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

Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking

The potential of the diverse chemistries present in natural products (NP) for biotechnology and medicine remains untapped because NP databases are not searchable with raw data and the NP community has no way to share data other than in published papers. Although mass spectrometry techniques are well-suited to high-throughput characterization of natural products, there is a pressing need for an infrastructure to enable sharing and curation of data. We present Global Natural Products Social molecular networking (GNPS, http://gnps.ucsd.edu), an open-access knowledge base for community wide organization and sharing of raw, processed or identified tandem mass (MS/MS) spectrometry data. In GNPS crowdsourced curation of freely available community-wide reference MS libraries will underpin improved annotations. Data-driven social-networking should facilitate identification of spectra and foster collaborations. We also introduce the concept of ‘living data’ through continuous reanalysis of deposited data

Faith and science in an unjust world. : V. 1. Report of the WCC conference on faith, science and the future.

Genevaxiv, 392 p.; 22 cm

New Directions In Theology Today : Man:The New Humanism

LondonVol. VI.,207 p.; 21 c

Faith and science in an unjust world. : V. 2. Report of the WCC conference on faith, science and the future.

Genevaviii, 214 p.; 22 cm

We Believe : an Interpretation of the United Church Statement of Faith

Philadelphia132 p.; 21 c

Tangled World

New York158 p.; 21 c

Design of a Large Scale Data Stream Recorder

Abstract: Presently, digital continuous media (CM) are well established as an integral part of many applications. In recent years, a considerable amount of research has focused on the efficient retrieval of such media. Scant attention has been paid to servers that can record such streams in real time. However, more and more devices produce direct digital output streams. Hence, the need arises to capture and store these streams with an efficient data stream recorder that can handle both recording and playback of many streams simultaneously and provide a central repository for all data. We propose a design for a large scale data stream recorder. Our goal was to introduce a unified architecture that integrates multi-stream recording and retrieval in a coherent manner. The discussion raises practical issues such as support for multizone disk drives, variable bit rate media, and disk drives that have a different write than read bandwidth. We provide initial solutions for some issues while others will need to be investigated further.

Location-based Spatial Queries with Data Sharing in Wireless Broadcast Environments

Location-based spatial queries (LBSQs) refer to spatial queries whose answers rely on the location of the inquirer. Efficient processing of LBSQs is of critical importance with the everincreasing deployment and use of mobile technologies. We show that LBSQs have certain unique characteristics that traditional spatial query processing in centralized databases does not address. For example, a significant challenge is presented by wireless broadcasting environments, which often translates to high-latency database access. In this paper, we present a novel query processing technique that, while maintaining high scalability and accuracy, manages to reduce the latency considerably in answering locationbased spatial queries. Our approach is based on peer-to-peer sharing, which enables us to process queries without delay at a mobile host by using query results cached in its neighboring mobile peers. We demonstrate the feasibility of our approach through a probabilistic analysis, and we illustrate the appeal of our technique using extensive simulation results