| 11. |
- de Wit, Meike, et al.
(författare)
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Colorectal cancer candidate biomarkers identified by tissue secretome proteome profiling
- 2014
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Ingår i: Journal of Proteomics. - : Elsevier BV. - 1874-3919 .- 1876-7737. ; 99, s. 26-39
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a major health problem. Biomarkers associated with molecular changes in cancer cells can aid early detection, diagnosis, prognosis, therapy selection, and disease monitoring. Tumor tissue secretomes are a rich source of candidate biomarkers. To identify CRC protein biomarkers, secretomes of four pairs of human CRC tissue and patient-matched normal colon tissue samples, and secretomes of five CRC cell lines were analyzed by GeLC-MS/MS. Subsequent data analysis was based on label-free spectral counting, Ingenuity Pathway Analysis, Secretome/SignalP, STRING and Cytoscape, resulting in 2703 protein identifications in the tissue secretomes, of which 409 proteins were significantly more present in CRC samples than in controls. Biomarker selection of 76 candidates was based on consistent and abundant over-representation in cancer-compared to control-secretomes, and presumed neoplastic origin. Overlap analysis with previously obtained datasets revealed 21 biomarkers suited for early detection of CRC. Immunohistochemistry confirmed overexpression in CRC of one candidate marker (MCM5). In conclusion, a human reference dataset of 76 candidate biomarkers was identified for which we illustrate that combination with existing pre-clinical datasets allows pre-selection of biomarkers for blood- or stool-based assays to support clinical management of CRC. Further dedicated validation studies are required to demonstrate their clinical applicability. Biological significance Tissue secretome proteomes are a rich source of candidate biomarkers. Several secretome proteome datasets have been obtained from pre-clinical in vitro and in vivo colorectal cancer (CRC) model systems, yielding promising CRC biomarkers obtained under well-defined experimentally controlled conditions. However, which of these biomarker proteins are actually secreted by human CRC samples was not known. To our knowledge, this is the first study that directly compares secretome proteomes from clinically relevant human CRC tissues to patient-matched normal colon tissues. We identified 76 human CRC protein biomarkers that may facilitate blood-based or stool-based assay development to support clinical management of CRC. Overlap analysis with datasets from well-defined pre-clinical studies helps to determine what clinical application suits these human CRC biomarkers best, i.e. early detection, diagnosis, prognosis, therapy selection, and/or disease monitoring of CRC. This is demonstrated for a CRC mouse model dataset, revealing 21 human CRC biomarkers suited for early detection of CRC.
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| 12. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 13. |
- Pham, M N., et al.
(författare)
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Fasting and meal-stimulated residual beta cell function is positively associated with serum concentrations of proinflammatory cytokines and negatively associated with anti-inflammatory and regulatory cytokines in patients with longer term type 1 diabetes
- 2013
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Ingår i: Diabetologia. - : Springer Verlag (Germany). - 0012-186X .- 1432-0428. ; 56:6, s. 1356-1363
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Tidskriftsartikel (refereegranskat)abstract
- Cytokines may promote or inhibit disease progression in type 1 diabetes. We investigated whether systemic proinflammatory, anti-inflammatory and regulatory cytokines associated differently with fasting and meal-stimulated beta cell function in patients with longer term type 1 diabetes. less thanbrgreater than less thanbrgreater thanThe beta cell function of 118 patients with type 1 diabetes of duration of 0.75-4.97 years was tested using a standardised liquid mixed meal test (MMT). Serum samples obtained at -5 to 120 min were analysed by multiplex bead-based technology for proinflammatory (IL-6, TNF-alpha), anti-inflammatory (IL-1 receptor antagonist [IL-1RA]) and regulatory (IL-10, TGF-beta(1-3)) cytokines, and by standard procedures for C-peptide. Differences in beta cell function between patient groups were assessed using stepwise multiple regression analysis adjusting for sex, age, duration of diabetes, BMI, HbA(1c) and fasting blood glucose. less thanbrgreater than less thanbrgreater thanHigh fasting systemic concentrations of the proinflammatory cytokines IL-6 and TNF-alpha were associated with increased fasting and stimulated C-peptide concentrations even after adjustment for confounders (p andlt; 0.03). Interestingly, increased concentrations of anti-inflammatory/regulatory IL-1RA, IL-10, TGF-beta(1) and TGF-beta(2) were associated with lower fasting and stimulated C-peptide levels (p andlt; 0.04), losing significance on adjustment for anthropometric variables. During the MMT, circulating concentrations of IL-6 and TNF-alpha increased (p andlt; 0.001) while those of IL-10 and TGF-beta(1) decreased (p andlt; 0.02) and IL-1RA and TGF-beta(2) remained unchanged. less thanbrgreater than less thanbrgreater thanThe association between better preserved beta cell function in longer term type 1 diabetes and increased systemic proinflammatory cytokines and decreased anti-inflammatory and regulatory cytokines is suggestive of ongoing inflammatory disease activity that might be perpetuated by the remaining beta cells. These findings should be considered when designing immune intervention studies aimed at patients with longer term type 1 diabetes and residual beta cell function.
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