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OBJECTIVES/GOALS: The Oregon Clinical and Translational Research Institute (OCTRI) Clinical Research Navigator program provides a single point of entry for clinical and translational research services, support, advice and guidance. We provide data to illustrate the Navigator model at OHSU and examine continued opportunities to optimize research resources. METHODS/STUDY POPULATION: Requests and activities performed by the OCTRI Navigator program, staffed by 3 FTE (2 Assistant Navigators and 1 Assistant Director) were analyzed. Navigator receives requests through multiple methods: a digital form (REDCap®), email, phone calls. Requests for services and support include focused need for a core or a broad request for multiple services for start-up: informatics, the clinical and translational research center, regulatory knowledge and support, recruitment, qualitative methods, community research, biostatistics or broad consultations. Requests are tracked in SPARCRequest. Navigator also supports wayfinding to institutional resources outside of the CTSA, matchmaking for sponsors seeking investigators, and serves as a connector and facilitator across programs. RESULTS/ANTICIPATED RESULTS: OCTRI Clinical Research Navigator triaged an average of 964 research requests for 613 projects with 388 unique investigators annually between 2018-2022. Navigator also fields more than 80 calls each year that are unrelated to CTSA projects. Project requests are examined to illustrate trends in projects requesting multiple services and display how Navigator simplifies project intake and connects researchers to resources they may have not recognized they needed. Project attributes including funding type and funding status are included in this review. DISCUSSION/SIGNIFICANCE: CTSA resources are essential to the infrastructure available to researchers. While absolute numbers of requests provide little insight into the impact each CTSA hub may have, the timing and clustering trends of projects with multiple program requests shows how a combination of technology and experienced staff can efficiently support researchers.

Abstract We analyse the short‐ and long‐term consequences for atmospheric greenhouse gas (GHG) concentrations of forest management strategies and forest product uses in Sweden by comparing the modelled consequences of forest resource use vs. increased conservation at different levels of GHG savings from carbon sequestration and product substitution with bioenergy and other forest products. Increased forest set‐asides for conservation resulted in larger GHG reductions only in the short term and only when substitution effects were low. In all other cases, forest use was more beneficial. In all scenarios, annual carbon dioxide (CO2) sequestration rates declined in conservation forests as they mature, eventually approaching a steady state. Forest set‐asides are thus associated with increasing opportunity costs corresponding to foregone wood production and associated mitigation losses. Substitution and sequestration rates under all other forest management strategies rise, providing support for sustained harvest and cumulative mitigation gains. The impact of increased fertilization was everywhere beneficial to the climate and surpassed the mitigation potential of the other scenarios. Climate change can have large—positive or negative—influence on outcomes. Despite uncertainties, the results indicate potentially large benefits from forest use for wood production. These benefits, however, are not clearly linked with forestry in UNFCCC reporting, and the European Union's Land Use, Land‐Use Change and Forestry carbon accounting, framework may even prevent their full realization. These reporting and accounting frameworks may further have the consequence of encouraging land set‐asides and reduced forest use at the expense of future biomass production. Further, carbon leakage and resulting biodiversity impacts due to increased use of more GHG‐intensive products, including imported products associated with deforestation and land degradation, are inadequately assessed. Considerable opportunity to better mobilize the climate change mitigation potential of Swedish forests therefore remains.

Abstract Background RNA editing leads to post-transcriptional variation in protein sequences and has important biological implications. We sought to elucidate the landscape of RNA editing events across pediatric cancers. Methods Using RNA-Seq data mapped by a pipeline designed to minimize mapping ambiguity, we investigated RNA editing in 711 pediatric cancers from the St. Jude/Washington University Pediatric Cancer Genome Project focusing on coding variants which can potentially increase protein sequence diversity. We combined de novo detection using paired tumor DNA-RNA data with analysis of known RNA editing sites. Results We identified 722 unique RNA editing sites in coding regions across pediatric cancers, 70% of which were nonsynonymous recoding variants. Nearly all editing sites represented the canonical A-to-I (n = 706) or C-to-U sites (n = 14). RNA editing was enriched in brain tumors compared to other cancers, including editing of glutamate receptors and ion channels involved in neurotransmitter signaling. RNA editing profiles of each pediatric cancer subtype resembled those of the corresponding normal tissue profiled by the Genotype-Tissue Expression (GTEx) project. Conclusions In this first comprehensive analysis of RNA editing events in pediatric cancer, we found that the RNA editing profile of each cancer subtype is similar to its normal tissue of origin. Tumor-specific RNA editing events were not identified indicating that successful immunotherapeutic targeting of RNA-edited peptides in pediatric cancer should rely on increased antigen presentation on tumor cells compared to normal but not on tumor-specific RNA editing per se.

