Digitala Vetenskapliga Arkivet

Change search
Refine search result
1 - 15 of 15
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Asgard, Rikard
    et al.
    Uppsala Univ, Dept Pharmaceut Biosci., Uppsala, Sweden.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Golkar, Siv Osterman
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hellman, Bjorn
    Uppsala Univ, Dept Pharmaceut Biosci., Uppsala, Sweden.
    Czene, Stefan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Evidence for different mechanisms of action behind the mutagenic effects of 4-NOPD and OPD: the role of DNA damage, oxidative stress and an imbalanced nucleotide pool2013In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 28, no 6, p. 637-644Article in journal (Refereed)
    Abstract [en]

    The mutagenicity of 4-nitro-o-phenylenediamine (4-NOPD) and o-phenylenediamine (OPD) was compared using the Mouse Lymphoma Assay (MLA) with or without metabolic activation (S9). As expected, OPD was found to be a more potent mutagen than 4-NOPD. To evaluate possible mechanisms behind their mutagenic effects, the following end points were also monitored in cells that had been exposed to similar concentrations of the compounds as in the MLA: general DNA damage (using a standard protocol for the Comet assay); oxidative DNA damage (using a modified procedure for the Comet assay in combination with the enzyme hOGG1); reactive oxygen species (ROS; using the CM-H(2)DCFDA assay); and the balance of the nucleotide pool (measured after conversion to the corresponding nucleosides dC, dT, dG and dA using high-performance liquid chromatography). Both compounds increased the level of general DNA damage. Again, OPD was found to be more potent than 4-NOPD (which only increased the level of general DNA damage in the presence of S9). Although less obvious for OPD, both compounds increased the level of oxidative DNA damage. However, an increase in intracellular ROS was only observed in cells exposed to 4-NOPD, both with and without S9 (which in itself induced oxidative stress). Both compounds decreased the concentrations of dA, dT and dC. A striking effect of OPD was the sharp reduction of dA observed already at very low concentration, both with and without S9 (which in itself affected the precursor pool). Taken together, our results indicate that indirect effects on DNA, possibly related to an unbalanced nucleotide pool, mediate the mutagenicity and DNA-damaging effects of 4-NOPD and OPD to a large extent. Although induction of intracellular oxidative stress seems to be a possible mechanism behind the genotoxicity of 4-NOPD, this pathway seems to be of less importance for the more potent mutagen OPD.

  • 2. Assi, Nada
    et al.
    Fages, Anne
    Vineis, Paolo
    Chadeau-Hyam, Marc
    Stepien, Magdalena
    Duarte-Salles, Talita
    Byrnes, Graham
    Boumaza, Houda
    Knueppel, Sven
    Kuehn, Tilman
    Palli, Domenico
    Bamia, Christina
    Boshuizen, Hendriek
    Bonet, Catalina
    Overvad, Kim
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Travis, Ruth
    Gunter, Marc J.
    Lund, Eiliv
    Dossus, Laure
    Elena-Herrmann, Benedicte
    Riboli, Elio
    Jenab, Mazda
    Viallon, Vivian
    Ferrari, Pietro
    A statistical framework to model the meeting-in-the-middle principle using metabolomic data: application to hepatocellular carcinoma in the EPIC study2015In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 30, no 6, p. 743-753Article in journal (Refereed)
    Abstract [en]

