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  • 1
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(12), p.e82755
    Description: Autoimmune pancreatitis (AIP) is defined by characteristic lymphoplasmacytic infiltrate, ductal strictures and a pancreatic enlargement or mass that can mimic pancreatic cancer (PaCa). The distinction between this benign disease and pancreatic cancer can be challenging. However, an accurate diagnosis may pre-empt the misdiagnosis of cancer, allowing the appropriate medical treatment of AIP and, consequently, decreasing the number of unnecessary pancreatic resections. Mass spectrometry (MS) and two-dimensional differential gel electrophoresis (2D-DIGE) have been applied to analyse serum protein alterations associated with AIP and PaCa, and to identify protein signatures indicative of the diseases. Patients' sera were immunodepleted from the 20 most prominent serum proteins prior to further 2D-DIGE and image analysis. The identity of the most-discriminatory proteins detected, was performed by MS and ELISAs were applied to confirm their expression. Serum profiling data analysis with 2D-DIGE revealed 39 protein peaks able to discriminate between AIP and PaCa. Proteins were purified and further analysed by MALDI-TOF-MS. Peptide mass fingerprinting led to identification of eleven proteins. Among them apolipoprotein A-I, apolipoprotein A-II, transthyretin, and tetranectin were identified and found as 3.0-, 3.5-, 2-, and 1.6-fold decreased in PaCa sera, respectively, whereas haptoglobin and apolipoprotein E were found to be 3.8- and 1.6-fold elevated in PaCa sera. With the exception of haptoglobin the ELISA results of the identified proteins confirmed the 2D-DIGE image analysis characteristics. Integration of the identified serum proteins as AIP markers may have considerable potential to provide additional information for the diagnosis of AIP to choose the appropriate treatment.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 2
    Language: English
    In: PLoS ONE, 01 January 2014, Vol.9(3), p.e90461
    Description: In pancreatic cancer, there is a clear unmet need to identify new serum markers for either early diagnosis, therapeutic stratification or patient monitoring. Proteomic analysis of tumor cell secretomes is a promising approach to indicate proteins released from tumor cells in vitro. Ectodomain shedding of transmembrane proteins has previously been shown to contribute significant fractions the tumor cell secretomes and to generate valuable serum biomarkers. Here we introduce a soluble form of the giant cadherin Fat1 as a novel biomarker candidate. Fat1 expression and proteolytic processing was analyzed by mass spectrometry and Western blotting using pancreatic cancer cell lines as compared to human pancreatic ductal epithelial cells. RNA expression in cancer tissues was assessed by in silico analysis of publically available microarray data. Involvement of ADAM10 (A Disintegrin and metalloproteinase domain-containing protein 10) in Fat1 ectodomain shedding was analyzed by chemical inhibition and knockdown experiments. A sandwich ELISA was developed to determine levels of soluble Fat1 in serum samples. In the present report we describe the release of high levels of the ectodomain of Fat1 cadherin into the secretomes of human pancreatic cancer cells in vitro, a process that is mediated by ADAM10. We confirm the full-length and processed heterodimeric form of Fat1 expressed on the plasma membrane and also show the p60 C-terminal transmembrane remnant fragment corresponding to the shed ectodomain. Fat1 and its sheddase ADAM10 are overexpressed in pancreatic adenocarcinomas and ectodomain shedding is also recapitulated in vivo leading to increased Fat1 serum levels in some pancreatic cancer patients. We suggest that soluble Fat1 may find an application as a marker for patient monitoring complementing carbohydrate antigen 19-9 (CA19-9). In addition, detailed analysis of the diverse processed protein isoforms of the candidate tumor suppressor Fat1 can also contribute to our understanding of cell biology and tumor behavior.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: Life Sciences, 2011, Vol.89(9), pp.304-312
    Description: Members of the epidermal growth factor receptor (EGFR) family represent validated targets for anti-cancer therapy and EGFR inhibitors have also shown efficacy in pancreatic carcinoma. We here described in detail molecular forms of the EGF receptor released by pancreatic cancer cells. We found peptides specific for the EGFR in the secretomes of five pancreatic cancer cell lines. Secretomes from cultured cancer cells are widely used as sources for serum biomarker discovery. The detailed analysis of EGFR forms in secretomes of human pancreatic cancer cells is a compilation of results from mass spectrometry (MS) and Western blotting with intracellular and extracellular domain specific antibodies. Pancreatic cancer cells secrete a 110 kDa soluble form of the EGFR (sEGFR) representing the ligand binding extracellular EGFR domains and presumably released by ectodomain shedding. At the same time, as constituents of exosomes, the EGFR is released as full-length intact receptor (170 kDa) and as a 65 kDa processed form, the C-terminal remnant fragment that corresponds to the intracellular kinase domain. The detailed characterization of diverse EGFR forms released by pancreatic cancer cells in vitro and presumably in vivo bears important implications for functional studies, for the validation of soluble EGFR as a serum biomarker and for the design of targeted therapies.
    Keywords: Egfr Forms ; Secretome ; Exosome ; Proteomics ; Targeted Therapy ; Biomarker ; Pancreatic Cancer ; Sciences (General) ; Biology
    ISSN: 0024-3205
    E-ISSN: 1879-0631
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  • 4
    In: Pancreas, 2016, Vol.45(9), pp.1309-1319
    Description: OBJECTIVES: The lack of specific biochemical markers is a major drawback for the diagnosis of autoimmune pancreatitis (AIP). The aims were to characterize the autoantibody profiles in AIP and pancreatic ductal adenocarcinoma (PDAC) and to identify circulating autoantibodies that could be diagnostic markers differentiating PDAC and the AIP subtypes. METHODS: Tissue lysates obtained from the resected pancreas of patients with AIP and patients with PDAC were separated by 2-dimensional polyacrylamide gel electrophoresis subsequently immunoblotted with autologous sera. The immunoreactive spots were subjected to nanoscale liquid chromatography–electrospray ionization tandem mass spectrometry to identify serum autoantibodies to tissue-derived autoantigens associated with AIP and PDAC. Autoantibody concentrations for selected autoantigens were assessed by enzyme-linked immunosorbent assays. RESULTS: A total of 115 immunoreactive spots were identified by 2-dimensional polyacrylamide gel electrophoresis/immunobloting. Nanoscale liquid chromatography–electrospray ionization tandem mass spectrometry–based analysis revealed 68 autoantigens in AIP, 26 in PDAC, and 21 present in both diseases. Assessment of 13 selected AIP autoantibody serum levels revealed that 7 of them had significantly higher titers in AIP versus PDAC. IgG-directed against transaldolase could significantly differentiate between the 2 AIP subtypes. CONCLUSIONS: The novel panel of AIP autoantibodies is promising to supplement the predictive tests for AIP of the currently known autoantigens and represent a basis for a combined blood test to differentiate AIP from PDAC in the future.
    Keywords: Carcinoma, Pancreatic Ductal ; Pancreatic Neoplasms ; Pancreatitis;
    ISSN: 0885-3177
    E-ISSN: 15364828
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