| 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. |
- Farnebo, Lovisa, et al.
(författare)
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Combining factors on protein and gene level to predict radioresponse in head and neck cancer cell lines
- 2011
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Ingår i: Journal of Oral Pathology & Medicine. - : John Wiley and sons. - 0904-2512 .- 1600-0714. ; 40:10, s. 739-746
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Radiotherapy is the main therapy for head and neck squamous cell carcinoma (HNSCC); however, treatment resistance and local recurrence are significant problems, highlighting the need for predictive markers. In this study, we evaluated selected proteins, mutations, and single nucleotide polymorphisms (SNPs) involved in apoptosis, cell proliferation, and DNA repair alone or combined as predictive markers for radioresponse in 42 HNSCC cell lines. METHODS: The expression of epidermal growth factor receptor, survivin, Bax, Bcl-2, Bcl-XL, cyclooxygenase-2, and heat shock protein 70 was analyzed by ELISA. Furthermore, mutations and SNPs in the p53 gene as well as SNPs in the MDM2, XRCC1, and XRCC3 genes were analyzed for their relation to radioresponse. To enable the evaluation of the predictive value of several factors combined, each cell line was allocated points based on the number of negative points (NNP) system, and the NNP sum was correlated with radioresponse. RESULTS: Survivin was the only factor that alone was significantly correlated with the intrinsic radiosensitivity (r=0.36, p=0.02). The combination of survivin, Bax, Bcl-2, Bcl-XL, cyclooxygenase-2, and the p53 Arg72Pro polymorphism was found to most strongly correlate with radioresponse (r=0.553, p<0.001). CONCLUSION: These data indicate that the intrinsic radiosensitivity of 42 HNSCC cell lines can be predicted by a panel of factors on both the protein and gene levels. Moreover, among the investigated factors, survivin was the most promising biomarker of radioresponse.
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| 3. |
- Grafström, Roland C, et al.
(författare)
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Toward the Replacement of Animal Experiments through the Bioinformatics-driven Analysis of 'Omics' Data from Human Cell Cultures
- 2015
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Ingår i: ATLA (Alternatives to Laboratory Animals). - : SAGE Publications. - 0261-1929 .- 2632-3559. ; 43:5, s. 325-332
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Tidskriftsartikel (refereegranskat)abstract
- This paper outlines the work for which Roland Grafström and Pekka Kohonen were awarded the 2014 Lush Science Prize. The research activities of the Grafström laboratory have, for many years, covered cancer biology studies, as well as the development and application of toxicity-predictive in vitro models to determine chemical safety. Through the integration of in silico analyses of diverse types of genomics data (transcriptomic and proteomic), their efforts have proved to fit well into the recently-developed Adverse Outcome Pathway paradigm. Genomics analysis within state-of-the-art cancer biology research and Toxicology in the 21st Century concepts share many technological tools. A key category within the Three Rs paradigm is the Replacement of animals in toxicity testing with alternative methods, such as bioinformatics-driven analyses of data obtained from human cell cultures exposed to diverse toxicants. This work was recently expanded within the pan-European SEURAT-1 project (Safety Evaluation Ultimately Replacing Animal Testing), to replace repeat-dose toxicity testing with data-rich analyses of sophisticated cell culture models. The aims and objectives of the SEURAT project have been to guide the application, analysis, interpretation and storage of 'omics' technology-derived data within the service-oriented sub-project, ToxBank. Particularly addressing the Lush Science Prize focus on the relevance of toxicity pathways, a 'data warehouse' that is under continuous expansion, coupled with the development of novel data storage and management methods for toxicology, serve to address data integration across multiple 'omics' technologies. The prize winners' guiding principles and concepts for modern knowledge management of toxicological data are summarised. The translation of basic discovery results ranged from chemical-testing and material-testing data, to information relevant to human health and environmental safety.
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| 4. |
- 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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| 5. |
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| 6. |
- Jerhammar, Fredrik, et al.
