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1.  An Endotoxin Tolerance Signature Predicts Sepsis and Organ Dysfunction at Initial Clinical Presentation 
EBioMedicine  2014;1(1):64-71.
Sepsis involves aberrant immune responses to infection, but the exact nature of this immune dysfunction remains poorly defined. Bacterial endotoxins like lipopolysaccharide (LPS) are potent inducers of inflammation, which has been associated with the pathophysiology of sepsis, but repeated exposure can also induce a suppressive effect known as endotoxin tolerance or cellular reprogramming. It has been proposed that endotoxin tolerance might be associated with the immunosuppressive state that was primarily observed during late-stage sepsis. However, this relationship remains poorly characterised. Here we clarify the underlying mechanisms and timing of immune dysfunction in sepsis.
We defined a gene expression signature characteristic of endotoxin tolerance. Gene-set test approaches were used to correlate this signature with early sepsis, both newly and retrospectively analysing microarrays from 593 patients in 11 cohorts. Then we recruited a unique cohort of possible sepsis patients at first clinical presentation in an independent blinded controlled observational study to determine whether this signature was associated with the development of confirmed sepsis and organ dysfunction.
All sepsis patients presented an expression profile strongly associated with the endotoxin tolerance signature (p < 0.01; AUC 96.1%). Importantly, this signature further differentiated between suspected sepsis patients who did, or did not, go on to develop confirmed sepsis, and predicted the development of organ dysfunction.
Our data support an updated model of sepsis pathogenesis in which endotoxin tolerance-mediated immune dysfunction (cellular reprogramming) is present throughout the clinical course of disease and related to disease severity. Thus endotoxin tolerance might offer new insights guiding the development of new therapies and diagnostics for early sepsis.
PMCID: PMC4326653
Sepsis; Severe sepsis; Diagnosis; Cellular reprogramming; Endotoxin tolerance; Signature; Immune dysfunction
2.  A Systems Biology Approach to the Analysis of Subset-Specific Responses to Lipopolysaccharide in Dendritic Cells 
PLoS ONE  2014;9(6):e100613.
Dendritic cells (DCs) are critical for regulating CD4 and CD8 T cell immunity, controlling Th1, Th2, and Th17 commitment, generating inducible Tregs, and mediating tolerance. It is believed that distinct DC subsets have evolved to control these different immune outcomes. However, how DC subsets mount different responses to inflammatory and/or tolerogenic signals in order to accomplish their divergent functions remains unclear. Lipopolysaccharide (LPS) provides an excellent model for investigating responses in closely related splenic DC subsets, as all subsets express the LPS receptor TLR4 and respond to LPS in vitro. However, previous studies of the LPS-induced DC transcriptome have been performed only on mixed DC populations. Moreover, comparisons of the in vivo response of two closely related DC subsets to LPS stimulation have not been reported in the literature to date. We compared the transcriptomes of murine splenic CD8 and CD11b DC subsets after in vivo LPS stimulation, using RNA-Seq and systems biology approaches. We identified subset-specific gene signatures, which included multiple functional immune mediators unique to each subset. To explain the observed subset-specific differences, we used a network analysis approach. While both DC subsets used a conserved set of transcription factors and major signalling pathways, the subsets showed differential regulation of sets of genes that ‘fine-tune’ the network Hubs expressed in common. We propose a model in which signalling through common pathway components is ‘fine-tuned’ by transcriptional control of subset-specific modulators, thus allowing for distinct functional outcomes in closely related DC subsets. We extend this analysis to comparable datasets from the literature and confirm that our model can account for cell subset-specific responses to LPS stimulation in multiple subpopulations in mouse and man.
PMCID: PMC4065045  PMID: 24949855
3.  Coordinate direct input of both KRAS and IGF1 receptor to activation of PI 3-kinase in KRAS mutant lung cancer 
Cancer discovery  2013;3(5):548-563.