We describe the management and clinical decision making in a cardiogenic shock patient with a free-floating left ventricular thrombus found during temporary mechanical support with an Impella CP. The management of these patients can be challenging because there are no guidelines or data to support any particular treatment strategy. (Level of Difficulty: Intermediate.)

Forests and trees are key to solving water availability problems in the face of climate change and to achieving the United Nations Sustainable Development Goals. A recent global assessment of forest and water science posed the question: How do forests matter for water? Here we synthesize science from that assessment, which shows that forests and water are an integrated system. We assert that forests, from the tops of their canopies to the base of the soils in which trees are rooted, must be considered a key component in the complex temporal and spatial dimensions of the hydrologic cycle. While it is clear that forests influence both downstream and downwind water availability, their actual impact depends on where they are located and their processes affected by natural and anthropogenic conditions. A holistic approach is needed to manage the connections between forests, water and people in the face of current governance systems that often ignore these connections. We need policy interventions that will lead to forestation strategies that decrease the dangerous rate of loss in forest cover and that—where appropriate—increase the gain in forest cover. We need collective interventions that will integrate transboundary forest and water management to ensure sustainability of water supplies at local, national and continental scales. The United Nations should continue to show leadership by providing forums in which interventions can be discussed, negotiated and monitored, and national governments must collaborate to sustainably manage forests to ensure secure water supplies and equitable and sustainable outcomes.

OBJECTIVES/GOALS: The research project aimed to understand the perceived effectiveness of research recruitment methods, including informatics tool utilization, so that best practices can be established and outcomes measured longitudinally. METHODS/STUDY POPULATION: The mixed-methods study was conducted by the Oregon Clinical and Translational Science Institute, the CTSA at Oregon Health and Sciences University. A survey, clinical trial accrual data, and interviews were used to assess the study aims. The survey asked about utilization and value of specific recruitment tools and methods. Accrual data was obtained from the clinical trial management system and analyzed using parameters from the CTSA “Accrual Metric”. The metric was calculated for clinical trials enrolling during 2017. Interviews were conducted with researchers identified by the survey and over or under-enrolled accrual data, and inquired about recruitment facilitators and barriers. RESULTS/ANTICIPATED RESULTS: The most frequently mentioned facilitator of recruitment was direct patient contact, either in the healthcare setting (58.4% of survey respondents) or through patient outreach (32%). A lack of resources was considered a key barrier (21% of survey respondents) and a stated need (27%). Interview data expanded on these findings, as 23% of interviewees indicated a collaborative culture, which includes clinic integration, was key to recruitment success. Additionally, 20% of interviewees identified resources (i.e. funding, staff, time) as their greatest need. Notably, 13% of studies with an accrual ratio of “0” had frequent staff turnover. DISCUSSION/SIGNIFICANCE OF IMPACT: This approach allowed for a uniquely targeted analysis of accrual facilitators and barriers. Use of the CTSA accrual metric identified high-value interview respondents and will allow for investigation into additional accrual questions, such as the impact of funding sources and departmental factors.

Pediatric osteosarcoma is characterized by multiple somatic chromosomal lesions, including structural variations (SVs) and copy number alterations (CNAs). To define the landscape of somatic mutations in pediatric osteosarcoma, we performed whole-genome sequencing of DNA from 20 osteosarcoma tumor samples and matched normal tissue in a discovery cohort, as well as 14 samples in a validation cohort. Single-nucleotide variations (SNVs) exhibited a pattern of localized hypermutation called kataegis in 50% of the tumors. We identified p53 pathway lesions in all tumors in the discovery cohort, nine of which were translocations in the first intron of the TP53 gene. Beyond TP53, the RB1, ATRX, and DLG2 genes showed recurrent somatic alterations in 29%–53% of the tumors. These data highlight the power of whole-genome sequencing for identifying recurrent somatic alterations in cancer genomes that may be missed using other methods.