(författare)
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Identification of Key Regulator Genes Linked to Radioresistance in Head and Neck Squamous Cell Carcinoma by Bioinformatic Processing of Transcript Data
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Purpose: We analyzed basal expression patterns of cell lines with different intrinsic radiosensitivity to discover predictive markers of radiotherapy response. Experimental Design: Five head and neck squamous cell carcinoma (HNSCC) cell lines were selected for microarray analysis. Two cell lines showed high resistance to radiation, two cell lines showed an intermediate resistance and one cell line was sensitive and therefore used as reference to other cell lines. Three gene lists were generated from this analysis; one list with commonly deregulated genes in all cell lines compared to the reference and two lists with deregulated genes for the intermediate and highly resistant cell lines compared to the reference, respectively. Gene Ontology enrichment profiling and Ingenuity Pathway Analysis was applied on all gene lists. Key transcript findings were verified at the protein level by Western blot. Results: Expression analysis of the high and intermediate resistant cell lines compared to the reference resulted in approximately 1300 significantly altered transcripts, respectively; 552 transcripts were found commonly differently expressed. The deregulated transcripts enriched several GO-categories under biological process, cellular component and molecular function as well as multiple molecular networks in Ingenuity Pathway Analysis. A transcriptional profile of 28 key-regulator genes from the molecular networks was generated from the four resistant lines compared to the reference. Finally, immunoblot analysis supported deregulation at the protein level of markers implicated from the transcriptional-profile. Conclusions: Novel markers for prediction of radiation sensitivity could be proposed from bioinformatic processing of gene-expression profiles in HNSCC carcinoma cells.
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| 7. |
- Jerhammar, Fredrik, 1979-
(författare)
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Predictive Markers of Treatment Resistance in Head and Neck Squamous Cell Carcinoma
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Head and neck cancer is a common malignancy with approximately 600 000 new cases yearly. Disappointingly, the overall survival has not increased over the last decades. The concept of personalized medicine, i.e. to treat every patient with an individually planned treatment regime has gathered increased interest, but requires the establishment of novel biomarkers that can predict treatment response.The aim of this thesis is to propose novel predictive single markers or combinations of markers of response to radiation, cisplatin and cetuximab. The general methodology is to evaluate common differences of cell lines resistant to radiation, cisplatin or cetuximab compared to sensitive counterparts.In paper I, we analysed the expression of 14 proteins involved in growth control and/or apoptosis by western blot and related them to intrinsic radiosensitivity (IR) in nine cell lines. No factor had a significant correlation to IR on its own. A combination of EGFR, survivin, Bak, Smad4, and Hsp70 had the best correlation to IR (R=0.886, p=0.001). Additionally, we analysed the presence of p53 mutations in the cell lines. All cell lines had at least one missense, splice site or loss of transcript mutation. To be able to combine protein expression and presence of p53 mutations we created a system designated the number of negative points (NNP). With this system we could extract that expression of EGFR, survivin, and p53 missense or splice site mutations had the best correlation to IR (R=0.990, p<0.001).In paper II we conducted a gene expression microarray analysis of three cell lines, from which common deregulations in two cisplatin resistant cell lines was compared to a cisplatin sensitive cell line. From a bioinformatic approach of gene ontology and molecular network analysis, we defined a transcriptional profile of 20 genes. Finally, key findings were analysed in a larger panel of cell lines, where high MMP-7 expression correlated with higher cisplatin resistance.Paper III compared 4 cell lines with high IR to a radiosensitive equivalent. Using a similar bioinformatic approach as paper II, we established a transcriptional profile of 14 genes. Analysis in a larger panel of cell lines revealed that FN1 expression predicts higher IR.Paper IV establishes the cetuximab sensitivity of 35 cell lines of which 12 were resistant and five were sensitive to cetuximab. After whole genome gene copy number analysis of five cetuximab resistant and five cetuximab sensitive cell lines, and verification of key findings in a larger cell line panel, the results show that the amplification of the YAP1 gene is coupled to cetuximab resistance.In summary, this thesis proposes a number of novel markers of resistance to radiation, cisplatin, and cetuximab which could influence treatment choice in the future, following verifications in primary tumor material.
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| 8. |
- Kohonen, Pekka, et al.
(författare)
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Cancer Biology, Toxicology and Alternative Methods Development Go Hand-in-Hand
- 2014
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 115:1, s. 50-58
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Forskningsöversikt (refereegranskat)abstract
- Toxicological research faces the challenge of integrating knowledge from diverse fields and novel technological developments generally in the biological and medical sciences. We discuss herein the fact that the multiple facets of cancer research, including discovery related to mechanisms, treatment and diagnosis, overlap many up and coming interest areas in toxicology, including the need for improved methods and analysis tools. Common to both disciplines, in vitro and in silico methods serve as alternative investigation routes to animal studies. Knowledge on cancer development helps in understanding the relevance of chemical toxicity studies in cell models, and many bioinformatics-based cancer biomarker discovery tools are also applicable to computational toxicology. Robotics-aided cell-based high throughput screening, microscale immunostaining techniques, and gene expression profiling analyses are common tools in cancer research, and when sequentially combined, form a tiered approach to structured safety evaluation of thousands of environmental agents, novel chemicals or engineered nanomaterials. Comprehensive tumour data collections in databases have been translated into clinically useful data, and this concept serves as template for computer-driven evaluation of toxicity data into meaningful results. Future “cancer research-inspired knowledge management” of toxicological data will aid the translation of basic discovery results and chemicals- and materials-testing data to information relevant to human health and environmental safety.
