Publications by authors named "Andrew Blake"

57 Publications

TET2 drives 5hmc marking of GATA6 and epigenetically defines pancreatic ductal adenocarcinoma transcriptional subtypes.

Gastroenterology 2021 Apr 26. Epub 2021 Apr 26.

Department of Oncology, University of Oxford, OX3 7DQ. Electronic address:

Background And Aims: Pancreatic ductal adenocarcinoma (PDAC) is characterised by advanced disease stage at presentation, aggressive disease biology and resistance to therapy resulting in extremely poor five-year survival <10%. PDAC is classified into transcriptional subtypes with distinct survival characteristics, although how these arise is not known. Epigenetic deregulation, rather than genetics, has been proposed to underpin progression but exactly why is unclear and hindered by technical limitations of analysing clinical samples.

Methods: Genome-wide epigenetic mapping of DNA modifications 5-methylcytosine (5mc) and 5-hydroxymethylcytosine (5hmc) using oxidative bisulphite sequencing (oxBS) from formalin embedded sections. Bioinformatics using iCluster and mutational profiling to identify overlap with transcriptional signatures in FFPE from resected patients and confirmation in vivo.

Results: We find that aggressive squamous-like PDAC subtypes result from epigenetic inactivation of loci including GATA6 that promote differentiated classical-pancreatic subtypes. We show that squamous-like PDAC transcriptional subtypes are associated with greater loss of 5hmc due to reduced expression of the 5mc-hydroxylase TET2. Furthermore, we find that SMAD4 directly supports TET2 levels in classical-pancreatic tumors and loss of SMAD4 expression is associated reduced 5hmc, GATA6 and squamous-like tumors. Importantly, enhancing TET2 stability using Metformin and VitaminC/ascorbic acid (AA) restores 5hmc and GATA6 levels, reverting squamous-like tumor phenotypes and WNT-dependence in vitro and in vivo.

Conclusions: We identify epigenetic deregulation of pancreatic differentiation as an underpinning event behind the emergence of transcriptomic subtypes in PDAC. Our data shows that restoring epigenetic control increases biomarkers of classical-pancreatic tumors which are associated with improved therapeutic responses and survival.
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http://dx.doi.org/10.1053/j.gastro.2021.04.044DOI Listing
April 2021

Ultra-Low DNA Input into Whole Genome Methylation Assays and Detection of Oncogenic Methylation and Copy Number Variants in Circulating Tumour DNA.

Epigenomes 2021 Feb 19;5. Epub 2021 Feb 19.

Institute of Cancer & Genomic Sciences, University of Birmingham, Vincent Drive, Birmingham B15 2TT, UK.

Abnormal CpG methylation in cancer is ubiquitous and generally detected in tumour specimens using a variety of techniques at a resolution encompassing single CpG loci to genome wide coverage. Analysis of samples with very low DNA inputs, such as formalin fixed (FFPE) biopsy specimens from clinical trials or circulating tumour DNA is challenging at the genome-wide level because of lack of available input. We present the results of low input experiments into the Illumina Infinium HD methylation assay on FFPE specimens and ctDNA samples.

Methods: For all experiments, the Infinium HD assay for methylation was used. In total, forty-eight FFPE specimens were used at varying concentrations (lowest input 50 ng); eighteen blood derived specimens (lowest input 10 ng) and six matched ctDNA input (lowest input 10 ng)/fresh tumour specimens (lowest input 250 ng) were processed. Downstream analysis was performed in R/Bioconductor for quality control metrics and differential methylation analysis as well as copy number calls.

Results: Correlation coefficients for CpG methylation were high at the probe level averaged R2 = 0.99 for blood derived samples and R2 > 0.96 for the FFPE samples. When matched ctDNA/fresh tumour samples were compared, R2 > 0.91 between the two. Results of differential methylation analysis did not vary significantly by DNA input in either the blood or FFPE groups. There were differences seen in the ctDNA group as compared to their paired tumour sample, possibly because of enrichment for tumour material without contaminating normal. Copy number variants observed in the tumour were generally also seen in the paired ctDNA sample with good concordance via DQ plot.

Conclusions: The Illumina Infinium HD methylation assay can robustly detect methylation across a range of sample types, including ctDNA, down to an input of 10 ng. It can also reliably detect oncogenic methylation changes and copy number variants in ctDNA. These findings demonstrate that these samples can now be accessed by methylation array technology, allowing analysis of these important sample types.
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http://dx.doi.org/10.3390/epigenomes5010006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610445PMC
February 2021

In-depth Clinical and Biological Exploration of DNA Damage Immune Response as a Biomarker for Oxaliplatin Use in Colorectal Cancer.

Clin Cancer Res 2021 Jan 7;27(1):288-300. Epub 2020 Oct 7.

MRC Clinical Trials Unit, University College London, London, United Kingdom.

Purpose: The DNA damage immune response (DDIR) assay was developed in breast cancer based on biology associated with deficiencies in homologous recombination and Fanconi anemia pathways. A positive DDIR call identifies patients likely to respond to platinum-based chemotherapies in breast and esophageal cancers. In colorectal cancer, there is currently no biomarker to predict response to oxaliplatin. We tested the ability of the DDIR assay to predict response to oxaliplatin-based chemotherapy in colorectal cancer and characterized the biology in DDIR-positive colorectal cancer.

Experimental Design: Samples and clinical data were assessed according to DDIR status from patients who received either 5-fluorouracil (5-FU) or 5FUFA (bolus and infusion 5-FU with folinic acid) plus oxaliplatin (FOLFOX) within the FOCUS trial ( = 361, stage IV), or neoadjuvant FOLFOX in the FOxTROT trial ( = 97, stage II/III). Whole transcriptome, mutation, and IHC data of these samples were used to interrogate the biology of DDIR in colorectal cancer.