    Metabolomics is a potentially powerful tool for identification of biomarkers associated with lifestyle exposures and risk of various diseases. This is the rationale of the 'meeting-in-the-middle' concept, for which an analytical framework was developed in this study. In a nested case-control study on hepatocellular carcinoma (HCC) within the European Prospective Investigation into Cancer and nutrition (EPIC), serum H-1 nuclear magnetic resonance (NMR) spectra (800 MHz) were acquired for 114 cases and 222 matched controls. Through partial least square (PLS) analysis, 21 lifestyle variables (the 'predictors', including information on diet, anthropometry and clinical characteristics) were linked to a set of 285 metabolic variables (the 'responses'). The three resulting scores were related to HCC risk by means of conditional logistic regressions. The first PLS factor was not associated with HCC risk. The second PLS metabolomic factor was positively associated with tyrosine and glucose, and was related to a significantly increased HCC risk with OR = 1.11 (95% CI: 1.02, 1.22, P = 0.02) for a 1SD change in the responses score, and a similar association was found for the corresponding lifestyle component of the factor. The third PLS lifestyle factor was associated with lifetime alcohol consumption, hepatitis and smoking, and had negative loadings on vegetables intake. Its metabolomic counterpart displayed positive loadings on ethanol, glutamate and phenylalanine. These factors were positively and statistically significantly associated with HCC risk, with 1.37 (1.05, 1.79, P = 0.02) and 1.22 (1.04, 1.44, P = 0.01), respectively. Evidence of mediation was found in both the second and third PLS factors, where the metabolomic signals mediated the relation between the lifestyle component and HCC outcome. This study devised a way to bridge lifestyle variables to HCC risk through NMR metabolomics data. This implementation of the 'meeting-in-the-middle' approach finds natural applications in settings characterised by high-dimensional data, increasingly frequent in the omics generation.

  • 3. Di Bucchianico, S.
    et al.
    Cappellini, F.
    Le Bihanic, F.
    Zhang, Yuning
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.
    Dreij, K.
    Karlsson, H. L.
    Genotoxicity of TiO2 nanoparticles assessed by mini-gel comet assay and micronucleus scoring with flow cytometry2017In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 32, no 1, p. 127-137Article in journal (Refereed)
    Abstract [en]

    The widespread production and use of nanoparticles calls for faster and more reliable methods to assess their safety. The main aim of this study was to investigate the genotoxicity of three reference TiO2 nanomaterials (NM) within the frame of the FP7-NANoREG project, with a particular focus on testing the applicability of mini-gel comet assay and micronucleus (MN) scoring by flow cytometry. BEAS-2B cells cultured under serum-free conditions were exposed to NM100 (anatase, 50-150 nm), NM101 (anatase, 5-8 nm) and NM103 (rutile, 20-28 nm) for 3, 24 or 48 h mainly at concentrations 1-30 μg/ml. In the mini-gel comet assay (eight gels per slide), we included analysis of (i) DNA strand breaks, (ii) oxidised bases (Fpg-sensitive sites) and (iii) light-induced DNA damage due to photocatalytic activity. Furthermore, MN assays were used and we compared the results of more high-throughput MN scoring with flow cytometry to that of cytokinesis-block MN cytome assay scored manually using a microscope. Various methods were used to assess cytotoxic effects and the results showed in general no or low effects at the doses tested. A weak genotoxic effect of the tested TiO2 materials was observed with an induction of oxidised bases for all three materials of which NM100 was the most potent. When the comet slides were briefly exposed to lab light, a clear induction of DNA strand breaks was observed for the anatase materials, but not for the rutile. This highlights the risk of false positives when testing photocatalytically active materials if light is not properly avoided. A slight increase in MN formation for NM103 was observed in the different MN assays at the lower doses tested (1 and 5 μg/ml). We conclude that mini-gel comet assay and MN scoring using flow cytometry successfully can be used to efficiently study cytotoxic and genotoxic properties of nanoparticles.

  • 4.
    Golkar, Siv Österman
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Czene, Stefan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. AstraZeneca R&D, Safety Assessment, Dept Genet Toxicol, AstraZeneca, Södertälje, Sweden.
    Gokarakonda, Amulya
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Intracellular deoxyribonucleotide pool imbalance and DNA damage in cells treated with hydroxyurea, an inhibitor of ribonucleotide reductase2013In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 28, no 6, p. 653-660Article in journal (Refereed)
    Abstract [en]

    Imbalance in the nucleotide pool of mammalian cells has been shown to result in genotoxic damage. The goal of this study was to devise a sensitive, reproducible and simple method for detection of nucleotide pool changes in mammalian cells that could be used for problem-solving activities in drug development, e.g. mechanistic explanation of a positive response in a mammalian in vitro genotoxicity test. The method evaluated in this study is based on ethanol extraction of the total nucleotide pool, heat treatment and filtration, treatment with calf intestine alkaline phosphatase to convert nucleotides to nucleosides and analysis of the nucleosides by high-performance liquid chromatography with ultraviolet detection. The method was applied to measure the intracellular levels of deoxyribonucleotides in mouse lymphoma (ML) L5178Y cells treated with various concentrations of a model compound, hydroxyurea (HU), a ribonucleotide reductase inhibitor. DNA strand breakage and micronuclei formation were assessed in the same experiments. Imbalance of nucleotide pool (i.e. changes in the relative ratios between individual nucleotide pools) in HU-treated ML cells has been observed already at a concentration of 0.01 mmol/l, whereas genotoxic effects became apparent only at higher concentrations of HU (i.e. 0.25 mmol/l and higher) as indicated by formation of DNA strand breaks and micronuclei.