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| 9. |
- Lampa, Samuel, et al.
(författare)
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RDFIO : extending Semantic MediaWiki for interoperable biomedical data management
- 2017
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Ingår i: Journal of Biomedical Semantics. - : Springer Science and Business Media LLC. - 2041-1480. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Biological sciences are characterised not only by an increasing amount but also the extreme complexity of its data. This stresses the need for efficient ways of integrating these data in a coherent description of biological systems. In many cases, biological data needs organization before integration. This is not seldom a collaborative effort, and it is thus important that tools for data integration support a collaborative way of working. Wiki systems with support for structured semantic data authoring, such as Semantic MediaWiki, provide a powerful solution for collaborative editing of data combined with machine-readability, so that data can be handled in an automated fashion in any downstream analyses. Semantic MediaWiki lacks a built-in data import function though, which hinders efficient round-tripping of data between interoperable Semantic Web formats such as RDF and the internal wiki format.RESULTS: To solve this deficiency, the RDFIO suite of tools is presented, which supports importing of RDF data into Semantic MediaWiki, with metadata needed to export it again in the same RDF format, or ontology. Additionally, the new functionality enables mash-ups of automated data imports combined with manually created data presentations. The application of the suite of tools is demonstrated by importing drug discovery related data about rare diseases from Orphanet and acid dissociation constants from Wikidata. The RDFIO suite of tools is freely available for download via pharmb.io/project/rdfio .CONCLUSIONS: Through a set of biomedical demonstrators, it is demonstrated how the new functionality enables a number of usage scenarios where the interoperability of SMW and the wider Semantic Web is leveraged for biomedical data sets, to create an easy to use and flexible platform for exploring and working with biomedical data.
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| 10. |
- Lampa, Samuel, 1983-
(författare)
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Reproducible Data Analysis in Drug Discovery with Scientific Workflows and the Semantic Web
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The pharmaceutical industry is facing a research and development productivity crisis. At the same time we have access to more biological data than ever from recent advancements in high-throughput experimental methods. One suggested explanation for this apparent paradox has been that a crisis in reproducibility has affected also the reliability of datasets providing the basis for drug development. Advanced computing infrastructures can to some extent aid in this situation but also come with their own challenges, including increased technical debt and opaqueness from the many layers of technology required to perform computations and manage data. In this thesis, a number of approaches and methods for dealing with data and computations in early drug discovery in a reproducible way are developed. This has been done while striving for a high level of simplicity in their implementations, to improve understandability of the research done using them. Based on identified problems with existing tools, two workflow tools have been developed with the aim to make writing complex workflows particularly in predictive modelling more agile and flexible. One of the tools is based on the Luigi workflow framework, while the other is written from scratch in the Go language. We have applied these tools on predictive modelling problems in early drug discovery to create reproducible workflows for building predictive models, including for prediction of off-target binding in drug discovery. We have also developed a set of practical tools for working with linked data in a collaborative way, and publishing large-scale datasets in a semantic, machine-readable format on the web. These tools were applied on demonstrator use cases, and used for publishing large-scale chemical data. It is our hope that the developed tools and approaches will contribute towards practical, reproducible and understandable handling of data and computations in early drug discovery.
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| 11. |
- Martens, Marvin, et al.
(författare)
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ELIXIR and Toxicology : a community in development
- 2021
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Ingår i: F1000 Research. - : F1000 Research Ltd. - 2046-1402. ; 10, s. 1129-1129
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Tidskriftsartikel (refereegranskat)abstract
- Toxicology has been an active research field for many decades, with academic, industrial and government involvement. Modern omics and computational approaches are changing the field, from merely disease-specific observational models into target-specific predictive models. Traditionally, toxicology has strong links with other fields such as biology, chemistry, pharmacology and medicine. With the rise of synthetic and new engineered materials, alongside ongoing prioritisation needs in chemical risk assessment for existing chemicals, early predictive evaluations are becoming of utmost importance to both scientific and regulatory purposes. ELIXIR is an intergovernmental organisation that brings together life science resources from across Europe. To coordinate the linkage of various life science efforts around modern predictive toxicology, the establishment of a new ELIXIR Community is seen as instrumental. In the past few years, joint efforts, building on incidental overlap, have been piloted in the context of ELIXIR. For example, the EU-ToxRisk, diXa, HeCaToS, transQST, and the nanotoxicology community have worked with the ELIXIR TeSS, Bioschemas, and Compute Platforms and activities. In 2018, a core group of interested parties wrote a proposal, outlining a sketch of what this new ELIXIR Toxicology Community would look like. A recent workshop (held September 30th to October 1st, 2020) extended this into an ELIXIR Toxicology roadmap and a shortlist of limited investment-high gain collaborations to give body to this new community. This Whitepaper outlines the results of these efforts and defines our vision of the ELIXIR Toxicology Community and how it complements other ELIXIR activities.