Results: Contrary to our hypothesis, DDIR-negative patients displayed a trend toward improved outcome for oxaliplatin-based chemotherapy compared with DDIR-positive patients. DDIR positivity was associated with microsatellite instability (MSI) and colorectal molecular subtype 1. Refinement of the DDIR signature, based on overlapping IFN-related chemokine signaling associated with DDIR positivity across colorectal cancer and breast cancer cohorts, further confirmed that the DDIR assay did not have predictive value for oxaliplatin-based chemotherapy in colorectal cancer.

Conclusions: DDIR positivity does not predict improved response following oxaliplatin treatment in colorectal cancer. However, data presented here suggest the potential of the DDIR assay in identifying immune-rich tumors that may benefit from immune checkpoint blockade, beyond current use of MSI status.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3237DOI Listing
January 2021

Image-based consensus molecular subtype (imCMS) classification of colorectal cancer using deep learning.

Gut 2021 Mar 20;70(3):544-554. Epub 2020 Jul 20.

Department of Oncology, University of Oxford, Oxford, UK

Objective: Complex phenotypes captured on histological slides represent the biological processes at play in individual cancers, but the link to underlying molecular classification has not been clarified or systematised. In colorectal cancer (CRC), histological grading is a poor predictor of disease progression, and consensus molecular subtypes (CMSs) cannot be distinguished without gene expression profiling. We hypothesise that image analysis is a cost-effective tool to associate complex features of tissue organisation with molecular and outcome data and to resolve unclassifiable or heterogeneous cases. In this study, we present an image-based approach to predict CRC CMS from standard H&E sections using deep learning.

Design: Training and evaluation of a neural network were performed using a total of n=1206 tissue sections with comprehensive multi-omic data from three independent datasets (training on FOCUS trial, n=278 patients; test on rectal cancer biopsies, GRAMPIAN cohort, n=144 patients; and The Cancer Genome Atlas (TCGA), n=430 patients). Ground truth CMS calls were ascertained by matching random forest and single sample predictions from CMS classifier.

Results: Image-based CMS (imCMS) accurately classified slides in unseen datasets from TCGA (n=431 slides, AUC)=0.84) and rectal cancer biopsies (n=265 slides, AUC=0.85). imCMS spatially resolved intratumoural heterogeneity and provided secondary calls correlating with bioinformatic prediction from molecular data. imCMS classified samples previously unclassifiable by RNA expression profiling, reproduced the expected correlations with genomic and epigenetic alterations and showed similar prognostic associations as transcriptomic CMS.

Conclusion: This study shows that a prediction of RNA expression classifiers can be made from H&E images, opening the door to simple, cheap and reliable biological stratification within routine workflows.
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http://dx.doi.org/10.1136/gutjnl-2019-319866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873419PMC
March 2021

Immune status is prognostic for poor survival in colorectal cancer patients and is associated with tumour hypoxia.

Br J Cancer 2020 10 20;123(8):1280-1288. Epub 2020 Jul 20.

Precision Medicine Centre of Excellence, Centre for Cell Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.

Background: Immunohistochemical quantification of the immune response is prognostic for colorectal cancer (CRC). Here, we evaluate the suitability of alternative immune classifiers on prognosis and assess whether they relate to biological features amenable to targeted therapy.

Methods: Overall survival by immune (CD3, CD4, CD8, CD20 and FOXP3) and immune-checkpoint (ICOS, IDO-1 and PD-L1) biomarkers in independent CRC cohorts was evaluated. Matched mutational and transcriptomic data were interrogated to identify associated biology.

Results: Determination of immune-cold tumours by combined low-density cell counts of CD3, CD4 and CD8 immunohistochemistry constituted the best prognosticator across stage II-IV CRC, particularly in patients with stage IV disease (HR 1.98 [95% CI: 1.47-2.67]). These immune-cold CRCs were associated with tumour hypoxia, confirmed using CAIX immunohistochemistry (P = 0.0009), which may mediate disease progression through common biology (KRAS mutations, CRIS-B subtype and SPP1 mRNA overexpression).

Conclusions: Given the significantly poorer survival of immune-cold CRC patients, these data illustrate that assessment of CD4-expressing cells complements low CD3 and CD8 immunohistochemical quantification in the tumour bulk, potentially facilitating immunophenotyping of patient biopsies to predict prognosis. In addition, we found immune-cold CRCs to associate with a difficult-to-treat, poor prognosis hypoxia signature, indicating that these patients may benefit from hypoxia-targeting clinical trials.
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http://dx.doi.org/10.1038/s41416-020-0985-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555485PMC
October 2020

Deficits in the vesicular acetylcholine transporter alter lifespan and behavior in adult Drosophila melanogaster.

Neurochem Int 2020 07 18;137:104744. Epub 2020 Apr 18.