  • 5. Honma, Masamitsu
    et al.
    Kitazawa, Airi
    Cayley, Alex
    Williams, Richard V.
    Barber, Chris
    Hanser, Thierry
    Saiakhov, Roustem
    Chakravarti, Suman
    Myatt, Glenn J.
    Cross, Kevin P.
    Benfenati, Emilio
    Raitano, Giuseppa
    Mekenyan, Ovanes
    Petkov, Petko
    Bossa, Cecilia
    Benigni, Romualdo
    Battistelli, Chiara Laura
    Giuliani, Alessandro
    Tcheremenskaia, Olga
    DeMeo, Christine
    Norinder, Ulf
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Swetox, Karolinska Institutet, Sweden.
    Koga, Hiromi
    Jose, Ciloy
    Jeliazkova, Nina
    Kochev, Nikolay
    Paskaleva, Vesselina
    Yang, Chihae
    Daga, Pankaj R.
    Clark, Robert D.
    Rathman, James
    Improvement of quantitative structure-activity relationship (QSAR) tools for predicting Ames mutagenicity: outcomes of the Ames/QSAR International Challenge Project2019In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 34, no 1, p. 3-16Article in journal (Refereed)
    Abstract [en]

    The International Conference on Harmonization (ICH) M7 guideline allows the use of in silico approaches for predicting Ames mutagenicity for the initial assessment of impurities in pharmaceuticals. This is the first international guideline that addresses the use of quantitative structure-activity relationship (QSAR) models in lieu of actual toxicological studies for human health assessment. Therefore, QSAR models for Ames mutagenicity now require higher predictive power for identifying mutagenic chemicals. To increase the predictive power of QSAR models, larger experimental datasets from reliable sources are required. The Division of Genetics and Mutagenesis, National Institute of Health Sciences (DGM/NIHS) of Japan recently established a unique proprietary Ames mutagenicity database containing 12140 new chemicals that have not been previously used for developing QSAR models. The DGM/NIHS provided this Ames database to QSAR vendors to validate and improve their QSAR tools. The Ames/QSAR International Challenge Project was initiated in 2014 with 12 QSAR vendors testing 17 QSAR tools against these compounds in three phases. We now present the final results. All tools were considerably improved by participation in this project. Most tools achieved >50% sensitivity (positive prediction among all Ames positives) and predictive power (accuracy) was as high as 80%, almost equivalent to the inter-laboratory reproducibility of Ames tests. To further increase the predictive power of QSAR tools, accumulation of additional Ames test data is required as well as re-evaluation of some previous Ames test results. Indeed, some Ames-positive or Ames-negative chemicals may have previously been incorrectly classified because of methodological weakness, resulting in false-positive or false-negative predictions by QSAR tools. These incorrect data hamper prediction and are a source of noise in the development of QSAR models. It is thus essential to establish a large benchmark database consisting only of well-validated Ames test results to build more accurate QSAR models.