Though to-date the European Union (EU) has played the most significant leadership role in international negotiations to reduce greenhouse gas (GHG) emissions, the emission-reducing performance of individual EU Member states has for many been less than stellar. Several EU15 Member states continue to raise rather than lower emissions. Analysing the most successful policy instruments, this paper argues EU policy efforts could benefit from three important innovations. The following strategies – the adoption of an EU-wide FIT (feed-in tariff), an EU-wide carbon tax and more flexibility in the trading of carbon credits – could significantly improve emission reductions, their relative cost-efficiency and spread burden-sharing more evenly across technologies and Member states. This raises important questions, both about the effectiveness of EU and Kyoto-style commitments, as well as the EU Emission Trading Scheme (ETS). The commitment strategy, and in particular the EU ETS mechanism, have had the smallest impact on emission reductions. The proposed set of strategies could make a far greater contribution to future EU efforts and potentially lock in the impressive progress already made. Such a policy shift, if successful, would also greatly enhance the EU’s already significant credibility and bargaining power in international climate negotiations.

The Water Framework Directive (WFD) is an ambitious piece of legislation designed to protect and improve water quality throughout Europe. However, forests are only mentioned once in the WFD, and forestry is not mentioned at all, despite its potential implications for streams, rivers and lakes. Here we present a transdisciplinary commentary on the WFD and its implications for forests and forestry in Sweden. This commentary has been prepared by forestry stakeholders, biophysical and social scientists. While we were cognizant of a large body of discipline-specific research, there are very few inter- or trans-disciplinary commentaries which link academic and stakeholder perspectives on the WFD. We had originally felt that there would be little commonality in our concerns. However, we found significant areas of agreement. Our key areas of concern about the implications of the WFD for forestry in Sweden included: (i) concerns about what is meant by good ecological status and how it is assessed; (ii) a perceived lack of clarity in the legal framework; (iii) an inadequate environmental impact assessment process; and (iv) uncertainties about appropriate programs of measures for improving water quality. We were also concerned that ecosystem services provided by forests and the positive effects of forestry on water quality are inadequately recognized in the WFD.