Neuroscience Program, Department of Biological Sciences, Delaware State University, Dover, DE, 19901, USA. Electronic address:

The neurotransmitter acetylcholine (ACh) is involved in critical organismal functions that include locomotion and cognition. Importantly, alterations in the cholinergic system are a key underlying factor in cognitive defects associated with aging. One essential component of cholinergic synaptic transmission is the vesicular ACh transporter (VAChT), which regulates the packaging of ACh into synaptic vesicles for extracellular release. Mutations that cause a reduction in either protein level or activity lead to diminished locomotion ability whereas complete loss of function of VAChT is lethal. While much is known about the function of VAChT, the direct role of altered ACh release and its association with either an impairment or an enhancement of cognitive function are still not fully understood. We hypothesize that point mutations in Vacht cause age-related deficits in cholinergic-mediated behaviors such as locomotion, and learning and memory. Using Drosophila melanogaster as a model system, we have studied several mutations within Vacht and observed their effect on survivability and locomotive behavior. Here we report for the first time a weak hypomorphic Vacht allele that shows a differential effect on ACh-linked behaviors. We also demonstrate that partially rescued Vacht point mutations cause an allele-dependent deficit in lifespan and defects in locomotion ability. Moreover, using a thorough data analytics strategy to identify exploratory behavioral patterns, we introduce new paradigms for measuring locomotion-related activities that could not be revealed or detected by a simple measure of the average speed alone. Together, our data indicate a role for VAChT in the maintenance of longevity and locomotion abilities in Drosophila and we provide additional measurements of locomotion that can be useful in determining subtle changes in Vacht function on locomotion-related behaviors.
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http://dx.doi.org/10.1016/j.neuint.2020.104744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247942PMC
July 2020

Commentary: Screens, Teens, and Psychological Well-Being: Evidence From Three Time-Use-Diary Studies.

Front Psychol 2020 18;11:181. Epub 2020 Feb 18.

Department of Psychology, University of Georgia, Athens, GA, United States.

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http://dx.doi.org/10.3389/fpsyg.2020.00181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040178PMC
February 2020

Increased Support for Same-sex Marriage in the US: Disentangling Age, Period, and Cohort Effects.

J Homosex 2020 Jan 4:1-11. Epub 2020 Jan 4.

Rawls College of Business, Texas Tech University, Lubbock, Texas, USA.

Previous research established a substantial increase in support for same-sex marriage in the US, but it is unclear if this increase is due to cohort (a change that affects only the younger generation) or time period (a change that affects those of all ages). In a nationally representative sample of American adults ( = 13,483) in 1988 and 2004-2018, increased support for same-sex marriage was primarily due to time period (from 11.1% in 1988 to 66.7% in 2018). There was a smaller cohort effect, with a fairly linear increase between cohorts born in the 1960s and those born in the 1990s. Time period increases in support for same-sex marriage appeared among across gender, race, education levels, regions, and levels of religious service attendance, though differences in support still remain. The results suggest Americans of all ages modified their beliefs about same-sex marriage over time.
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http://dx.doi.org/10.1080/00918369.2019.1705672DOI Listing
January 2020

Exploiting differential Wnt target gene expression to generate a molecular biomarker for colorectal cancer stratification.

Gut 2020 06 28;69(6):1092-1103. Epub 2019 Sep 28.

Intestinal Stem Cell Biology Lab, Wellcome Trust Centre Human Genetics, University of Oxford, Oxford, UK

Objective: Pathological Wnt pathway activation is a conserved hallmark of colorectal cancer. Wnt-activating mutations can be divided into: i) ligand-independent (LI) alterations in intracellular signal transduction proteins (, β-catenin), causing constitutive pathway activation and ii) ligand-dependent (LD) mutations affecting the synergistic R-Spondin axis (, -fusions) acting through amplification of endogenous Wnt signal transmembrane transduction. Our aim was to exploit differential Wnt target gene expression to generate a mutation-agnostic biomarker for LD tumours.

Design: We undertook harmonised multi-omic analysis of discovery (n=684) and validation cohorts (n=578) of colorectal tumours collated from publicly available data and the Stratification in Colorectal Cancer Consortium. We used mutation data to establish molecular ground truth and subdivide lesions into LI/LD tumour subsets. We contrasted transcriptional, methylation, morphological and clinical characteristics between groups.

Results: Wnt disrupting mutations were mutually exclusive. Desmoplastic stromal upregulation of may compensate for absence of epithelial mutation in a subset of stromal-rich tumours. Key Wnt negative regulator genes were differentially expressed between LD/LI tumours, with targeted hypermethylation of some genes (, ) occurring even in CIMP-negative LD cancers. mRNA expression was used as a discriminatory molecular biomarker to distinguish LD/LI tumours (area under the curve >0.93).

Conclusions: Epigenetic suppression of appropriate Wnt negative feedback loops is selectively advantageous in LD tumours and differential expression in LD/LI lesions can be exploited as a molecular biomarker. Distinguishing between LD/LI tumour types is important; patients with LD tumours retain sensitivity to Wnt ligand inhibition and may be stratified at diagnosis to clinical trials of Porcupine inhibitors.
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http://dx.doi.org/10.1136/gutjnl-2019-319126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212029PMC
June 2020

The efficacy of Euler diagrams and linear diagrams for visualizing set cardinality using proportions and numbers.

PLoS One 2019 28;14(3):e0211234. Epub 2019 Mar 28.

Bloomberg, London, United Kingdom.

This paper presents the first empirical investigation that compares Euler and linear diagrams when they are used to represent set cardinality. A common approach is to use area-proportional Euler diagrams but linear diagrams can exploit length-proportional straight-lines for the same purpose. Another common approach is to use numerical annotations. We first conducted two empirical studies, one on Euler diagrams and the other on linear diagrams. These suggest that area-proportional Euler diagrams with numerical annotations and length-proportional linear diagrams without numerical annotations support significantly better task performance. We then conducted a third study to investigate which of these two notations should be used in practice. This suggests that area-proportional Euler diagrams with numerical annotations most effectively supports task performance and so should be used to visualize set cardinalities. However, these studies focused on data that can be visualized reasonably accurately using circles and the results should be taken as valid within that context. Future work needs to determine whether the results generalize both to when circles cannot be used and for other ways of encoding cardinality information.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211234PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438608PMC
January 2020

The complex physiology of Cellvibrio japonicus xylan degradation relies on a single cytoplasmic β-xylosidase for xylo-oligosaccharide utilization.

