| 1. |
- Ansell, Anna, et al.
(författare)
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Matrix metalloproteinase-7 and -13 expression associate to cisplatin resistance in head and neck cancer cell lines.
- 2009
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Ingår i: Oral Oncology. - : Elsevier. - 1368-8375 .- 1879-0593. ; 45:10, s. 866-871
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Tidskriftsartikel (refereegranskat)abstract
- Concomitant chemoradiotherapy is a common treatment for advanced head and neck squamous cell carcinomas (HNSCC). Cisplatin is the backbone of chemotherapy regimens used to treat HNSCC. Therefore, the aim of this study was to identify predictive markers for cisplatin treatment outcome in HNSCC. The intrinsic cisplatin sensitivity (ICS) was determined in a panel of tumour cell lines. From this panel, one sensitive and two resistant cell lines were selected for comparative transcript profiling using microarray analysis. The enrichment of Gene Ontology (GO) categories in sensitive versus resistant cell lines were assessed using the Gene Ontology Tree Machine bioinformatics tool. In total, 781 transcripts were found to be differentially expressed and 11 GO categories were enriched. Transcripts contributing to this enrichment were further analyzed using Ingenuity Pathway Analysis (IPA) for identification of key regulator genes. IPA recognized 20 key regulator genes of which five were differentially expressed in sensitive versus resistant cell lines. The mRNA level of these five genes was further assessed in a panel of 25 HNSCC cell lines using quantitative real-time PCR. Among these key regulators, MMP-7 and MMP-13 are implicated as potential biomarkers of ICS. Taken together, genome-wide transcriptional analysis identified single genes, GO categories as well as molecular networks that are differentially expressed in HNSCC cell lines with different ICS. Furthermore, two novel predictive biomarkers for cisplatin resistance, MMP-7 and MMP-13, were identified.
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| 2. |
- Hammerling, Ulf, et al.
(författare)
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Comparative hazard characterization in food toxicology
- 2009
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Ingår i: Critical reviews in food science and nutrition. - : Informa UK Limited. - 1040-8398 .- 1549-7852. ; 49:7, s. 626-669
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Forskningsöversikt (refereegranskat)abstract
- Historically, different approaches have been adopted for comparing and characterizing hazards that can be found in the very complex mixture of substances present in food. In this review a variety of prominent risk assessment models are evaluated in the context of food safety. In their current state of refinement, though, they show limited applicability for comparative hazard characterization and impact magnitude scoring of adverse effects of substances in food. Nonetheless, some existing models hold building blocks and modelling concepts that appear promising for further development and integration. Thus, a new, dedicated, and generally accepted model is needed that is capable of generating relevant "Impact Magnitude Score" (IMS) values for comparing potentially toxic substances in food. A brief outline of requirements for a model (Guided Toxicology-assessment of Health Impact; GTHI) is presented that considers "severity" (S), "duration" (D), and "proportion of population affected" (P). An important demand on such a model is to provide significantly improved food safety evaluation amenable to regulatory agencies and consumers. This review is based on a project entitled "Promoting food safety through a new integrated risk analysis approach for foods" (acronym: "SAFE FOODS") that is under the subsidy of the European Commission.
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| 3. |
- Roberg, Karin, 1957-, et al.