OBJECTIVES/SPECIFIC AIMS: A growing concern about the declining physician-scientist workforce prompted the 2014 National Institutes of Health (NIH) Physician Scientist Workforce to recommended that “tools for assessing the strength of the biomedical workforce” be developed. To aid strategic planning, the Oregon Clinical and Translational Research Institute convened key stakeholders at its home university, Oregon Health and Science University (OHSU), to survey the local landscape of physician scientists. Surprisingly, few consensus methods were available to measure and benchmark OHSU with respect to national comparators. To address this deficit, we sought to develop clear and objective metrics describing physician-scientist success at our institution. By focusing on local funding, we were able to generate more complete and robust data than others have reported. These data also permit us to compare ourselves to the national workforce, using well-curated and accessible national databases. The goal of the analyses is to contribute to strategic decision-making by portraying the local physician-scientist workforce, comparing it to the national landscape, and making recommendations about mechanisms to address potential opportunities. This has led us to develop a simple quantitative dashboard, which now permits OHSU to craft strategic targets and address successes and opportunities. These approaches are likely to be valuable elsewhere. METHODS/STUDY POPULATION: OHSU is a medium-sized academic health center in Portland, Oregon with over 1200 principal investigators and over $230M in NIH funding. The primary focus of our investigation was physician-scientists who receive extramural funding. To align with other analyses, we distinguish physician-scientists with an M.D. only, or with an M.D. and a master’s degree, from physician-scientists who hold an M.D./Ph.D. For this distinction, we use the indicator “M.D.-only” to indicate the former. The study design consisted of (a) selection of available and relevant national level data on the physician-scientist workforce, (b) curating of local level data to align it with the national indicators, (c) comparing the 2 sets of data to look for differences in trends over time, and (d) supplementing the analyses with additional local data not available at the national level. Key comparisons were tested for statistical significance and plotted on a dashboard, which was then reviewed by an OHSU internal working group focused on physician-scientists. Data elements included degrees, age, gender, and grants awarded. National data come directly from the NIH Data Book, updated for fiscal year 2016. The NIH makes all funded project data available in the publicly downloadable ExPORTER Data Catalog. These project data were used to supplement the summarized data available from the NIH Data Book, allowing us to extract OHSU investigators and to complete the K to R comparative analysis. For analyses of OHSU investigators holding funding other than RPGs, we relied on institutional data from the OHSU grants and contracts office. Demographic data on OHSU investigators were obtained from departmental and human resource records. The time period for these analyses was 1998–2016. RESULTS/ANTICIPATED RESULTS: At OHSU, as nationally, there has been an increase in RPG-holding Ph.D.s but not in RPG-holding physician-scientists. At OHSU, nearly three-fourth of physician-scientist RPGs hold an M.D.-only degree, compared with nationally, where nearly half of physician-scientists are M.D./Ph.D.s. The percent of younger, early-career, RPG-holding physician-scientists has declined precipitously at OHSU and nationally. At OHSU, the percentage of RPGs held by women physician-scientists is below the national figure. Funding sources for physician-scientists at OHSU were more diverse than for Ph.D. scientists, and physician-scientists comprise the majority of Principal Investigators on clinical trials. These non-RPG sources of funding remain a critical source of support, although local analyses of time spent on research indicate that physician-scientists with NIH funding spend a greater percentage of their time on research than those without. OHSU PI’s have had success in transitioning from K08 and K23 grants to R-level grants, with similar percentages receiving RPGs within 5 years. A dashboard comparing these trends was developed. DISCUSSION/SIGNIFICANCE OF IMPACT: There were 3 key impacts from our analyses. First, we developed and disseminated a dashboard with both local data and national comparators. Second, in consultation with institutional leadership, we selected target values to define success for each metric. Third, we recommended actions that will help OHSU meet the selected targets. A major accomplishment of this structured approach has been the identification of opportunities for change that were not recognized previously. For example, leadership was not aware of the substantial and growing deficit in female physician-scientists at OHSU, compared with the impressive increases nationally. Thus, to reduce gender disparity at OHSU, we have recommended purposeful recruitment; one approach is to target female graduates of Medical Scientist Training Programs for faculty positions, as this group has better success at achieving R-level funding than do M.D.-only applicants. Another outcome is to help set ambitious but reasonable targets for improving the local landscape. Thus, we aim to reduce the average age of RGP-holding physician-scientists at OHSU by one year during the next 5 years. Although reversing current trends will not be easy, our analyses suggest that the average age of RPG level physician-scientists at OHSU would decrease were OHSU were to match the national-level proportions of women and M.D./Ph.D. physician-scientists. In addition to targeting gender disparities, we have recently implemented a program that supplements funding for recruiting young physician scientists, and then supporting their pursuit of RPG funding. Locally, a bright spot is the K to RPG transition rate for K23 awardees, which compare favorably with national data, an outcome that we plan to maintain. In analyzing this area of success, one reason is our strong mentorship program, called OCTRI Scholars, which is provided through our CTSA-sponsored institute. This has fostered an atmosphere of success among young physician-scientists and is one of the reasons that we endorse recommendation #9 from the PSWR, suggesting that Clinical and Translational Science Award (CTSA) Institutes play pivotal roles in monitoring and enhancing the success of the physician-scientist workforce. Thus, several perceived deficiencies might be addressed with adjustment of 1 or 2 specific institutional policies. While the specific opportunities and strengths may be different at other institutions, our proposed dashboard, which couples publicly curated, freely accessible databases, with readily available institutional resources, should help institutions to set and achieve their own goals.

In July 2016, the European Commission (EC) published a legislative proposal for incorporating greenhouse gas emissions and removals due to Land Use, Land Use Change and Forestry (LULUCF) into its 2030 Climate and Energy Framework. The Climate and Energy Framework aims at a total emission reduction of 40% by 2030 for all sectors together as part of the Paris Agreement. The LULUCF proposal regulates a “no debit” target for LULUCF (Forests and Agricultural soils), and regulates the accounting of any additional mitigation potential that might be expected of it. We find that the forest share of the LULUCF sector can achieve much more than what is in the regulation now. We elaborate a strategy for unlocking European Union (EU) forests and forest sector potential based on the concept of “climate smart forestry” (CSF). We find that to-date, European policy has not firmly integrated forest potential into the EU climate policy framework. Nor have climate objectives been firmly integrated into those of the forest and forest sector at either the EU or national level. Yet a wide range of measures can be applied to provide positive incentives for more firmly integrating these climate objectives into the forest and forest sector framework. With the right set of incentives in place at EU and Member States levels, we find the current literature supports the view that the EU has the potential to achieve an additional combined mitigation impact through CSF of 441 Mt CO2/year by 2050. In addition, CSF, through reducing and/or removing greenhouse gas emissions, adapting and building forest resilience, and sustainably increasing forest productivity and incomes, tackles multiple policy goals.