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| 12. |
- Nilsson, Cathrine, 1978-, et al.
(författare)
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Intrinsic differences in cisplatin sensitivity of head and neck cancer celllines correlates to lysosomal pH
- 2010
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Ingår i: Head and Neck. - : John Wiley & Sons. - 1043-3074 .- 1097-0347. ; 32:9, s. 1185-1194
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Tidskriftsartikel (refereegranskat)abstract
- Cisplatin is part of the treatment regime of head and neck squamous cell carcinomas (HNSCC). In order to predict the clinical outcome of the treatment, markers for evaluation of the intrinsic cisplatin sensitivity are inquired. In this study we characterize the lysosomal compartment and compare cisplatin sensitivity in five HNSCC lines and normal oral keratinocytes (NOKs). Cisplatin sensitivity differed 3-fold between the least and most sensitive cell lines, and the cisplatin LD50 correlated significantly to lysosomal pH, which varied from 4.3 in NOKs to 4.9 in the most resistant HNSCC line. Lysosomes are acidified by the V0V1-ATPase complex located in the lysosomal membrane. Interestingly, in cell lines exhibiting high lysosomal pH, we found decreased expression of the V0V1-ATPase B2 subunit, possibly explaining the defective acidification. In all cell lines, exposure to cisplatin caused activation of caspase-3. Cisplatin exposure was accompanied by lysosomal membrane permeabilization and inhibition of the llysosomal cathepsins B, D and L partly prevented cell death. No correlation between cisplatin sensitivity and expression of cathepsins B, D and L or secretion of their respective proforms into the culture medium was found in the cell lines studied. We conclude that lysosomal pH and expression of V0V1-ATPase subunits are possible future markers of intrinsic cisplatin sensitivity.
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| 13. |
- Pournara, Angeliki, et al.
(författare)
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Arsenic alters global histone modifications in lymphocytes in vitro and in vivo
- 2016
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Ingår i: Cell Biology and Toxicology. - : Springer Science and Business Media LLC. - 0742-2091 .- 1573-6822. ; 32:4, s. 275-84
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Forskningsöversikt (refereegranskat)abstract
- Arsenic, an established carcinogen and toxicant, occurs in drinking water and food and affects millions of people worldwide. Arsenic appears to interfere with gene expression through epigenetic processes, such as DNA methylation and post-translational histone modifications. We investigated the effects of arsenic on histone residues in vivo as well as in vitro. Analysis of H3K9Ac and H3K9me3 in CD4+ and CD8+ sorted blood cells from individuals exposed to arsenic through drinking water in the Argentinean Andes showed a significant decrease in global H3K9me3 in CD4+ cells, but not CD8+ cells, with increasing arsenic exposure. In vitro studies of inorganic arsenic-treated T lymphocytes (Jurkat and CCRF-CEM, 0.1, 1, and 100 μg/L) showed arsenic-related modifications of H3K9Ac and changes in the levels of the histone deacetylating enzyme HDAC2 at very low arsenic concentrations. Further, in vitro exposure of kidney HEK293 cells to arsenic (1 and 5 μM) altered the protein levels of PCNA and DNMT1, parts of a gene expression repressor complex, as well as MAML1. MAML1 co-localized and interacted with components of this complex in HEK293 cells, and in silico studies indicated that MAML1 expression correlate with HDAC2 and DNMT1 expression in kidney cells. In conclusion, our data suggest that arsenic exposure may lead to changes in the global levels of H3K9me3 and H3K9Ac in lymphocytes. Also, we show that arsenic exposure affects the expression of PCNA and DNMT1—proteins that are part of a gene expression silencing complex.
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| 14. |
- 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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| 15. |
- Spjuth, Ola, 1977-, et al.
