Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Realising the Data Hubs Concept for Urban Research in Australia

Abstract: Discovering and accessing relevant data is a problem often faced by urban researchers, policy and decision-makers across Australia. To address this, several public, private and academic entities are establishing Data Hubs; online catalogues for data discovery, access and interrogation. Data Hubs are typically web services accessible via a portal, however often narrow geographic or application focus, and provide varied levels of analytical and visualisation capability. The Australian Urban Research Infrastructure Network (AURIN) is an initiative focused on providing urban researchers, policy and decision-makers better access to comprehensive datasets through a dedicated e-Infrastructure platform. The AURIN portal will facilitate programmatic access to data held in many emerging Data Hubs across Australia. AURIN is implementing a federated data approach, providing a single access point and common interface for interrogating datasets. This paper outlines the Data Hub concept, describing the process and benefits of Data Hub integration within the AURIN e-infrastructure context. Citation: Delany, P. & Petit, C. (2014). Realising the Data Hubs Concept for Urban Research in Australia. In: Campbell P. and Perez P. (Eds), Proceedings of the International Symposium of Next Generation Infrastructure, 1-4 October 2013, SMART Infrastructure Facility, University of Wollongong, Australia

The design of a flexible web-based analytical platform for urban research: systems paper

© 2012 ACM This is a restricted version of a paper from the 20th ACM SIGSPATIAL International Conference on Advances in Geographic Information Systems (ACM SIGSPATIAL GIS 2012) published by ACM. http://acmgis2012.cs.umd.eduIn this paper, we present the functional capabilities scoping for a novel eResearch infrastructure providing urban researchers with access to datasets and analytical tools. The AURIN portal provides a “lab in a browser” environment, leveraging a complex, loosely-coupled internal architecture and a growing number of federated data sources. Datasets can be “shopped” for, visually explored and analyzed using a growing number of analytical capabilities orchestrated in a workflow environment. While spatial analytical tasks are at the heart of most targeted research disciplines, AURIN aims to reach beyond the scope of traditional GIS and map-based portals. In this paper, we discuss how the functional requirements of AURIN can be realized to enable exploratory and confirmatory data analysis supported by high performance Web based infrastructure.6-9 Novembe