(författare)
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Multiple genotypic aberrances associate to terminal differentiation-deficiency of an oral squamous cell carcinoma in serum-free culture
- 2008
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Ingår i: Differentiation. - : Elsevier BV. - 0301-4681 .- 1432-0436. ; 76:8, s. 868-880
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Tidskriftsartikel (refereegranskat)abstract
- Oral squamous cell carcinoma (OSCC) lines proliferative in the serum-free conditions devised for normal oral keratinocytes (NOK) are virtually absent, complicating studies of carcinogenesis. A tongue squamous cell carcinoma generated under conditions for normal cell culture an apparently immortal line (termed LK0412) that has undergone ≥200 population doublings from over a year in culture. LK0412 exhibited epithelial morphology, intermediate filaments, desmosomes, and cytokeratin. Soft agar growth and tumorigenicity in athymic nude mice indicated the malignant phenotype. Compared with NOK, LK0412 exhibited increased indices for proliferation and apoptosis, and a decreased terminal differentiation index. Fetal bovine serum inhibited growth and increased apoptosis but failed to induce terminal differentiation of LK0412; the latter outcome differed clearly from that in NOK. Gene ontology assessment of transcript profiles implicated multiple alterations in biological processes, molecular functions, and cellular components in LK0412. Genetic changes, some that were confirmed to the protein level, included previously proposed OSCC markers, i.e., BAX, CDC2, and TP53, as well as multiple cancer-associated genes not considered for OSCC, e.g., BST2, CRIP1, ISG15, KLRC1, NEDD9, NNMT, and TWIST1. Elevation of p53 protein agreed with a missense mutation detectable in both the LK0412 line and the original tumor specimen. Moderate differentiation characterized the original tumor as well as tumors generated from inoculation of LK0412 in mice. Overall, the results suggest that the LK0412 cell line represent a subgroup of OSCC with unique genomic and phenotypic profiles. LK0412 should be useful to exploration of OSCC development, particularly the deregulated growth and differentiation responsiveness to serum factors.
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| 4. |
- Staab, Claudia A, et al.
(författare)
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Bioinformatics processing of protein and transcript profiles of normal and transformed cell lines indicates functional impairment of transcriptional regulators in buccal carcinoma
- 2007
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 6:9, s. 3705-3717
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Tidskriftsartikel (refereegranskat)abstract
- Normal and two transformed buccal keratinocyte lines were cultured under a standardized condition to explore mechanisms of carcinogenesis and tumor marker expression at transcript and protein levels. An approach combining three bioinformatic programs allowed coupling of abundant proteins and large-scale transcript data to low-abundance transcriptional regulators. The analysis identified previously proposed and suggested novel protein biomarkers, gene ontology categories, molecular networks, and functionally impaired key regulator genes for buccal/oral carcinoma. © 2007 American Chemical Society.
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| 5. |
- Staab, Claudia A., et al.
(författare)
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Medium-chain fatty acids and glutathione derivatives as inhibitors of S-nitrosoglutathione reduction mediated by alcohol dehydrogenase 3
- 2009
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Ingår i: Chemico-Biological Interactions. - : Elsevier. - 0009-2797 .- 1872-7786. ; 180:1, s. 113-118
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol dehydrogenase 3 (ADH3) has emerged as an important regulator of protein S-nitrosation in its function as S-nitrosoglutathione (GSNO) reductase. GSNO depletion is associated with various disease conditions, emphasizing the potential value of a specific ADH3 inhibitor. The present study investigated inhibition of ADH3-mediated GSNO reduction by various substrate analogues, including medium-chain fatty acids and glutathione derivatives. The observed inhibition type was non-competitive. Similar to the Michaelis constants for the corresponding omega-hydroxy fatty acids, the inhibition constants for fatty acids were in the micromolar range and showed a clear dependency on chain length with optimal inhibitory capacity for eleven and twelve carbons. The most efficient inhibitors found were undecanoic acid, dodecanoic acid and dodecanedioic acid, with no significant difference in inhibition constant. All glutathione-derived inhibitors displayed inhibition constants in the millimolar range, at least three orders of magnitudes higher than the Michaelis constants of the high-affinity substrates GSNO and S-hydroxymethylglutathione. The experimental results as well as docking simulations with GSNO and S-methylglutathione suggest that for ADH3 ligands with a glutathione scaffold, in contrast to fatty acids, a zinc-binding moiety is imperative for correct orientation and stabilization of the hydrophilic glutathione scaffold within a predominantly hydrophobic active site.
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