Mol Microbiol 2018 03 8;107(5):610-622. Epub 2018 Jan 8.

Department of Biological Sciences, University of Maryland - Baltimore County, Baltimore, Maryland, USA.

Lignocellulose degradation by microbes plays a central role in global carbon cycling, human gut metabolism and renewable energy technologies. While considerable effort has been put into understanding the biochemical aspects of lignocellulose degradation, much less work has been done to understand how these enzymes work in an in vivo context. Here, we report a systems level study of xylan degradation in the saprophytic bacterium Cellvibrio japonicus. Transcriptome analysis indicated seven genes that encode carbohydrate active enzymes were up-regulated during growth with xylan containing media. In-frame deletion analysis of these genes found that only gly43F is critical for utilization of xylo-oligosaccharides, xylan, and arabinoxylan. Heterologous expression of gly43F was sufficient for the utilization of xylo-oligosaccharides in Escherichia coli. Additional analysis found that the xyn11A, xyn11B, abf43L, abf43K, and abf51A gene products were critical for utilization of arabinoxylan. Furthermore, a predicted transporter (CJA_1315) was required for effective utilization of xylan substrates, and we propose this unannotated gene be called xntA (xylan transporter A). Our major findings are (i) C. japonicus employs both secreted and surface associated enzymes for xylan degradation, which differs from the strategy used for cellulose degradation, and (ii) a single cytoplasmic β-xylosidase is essential for the utilization of xylo-oligosaccharides.
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http://dx.doi.org/10.1111/mmi.13903DOI Listing
March 2018

Pharmacodynamic effects of daclizumab in the intrathecal compartment.

Ann Clin Transl Neurol 2017 07 29;4(7):478-490. Epub 2017 May 29.

Neuroimmunological Diseases Unit National Institute of Neurological Disorders and Stroke (NINDS) Bethesda Maryland.

Objective: It was previously demonstrated that daclizumab therapy normalizes cellular cerebrospinal fluid (CSF) abnormalities typical of multiple sclerosis (MS) in the majority of treated patients. However, CSF cells represent only the mobile portion of intrathecal immune responses. Therefore, we asked whether daclizumab also reverses compartmentalized inflammation and if not, whether residual inflammation correlates with clinical response to the drug.

Methods: Forty MS patients treated with an intravenous or subcutaneous injection of daclizumab were followed for up to 16 years in two open-label clinical trials. MRI contrast-enhancing lesions (CELs), clinical scales, and CSF biomarkers quantified residual disease.

Results: Rapid decreases in CELs, sustained throughout the observation period, were observed with daclizumab treatment. Daclizumab therapy induced modest but statistically significant ( < 0.0001) decreases in CSF levels of T-cell activation marker CD27 and IgG index. Interleukin 2 (IL-2) CSF levels increased from baseline levels during treatment, consistent with reduced IL-2 consumption by T cells, as a consequence of daclizumab's saturation of high-affinity IL-2 receptors. CSF levels of IL-12p40, chitinase-3-like protein-1 (CHI3L1), chemokine C-X-C motif ligand 13, and neurofilament light chain (NFL) were also significantly reduced by daclizumab. Among them, inhibition of CHI3L1 correlated with inhibition of NFL and with lack of disease progression.

Interpretation: These observations confirm daclizumab's direct pharmacodynamics effects on immune cells within central nervous system tissues and identify inhibition of CSF biomarkers of myeloid lineage as a stronger determinant of reduction in clinical MS activity than inhibition of biomarkers of adaptive immunity.
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http://dx.doi.org/10.1002/acn3.427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497534PMC
July 2017

Novel gene function revealed by mouse mutagenesis screens for models of age-related disease.

Nat Commun 2016 08 18;7:12444. Epub 2016 Aug 18.

The Nuffield Laboratory of Ophthalmology &NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford OX3 9DU, UK.

Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss.
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http://dx.doi.org/10.1038/ncomms12444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992138PMC
August 2016

Hypofractionated Conformal Radiotherapy with Concurrent Full-Dose Gemcitabine Versus Standard Fractionation Radiotherapy with Concurrent Fluorouracil for Unresectable Pancreatic Cancer: a Multi-Institution Experience.

J Gastrointest Cancer 2016 Jun;47(2):196-201

Department of Radiation Oncology, Cardinal Bernardin Cancer Center, Stritch School of Medicine, Loyola University Chicago, 2160 S 1st Ave Maguire Center, Rm 2932, Maywood, IL, 60153, USA.

Purpose/objective(s): The purpose of this study was to compare oncologic outcomes and toxicity profile of hypofractionated conformal radiotherapy (RT) with concurrent full-dose gemcitabine versus standard fractionation RT with concurrent 5-fluorouracil (5-FU) in the treatment of unresectable non-metastatic pancreatic cancer.

Materials/methods: Patients with unresectable non-metastatic adenocarcinoma of the pancreas treated at three institutions were included. All patients were treated with chemoradiotherapy (CRT) consisting of either hypofractionated RT to the gross disease concurrent with a full-dose gemcitabine-based regimen versus standard fractionation RT to the tumor and elective nodes concurrent with 5-FU. End points included rates of gastrointestinal (GI) toxicities, overall survival (OS), and distant metastasis free survival (DMFS).

Results: From January 1999 to December 2009, 170 patients were identified (118 RT/gemcitabine, 52 RT/5-FU). There were no differences in demographic or clinical factors. Acute GI toxicities (grades <3 versus ≥3) were 82.2 and 17.8 %, respectively, for patients treated with RT/gemcitabine and 78.9 and 21.2 % for those treated with RT/5-FU (p = 0.67). Late GI toxicities (grades <3 versus ≥3) were 88.1 and 11.9 %, respectively, for RT/gemcitabine and 80.8 and 19.2 % for RT/5-FU (p = 0.23). OS for RT/gemcitabine and RT/5-FU were 52 versus 36 % at 1 year and 14 versus 6 % at 2 years favoring the RT/gemcitabine group (p = 0.02). DMFS at 1 and 2 years for RT/gemcitabine were 41 and 11 % versus 24 and 4 % for RT/5-FU (p = 0.02).

