than nocturnal vigilance. Deployment to a threatening environment can engender nocturnal vigilance, which appears to be a salient feature of sleep disturbance in formerly deployed veterans. The purpose of this analysis is to characterize sleep-interfering thoughts and behaviors observed in an ongoing pilot study of a novel 2-session intervention incorporating various cognitive techniques to improve sleep in veterans. METHODS/STUDY POPULA-TION: To date, 10 formerly deployed US veterans with disturbed sleep have been recruited from the greater DC area. Participants are assessed at baseline, receive 2 intervention sessions, and are again assessed in 3 months. Sleep-interfering thoughts and behaviors are evaluated via self-report forms including the Fear of Sleep Inventory (FoSI), interviews, and prospective diaries. A portion of both intervention sessions addresses vigilant behaviors and sleep-interfering thoughts by teaching participants 1 of 4 techniques that target nocturnal vigilance: cognitive defusion, body scan, self-guided pleasant imagery, and dream rescripting. RESULTS/ANTICIPATED RESULTS: All of the first 10 participants endorsed sleep-interfering thoughts on the Fear of Sleep Index (FOSI) at a severity level of at least "a few times per month" (rating of ≥1), including several regarding previous trauma (#5) and nightmares (#10 and #16). Other elicited thoughts included thoughts about their environment (n = 6), sleep (n = 5), social or occupational concerns (n = 8), nightmares (n = 5), and health (n = 4). All of the first 10 participants endorsed vigilant behaviors, including being over-attentive to their environment (n = 7), checking behaviors (n = 6), and being "on-guard" (n = 8). Cognitive technique was selected by the participant in collaboration with the facilitator. Customized recommendations were given as to the timing and duration of practice, but all participants were instructed to practice at least once daily. Three participants (n = 3) were fully compliant with their cognitive technique recommendations (choosing a body scan or imagery), 5 were partially compliant, and 2 were not compliant (both chose cognitive defusion). There was a significant reduction in sleep onset latency and wake after sleep onset from baseline to posttreatment (p < 0.05). DISCUSSION/SIGNIFICANCE OF IMPACT: The preliminary data suggests that veterans exhibit cognitive and behavioral patterns that involve vigilance and interfere with sleep and demonstrates the need for an intervention targeting the link between nocturnal vigilance and sleep disturbance. More veteran participants and feedback are needed to optimize the efficacy and effectiveness of this sleep training.