Using a panel of non-small cell lung cancer (NSCLC) lines, we show here that MEK and RAF inhibitors are selectively toxic for the KRAS mutant genotype, while PI 3-kinase (PI3K), AKT and mTOR inhibitors are not. IGF1 receptor (IGF1R) tyrosine kinase inhibitors also show selectivity for KRAS mutant lung cancer lines. Combinations of IGF1R and MEK inhibitors resulted in strengthened inhibition of KRAS mutant lines and also showed improved effectiveness in autochthonous mouse models of Kras induced NSCLC. PI3K pathway activity is dependent on basal IGF1R activity in KRAS mutant, but not wild-type, lung cancer cell lines. KRAS is needed for both MEK and PI3K pathway activity in KRAS mutant, but not wild-type, lung cancer cells, while acute activation of KRAS causes stimulation of PI3K dependent upon IGF1R kinase activity. Coordinate direct input of both KRAS and IGF1R is thus required to activate PI3K in KRAS mutant lung cancer cells.
PMCID: PMC3650991  PMID: 23454899
4.  Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies 
Cell Research  2012;22(8):1227-1245.
Oncogenic mutations in RAS genes are very common in human cancer, resulting in cells with well-characterized selective advantages, but also less well-understood vulnerabilities. We have carried out a large-scale loss-of-function screen to identify genes that are required by KRAS-transformed colon cancer cells, but not by derivatives lacking this oncogene. Top-scoring genes were then tested in a larger panel of KRAS mutant and wild-type cancer cells. Cancer cells expressing oncogenic KRAS were found to be highly dependent on the transcription factor GATA2 and the DNA replication initiation regulator CDC6. Extending this analysis using a collection of drugs with known targets, we found that cancer cells with mutant KRAS showed selective addiction to proteasome function, as well as synthetic lethality with topoisomerase inhibition. Combination targeting of these functions caused improved killing of KRAS mutant cells relative to wild-type cells. These observations suggest novel targets and new ways of combining existing therapies for optimal effect in RAS mutant cancers, which are traditionally seen as being highly refractory to therapy.
PMCID: PMC3411175  PMID: 22613949
KRAS; synthetic lethal; oncogene addiction; proteasome; topoisomerase
5.  Data shopping in an open marketplace: Introducing the Ontogrator web application for marking up data using ontologies and browsing using facets 
Standards in Genomic Sciences  2011;4(2):286-292.
In the future, we hope to see an open and thriving data market in which users can find and select data from a wide range of data providers. In such an open access market, data are products that must be packaged accordingly. Increasingly, eCommerce sellers present heterogeneous product lines to buyers using faceted browsing. Using this approach we have developed the Ontogrator platform, which allows for rapid retrieval of data in a way that would be familiar to any online shopper. Using Knowledge Organization Systems (KOS), especially ontologies, Ontogrator uses text mining to mark up data and faceted browsing to help users navigate, query and retrieve data. Ontogrator offers the potential to impact scientific research in two major ways: 1) by significantly improving the retrieval of relevant information; and 2) by significantly reducing the time required to compose standard database queries and assemble information for further research. Here we present a pilot implementation developed in collaboration with the Genomic Standards Consortium (GSC) that includes content from the StrainInfo, GOLD, CAMERA, Silva and Pubmed databases. This implementation demonstrates the power of ontogration and highlights that the usefulness of this approach is fully dependent on both the quality of data and the KOS (ontologies) used. Ideally, the use and further expansion of this collaborative system will help to surface issues associated with the underlying quality of annotation and could lead to a systematic means for accessing integrated data resources.
PMCID: PMC3111990  PMID: 21677865
6.  Artesunate Misuse and Plasmodium falciparum Malaria in Traveler Returning from Africa 
Emerging Infectious Diseases  2010;16(10):1608-1610.
Plasmodium falciparum malaria developed in an African-born traveler who returned to Canada after visiting Nigeria. While there, she took artesunate prophylactically. Isolates had an elevated 50% inhibitory concentration to artemisinin, artesunate, and artemether, compared with that of other African isolates. Inappropriate use of artemisinin derivatives can reduce P. falciparum susceptibility.
PMCID: PMC3294395  PMID: 20875291
Malaria; Plasmodium falciparum; parasites; artemisinin; travel; Africa; dispatch
7.  Multifunctional crop trait ontology for breeders' data: field book, annotation, data discovery and semantic enrichment of the literature 
AoB Plants  2010;2010:plq008.
The ‘Crop Ontology’ database we describe provides a controlled vocabulary for several economically important crops. It facilitates data integration and discovery from global databases and digital literature. This allows researchers to exploit comparative phenotypic and genotypic information of crops to elucidate functional aspects of traits.
