OBJECTIVES/GOALS: Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). In this study, we perform an epigenetic-focused functional genomics screen in GBM organoids and identify WDR5 as an essential epigenetic regulator in the SOX2-enriched, therapy resistant cancer stem cell niche. METHODS/STUDY POPULATION: Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche. Our niche-specific screens identified WDR5, an H3K4 histone methyltransferase responsible for activating specific gene expression, as indispensable for GBM CSC growth and survival. RESULTS/ANTICIPATED RESULTS: In GBM CSC models, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, required for stem cell maintenance and including the POU5F1(OCT4)::SOX2 motif. We incorporated a SOX2/OCT4 motif driven GFP reporter system into our CSC cell models and found that WDR5 inhibitor treatment resulted in dose-dependent silencing of stem cell reporter activity. Further, WDR5 inhibitor treatment altered the stem cell state, disrupting CSC in vitro growth and self-renewal as well as in vivo tumor growth. DISCUSSION/SIGNIFICANCE: Our results unveiled the role of WDR5 in maintaining the CSC state in GBM and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers. This conceptual and experimental framework can be applied to many cancers, and can unmask unique microenvironmental biology and rationally designed combination therapies.

In North America, terrestrial records of biodiversity and climate change that span Marine Oxygen Isotope Stage (MIS) 5 are rare. Where found, they provide insight into how the coupling of the ocean–atmosphere system is manifested in biotic and environmental records and how the biosphere responds to climate change. In 2010–2011, construction at Ziegler Reservoir near Snowmass Village, Colorado (USA) revealed a nearly continuous, lacustrine/wetland sedimentary sequence that preserved evidence of past plant communities between ~140 and 55 ka, including all of MIS 5. At an elevation of 2705 m, the Ziegler Reservoir fossil site also contained thousands of well-preserved bones of late Pleistocene megafauna, including mastodons, mammoths, ground sloths, horses, camels, deer, bison, black bear, coyotes, and bighorn sheep. In addition, the site contained more than 26,000 bones from at least 30 species of small animals including salamanders, otters, muskrats, minks, rabbits, beavers, frogs, lizards, snakes, fish, and birds. The combination of macro- and micro-vertebrates, invertebrates, terrestrial and aquatic plant macrofossils, a detailed pollen record, and a robust, directly dated stratigraphic framework shows that high-elevation ecosystems in the Rocky Mountains of Colorado are climatically sensitive and varied dramatically throughout MIS 5.

Giant ragweed has been increasing as a major weed of row crops in the last 30 yr, but quantitative data regarding its pattern and mechanisms of spread in crop fields are lacking. To address this gap, we conducted a Web-based survey of certified crop advisors in the U.S. Corn Belt and Ontario, Canada. Participants were asked questions regarding giant ragweed and crop production practices for the county of their choice. Responses were mapped and correlation analyses were conducted among the responses to determine factors associated with giant ragweed populations. Respondents rated giant ragweed as the most or one of the most difficult weeds to manage in 45% of 421 U.S. counties responding, and 57% of responding counties reported giant ragweed populations with herbicide resistance to acetolactate synthase inhibitors, glyphosate, or both herbicides. Results suggest that giant ragweed is increasing in crop fields outward from the east-central U.S. Corn Belt in most directions. Crop production practices associated with giant ragweed populations included minimum tillage, continuous soybean, and multiple-application herbicide programs; ecological factors included giant ragweed presence in noncrop edge habitats, early and prolonged emergence, and presence of the seed-burying common earthworm in crop fields. Managing giant ragweed in noncrop areas could reduce giant ragweed migration from noncrop habitats into crop fields and slow its spread. Where giant ragweed is already established in crop fields, including a more diverse combination of crop species, tillage practices, and herbicide sites of action will be critical to reduce populations, disrupt emergence patterns, and select against herbicide-resistant giant ragweed genotypes. Incorporation of a cereal grain into the crop rotation may help suppress early giant ragweed emergence and provide chemical or mechanical control options for late-emerging giant ragweed.

We describe eleven mid-western Canadian aboriginal infants with a unique, progressive muscle disorder. All except one had muscle biopsy and/or autopsy. The infants were normal newborns who rapidly developed rigidity of all skeletal muscles, with early, respiratory insufficiency. Death occurred before 18 months of age. Electromyography showed increased insertion activity and profuse fibrillation potentials; motor unit potentials and interference pattern are normal until late in the course. Pathologic features include progressive, granular to powdery Z-band transformation, myofibrillar loss, and muscle regeneration. SDS-gel electrophoresis of one muscle sample revealed increased 54kDa and reduced 80kDa protein fractions. This disease differs from other conditions with Z-band alterations because of continuous muscle activity and relentless clinical progression. The clinical features, elevated serum creatine kinase, electromyographic and muscle biopsy findings suggest a dystrophic process. The recognition of this condition as an autosomal recessive disorder allows appropriate genetic counselling.