Conclusions: RT/gemcitabine was equivalent in toxicity to RT/5-FU but was associated with superior OS and DMFS. When RT is used in the treatment of unresectable pancreatic cancer, hypofractionated conformal RT with concurrent full-dose gemcitabine may be the preferred approach.
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http://dx.doi.org/10.1007/s12029-016-9821-9DOI Listing
June 2016

Insufficient disease inhibition by intrathecal rituximab in progressive multiple sclerosis.

Ann Clin Transl Neurol 2016 03 1;3(3):166-79. Epub 2016 Feb 1.

Neuroimmunological Diseases Unit National Institute of Neurological Disorders and Stroke (NINDS) Bethesda Maryland; NIH Center for Human Immunology (CHI)the National Institutes of Health (NIH) Bethesda Maryland.

Objective: Inaccessibility of the inflammation compartmentalized to the central nervous system (CNS) may underlie the lack of efficacy of immunomodulatory treatments in progressive multiple sclerosis (MS). The double blind combination of Rituximab by IntraVenous and IntraThecAl injection versus placebo in patients with Low-Inflammatory SEcondary progressive MS (RIVITALISE; NCT01212094) trial was designed to answer: (1) Whether an induction dose of intravenous and intrathecal rituximab efficiently depletes CNS B cells? and (2) If so, whether this leads to global inhibition of CNS inflammation and slowing of CNS tissue destruction?

Methods: Patients aged 18-65 years were randomly assigned to rituximab or placebo. Protocol-stipulated interim analysis quantified the efficacy of B-cell depletion.

Results: The efficacy on cerebrospinal fluid (CSF) biomarkers failed to reach criteria for continuation of the trial. B-cell-related CSF biomarkers (sCD21 and B-cell activating factor) changed only in the active-treatment arm. While CSF B cells were killed robustly (median -79.71%, P = 0.0176), B cells in CNS tissue were depleted inadequately (~-10-20%, P < 0.0001). Consequently, the T-cell-specific CSF biomarker sCD27 decreased slightly (-10.97%, P = 0.0005), while axonal damage marker, neurofilament light chain did not change. Insufficient saturation of CD20, lack of lytic complement, and paucity of cytotoxic CD56(dim) NK cells contribute to decreased efficacy of rituximab in the CNS.

Interpretation: Biomarker studies reliably quantified complementary pharmacodynamic effects of rituximab in the CNS, exposed causes for poor efficacy and determined that RIVITALISE trial would be underpowered to measure efficacy on clinical outcomes. Identified mechanisms for poor efficacy are applicable to all CNS-inflammation targeting monoclonal antibodies.
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http://dx.doi.org/10.1002/acn3.293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774261PMC
March 2016

Patients with MS under daclizumab therapy mount normal immune responses to influenza vaccination.

Neurol Neuroimmunol Neuroinflamm 2016 Feb 27;3(1):e196. Epub 2016 Jan 27.

Neuroimmunological Diseases Unit, Neuroimmunology Branch (Y.C.L., P.W., A.B., E.R., B.B.) and Clinical Neuroscience Program (T.W.), National Institute of Neurological Diseases and Stroke, NIH, Bethesda, MD; FDA (J.M., L.R.K., H.G.), CBER; and NIH Center for Human Immunology (B.B.), NIH, Bethesda, MD.

Objective: The purpose of this study was to assess the potential immunosuppressive role of daclizumab, a humanized monoclonal antibody against the α chain of the interleukin 2 receptor, in vivo, by comparing immune responses to the 2013 seasonal influenza vaccination between patients with multiple sclerosis (MS) on long-term daclizumab therapy and controls.

Methods: Previously defined subpopulations of adaptive immune cells known to correlate with the immune response to the influenza vaccination were evaluated by 12-color flow cytometry in 23 daclizumab-treated patients with MS and 14 MS or healthy controls before (D0) and 1 day (D1) and 7 days (D7) after administration of the 2013 Afluria vaccine. Neutralizing antibody titers and CD4(+), CD8(+) T cell, B cell, and natural killer cell proliferation to 3 strains of virus contained in the Afluria vaccine were assessed at D0, D7, and 180 days postvaccination.

Results: Daclizumab-treated patients and controls demonstrated comparable, statistically significant expansions of previously defined subpopulations of activated CD8(+) T cells and B cells that characterize the development of effective immune responses to the influenza vaccine, while proliferation of T cells to influenza and control antigens was diminished in the daclizumab cohort. All participants fulfilled FDA criteria for seroconversion or seroprotection in antibody assays.

Conclusion: Despite the mild immunosuppressive effects of daclizumab in vivo demonstrated by an increased incidence of infectious complications in clinical trials, patients with MS under daclizumab therapy mount normal antibody responses to influenza vaccinations.
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http://dx.doi.org/10.1212/NXI.0000000000000196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4733151PMC
February 2016

A mouse informatics platform for phenotypic and translational discovery.

Mamm Genome 2015 Oct 28;26(9-10):413-21. Epub 2015 Aug 28.

MRC Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Harwell, OX11 0RD, UK.

