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      Novel In Situ Collection of Tumor Interstitial Fluid from a Head and Neck Squamous Carcinoma Reveals a Unique Proteome with Diagnostic Potential

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          Abstract

          Introduction

          Tumors lack normal drainage of secreted fluids and consequently build up tumor interstitial fluid (TIF). Unlike other bodily fluids, TIF likely contains a high proportion of tumor-specific proteins with potential as biomarkers.

          Methods

          Here, we evaluated a novel technique using a unique ultrafiltration catheter for in situ collection of TIF and used it to generate the first catalog of TIF proteins from a head and neck squamous cell carcinoma (HNSCC). To maximize proteomic coverage, TIF was immunodepleted for high abundance proteins and digested with trypsin, and peptides were fractionated in three dimensions prior to mass spectrometry.

          Results

          We identified 525 proteins with high confidence. The HNSCC TIF proteome was distinct compared to proteomes of other bodily fluids. It contained a relatively high proportion of proteins annotated by Gene Ontology as “extracellular” compared to other secreted fluid and cellular proteomes, indicating minimal cell lysis from our in situ collection technique. Several proteins identified are putative biomarkers of HNSCC, supporting our catalog’s value as a source of potential biomarkers.

          Conclusions

          In all, we demonstrate a reliable new technique for in situ TIF collection and provide the first HNSCC TIF protein catalog with value as a guide for others seeking to develop tumor biomarkers.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s12014-010-9050-3) contains supplementary material, which is available to authorized users.

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          Most cited references19

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          Empirical statistical model to estimate the accuracy of peptide identifications made by MS/MS and database search.

          We present a statistical model to estimate the accuracy of peptide assignments to tandem mass (MS/MS) spectra made by database search applications such as SEQUEST. Employing the expectation maximization algorithm, the analysis learns to distinguish correct from incorrect database search results, computing probabilities that peptide assignments to spectra are correct based upon database search scores and the number of tryptic termini of peptides. Using SEQUEST search results for spectra generated from a sample of known protein components, we demonstrate that the computed probabilities are accurate and have high power to discriminate between correctly and incorrectly assigned peptides. This analysis makes it possible to filter large volumes of MS/MS database search results with predictable false identification error rates and can serve as a common standard by which the results of different research groups are compared.
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            Annual report to the nation on the status of cancer, 1975-2001, with a special feature regarding survival.

            The American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR) collaborate annually to provide updated information regarding cancer occurrence and trends in the U.S. This year's report features a special section on cancer survival. Information concerning cancer cases was obtained from the NCI, CDC, and NAACCR and information concerning recorded cancer deaths was obtained from the CDC. The authors evaluated trends in age-adjusted cancer incidence and death rates by regression models and described and compared survival rates over time and across racial/ethnic populations. Incidence rates for all cancers combined decreased from 1991 through 2001, but stabilized from 1995 through 2001 when adjusted for delay in reporting. The incidence rates for female lung cancer decreased (although not statistically significant for delay adjusted) and mortality leveled off for the first time after increasing for many decades. Colorectal cancer incidence rates also decreased. Death rates decreased for all cancers combined (1.1% per year since 1993) and for many of the top 15 cancers occurring in men and women. The 5-year relative survival rates improved for all cancers combined and for most, but not all, cancers over 2 diagnostic periods (1975-1979 and 1995-2000). However, cancer-specific survival rates were lower and the risk of dying from cancer, once diagnosed, was higher in most minority populations compared with the white population. The relative risk of death from all cancers combined in each racial and ethnic population compared with non-Hispanic white men and women ranged from 1.16 in Hispanic white men to 1.69 in American Indian/Alaska Native men, with the exception of Asian/Pacific Islander women, whose risk of 1.01 was similar to that of non-Hispanic white women. The continued measurable declines for overall cancer death rates and for many of the top 15 cancers, along with improved survival rates, reflect progress in the prevention, early detection, and treatment of cancer. However, racial and ethnic disparities in survival and the risk of death from cancer, and geographic variation in stage distributions suggest that not all segments of the U.S. population have benefited equally from such advances. Published 2004 by the American Cancer Society.
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              Salivary proteomics for oral cancer biomarker discovery.

              This study aims to explore the presence of informative protein biomarkers in the human saliva proteome and to evaluate their potential for detection of oral squamous cell carcinoma (OSCC). Whole saliva samples were collected from patients (n = 64) with OSCC and matched healthy subjects (n = 64). The proteins in pooled whole saliva samples of patients with OSCC (n = 16) and matched healthy subjects (n = 16) were profiled using shotgun proteomics based on C4 reversed-phase liquid chromatography for prefractionation, capillary reversed-phase liquid chromatography with quadruple time-of-flight mass spectrometry, and Mascot sequence database searching. Immunoassays were used for validation of the candidate biomarkers on a new group of OSCC (n = 48) and matched healthy subjects (n = 48). Receiver operating characteristic analysis was exploited to evaluate the diagnostic value of discovered candidate biomarkers for OSCC. Subtractive proteomics revealed several salivary proteins at differential levels between the OSCC patients and matched control subjects. Five candidate biomarkers were successfully validated using immunoassays on an independent set of OSCC patients and matched healthy subjects. The combination of these candidate biomarkers yielded a receiver operating characteristic value of 93%, sensitivity of 90%, and specificity of 83% in detecting OSCC. Patient-based saliva proteomics is a promising approach to searching for OSCC biomarkers. The discovery of these new targets may lead to a simple clinical tool for the noninvasive diagnosis of oral cancer. Long-term longitudinal studies with large populations of individuals with oral cancer and those who are at high risk of developing oral cancer are needed to validate these potential biomarkers.
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                Author and article information

                Contributors
                tgriffin@umn.edu
                Journal
                Clin Proteomics
                Clinical Proteomics
                Humana Press Inc (New York )
                1542-6416
                1559-0275
                25 July 2010
                25 July 2010
                September 2010
                : 6
                : 3
                : 75-82
                Affiliations
                [1 ]Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455 USA
                [2 ]Department of Otolaryngology, Hennepin County Medical Center, Minneapolis, MN 55415 USA
                [3 ]Department of Otolaryngology, University of Minnesota Medical School, Minneapolis, MN 55455 USA
                [4 ]Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN 55455 USA
                [5 ]Key Laboratory for Cell Proliferation and Regulation Biology, Ministry of Education, Beijing Normal University, Beijing, 100875 China
                [6 ]Department of Oral Medicine, Diagnosis and Radiology, School of Dentistry, University of Minnesota, Minneapolis, MN 55455 USA
                [7 ]Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455 USA
                Article
                9050
                10.1007/s12014-010-9050-3
                2937136
                20930922
                008045fb-9008-4257-8c31-a64a383c1b81
                © The Author(s) 2010
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                © Springer Science+Business Media, LLC 2010

                Molecular medicine
                biomarker discovery,head and neck squamous cell carcinoma,in situ collection,tumor interstitial fluid

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