The collaborative London based non-governmental organization network ELRHA (Enhancing Learning and Research for Humanitarian Assistance) supports partnerships between higher education institutions and humanitarian organizations worldwide with the objective to enhance the professionalization of the humanitarian sector. While coordination and control of the humanitarian sector has plagued the response to every major crisis, concerns highlighted by the 2010 Haitian earthquake response further catalyzed and accelerated the need to ensure competency-based professionalization of the humanitarian health care work force. The Harvard Humanitarian Initiative sponsored an independent survey of established academically affiliated training centers in North America that train humanitarian health care workers to determine their individual training center characteristics and preferences in the potential professionalization process. The survey revealed that a common thread of profession-specific skills and core humanitarian competencies were being offered in both residential and online programs with additional programs offering opportunities for field simulation experiences and more advanced degree programs. This study supports the potential for the development of like-minded academic affiliated and competency-based humanitarian health programs to organize themselves under ELRHA's regional “consultation hubs” worldwide that can assist and advocate for improved education and training opportunities in less served developing countries.

Burkle Jr FM, WallsAE, HeckJP, SorensenBS, CranmerHH, JohnsonK, LevineAC, KaydenS, CahillB, VanRooyenMJ. Academic Affiliated Training Centers in Humanitarian Health, Part I: Program Characteristics and Professionalization Preferences of Centers in North America. Prehosp Disaster Med. 2013:28(2):1-8.

Contemporary theology exhibits a lively interest in using the traditional doctrine of the munus triplex (the threefold mediatorial office of Christ as prophet, priest and king) to unify our understanding of the person and work of Jesus Christ and ground it in the Old Testament witness. This article explores Karl Barth's contribution to this trend and draws from it a set of reflections for the church today. Scholarly consensus suggests that Barth offers an exceptionally robust development of the munus triplex in shaping the formal structure and material content of his doctrine of reconciliation. In this article I contend that his use of this concept is actually quite superficial in nature. As scholars are wont to point out, Barth incorporates the munus triplex into eye-catching summary statements throughout CD IV – but these statements are more ambiguous than they might at first seem. A closer examination of the details of his account of the work of Christ, and particularly his hamartiology, demonstrates that the munus triplex does not substantially inform his treatment of these subjects, and that his own unique christological concerns provide the determining influence. While Barth was eager to align his position with that of Reformed orthodoxy, focusing on the munus triplex ultimately distracts the reader from his primary concerns. Much the same is true for the church today – when used as a sufficient interpretative device for offering an account of the person and work of Jesus Christ, the munus triplex suffers the fate of many an artificial schema for biblical interpretation, distracting us from the breadth and depth of the biblical witness by offering an overly tidy, artificially organised account of the material. Nevertheless, when modestly employed, it remains a significant though limited conceptual device for understanding Christ's person and work, which the church should employ in several ways so as to integrate the Old and New Testaments in its proclamation of the Gospel.

We compared the duration of antimicrobial effectiveness of 2 different antimicrobial catheters. The baseline activity of minocycline-rifampin catheters was greater than that of silver-platinum-carbon catheters against Staphylococcus aureus, Staphylococcus epidermidis, and Enterococcus faecalis. The antimicrobial activity of the minocycline-rifampin catheters against these pathogens persisted for up to 12 days, while that of the silver-platinum-carbon catheters was depleted by day 10 (P< .05).

Background. This study assessed the relationship of early adolescent marijuana use to performance of developmental tasks integral to the transition to young adulthood. The tasks concerned intimacy, education, and work and social conformity.

Methods. African American (N = 617) and Puerto Rican (N = 531) youths completed questionnaires in their classrooms. Five years later they were individually interviewed. Logistic regression analysis estimated the increased likelihood that early marijuana users would make an inadequate transition to young adult social roles.

Results. Analyses examining the association between early marijuana use and 20 outcome variables found significant relationships for 10 of them: (a) having lower educational and occupational expectations; (b) being suspended or expelled from school, fired from jobs, ‘high’ at school or work, collecting welfare; and (c) rebelliousness, not participating in productive activities, not attending church, and being an unmarried parent. Marijuana use was not related to any of the intimate relationship measures. These finding emerged with controls on gender, ethnicity, age and mother's education.

Conclusions. Among African Americans and Puerto Ricans, early marijuana use predicts less adequate performance on some developmental tasks integral to becoming an independent young adult. Marijuana is not a benign drug and is associated with future risks for the individual and society at large.