The International Mouse Phenotyping Consortium (IMPC) is providing the world's first functional catalogue of a mammalian genome by characterising a knockout mouse strain for every gene. A robust and highly structured informatics platform has been developed to systematically collate, analyse and disseminate the data produced by the IMPC. As the first phase of the project, in which 5000 new knockout strains are being broadly phenotyped, nears completion, the informatics platform is extending and adapting to support the increasing volume and complexity of the data produced as well as addressing a large volume of users and emerging user groups. An intuitive interface helps researchers explore IMPC data by giving overviews and the ability to find and visualise data that support a phenotype assertion. Dedicated disease pages allow researchers to find new mouse models of human diseases, and novel viewers provide high-resolution images of embryonic and adult dysmorphologies. With each monthly release, the informatics platform will continue to evolve to support the increased data volume and to maintain its position as the primary route of access to IMPC data and as an invaluable resource for clinical and non-clinical researchers.
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http://dx.doi.org/10.1007/s00335-015-9599-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602054PMC
October 2015

Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics.

Nat Genet 2015 Sep 27;47(9):969-978. Epub 2015 Jul 27.

Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany.

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.
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http://dx.doi.org/10.1038/ng.3360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564951PMC
September 2015

Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis.

PLoS Pathog 2015 May 28;11(5):e1004884. Epub 2015 May 28.

Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, United States of America.

The fungus Cryptococcus is a major cause of meningoencephalitis in HIV-infected as well as HIV-uninfected individuals with mortalities in developed countries of 20% and 30%, respectively. In HIV-related disease, defects in T-cell immunity are paramount, whereas there is little understanding of mechanisms of susceptibility in non-HIV related disease, especially that occurring in previously healthy adults. The present description is the first detailed immunological study of non-HIV-infected patients including those with severe central nervous system (s-CNS) disease to 1) identify mechanisms of susceptibility as well as 2) understand mechanisms underlying severe disease. Despite the expectation that, as in HIV, T-cell immunity would be deficient in such patients, cerebrospinal fluid (CSF) immunophenotyping, T-cell activation studies, soluble cytokine mapping and tissue cellular phenotyping demonstrated that patients with s-CNS disease had effective microbiological control, but displayed strong intrathecal expansion and activation of cells of both the innate and adaptive immunity including HLA-DR+ CD4+ and CD8+ cells and NK cells. These expanded CSF T cells were enriched for cryptococcal-antigen specific CD4+ cells and expressed high levels of IFN-γ as well as a lack of elevated CSF levels of typical T-cell specific Th2 cytokines -- IL-4 and IL-13. This inflammatory response was accompanied by elevated levels of CSF NFL, a marker of axonal damage, consistent with ongoing neurological damage. However, while tissue macrophage recruitment to the site of infection was intact, polarization studies of brain biopsy and autopsy specimens demonstrated an M2 macrophage polarization and poor phagocytosis of fungal cells. These studies thus expand the paradigm for cryptococcal disease susceptibility to include a prominent role for macrophage activation defects and suggest a spectrum of disease whereby severe neurological disease is characterized by immune-mediated host cell damage.
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http://dx.doi.org/10.1371/journal.ppat.1004884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447450PMC
May 2015

Daclizumab reverses intrathecal immune cell abnormalities in multiple sclerosis.

Ann Clin Transl Neurol 2015 May 7;2(5):445-55. Epub 2015 Apr 7.

Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke (NINDS), National Institutes of Health (NIH) Bethesda, Maryland ; NIH Center for Human Immunology (CHI), NIH Bethesda, Maryland.

Objective: Novel treatments such as natalizumab and fingolimod achieve their therapeutic efficacy in multiple sclerosis (MS) by blocking access of subsets of immune cells into the central nervous system, thus creating nonphysiological intrathecal immunity. In contrast, daclizumab, a humanized monoclonal antibody against the alpha chain of the IL-2 receptor, has a unique mechanism of action with multiple direct effects on innate immunity. As cellular intrathecal abnormalities corresponding to MS have been well defined, we asked how daclizumab therapy affects these immunological hallmarks of the MS disease process.

Methods: Nineteen subpopulations of immune cells were assessed in a blinded fashion in the blood and 50-fold concentrated cerebrospinal fluid (CSF) cell pellet in 32 patients with untreated relapsing-remitting MS (RRMS), 22 daclizumab-treated RRMS patients, and 11 healthy donors (HDs) using 12-color flow cytometry.

Results: Long-term daclizumab therapy normalized all immunophenotyping abnormalities differentiating untreated RRMS patients from HDs. Specifically, strong enrichment of adaptive immune cells (CD4+ and CD8+ T cells and B cells) in the CSF was reversed. Similarly, daclizumab controlled MS-related increases in the innate lymphoid cells (ILCs) and lymphoid tissue inducer cells in the blood and CSF, and reverted the diminished proportion of intrathecal monocytes. The only marker that distinguished daclizumab-treated MS patients from HDs was the expansion of immunoregulatory CD56(bright) NK cells.

Interpretation: Normalization of immunological abnormalities associated with MS by long-term daclizumab therapy suggests that this drug's effects on ILCs, NK cells, and dendritic cell-mediated antigen presentation to CD4+ and CD8+ T cells are critical in regulating the MS disease process.
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http://dx.doi.org/10.1002/acn3.181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4435700PMC
May 2015

Applying the ARRIVE Guidelines to an In Vivo Database.

PLoS Biol 2015 May 20;13(5):e1002151. Epub 2015 May 20.

Mammalian Genetics Unit, Medical Research Council, Harwell, United Kingdom.

The Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines were developed to address the lack of reproducibility in biomedical animal studies and improve the communication of research findings. While intended to guide the preparation of peer-reviewed manuscripts, the principles of transparent reporting are also fundamental for in vivo databases. Here, we describe the benefits and challenges of applying the guidelines for the International Mouse Phenotyping Consortium (IMPC), whose goal is to produce and phenotype 20,000 knockout mouse strains in a reproducible manner across ten research centres. In addition to ensuring the transparency and reproducibility of the IMPC, the solutions to the challenges of applying the ARRIVE guidelines in the context of IMPC will provide a resource to help guide similar initiatives in the future.
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http://dx.doi.org/10.1371/journal.pbio.1002151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439173PMC
May 2015

The BioMart community portal: an innovative alternative to large, centralized data repositories.

Nucleic Acids Res 2015 Jul 20;43(W1):W589-98. Epub 2015 Apr 20.

Oncology Computational Biology, Pfizer, La Jolla, USA.

The BioMart Community Portal (www.biomart.org) is a community-driven effort to provide a unified interface to biomedical databases that are distributed worldwide. The portal provides access to numerous database projects supported by 30 scientific organizations. It includes over 800 different biological datasets spanning genomics, proteomics, model organisms, cancer data, ontology information and more. All resources available through the portal are independently administered and funded by their host organizations. The BioMart data federation technology provides a unified interface to all the available data. The latest version of the portal comes with many new databases that have been created by our ever-growing community. It also comes with better support and extensibility for data analysis and visualization tools. A new addition to our toolbox, the enrichment analysis tool is now accessible through graphical and web service interface. The BioMart community portal averages over one million requests per day. Building on this level of service and the wealth of information that has become available, the BioMart Community Portal has introduced a new, more scalable and cheaper alternative to the large data stores maintained by specialized organizations.
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http://dx.doi.org/10.1093/nar/gkv350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489294PMC
July 2015

Cerebrospinal fluid markers reveal intrathecal inflammation in progressive multiple sclerosis.

Ann Neurol 2015 Jul 16;78(1):3-20. Epub 2015 Apr 16.

Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.

Objective: The management of complex patients with neuroimmunological diseases is hindered by an inability to reliably measure intrathecal inflammation. Currently implemented laboratory tests developed >40 years ago either are not dynamic or fail to capture low levels of central nervous system (CNS) inflammation. Therefore, we aimed to identify and validate biomarkers of CNS inflammation in 2 blinded, prospectively acquired cohorts of untreated patients with neuroimmunological diseases and embedded controls, with the ultimate goal of developing clinically useful tools.

Methods: Because biomarkers with maximum utility reflect immune phenotypes, we included an assessment of cell specificity in purified primary immune cells. Biomarkers were quantified by optimized electrochemiluminescent immunoassays.

Results: Among markers with cell-specific secretion, soluble CD27 is a validated biomarker of intrathecal T-cell activation, with an area under the receiver operating characteristic curve of 0.97. Comparing the quantities of cerebrospinal fluid (CSF) immune cells and their respective cell-specific soluble biomarkers (released by CSF cells as well as their counterparts in CNS tissue) provided invaluable information about stationary CNS immune responses, previously attainable via brain biopsy only. Unexpectedly, progressive and relapsing-remitting multiple sclerosis (MS) patients have comparable numbers of activated intrathecal T and B cells, which are preferentially embedded in CNS tissue in the former group.

Interpretation: The cell-specific biomarkers of intrathecal inflammation may improve diagnosis and management of neuroimmunological diseases and provide pharmacodynamic markers for future therapeutic developments in patients with intrathecal inflammation that is not captured by imaging, such as in progressive MS.
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http://dx.doi.org/10.1002/ana.24408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568079PMC
July 2015

The International Mouse Phenotyping Consortium Web Portal, a unified point of access for knockout mice and related phenotyping data.

Nucleic Acids Res 2014 Jan 4;42(Database issue):D802-9. Epub 2013 Nov 4.

European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK, Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire OX11 0RD, UK and Mouse Informatics Group, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

The International Mouse Phenotyping Consortium (IMPC) web portal (http://www.mousephenotype.org) provides the biomedical community with a unified point of access to mutant mice and rich collection of related emerging and existing mouse phenotype data. IMPC mouse clinics worldwide follow rigorous highly structured and standardized protocols for the experimentation, collection and dissemination of data. Dedicated 'data wranglers' work with each phenotyping center to collate data and perform quality control of data. An automated statistical analysis pipeline has been developed to identify knockout strains with a significant change in the phenotype parameters. Annotation with biomedical ontologies allows biologists and clinicians to easily find mouse strains with phenotypic traits relevant to their research. Data integration with other resources will provide insights into mammalian gene function and human disease. As phenotype data become available for every gene in the mouse, the IMPC web portal will become an invaluable tool for researchers studying the genetic contributions of genes to human diseases.
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http://dx.doi.org/10.1093/nar/gkt977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964955PMC
January 2014

Efficient human pose estimation from single depth images.

IEEE Trans Pattern Anal Mach Intell 2013 Dec;35(12):2821-40

Microsoft Research, Cambridge.

We describe two new approaches to human pose estimation. Both can quickly and accurately predict the 3D positions of body joints from a single depth image without using any temporal information. The key to both approaches is the use of a large, realistic, and highly varied synthetic set of training images. This allows us to learn models that are largely invariant to factors such as pose, body shape, field-of-view cropping, and clothing. Our first approach employs an intermediate body parts representation, designed so that an accurate per-pixel classification of the parts will localize the joints of the body. The second approach instead directly regresses the positions of body joints. By using simple depth pixel comparison features and parallelizable decision forests, both approaches can run super-real time on consumer hardware. Our evaluation investigates many aspects of our methods, and compares the approaches to each other and to the state of the art. Results on silhouettes suggest broader applicability to other imaging modalities.
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http://dx.doi.org/10.1109/TPAMI.2012.241DOI Listing
December 2013

A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N mouse strains.