  • 6.
    Honma, Masamitsu
    et al.
    Division of Genetics and Mutagenesis, National Institute of Health Sciences, Kawasaki Ku, Japan.
    Kitazawa, Airi
    Division of Genetics and Mutagenesis, National Institute of Health Sciences, Kawasaki Ku, Japan.
    Cayley, Alex
    Lhasa Limited, Leeds, England.
    Williams, Richard V.
    Lhasa Limited, Leeds, England.
    Barber, Chris
    Lhasa Limited, Leeds, England.
    Hanser, Thierry
    Lhasa Limited, Leeds, England.
    Saiakhov, Roustem
    MultiCASE Inc., Beachwood, USA.
    Chakravarti, Suman
    MultiCASE Inc., Beachwood, USA.
    Myatt, Glenn J.
    Leadscope Inc., Columbus, USA.
    Cross, Kevin P.
    Leadscope Inc., Columbus, USA.
    Benfenati, Emilio
    Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy.
    Raitano, Giuseppa
    Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy.
    Mekenyan, Ovanes
    Laboratory of Mathematical Chemistry, As Zlatarov University, Bourgas, Bulgaria.
    Petkov, Petko
    Laboratory of Mathematical Chemistry, As Zlatarov University, Bourgas, Bulgaria.
    Bossa, Cecilia
    Istituto Superiore di Sanita', Rome, Italy.
    Benigni, Romualdo
    Istituto Superiore di Sanita', Rome, Italy; Alpha-Pretox, Rome, Italy.
    Battistelli, Chiara Laura
    Istituto Superiore di Sanita', Rome, Italy.
    Giuliani, Alessandro
    Istituto Superiore di Sanita', Rome, Italy.
    Tcheremenskaia, Olga
    Istituto Superiore di Sanita', Rome, Italy.
    DeMeo, Christine
    Prous Institute, Barcelona, Spain.
    Norinder, Ulf
    Unit of Toxicology Sciences, Karolinska Institute, Södertälje, Sweden; Department of Computer and Systems Sciences, Stockholm University, Kista, Sweden.
    Koga, Hiromi
    Fujitsu Kyushu Systems Limited, Fukuoka, Japan.
    Jose, Ciloy
    Fujitsu Kyushu Systems Limited, Fukuoka, Japan.
    Jeliazkova, Nina
    IdeaConsult Ltd., Sofia, Bulgaria.
    Kochev, Nikolay
    IdeaConsult Ltd., Sofia, Bulgaria; Department of Analytical Chemistry and Computer Chemistry, University of Plovdiv, Plovdiv, Bulgaria.
    Paskaleva, Vesselina
    Department of Analytical Chemistry and Computer Chemistry, University of Plovdiv, Plovdiv, Bulgaria.
    Yang, Chihae
    Molecular Networks GmbH, Nürnberg, Germany; Altamira LLC, Columbus, USA.
    Daga, Pankaj R.
    Simulations Plus Inc., Lancaster, USA.
    Clark, Robert D.
    Simulations Plus Inc., Lancaster, USA.
    Rathman, James
    Molecular Networks GmbH, Nürnberg, Germany; Altamira LLC, Columbus, USA; Ohio State University, Columbus, USA.
    Improvement of quantitative structure-activity relationship (QSAR) tools for predicting Ames mutagenicity: outcomes of the Ames/QSAR International Challenge Project2019In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 34, no 1, p. 3-16Article in journal (Refereed)
    Abstract [en]

    The International Conference on Harmonization (ICH) M7 guideline allows the use of in silicoapproaches for predicting Ames mutagenicity for the initial assessment of impurities in pharmaceuticals. This is the first international guideline that addresses the use of quantitative structure–activity relationship (QSAR) models in lieu of actual toxicological studies for human health assessment. Therefore, QSAR models for Ames mutagenicity now require higher predictive power for identifying mutagenic chemicals. To increase the predictive power of QSAR models, larger experimental datasets from reliable sources are required. The Division of Genetics and Mutagenesis,National Institute of Health Sciences (DGM/NIHS) of Japan recently established a unique proprietary Ames mutagenicity database containing 12140 new chemicals that have not been previously used for developing QSAR models. The DGM/NIHS provided this Ames database to QSAR vendors to validate and improve their QSAR tools. The Ames/QSAR International Challenge Project was initiated in 2014 with 12 QSAR vendors testing 17 QSAR tools against these compounds in three phases. We now present the final results. All tools were considerably improved by participation in this project. Most tools achieved >50% sensitivity (positive prediction among all Ames positives) and predictive power (accuracy) was as high as 80%, almost equivalent to the inter-laboratory reproducibility of Ames tests. To further increase the predictive power of QSAR tools, accumulation of additional Ames test data is required as well as re-evaluation of some previous Ames test results. Indeed, some Ames-positive or Ames-negative chemicals may have previously been incorrectly classified because of methodological weakness, resulting in false-positive or false-negative predictions by QSAR tools. These incorrect data hamper prediction and are a source of noise in the development of QSAR models. It is thus essential to establish a large benchmark database consisting only of well-validated Ames test results to build more accurate QSAR models.