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The effect of family history, alcohol expectancies, and sex differences on hangover symptoms following intravenous alcohol self-administration in nondependent drinkers Corbin Daniel Ester, Bethany Stangl, Aruna Gogineni, Lauren Blau, Vatsalya Vatsalya and Vijay Ramchandani National Institutes of Health, New York, NY, USA OBJECTIVES/SPECIFIC AIMS: The current study examined hangover following IV alcohol self-administration (IV-ASA) using the Computer-Assisted Infusion System. The goal of the study was to identify predictors of hangover, including drinking history, alcohol sensitivity, family history, expectancies, and sex differences in nondependent drinkers. METHODS/STUDY POPULATION: The study sample included 89 healthy, nondependent drinkers aged 21-45 years. After a screening to exclude any medical illness or psychiatric disorders, participants completed an IV-ASA session. Each session consisted of a 25-minute priming phase, during which participants were prompted to press a button to receive individually standardized alcohol infusions, followed by a 2-hour "open bar" phase, during which they were instructed to recreate a typical drinking experience. Results from the IV-ASA included peak and average BrAC. Drinking patterns were assessed using the Alcohol Use Disorders Identification Test, which provided 3 subscales: consumption (AUDIT-C), dependence (AUDIT-D), and harmful drinking (AUDIT-H). Subjective response to alcohol was measured using the Drug Effects Questionnaire (DEQ). The Alcohol Hangover Scale (AHS) was used to assess hangover for the period between participants' departure from the study unit and 10 AM the next morning. The Alcohol Effects Questionnaire (AEFQ) is a measure which includes 40 true/false statements about how alcohol typically makes respondents feel, and was used to measure alcohol expectancies. RESULTS/ ANTICIPATED RESULTS: Results showed that 78% of participants endorsed having at least 1 hangover symptom following IV-ASA. The most commonly reported items were tired, thirsty, headache, and hangover. There was no association between hangover scores and the AUDIT-C or IV-ASA. Because alcohol consumption was not related to hangover symptoms, risky drinking behavior was examined. Results indicated that participants endorsing 4 or more items on the AUDIT-D plus AUDIT-H subscales showed significantly higher average hangover scores. Linear regression analyses indicated that alcohol hangover scores were associated with DEQ items feel, high, and intoxicated. Ongoing analyses are examining additional predictors of hangover including family history, alcohol expectancies, sex differences, and other alcohol sensitivity measures. DISCUSSION/SIGNIFICANCE OF IMPACT: The results indicated that risky drinking patterns and alcohol response measures were positively associated with hangover symptoms in non-dependent drinks, while no correlation between consumption and hangover symptoms were found. Since previous research has shown than greater subjective response is associated with heavy drinking and predictive of alcohol use disorder, it is possible that hangover symptoms is a marker of this relationship. Since the role of hangover in the transition from heavy drinking to disorder still remains unclear, it will be important to characterize this relationship between alcohol sensitivity and hangover as a function of drinking patterns. This understanding may help to prevent this transition from at-risk drinking to alcohol dependent drinking.

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Pilot study: Implementing Brief Dialectical Behavior Therapy (DBT-A) group skills training in a public and alternative high school setting Tamika Zapolski, Matthew C. Aalsma, Michelle Salyers and Dennis Watson OBJECTIVES/SPECIFIC AIMS: Engagement in risky behaviors is not uncommon among adolescents. Two factors associated with risk taking are difficulty regulating emotions and impulsivity. Moreover, youth who exhibit higher scores on impulsivity-like personality traits (ie, negative urgency, positive urgency, sensation seeking, lack of premeditation, and lack of perseverance) are at even heightened risk. An effective intervention decreasing risk-taking behavior among adolescent populations in clinical settings is Dialectical Behavioral Therapy for Adolescents (DBT-A), which teaches skills on emotion regulation, distress tolerance, and mindfulness. However, DBT-A has yet to be tested as an intervention for youth in a nonclinical setting. The current study aimed to fill this gap in the literature. METHODS/STUDY POPULATION: A 9-week DBT-A skills group was implemented in a public high school classroom (7th-8th graders; N = 41) and an alternative high school for at risk youth (7th-12th graders; n = 21). Of the 41 youth from the public high school classroom participated, with preintervention and postintervention data provided by 30 participants (retention of 73%). RESULTS/ ANTICIPATED RESULTS: Results found a significant increase in mindfulness skills and marginally significant increase in emotion regulation skills. Although there was not an overall change in risky behavior among participants, those who were higher on lack of premeditation and positive urgency showed steeper improvements on the skills. The second study at the alternative high school is currently underway, with no current results to report. DISCUSSION/SIGNIFICANCE OF IMPACT: This study will demonstrate that DBT-A skills training is feasible in a school-based setting and shows promising preliminary evidence of decreasing risk of engagement in risky health behaviors among adolescents, particularly among high-risk youth.

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The impact of social influence and impulsivity on IV alcohol self-administration in non-dependent drinkers Alyssa Schneider, Bethany L. Stangl, Elgin R. Yalin, Jodi M. Gilman and Vijay Ramchandani National Institutes of Health, New York, NY, USA OBJECTIVES/SPECIFIC AIMS: Impulsivity is a significant predictor of alcohol use and drinking behavior, and has been shown to be a critical trait in those with alcohol use disorder. Suggestibility, or susceptibility to social influence, has been cambridge.org/jcts