OBJECTIVES/GOALS: Selinexor is a novel XPO1 inhibitor that blocks nuclear export, thus impairing DNA repair and causing apoptosis. Our goal was to conduct preclinical and clinical studies to test our hypothesis that selinexor’s efficacy is boosted by priming with temozolomide and is associated with a tissue biomarker. METHODS/STUDY POPULATION: We leveraged a team science approach through the NCI Cancer Therapy Evaluation Program (CTEP) to design preclinical experiments, develop a novel RNAseq analysis pipeline, and use pre-existing clinical experience to open an early phase clinical trial for recurrent glioblastoma. Team members included a CTEP medical officer, cancer biologist, pharmacist, industry scientist, translational scientist, and early career clinician scientist mentored by an expert clinician scientist. Based on preclinical results, participants in the clinical trial experimental arm will receive sequential temozolomide 150mg/m2 on days 1-5 and a starting dose of selinexor 60mg on days 8 and 15 of a 28-day cycle. Participants in the control arm will receive monotherapy temozolomide. RESULTS/ANTICIPATED RESULTS: Sequential treatment of U87 cells and intracranial xenografts had superior DNA damage (É£H2A.X, cleaved PARP) and overall survival compared to combination or single-agent (HR 0.25 [95% CI, 0.07-0.84]; p=0.01, log-rank). We used the top-scoring gene pair method to identify an RNAseq signature associated with response to selinexor. We then designed a trial for first recurrent MGMT methylated glioblastoma. Primary objectives are safety and preliminary efficacy. Secondary objectives are overall response rate, efficacy, and validation of a molecular signature. Phase 1 dose finding (n=12) will be followed by a randomized phase 2 (n=72); using proportional hazards regression, RHR 0.5 with p DISCUSSION/SIGNIFICANCE: The NCI CTEP Project Team employs team science as a framework to successfully develop multidisciplinary collaborations, build investigator trial experience, and lead the way to future research opportunities. Our trial addresses a significant unmet need to offer novel therapies and molecular biomarkers in glioblastoma.

Following the 2008 financial crisis, austerity measures have been introduced in many national contexts to reorganise public sector work and redesign labour laws and labour policies. At the same time, right-populist discourses and movements have arisen in ways that give both legitimacy and voice to the politics of austerity. Toronto, Canada, provides a world-renowned case of populist experimentation at the metropolitan scale, as the actions of Mayor Rob Ford typified this nexus of austerity and populism. Set in the context of Ford’s term as Mayor of Toronto (2010–2014), this article asks how the combined rise of austerity and right populism creates both new challenges and new opportunities for public sector labour in urban spaces. We argue that public sector unions are central in both the making and unmaking of populist austerity and identify potential trajectories for organised labour in the face of the continuation of austerity-driven politics.

Specimens of macroalgae are reported and described herein from newly discovered algal-Lagerstätten within the Llandoverian Earlton Formation at two localities separated by a distance of 45 km in the Timiskaming outlier of Ontario, Canada. Both localities are characterized by abundant specimens of the Codium-like bryopsidalean green alga Thalassocystis striata, the details of which, including within-assemblage morphological variation, compare closely to material from the type locality. Previously, this noncalcified taxon was known only from the Llandoverian Schoolcraft Formation in northern Michigan, ~500 km to the west. These new occurrences provide additional evidence that the alga-bearing intervals within the Earlton Formation at both Timiskaming localities correlate with the Schoolcraft Formation in the Michigan Basin. An associated noncalcified form at one of the Timiskaming localities is described as a new genus and species, Earltonella fredricksi LoDuca, n. gen. n. sp., the thallus architecture of which, with a creeping, runner-like stolon and numerous pinnate fronds, broadly resembles that of the living bryopsidalean alga Caulerpa. In broader terms, these new algal-Lagerstätten indicate that for a brief time during the late Llandoverian, as with other times during the Silurian, unusual conditions conducive to both the proliferation and preservation of expansive ‘seaweed meadows’ were established across regional-scale areas of the Laurentian epeiric sea.

This study analyses the experience and response of farmers within a multi-year collaborative research trial focused on the development of forage-based fallows in eight communities in the central Peruvian Andes. Quantitative data from a rural household survey were used to characterize farming household socioeconomic factors, livelihood strategies and soil and crop management practices of community members belonging to four participation groups with respect to the trials: 1) current participants near the end of the trial; 2.) those who participated early on, but dropped the trials after the first year; 3) those who participated in meetings but not directly in experiments; and 4) those who never participated meaningfully in the process. Furthermore, qualitative interviews of farmers in the four groups were used to examine trends and questions arising from the quantitative survey findings. Analysis of this mixed-methods dataset showed that better resource-endowed households (in terms of human and social capital, more livestock assets, higher levels of farm value production and income, and farm inputs) tended to be more likely to participate compared to households with lower levels of these variables. Our findings suggest that the differences in resource endowment among participation group households may be related to household life cycles, where access to resources change over time, reflecting the changing demography of a household. It was established that farm households with intermediate-age children, that is near the middle of a farm life cycle trajectory, are those with the most wherewithal to participate in trials and likely serve as examples and test cases for other farms with younger parents or older farmers with children moved away. Follow-up interviews indicated that farming households at either end of the farm life cycle trajectory may be using a ‘wait-and-see’ approach to the trials carried out by their neighbours who have more labour and other resources to deploy. In light of these findings, we suggest that participatory research should aim to ensure that the voices, challenges and opportunities of Non-participants are represented in the research process and experimental design. Additionally, greater consideration should be placed on understanding management by context issues in order to better target potential farming innovations such as improved fallows, at multiple levels, from the field to the household and to the community and beyond.