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PubMed | Eli Lilly and Company, Gilead Sciences Inc., ETH Zurich, Cedars Sinai Medical Center and 23 more.
Type: Journal Article | Journal: Clinical chemistry | Year: 2015

For many years, basic and clinical researchers have taken advantage of the analytical sensitivity and specificity afforded by mass spectrometry in the measurement of proteins. Clinical laboratories are now beginning to deploy these work flows as well. For assays that use proteolysis to generate peptides for protein quantification and characterization, synthetic stable isotope-labeled internal standard peptides are of central importance. No general recommendations are currently available surrounding the use of peptides in protein mass spectrometric assays.The Clinical Proteomic Tumor Analysis Consortium of the National Cancer Institute has collaborated with clinical laboratorians, peptide manufacturers, metrologists, representatives of the pharmaceutical industry, and other professionals to develop a consensus set of recommendations for peptide procurement, characterization, storage, and handling, as well as approaches to the interpretation of the data generated by mass spectrometric protein assays. Additionally, the importance of carefully characterized reference materials-in particular, peptide standards for the improved concordance of amino acid analysis methods across the industry-is highlighted. The alignment of practices around the use of peptides and the transparency of sample preparation protocols should allow for the harmonization of peptide and protein quantification in research and clinical care.

PubMed | University of Washington, Fred Hutchinson Cancer Research Center, Pacific Northwest National Laboratory, New York University and 7 more.
Type: | Journal: Methods in molecular biology (Clifton, N.J.) | Year: 2016

The Clinical Proteomic Tumor Analysis Consortium (CPTAC) of the National Cancer Institute (NCI) has launched an Assay Portal ( to serve as an open-source repository of well-characterized targeted proteomic assays. The portal is designed to curate and disseminate highly characterized, targeted mass spectrometry (MS)-based assays by providing detailed assay performance characterization data, standard operating procedures, and access to reagents. Assay content is accessed via the portal through queries to find assays targeting proteins associated with specific cellular pathways, protein complexes, or specific chromosomal regions. The position of the peptide analytes for which there are available assays are mapped relative to other features of interest in the protein, such as sequence domains, isoforms, single nucleotide polymorphisms, and posttranslational modifications. The overarching goals are to enable robust quantification of all human proteins and to standardize the quantification of targeted MS-based assays to ultimately enable harmonization of results over time and across laboratories.

PubMed | Georgetown University, U.S. National Institute of Standards and Technology, Spectragen Informatics, U.S. National Cancer Institute and ESAC Inc.
Type: Journal Article | Journal: Journal of proteome research | Year: 2016

The Clinical Proteomic Tumor Analysis Consortium (CPTAC) has produced large proteomics data sets from the mass spectrometric interrogation of tumor samples previously analyzed by The Cancer Genome Atlas (TCGA) program. The availability of the genomic and proteomic data is enabling proteogenomic study for both reference (i.e., contained in major sequence databases) and nonreference markers of cancer. The CPTAC laboratories have focused on colon, breast, and ovarian tissues in the first round of analyses; spectra from these data sets were produced from 2D liquid chromatography-tandem mass spectrometry analyses and represent deep coverage. To reduce the variability introduced by disparate data analysis platforms (e.g., software packages, versions, parameters, sequence databases, etc.), the CPTAC Common Data Analysis Platform (CDAP) was created. The CDAP produces both peptide-spectrum-match (PSM) reports and gene-level reports. The pipeline processes raw mass spectrometry data according to the following: (1) peak-picking and quantitative data extraction, (2) database searching, (3) gene-based protein parsimony, and (4) false-discovery rate-based filtering. The pipeline also produces localization scores for the phosphopeptide enrichment studies using the PhosphoRS program. Quantitative information for each of the data sets is specific to the sample processing, with PSM and protein reports containing the spectrum-level or gene-level (rolled-up) precursor peak areas and spectral counts for label-free or reporter ion log-ratios for 4plex iTRAQ. The reports are available in simple tab-delimited formats and, for the PSM-reports, in mzIdentML. The goal of the CDAP is to provide standard, uniform reports for all of the CPTAC data to enable comparisons between different samples and cancer types as well as across the major omics fields.

Suzuki K.,University of Tokyo | Hori A.,Yamagata University | Kawamoto K.,Yamagata University | Thangudu R.R.,U.S. National Center for Biotechnology Information | And 9 more authors.
Proteins: Structure, Function and Bioinformatics | Year: 2014

Feruloyl esterase (FAE) catalyzes the hydrolysis of the ferulic and diferulic acids present in plant cell wall polysaccharides, and tannase catalyzes the hydrolysis of tannins to release gallic acid. The fungal tannase family in the ESTHER database contains various enzymes, including FAEs and tannases. Despite the importance of FAEs and tannases in bioindustrial applications, three-dimensional structures of the fungal tannase family members have been unknown. Here, we determined the crystal structure of FAE B from Aspergillus oryzae (AoFaeB), which belongs to the fungal tannase family, at 1.5 Å resolution. AoFaeB consists of a catalytic α/β-hydrolase fold domain and a large lid domain, and the latter has a novel fold. To estimate probable binding models of substrates in AoFaeB, an automated docking analysis was performed. In the active site pocket of AoFaeB, residues responsible for the substrate specificity of the FAE activity were identified. The catalytic triad of AoFaeB comprises Ser203, Asp417, and His457, and the serine and histidine residues are directly connected by a disulfide bond of the neighboring cysteine residues, Cys202 and Cys458. This structural feature, the "CS-D-HC motif," is unprecedented in serine hydrolases. A mutational analysis indicated that the novel structural motif plays essential roles in the function of the active site. © 2014 Wiley Periodicals, Inc.

Toth P.P.,Johns Hopkins University | Grabner M.,HealthCore Inc. | Ramey N.,Rutgers University | Ramey N.,ESAC Inc. | Higuchi K.,Novartis
Atherosclerosis | Year: 2014

Objective: This study investigated real-world treatment patterns, healthcare utilization, and costs of hypertriglyceridemia in a large commercially insured United States population. Methods: This observational claims study was conducted among adult patients with TG>500mg/dL between 01/01/2007 and 04/30/2013. Patients were stratified into mutually exclusive cohorts based on their first available TG measurement (index date): TG≥1500 (Cohort A); 750≤TG<1500 (Cohort B), and 500300% increase in total all-cause costs in Cohort A. Conclusions: These results suggest that severe hypertriglyceridemia is undertreated and healthcare utilization and costs scale with magnitude of TG elevation. Patients with more severe hypertriglyceridemia received greater medical and pharmacy services. Managing severe hypertriglyceridemia more aggressively and preventing acute pancreatitis may generate cost savings. © 2014 The Authors.

Bhattacharya S.,Stanford University | Andorf S.,Stanford University | Gomes L.,Northrop Grumman | Dunn P.,Northrop Grumman | And 13 more authors.
Immunologic Research | Year: 2014

The immunology database and analysis portal (ImmPort) system is the archival repository and dissemination vehicle for clinical and molecular datasets created by research consortia funded by the National Institute of Allergy and Infectious Diseases Division of Allergy, Immunology, and Transplantation. With nearly 100 datasets now publicly available and hundreds of downloads per month, ImmPort is an important source for raw data and protocols from clinical trials, mechanistic studies, and novel methods for cellular and molecular measurements. To facilitate data transfer, templates for data representation and standard operating procedures have also been created and are also publicly available. ImmPort facilitates transparency and reproducibility in immunology research, serves as an important resource for education, and enables newly generated hypotheses and data-driven science. © Springer Science+Business Media 2014.

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