Genome Biol 2013 Jul 31;14(7):R82. Epub 2013 Jul 31.

Background: The mouse inbred line C57BL/6J is widely used in mouse genetics and its genome has been incorporated into many genetic reference populations. More recently large initiatives such as the International Knockout Mouse Consortium (IKMC) are using the C57BL/6N mouse strain to generate null alleles for all mouse genes. Hence both strains are now widely used in mouse genetics studies. Here we perform a comprehensive genomic and phenotypic analysis of the two strains to identify differences that may influence their underlying genetic mechanisms.

Results: We undertake genome sequence comparisons of C57BL/6J and C57BL/6N to identify SNPs, indels and structural variants, with a focus on identifying all coding variants. We annotate 34 SNPs and 2 indels that distinguish C57BL/6J and C57BL/6N coding sequences, as well as 15 structural variants that overlap a gene. In parallel we assess the comparative phenotypes of the two inbred lines utilizing the EMPReSSslim phenotyping pipeline, a broad based assessment encompassing diverse biological systems. We perform additional secondary phenotyping assessments to explore other phenotype domains and to elaborate phenotype differences identified in the primary assessment. We uncover significant phenotypic differences between the two lines, replicated across multiple centers, in a number of physiological, biochemical and behavioral systems.

Conclusions: Comparison of C57BL/6J and C57BL/6N demonstrates a range of phenotypic differences that have the potential to impact upon penetrance and expressivity of mutational effects in these strains. Moreover, the sequence variants we identify provide a set of candidate genes for the phenotypic differences observed between the two strains.
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http://dx.doi.org/10.1186/gb-2013-14-7-r82DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053787PMC
July 2013

Specular reflections and the estimation of shape from binocular disparity.

Proc Natl Acad Sci U S A 2013 Feb 22;110(6):2413-8. Epub 2013 Jan 22.

School of Psychology, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.

Binocular stereopsis is a powerful visual depth cue. To exploit it, the brain matches features from the two eyes' views and measures their interocular disparity. This works well for matte surfaces because disparities indicate true surface locations. However, specular (glossy) surfaces are problematic because highlights and reflections are displaced from the true surface in depth, leading to information that conflicts with other cues to 3D shape. Here, we address the question of how the visual system identifies the disparity information created by specular reflections. One possibility is that the brain uses monocular cues to identify that a surface is specular and modifies its interpretation of the disparities accordingly. However, by characterizing the behavior of specular disparities we show that the disparity signals themselves provide key information ("intrinsic markers") that enable potentially misleading disparities to be identified and rejected. We presented participants with binocular views of specular objects and asked them to report perceived depths by adjusting probe dots. For simple surfaces--which do not exhibit intrinsic indicators that the disparities are "wrong"--participants incorrectly treat disparities at face value, leading to erroneous judgments. When surfaces are more complex we find the visual system also errs where the signals are reliable, but rejects and interpolates across areas with large vertical disparities and horizontal disparity gradients. This suggests a general mechanism in which the visual system assesses the origin and utility of sensory signals based on intrinsic markers of their reliability.
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http://dx.doi.org/10.1073/pnas.1212417110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568321PMC
February 2013

BioMart Central Portal: an open database network for the biological community.

Database (Oxford) 2011 18;2011:bar041. Epub 2011 Sep 18.

Ontario Institute for Cancer Research, Toronto, M5G 0A3, Canada.

BioMart Central Portal is a first of its kind, community-driven effort to provide unified access to dozens of biological databases spanning genomics, proteomics, model organisms, cancer data, ontology information and more. Anybody can contribute an independently maintained resource to the Central Portal, allowing it to be exposed to and shared with the research community, and linking it with the other resources in the portal. Users can take advantage of the common interface to quickly utilize different sources without learning a new system for each. The system also simplifies cross-database searches that might otherwise require several complicated steps. Several integrated tools streamline common tasks, such as converting between ID formats and retrieving sequences. The combination of a wide variety of databases, an easy-to-use interface, robust programmatic access and the array of tools make Central Portal a one-stop shop for biological data querying. Here, we describe the structure of Central Portal and show example queries to demonstrate its capabilities.
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http://dx.doi.org/10.1093/database/bar041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263598PMC
January 2012

Meeting Report from the Second "Minimum Information for Biological and Biomedical Investigations" (MIBBI) workshop.

Stand Genomic Sci 2010 Dec 25;3(3):259-66. Epub 2010 Dec 25.

This report summarizes the proceedings of the second workshop of the 'Minimum Information for Biological and Biomedical Investigations' (MIBBI) consortium held on Dec 1-2, 2010 in Rüdesheim, Germany through the sponsorship of the Beilstein-Institute. MIBBI is an umbrella organization uniting communities developing Minimum Information (MI) checklists to standardize the description of data sets, the workflows by which they were generated and the scientific context for the work. This workshop brought together representatives of more than twenty communities to present the status of their MI checklists and plans for future development. Shared challenges and solutions were identified and the role of MIBBI in MI checklist development was discussed. The meeting featured some thirty presentations, wide-ranging discussions and breakout groups. The top outcomes of the two-day workshop as defined by the participants were: 1) the chance to share best practices and to identify areas of synergy; 2) defining a series of tasks for updating the MIBBI Portal; 3) reemphasizing the need to maintain independent MI checklists for various communities while leveraging common terms and workflow elements contained in multiple checklists; and 4) revision of the concept of the MIBBI Foundry to focus on the creation of a core set of MIBBI modules intended for reuse by individual MI checklist projects while maintaining the integrity of each MI project. Further information about MIBBI and its range of activities can be found at http://mibbi.org/.
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http://dx.doi.org/10.4056/sigs.147362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035314PMC
December 2010