  • 7.
    Lebedova, Jana
    et al.
    Karolinska Inst, Inst Environm Med, Nobels Vag 13, S-17177 Stockholm, Sweden.;Masaryk Univ, RECETOX, Kamenice 753-5,Pavilon A29, CZ-62500 Brno, Czech Republic..
    Hedberg, Yolanda
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Surface and Corrosion Science.
    Odnevall Wallinder, Inger
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Surface and Corrosion Science.
    Karlsson, Hanna L.
    Karolinska Inst, Inst Environm Med, Nobels Vag 13, S-17177 Stockholm, Sweden..
    Size-dependent genotoxicity of silver, gold and platinum nanoparticles studied using the mini-gel comet assay and micronucleus scoring with flow cytometry2018In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 33, no 1, p. 77-85Article in journal (Refereed)
    Abstract [en]

    Metallic nanoparticles (NPs) are promising nanomaterials used in different technological solutions as well as in consumer products. Silver (Ag), gold (Au) and platinum (Pt) represent three metallic NPs with current or suggested use in different applications. Pt is also used as vehicle exhaust catalyst leading to a possible exposure via inhalation. Despite their use, there is limited data on their genotoxic potential and possible size-dependent effects, particularly for Pt NPs. The aim of this study was to explore size-dependent genotoxicity of these NPs (5 and 50 nm) following exposure of human bronchial epithelial cells. We characterised the NPs and assessed the viability (Alamar blue assay), formation of DNA strand breaks (mini-gel comet assay) and induction of micronucleus (MN) analysed using flow cytometry (in vitro microflow kit). The results confirmed the primary size (5 and 50 nm) but showed agglomeration of all NPs in the serum free medium used. Slight reduced cell viability (tested up to 50 mu g/ml) was observed following exposure to the Ag NPs of both particle sizes as well as to the smallest (5 nm) Au NPs. Similarly, at non-cytotoxic concentrations, both 5 and 50 nm-sized Ag NPs, as well as 5 nm-sized Au NPs, increased DNA strand breaks whereas for Pt NPs only the 50 nm size caused a slight increase in DNA damage. No clear induction of MN was observed in any of the doses tested (up to 20 mu g/ml). Taken together, by using the comet assay our study shows DNA strand breaks induced by Ag NPs, without any obvious differences in size, whereas effects from Au and Pt NPs were size-dependent in the sense that the 5 nm-sized Au NPs and 50 nm-sized Pt NPs particles were active. No clear induction of MN was observed for the NPs.

  • 8.
    Norinder, Ulf
    et al.
    Swetox, Unit of Toxicology Sciences, Karolinska Institute, Södertälje, Sweden; Department of Computer and Systems Sciences, Stockholm University, Kista, Sweden.
    Ahlberg, Ernst
    AstraZeneca R&D Gothenburg, Mölndal, Sweden.
    Carlsson, Lars
    Computer Learning Research Centre, University of London Egham, Surrey, England.
    Predicting Ames Mutagenicity Using Conformal Prediction in the Ames/QSAR International Challenge Project2019In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 34, no 1, p. 33-40Article in journal (Refereed)
    Abstract [en]

    Valid and predictive models for classifying Ames mutagenicity have been developed using conformal prediction. The models are Random Forest models using signature molecular descriptors. The investigation indicates, on excluding not-strongly mutagenic compounds (class B), that the validity for mutagenic compounds is increased for the predictions based on both public and the Division of Genetics and Mutagenesis, National Institute of Health Sciences of Japan (DGM/NIHS) data while less so when using only the latter data source. The former models only result in valid predictions for the majority, non-mutagenic, class whereas the latter models are valid for both classes, i.e. mutagenic and non-mutagenic compounds. These results demonstrate the importance of data consistency manifested through the superior predictive quality and validity of the models based only on DGM/NIHS generated data compared to a combination of this data with public data sources.