(författare)
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A novel infrastructure for chemical safety predictions with focus on human health
- 2012
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Ingår i: Toxicology Letters. - : Elsevier BV. - 0378-4274 .- 1879-3169. ; 211:Supplm, s. S59-
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Tidskriftsartikel (refereegranskat)abstract
- A major objective of Computational Toxicology is to provide reliable and useful estimates in silico of (potentially) harmful actions of chemicals in humans. Predictive models are commonly based on in vitro and in vivo data, and aims at supporting risk assessment in various areas, including the environmental protection, food, and pharmaceutical sectors. The field is however hampered by the lack of standards, access to high quality data, validated predictive models, as well as means to connect toxicity data to genomics data.We present a framework and roadmap for a novel public infrastructure for predictive computational toxicology and chemical safety assessment, consisting of: (1) a repository capable of aggregating high quality toxicity data with gene expression data, (2) a repository where scientists can share and download predictive models for chemical safety, and (3) a user-friendly platform which makes the services and resources accessible for the scientific community. Databases under the framework will adhere to open standards and use standardized open exchange formats in order to interoperate with emerging international initiatives, such as the FP7-funded OpenTox and ToxBank projects.The infrastructure will strengthen and facilitate already ongoing activities within in silico toxicology, open up new possibilities for incorporating genomics data in chemicals safety modeling (toxicogenomics), as well as deepen the exploitation of signal transduction networks. The initiative will lay the foundation needed to boost decision support in risk assessment in a wide range of fields, including drug discovery, food safety, as well as agricultural and ecological safety assessment.
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| 16. |
- 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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| 17. |
- 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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| 18. |
- Willighagen, Egon, et al.
(författare)
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Computational toxicology using OpenTox & Bioclipse
- 2012
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Ingår i: Toxicology Letters. - : Elsevier BV. - 0378-4274 .- 1879-3169. ; 211, s. S60-S60
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Computational methods, e.g., OECD QSAR Toolbox and ToxPredict, are increasingly used to support chemicals toxicity assessment in academic settings, industry and governments. The in silico-based assessments complement experimental approaches and have potential to fill the knowledge gaps needed to broadly assess chemical hazards. We present here the interoperable Bioclipse–OpenTox platform as a novel alternative made freely and openly available.The interactive Bioclipse software is combined with remote computational toxicity prediction provided by services in the OpenTox network from various European institutes and SMEs. These online services apply machine learning methods for integration of a number of end points, e.g., Ames mutagenicity test in salmonella, Caco-2 cell model permeability and micronucleus assay in rodents. Coupling of such data to chemical structure assessments lead to prediction of site(s) for metabolism (using SMARTCyp), biodegradation (START), and toxicity mode prediction (Verhaar scheme). The OpenTox platform thus unifies how the services are accessed whereas the Bioclipse software provides the easy-to-use interface for interactively studying the toxic part of molecules. Additional predictive methods that are made accessible via the OpenTox network are automatically discovered by Bioclipse and models can be improved over time without any need to reinstall Bioclipse itself.
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| 19. |
- Willighagen, Egon, et al.
(författare)
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Computational toxicology using the OpenTox application programming interface and Bioclipse
- 2011
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Ingår i: BMC Research Notes. - : Springer Science and Business Media LLC. - 1756-0500. ; 4:1, s. 487-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Toxicity is a complex phenomenon involving the potential adverse effect on a range of biological functions. Predicting toxicity involves using a combination of experimental data (endpoints) and computational methods to generate a set of predictive models. Such models rely strongly on being able to integrate information from many sources. The required integration of biological and chemical information sources requires, however, a common language to express our knowledge ontologically, and interoperating services to build reliable predictive toxicology applications. Findings: This article describes progress in extending the integrative bio- and cheminformatics platform Bioclipse to interoperate with OpenTox, a semantic web framework which supports open data exchange and toxicology model building. The Bioclipse workbench environment enables functionality from OpenTox web services and easy access to OpenTox resources for evaluating toxicity properties of query molecules. Relevant cases and interfaces based on ten neurotoxins are described to demonstrate the capabilities provided to the user. The integration takes advantage of semantic web technologies, thereby providing an open and simplifying communication standard. Additionally, the use of ontologies ensures proper interoperation and reliable integration of toxicity information from both experimental and computational sources. Conclusions: A novel computational toxicity assessment platform was generated from integration of two open science platforms related to toxicology: Bioclipse, that combines a rich scriptable and graphical workbench environment for integration of diverse sets of information sources, and OpenTox, a platform for interoperable toxicology data and computational services. The combination provides improved reliability and operability for handling large data sets by the use of the Open Standards from the OpenTox Application Programming Interface. This enables simultaneous access to a variety of distributed predictive toxicology databases, and algorithm and model resources, taking advantage of the Bioclipse workbench handling the technical layers.
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