Background and aims
Agricultural crop databases maintained in gene banks of the Consultative Group on International Agricultural Research (CGIAR) are valuable sources of information for breeders. These databases provide comparative phenotypic and genotypic information that can help elucidate functional aspects of plant and agricultural biology. To facilitate data sharing within and between these databases and the retrieval of information, the crop ontology (CO) database was designed to provide controlled vocabulary sets for several economically important plant species.
Existing public ontologies and equivalent catalogues of concepts covering the range of crop science information and descriptors for crops and crop-related traits were collected from breeders, physiologists, agronomists, and researchers in the CGIAR consortium. For each crop, relationships between terms were identified and crop-specific trait ontologies were constructed following the Open Biomedical Ontologies (OBO) format standard using the OBO-Edit tool. All terms within an ontology were assigned a globally unique CO term identifier.
Principal results
The CO currently comprises crop-specific traits for chickpea (Cicer arietinum), maize (Zea mays), potato (Solanum tuberosum), rice (Oryza sativa), sorghum (Sorghum spp.) and wheat (Triticum spp.). Several plant-structure and anatomy-related terms for banana (Musa spp.), wheat and maize are also included. In addition, multi-crop passport terms are included as controlled vocabularies for sharing information on germplasm. Two web-based online resources were built to make these COs available to the scientific community: the ‘CO Lookup Service’ for browsing the CO; and the ‘Crops Terminizer’, an ontology text mark-up tool.
The controlled vocabularies of the CO are being used to curate several CGIAR centres' agronomic databases. The use of ontology terms to describe agronomic phenotypes and the accurate mapping of these descriptions into databases will be important steps in comparative phenotypic and genotypic studies across species and gene-discovery experiments.
PMCID: PMC3000699  PMID: 22476066
8.  The minimum information about a genome sequence (MIGS) specification 
Nature biotechnology  2008;26(5):541-547.
With the quantity of genomic data increasing at an exponential rate, it is imperative that these data be captured electronically, in a standard format. Standardization activities must proceed within the auspices of open-access and international working bodies. To tackle the issues surrounding the development of better descriptions of genomic investigations, we have formed the Genomic Standards Consortium (GSC). Here, we introduce the minimum information about a genome sequence (MIGS) specification with the intent of promoting participation in its development and discussing the resources that will be required to develop improved mechanisms of metadata capture and exchange. As part of its wider goals, the GSC also supports improving the ‘transparency’ of the information contained in existing genomic databases.
PMCID: PMC2409278  PMID: 18464787
9.  The Social Support Experiences of Major Junior Ice Hockey Players in a Physically Removed Region of Canada 
The present report from a larger project overviews the sources and types of social support resourced by 10 major junior athletes while they performed out of one physically removed Canadian region. Retrospective interviews and content analysis were conducted during three stages (3, 3, and 4 respondents). The data were segmented into meaning units, coded into a hierarchy of themes, and verified by each respondent and an expert panel (former athlete, coach, parent of former athlete). The respondents sought out three types of social support from four different sources (providers) that were adapted to their remote location, including teachers and general community support. Implications are considered in terms of applied research and practice with aspiring adolescent athletes located in removed locations.
Key pointsThe study extends knowledge about the sources and types of social support resourced by elite major junior ice hockey players located in one physically removed Canadian region.From the respondents’ views, three types of social support were sought from four different sources.Implications are considered in terms of sport psychology research and applied practice.
PMCID: PMC3794476  PMID: 24149469
Regional; social support; ice hockey
10.  maxdLoad2 and maxdBrowse: standards-compliant tools for microarray experimental annotation, data management and dissemination 
BMC Bioinformatics  2005;6:264.
maxdLoad2 is a relational database schema and Java® application for microarray experimental annotation and storage. It is compliant with all standards for microarray meta-data capture; including the specification of what data should be recorded, extensive use of standard ontologies and support for data exchange formats. The output from maxdLoad2 is of a form acceptable for submission to the ArrayExpress microarray repository at the European Bioinformatics Institute. maxdBrowse is a PHP web-application that makes contents of maxdLoad2 databases accessible via web-browser, the command-line and web-service environments. It thus acts as both a dissemination and data-mining tool.
maxdLoad2 presents an easy-to-use interface to an underlying relational database and provides a full complement of facilities for browsing, searching and editing. There is a tree-based visualization of data connectivity and the ability to explore the links between any pair of data elements, irrespective of how many intermediate links lie between them. Its principle novel features are:
• the flexibility of the meta-data that can be captured,
• the tools provided for importing data from spreadsheets and other tabular representations,
• the tools provided for the automatic creation of structured documents,
• the ability to browse and access the data via web and web-services interfaces.