  • 9.
    Norinder, Ulf
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Swetox, Karolinska Institutet, Sweden.
    Ahlberg, Ernst
    Carlsson, Lars
    Predicting Ames Mutagenicity Using Conformal Prediction in the Ames/QSAR International Challenge Project2019In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 34, no 1, p. 33-40Article in journal (Refereed)
    Abstract [en]

    Valid and predictive models for classifying Ames mutagenicity have been developed using conformal prediction. The models are Random Forest models using signature molecular descriptors. The investigation indicates, on excluding not-strongly mutagenic compounds (class B), that the validity for mutagenic compounds is increased for the predictions based on both public and the Division of Genetics and Mutagenesis, National Institute of Health Sciences of Japan (DGM/NIHS) data while less so when using only the latter data source. The former models only result in valid predictions for the majority, non-mutagenic, class whereas the latter models are valid for both classes, i.e. mutagenic and non-mutagenic compounds. These results demonstrate the importance of data consistency manifested through the superior predictive quality and validity of the models based only on DGM/NIHS generated data compared to a combination of this data with public data sources.

  • 10.
    Savolainen, Linda
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Cassel, Tobias
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    The XPD subunit of TFIIH is required for transcription-associated but not DNA double-strand break-induced recombination in mammalian cells2010In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 25, no 6, p. 623-629Article in journal (Other academic)
    Abstract [en]

    Mutations in the XPD gene can give rise to three phenotypically distinct disorders: xeroderma pigmentosum (XP),  trichothiodystrophy (TTD) or combined XP and Cockayne syndrome (CS) (XP/CS). The role of XPD in nucleotide excision repair explains the increased risk of skin cancer in XP patients, but not all the clinical phenotypes found in XP/CS or TTD patients. Here, we describe that the XPD defective UV5 cell line is impaired in transcription-associated recombination (TAR), which can be reverted by the introduction of the wild type XPD gene expressed from a vector. UV5 cells are defective in TAR, despite having intact transcription and homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Interestingly, we find reduced spontaneous HR in XPD defective cells, suggesting that transcription underlie a portion of spontaneous HR events. We also report that transcription-coupled repair (TCR) defective CSB cells, have a defect in TAR, but not in DSB-induced HR. However, the TAR defect may be associated with a general transcription defect in CSB deficient cells.  In conclusion, we show a novel role for the XPD protein in TAR, linking TAR with TCR.

  • 11.
    Shakeri Manesh, Sara
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sangsuwan, Traimate
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Pour Khavari, Ali
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Fotouhi, Asal
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Emami, S. Noushin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    MTH1, an 8-oxo-2'-deoxyguanosine triphosphatase, and MYH, a DNA glycosylase, cooperate to inhibit mutations induced by chronic exposure to oxidative stress of ionising radiation2017In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 32, no 3, p. 389-396Article in journal (Refereed)
    Abstract [en]

    Our previous results showed that in addition to the immediate interaction of ionising radiation with DNA (direct and indirect effect), low-dose and chronic low-dose rate of irradiation induce endogenous oxidative stress. During oxidative stress, free radicals react with DNA, nucleoside triphosphates (dNTPs), proteins and lipids, and modify their structures. The MYH and MTH1 genes play important roles in preventing mutations induced by 8-hydroxy-guanine, which is an oxidised product of guanine. In this study, we used short-hairpin RNA to permanently knockdown MYH and MTH1 proteins in human lymphoblastoid TK6 cells. Knockdown and wild-type cells were chronically exposed to low dose rates of gamma-radiation (between 1.4 and 30 mGy/h). The cells were also subjected to acute doses delivered at a high-dose rate. Growth rate, extracellular 8-hydroxy-2'-deoxyguanosine, clonogenic cell survival and mutant frequencies were analysed in all cell types. A reduced level of cell growth and survival as well as increased mutant frequencies were observed in cells lacking both MYH and MTH1 proteins as compared to cells lacking only MYH and wild-type cells. To sum up, our results suggest that low-dose rates elevate oxidative stress. MTH1 together with MYH plays an important role in protection against mutations induced by modified dNTPs during chronic oxidative stress. In addition, we found no dose-rate effect at the level of mutations in the wild-type TK6 and MYH-KD cells. Our data interestingly indicate a dose-rate threshold for mutation induction in MTH1/MYH double knockdown cells.