European economic integration drives a political economy of regionalism that—far more than traditional divisions between labor and capital—defines the principal axis of political-economic division in the New Europe. The New Economy drives a radical shift in EU policy from cohesion or redistribution toward innovation promotion, affecting distributional struggles and policy approaches at the EU, national and subnational levels. Shifting strategies pose significant challenges at the national and subnational levels with important implications for future EU, national and subnational economic and regional development policy goals. At the national level, and in particular less developed economies, the New Economy creates incentives for the increasing centralization of decision-making. EU-level reforms, such as the Lisbon Agenda and an increasing emphasis on cohesion as opposed to structural funding, do much to strengthen these trends. Subnational regions, at least in the near term, may be the principal losers. But such trends are likely to strengthen future demands for greater subnational political decentralization.

The conjugation of enzymes, fluorescent or radioactive labels, cross-linkers and other moieties to antibodies is a commonly performed procedure in biochemical research. Using reduced disulphides, conjugation can be an inconvenient, multistep, time- and material-consuming process. We have developed a reduction technique based on UV irradiation, which lacks these drawbacks. Antibodies are irradiated in a sealed vial for a few minutes by a common laboratory UV source in the presence of stannous ions, following the depletion of atmospheric oxygen. The preparation may subsequently be conjugated with thiol-reactive probes such as maleimide derivatives, with no need for any prior purification or concentration. This simple, rapid and effective reduction and conjugation process results in a fully functional immunoglobulin conjugate that can be used for a variety of biochemical applications.

The αvβ6 integrin is up-regulated in cancer and wound healing but it is not generally expressed in healthy adult tissue. There is increasing evidence that it has a role in cancer progression and will be a useful target for antibody-directed cancer therapies. We report a novel recombinant diabody antibody fragment that targets specifically αvβ6 and blocks its function. The diabody was engineered with a C-terminal hexahistidine tag (His tag), expressed in Pichia pastoris and purified by IMAC. Surface plasmon resonance (SPR) analysis of the purified diabody showed affinity in the nanomolar range. Pre-treatment of αvβ6-expressing cells with the diabody resulted in a reduction of cell migration and adhesion to LAP, demonstrating biological function-blocking activity. After radio-labeling, using the His-tag for site-specific attachment of (99m)Tc, the diabody retained affinity and targeted specifically to αvβ6-expressing tumors in mice bearing isogenic αvβ6 +/- xenografts. Furthermore, the diabody was specifically internalized into αvβ6-expressing cells, indicating warhead targeting potential. Our results indicate that the new αvβ6 diabody has a range of potential applications in imaging, function blocking or targeted delivery/internalization of therapeutic agents.

BackgroundMedulloblastoma is the most common malignant brain tumor in children. Despite recent improvements in cure rates, prediction of disease outcome remains a major challenge and survivors suffer from serious therapy-related side-effects. Recent data showed that patients with WNT-activated tumors have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects. This illustrates the potential benefits of a robust classification of medulloblastoma patients and a detailed knowledge of associated biological mechanisms.Methods and findingsTo get a better insight into the molecular biology of medulloblastoma we established mRNA expression profiles of 62 medulloblastomas and analyzed 52 of them also by comparative genomic hybridization (CGH) arrays. Five molecular subtypes were identified, characterized by WNT signaling (A; 9 cases), SHH signaling (B; 15 cases), expression of neuronal differentiation genes (C and D; 16 and 11 cases, respectively) or photoreceptor genes (D and E; both 11 cases). Mutations in beta-catenin were identified in all 9 type A tumors, but not in any other tumor. PTCH1 mutations were exclusively identified in type B tumors. CGH analysis identified several fully or partly subtype-specific chromosomal aberrations. Monosomy of chromosome 6 occurred only in type A tumors, loss of 9q mostly occurred in type B tumors, whereas chromosome 17 aberrations, most common in medulloblastoma, were strongly associated with type C or D tumors. Loss of the inactivated X-chromosome was highly specific for female cases of type C, D and E tumors. Gene expression levels faithfully reflected the chromosomal copy number changes. Clinicopathological features significantly different between the 5 subtypes included metastatic disease and age at diagnosis and histology. Metastatic disease at diagnosis was significantly associated with subtypes C and D and most strongly with subtype E. Patients below 3 yrs of age had type B, D, or E tumors. Type B included most desmoplastic cases. We validated and confirmed the molecular subtypes and their associated clinicopathological features with expression data from a second independent series of 46 medulloblastomas.ConclusionsThe new medulloblastoma classification presented in this study will greatly enhance the understanding of this heterogeneous disease. It will enable a better selection and evaluation of patients in clinical trials, and it will support the development of new molecular targeted therapies. Ultimately, our results may lead to more individualized therapies with improved cure rates and a better quality of life.