Within maxdLoad2 it is very straightforward to customise the meta-data that is being captured or change the definitions of the meta-data. These meta-data definitions are stored within the database itself allowing client software to connect properly to a modified database without having to be specially configured. The meta-data definitions (configuration file) can also be centralized allowing changes made in response to revisions of standards or terminologies to be propagated to clients without user intervention.
maxdBrowse is hosted on a web-server and presents multiple interfaces to the contents of maxd databases. maxdBrowse emulates many of the browse and search features available in the maxdLoad2 application via a web-browser. This allows users who are not familiar with maxdLoad2 to browse and export microarray data from the database for their own analysis. The same browse and search features are also available via command-line and SOAP server interfaces. This both enables scripting of data export for use embedded in data repositories and analysis environments, and allows access to the maxd databases via web-service architectures.
maxdLoad2 and maxdBrowse are portable and compatible with all common operating systems and major database servers. They provide a powerful, flexible package for annotation of microarray experiments and a convenient dissemination environment. They are available for download and open sourced under the Artistic License.
PMCID: PMC1298287  PMID: 16269077
11.  Identification of Novel Isoforms of the BH3 Domain Protein Bim Which Directly Activate Bax To Trigger Apoptosis 
Molecular and Cellular Biology  2002;22(11):3577-3589.
Bim (Bcl-2-interacting mediator of cell death) is a member of the BH3 domain-only subgroup of Bcl-2 family members, for which three splice variants have been described. Bim is expressed in many healthy cell types, where it is maintained in an inactive conformation through binding to the microtubule-associated dynein motor complex. Upon certain apoptotic stimuli, Bim is released from microtubules and mediates caspase-dependent apoptosis through a mechanism that is still unclear. Here, we have identified and characterized novel splice variants of human Bim mRNA. In particular, we show that a newly discovered, small protein isoform, BimAD, is also able to induce apoptosis strongly in several human cell lines. BimAD and the previously characterized isoform BimS are shown to be capable of heterodimerizing in vivo with both death antagonists (Bcl-2 and Bcl-XL) and death agonists (Bax). Mutants of BimAD that bind to Bax but not to Bcl-2 still promote apoptosis, indicating that Bim can regulate apoptosis through direct activation of the Bax-mediated cell death pathway without interaction with antiapoptotic Bcl-2 family members. Furthermore, we have shown that the interaction of the BimS and BimAD isoforms with Bax leads to a conformational change in this protein analogous to that triggered by the BH3-only protein Bid.
PMCID: PMC133811  PMID: 11997495
12.  Suppression of c-Myc-Induced Apoptosis by the Epstein-Barr Virus Gene Product BHRF1 
Journal of Virology  1998;72(10):8392-8395.
Constitutive expression of the c-myc proto-oncogene in growth factor-deprived fibroblasts promotes proliferation and induces apoptosis. In these cells, apoptosis can be inhibited by survival factors such as insulin-like growth factor I or the bcl-2 proto-oncogene product. Deregulated c-Myc expression is a common feature in Epstein-Barr virus-positive Burkitt’s lymphoma in which the c-myc gene is reciprocally translocated and placed under the control of one of the immunoglobulin loci. BHRF1 is an Epstein-Barr virus protein expressed early in the lytic cycle. BHRF1 is a member of the Bcl-2 family and has been shown to suppress apoptosis and to increase cell survival in different settings. In the present study, we report that BHRF1 inhibits c-Myc-induced apoptosis which occurs in the absence of survival factors. It does not, however, affect the capacity of c-Myc to promote cell growth. These findings demonstrate that BHRF1 has not only structural but also functional similarities to Bcl-2.
PMCID: PMC110225  PMID: 9733891

Results 1-12 (12)