  • 12. Shaposhnikov, Sergey
    et al.
    Larsson, Chatarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Henriksson, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Collins, Andrew
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Detection of Alu sequences and mtDNA in comets using padlock probes2006In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 21, no 4, p. 243-247Article in journal (Refereed)
    Abstract [en]

    Single cell gel electrophoresis, or the comet assay, is widely used to measure DNA damage and repair. However, the behaviour of the DNA under the conditions used for the comet assay is not fully understood. In developing a method for studying specific gene sequences within comets, using 'padlock probes' (circularizable oligonucleotide probes), we have first applied probes that hybridize to Alu repetitive elements and to mitochondrial DNA (mtDNA). During the sequence of stages in the comet assay, mtDNA progressively disperses into the surrounding agarose gel, showing no tendency to remain with nuclear DNA in the comets. In contrast, Alu probes remain associated with both tail and head DNA.

  • 13. Xun, Wei Wei
    et al.
    Brennan, Paul
    Tjonneland, Anne
    Vogel, Ulla
    Overvad, Kim
    Kaaks, Rudolf
    Canzian, Federico
    Boeing, Heiner
    Trichopoulou, Antonia
    Oustoglou, Erifili
    Giotaki, Zoi
    Johansson, Mattias
    Palli, Domenico
    Agnoli, Claudia
    Tumino, Rosario
    Sacerdote, Carlotta
    Panico, Salvatore
    Bueno-de-Mesquita, H Bas
    Peeters, Petra H M
    Lund, Eiliv
    Kumle, Merethe
    Rodríguez, Laudina
    Agudo, Antonio
    Sánchez, Maria-José
    Arriola, Larraitz
    Chirlaque, María-Dolores
    Barricarte, Aurelio
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Rasmuson, Torgny
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Khaw, Kay-Tee
    Wareham, Nicholas
    Key, Tim
    Riboli, Elio
    Vineis, Paolo
    Single-nucleotide polymorphisms (5p15.33, 15q25.1, 6p22.1, 6q27 and 7p15.3) and lung cancer survival in the European Prospective Investigation into Cancer and Nutrition (EPIC).2011In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 26, no 5, p. 657-666Article in journal (Refereed)
    Abstract [en]

    The single-nucleotide polymorphisms (SNPs) rs402710 (5p15.33), rs16969968 and rs8034191 (15q25.1) have been consistently identified by genome-wide association studies (GWAS) as significant predictors of lung cancer risk, while rs4324798 (6p22.1) was previously found to influence survival time in small-cell lung cancer (SCLC) patients. Using the same population of one of the original GWAS, we investigated whether the selected SNPs and 31 others (also identified in GWAS) influence survival time, assuming an additive model. The effect of each polymorphism on all cause survival was estimated in 1094 lung cancer patients, and lung cancer-specific survival in 763 patients, using Cox regression adjusted for a priori confounders and competing causes of death where appropriate. Overall, after 1558 person-years of post-diagnostic follow-up, 874 deaths occurred from all causes, including 690 from lung cancer. In the lung cancer-specific survival analysis (1102 person-years), only rs7452888 (6q27) and rs2710994 (7p15.3) modified survival, with adjusted hazard ratios of 1.19 (P = 0.009) and 1.32 (P = 0.011) respectively, taking competing risks into account. Some weak associations were identified in subgroup analysis for rs16969968 and rs8034191 (15q25.1) and rs4324798 (6p22.1) and survival in never-smokers, as well as for rs402710 in current smokers and SCLC patients. In conclusion, rs402710 (5p15.33), rs16969968 and rs8034191 (both 15q25.1) and rs4324798 (6p22.1) were found to be unrelated to survival times in this large cohort of lung cancer patients, regardless of whether the cause of death was from lung cancer or not. However, rs7452888 (6q27) was identified as a possible candidate SNP to influence lung cancer survival, while stratified analysis hinted at a possible role for rs8034191, rs16969968 (15q25.1) and rs4324798 (6p22.1) in influencing survival time in lung cancer patients who were never-smokers, based on a small sample.

  • 14.
    Åsgård, Rikard
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Haghdoost, Siamak
    Stockholm University.
    Osterman Golkar, Siv
    Stockholm University.
    Hellman, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Czene, Stefan
    Stockholm University.
    Evidence for different mechanisms of action behind the mutagenic effects of 4-NOPD and OPD: the role of DNA damage, oxidative stress and an imbalanced nucleotide pool2013In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 28, no 6, p. 637-644Article in journal (Refereed)
    Abstract [en]

    The mutagenicity of 4-nitro-o-phenylenediamine (4-NOPD) and o-phenylenediamine (OPD) was compared using the Mouse Lymphoma Assay (MLA) with or without metabolic activation (S9). As expected, OPD was found to be a more potent mutagen than 4-NOPD. To evaluate possible mechanisms behind their mutagenic effects, the following end points were also monitored in cells that had been exposed to similar concentrations of the compounds as in the MLA: general DNA damage (using a standard protocol for the Comet assay); oxidative DNA damage (using a modified procedure for the Comet assay in combination with the enzyme hOGG1); reactive oxygen species (ROS; using the CM-H(2)DCFDA assay); and the balance of the nucleotide pool (measured after conversion to the corresponding nucleosides dC, dT, dG and dA using high-performance liquid chromatography). Both compounds increased the level of general DNA damage. Again, OPD was found to be more potent than 4-NOPD (which only increased the level of general DNA damage in the presence of S9). Although less obvious for OPD, both compounds increased the level of oxidative DNA damage. However, an increase in intracellular ROS was only observed in cells exposed to 4-NOPD, both with and without S9 (which in itself induced oxidative stress). Both compounds decreased the concentrations of dA, dT and dC. A striking effect of OPD was the sharp reduction of dA observed already at very low concentration, both with and without S9 (which in itself affected the precursor pool). Taken together, our results indicate that indirect effects on DNA, possibly related to an unbalanced nucleotide pool, mediate the mutagenicity and DNA-damaging effects of 4-NOPD and OPD to a large extent. Although induction of intracellular oxidative stress seems to be a possible mechanism behind the genotoxicity of 4-NOPD, this pathway seems to be of less importance for the more potent mutagen OPD.

  • 15. Önfelt, Björn
    et al.
    Gostring, L.
    Lincoln, P.
    Norden, B.
    Onfelt, A.
    Cell studies of the DNA bis-intercalator Delta-Delta mu-C4(cpdppz)(2)-(phen)(4)Ru-2 (4+): toxic effects and properties as a light emitting DNA probe in V79 Chinese hamster cells2002In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 17, no 4, p. 317-320Article in journal (Refereed)
    Abstract [en]

    Coordination complexes of type [Ru(L)(3)](2+), where L is a nitrogen-containing aromatic bidentate ligand, can often be photolytically reduced, making them useful in studies of DNA- or protein-mediated electron transfer and in artifical photosynthesis model systems. Upon binding to DNA some Ru(L) complexes have been found to display strongly increased fluorescence compared with when free in solution, making those compounds interesting to test as DNA probes. Thus, they are becoming widely used in the chemistry community. Here, asynchronous cultures of V79 Chinese hamster cells were exposed to the DNA bis-intercalator DeltaDelta-DeltaDelta [mu-C4(cpdppz)(2)-(phen)(4)Ru-2](4+) at 10(-10)-10(-4) M. The extraordinarily strong binding of the compound to DNA was the reason for testing its possible interference with DNA metabolism in intact mammalian cells. Exposure for 1 h to 10(-10)-10(-4) M did not significantly decrease DNA synthesis. Cells exposed to 10(-5) M for 27 h showed no staining of the nucleus, while DNA was stained in cells electroporated in the presence of the compound. However, the Ru dimer was probably taken up by pinocytosis, because numerous minute precipitates could be observed in the cytoplasm. Treatment for 24 h at concentrations of 10(-10)-10(-5) M did not inhibit growth, as indicated by cell density and mitotic activity. Neither did it affect chromosomal arrangements during mitosis. However, at 10(-4) M the density of cultures was reduced by similar to45% and apoptotic cells were frequent, as opposed to mitoses. We also investigated the properties of the Ru dimer as a fluorescent DNA stain. The compound appears attractive as a red DNA stain when broad excitation in the visible range is desirable and extremely low background staining is essential. The low toxicity of the compound is a favourable trait in this context.

1 - 15 of 15
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf