| 1. |
- Abramsson-Zetterberg, Lilianne, et al.
(author)
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The impact of folate status and folic acid supplementation on the micronucleus frequency in human erythrocytes
- 2006
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In: Mutation Research. - : Elsevier BV. - 1383-5742 .- 1388-2139. ; 603:1, s. 33-40
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Journal article (peer-reviewed)abstract
- Folic acid has a well-documented stabilising effect on chromosomes. A correlation between folate status and chromosome stability in humans has been reported in studies that were restricted to certain subpopulations, e.g., folate-deficient persons. The goal of the present investigation was to clarify if there also is a correlation between folate status and chromosome stability among individuals without any folate deficiency. The method used here is the recently developed flow cytometry-based micronucleus assay in human transferrin-positive reticulocytes (MN-Trf-Ret). In a blood sample, separation of the very young reticulocytes from the mature erythrocytes makes this micronucleus assay possible. This investigation comprises three studies (cross-sectional, giving baseline data), two of which are connected to an intervention study. In the three cross-sectional studies (total number of subjects, 99) the frequency of MN-Trf-Ret (fMN-Trf-Ret) was measured and compared with the serum folate status. In two of the studies also serum homocysteine and Vitamin B12 were measured and compared with the baseline fMN-Trf-Ret. Combining the results from the three cross-sectional studies, a negative correlation between folate status and fMN-Trf-Ret was obtained (p < 0.05). The goal of the intervention studies was to clarify if different nutritional supplementations had any effect on the fMN-Trf-Ret and the cell proliferation (percentage polychromatic erythrocytes, PCE). Each of the two studies involved two groups, one placebo and one supplemented group. In one of the studies the supplementation was folic acid, 1000 μg/day during 1 week (n = 30, both sexes); in the other intervention study, folic acid (800 μg/day), B12 (20 μg/day) and B6 (4 mg/day) were taken during 1 week (n = 29, both sexes). No significant difference in %PCE or fMN-Trf-Ret between the two groups was found in either of the two intervention studies.
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| 2. |
- Fred, Charlotta, et al.
(author)
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Hemoglobin adducts and micronuclei in rodents after treatment with isoprene monoxide or butadiene monoxide
- 2005
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In: Mutation Research. - : Elsevier B.V.. - 1383-5742 .- 1388-2139. ; 585:1-2, s. 21-32
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Journal article (peer-reviewed)abstract
- 1,3-Butadiene and isoprene (2-methyl-1,3-butadiene) are chemically related substances that are carcinogenic to rodents. The overall aim of this work is to elucidate the role of the genotoxic action of diepoxide metabolites in the carcinogenesis of the dialkenes. In vivo doses of the diepoxide metabolites were measured through reaction products with hemoglobin (Hb adducts) in studies of induced micronuclei (MN) in rodents. In the reaction with N-terminal valine in Hb, diepoxybutane and isoprenediepoxide form ring-closed adducts, pyrrolidines [N,N-(2,3-dihydroxy-1,4-butadiyl)valine and N,N-(2,3-dihydroxy-2-methyl-1,4-butadiyl)valine, respectively]. The method applied for Hb-adduct measurement is based on tryptic degradation of the protein and liquid chromatography electrospray ionisation tandem mass spectrometry (LC–ESI-MS/MS) analysis. Mice were given single i.p. injections of the monoepoxides of butadiene and isoprene, 1,2-epoxy-3-butene or 1,2-epoxy-2-methyl-3-butene, respectively. Rats were treated in the same way with 1,2-epoxy-3-butene. In mice pyrrolidine adduct levels increased with increasing administered doses of the monoepoxides. The in vivo dose of diepoxybutane was on average twice as high (0.29 ± 0.059 mMh) as the in vivo dose of isoprenediepoxide (0.15 ± 0.053 mMh) per administered dose (mmol/kg body weight) of the monoepoxides. In mice the genotoxic effects of the two monoepoxides, measured as the increase in the frequencies of micronuclei (MN), were approximately linearly correlated to the in vivo doses of the diepoxides (except at the highest dose of diepoxybutane). In rats the pyrrolidine-adduct levels from diepoxybutane were below the limit of quantification at all administered doses of 1,2-epoxy-3-butene and no significant increase was observed in the frequency of MN. Measurement of the ring-closed adducts to N-termini in Hb by the applied method permits analysis of in vivo doses of diepoxybutane and isoprenediepoxide, which may be further used for the elucidation of the mechanisms of carcinogenesis of butadiene and isoprene.
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| 3. |
- Seitz, Nadja, et al.
(author)
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A novel statistical approach for the evaluation of comet assay data
- 2008
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In: Mutation Research. - : Elsevier. - 1383-5742 .- 1388-2139. ; 652:1, s. 38-45
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Journal article (peer-reviewed)abstract
- The present study forms part of a weight-of-evidence framework including genotoxicological studies in the upper Danube River basin, which aim at elucidating the reasons for the decline in fish catch. The major focus of this paper is the assessment of genotoxicity of sediments from the Danube River basin by use of the comet assay with RTL-W1 cells and with embryos of zebrafish (Danio rerio). A frequently discussed question in this type of approach is how to aggregate and compare the data obtained from genotoxicity testing. There is a need to develop mathematical method combining the information from dose–response curves and level of effectiveness (maximum genotoxic effect). For comparison and ranking of the genotoxic potential of samples from different locations along the Danube River, several methods based on EC50, Lowest Observed Effect Concentration (LOEC), and maximum induction factor were compared with respect to their validity. An evaluation system termed the “3-step, analysis” was developed to facilitate consideration of a maximum number of aspects of the raw data. The so-called “concentration-dependent induction factor” (CDI) introduces an index for a straightforward, precise and realistic assessment of the genotoxic potential of any kind of field sample or genotoxic agent.
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| 4. |
- Belyaev, I. Y.
(author)
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Radiation-induced DNA repair foci : Spatio-temporal aspects of formation, application for assessment of radiosensitivity and biological dosimetry
- 2010
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In: Mutation Research. - : Elsevier BV. - 1383-5742 .- 1388-2139. ; 704:03-jan, s. 132-141
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Journal article (peer-reviewed)abstract
- Several proteins involved in DNA repair and DNA damage signaling have been shown to produce discrete foci in response to ionizing radiation. These foci are believed to co-localize to DSB and referred to as ionizing radiation-induced foci (IRIF) or DNA repair foci. Recent studies have revealed that some residual IRIF remain in cells for a relatively long time after irradiation, and have indicated a possible correlation between radiosensitivity of cells and residual IRIF. Remarkably, residual foci are significantly larger in size than the initial foci. Increase in the size of IRIF with time upon irradiation has been found in various cell types and has partially been correlated with dynamics and fusion of initial foci. Although it is admitted that the number of IRIF reflect that of DSB, several studies report a lack of correlation between kinetics for IRIF and DSB and a lack of co-localization between DSB repair proteins. These studies suggest that some proportion of residual IRIF that depend on cell type, dose, and postirradiation time may represent alternations in chromatin structure after DSB have been repaired or misrepaired. While precise functions of residual foci are presently unknown, their possible link to remaining chromatin alternations, nuclear matrix, apoptosis, delayed repair and misrejoining of DSB, activity of several kinases, phosphatases, and checkpoint signaling has been suggested. Another intriguing possibility is that some of DNA repair foci may mark break-points at chromosomal aberrations (CA). While this possibility has not been confirmed substantially, the residual foci seem to be useful for biological dosimetry and estimation of individual radiosensitivity in radiotherapy of cancer.
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| 5. |
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| 6. |
- Hall, Janet, et al.
(author)
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Ionizing radiation biomarkers in epidemiological studies - An update
- 2017
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In: Mutation Research. - : Elsevier BV. - 1383-5742 .- 1388-2139. ; 771, s. 59-84
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Research review (peer-reviewed)abstract
- Recent epidemiology studies highlighted the detrimental health effects of exposure to low dose and low dose rate ionizing radiation (IR): nuclear industry workers studies have shown increased leukaemia and solid tumour risks following cumulative doses of < 100 mSv and dose rates of < 10 mGy per year; paediatric patients studies have reported increased leukaemia and brain tumours risks after doses of 30-60 mGy from computed tomography scans. Questions arise, however, about the impact of even lower doses and dose rates where classical epidemiological studies have limited power but where subsets within the large cohorts are expected to have an increased risk. Further progress requires integration of biomarkers or bioassays of individual exposure, effects and susceptibility to IR. The European DoReMi (Low Dose Research towards Multidisciplinary Integration) consortium previously reviewed biomarkers for potential use in IR epidemiological studies. Given the increased mechanistic understanding of responses to low dose radiation the current review provides an update covering technical advances and recent studies. A key issue identified is deciding which biomarkers to progress. A roadmap is provided for biomarker development from discovery to implementation and used to summarise the current status of proposed biomarkers for epidemiological studies. Most potential biomarkers remain at the discovery stage and for some there is sufficient evidence that further development is not warranted. One biomarker identified in the final stages of development and as a priority for further research is radiation specific mRNA transcript profiles.
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| 7. |
- Ljungman, Mats, et al.
(author)
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The role of H3K79 methylation in transcription and the DNA damage response
- 2019
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In: Mutation Research. - : ELSEVIER. - 1383-5742 .- 1388-2139. ; 780, s. 48-54
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Research review (peer-reviewed)abstract
- Chromatin plays a critical role in organizing and protecting DNA. However, chromatin acts as an impediment for transcription and DNA repair. Histone modifications, such as H3K79 methylation, promote transcription and genomic stability by enhancing transcription elongation and by serving as landing sites for proteins involved in the DNA damage response. This review summarizes the current understanding of the role of H3K79 methylation in transcription, how it affects genome stability and opportunities to develop impactful therapeutic interventions for cancer.
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| 8. |
- Pernot, Eileen, et al.
(author)
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Ionizing radiation biomarkers for potential use in epidemiological studies
- 2012
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In: Mutation Research. - : Elsevier BV. - 1383-5742 .- 1388-2139. ; 751:2, s. 258-286
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Research review (peer-reviewed)abstract
- Ionizing radiation is a known human carcinogen that can induce a variety of biological effects depending on the physical nature, duration, doses and dose-rates of exposure. However, the magnitude of health risks at low doses and dose-rates (below 100 mSv and/or 0.1 mSv min(-1)) remains controversial due to a lack of direct human evidence. It is anticipated that significant insights will emerge from the integration of epidemiological and biological research, made possible by molecular epidemiology studies incorporating biomarkers and bioassays. A number of these have been used to investigate exposure, effects and susceptibility to ionizing radiation, albeit often at higher doses and dose rates, with each reflecting time-limited cellular or physiological alterations. This review summarises the multidisciplinary work undertaken in the framework of the European project DoReMi (Low Dose Research towards Multidisciplinary Integration) to identify the most appropriate biomarkers for use in population studies. In addition to logistical and ethical considerations for conducting large-scale epidemiological studies, we discuss the relevance of their use for assessing the effects of low dose ionizing radiation exposure at the cellular and physiological level. We also propose a temporal classification of biomarkers that may be relevant for molecular epidemiology studies which need to take into account the time elapsed since exposure. Finally, the integration of biology with epidemiology requires careful planning and enhanced discussions between the epidemiology, biology and dosimetry communities in order to determine the most important questions to be addressed in light of pragmatic considerations including the appropriate population to be investigated (occupationally, environmentally or medically exposed), and study design. The consideration of the logistics of biological sample collection, processing and storing and the choice of biomarker or bioassay, as well as awareness of potential confounding factors, are also essential.
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| 9. |
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| 10. |
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| 11. |
- Zhuang, Shi-Mei, et al.
(author)
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Genetic analysis of Raf1, Mdm2, c-Myc, Cdc25a and Cdc25b proto-oncogenes in 2′,3′-dideoxycytidine- and 1,3-butadiene-induced lymphomas in B6C3F1 mice
- 2000
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In: Mutation Research. - 1383-5742 .- 1388-2139. ; 452:1, s. 19-26
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Journal article (peer-reviewed)abstract
- We have previously identified activation of ras proto-oncogenes and inactivation of tumor suppressor genes including p53, p16INK4a and p15INK4b in 2′,3′-dideoxycytidine (ddC)- and/or 1,3-butadiene (BD)-induced lymphomas derived from B6C3F1 (C57BL/6xC3H/He) mice, indicating that alterations of ras signaling pathway, p53 and pRb growth control pathways are important in the development of these chemically induced lymphomas. However, there is still a subset of tumors that displayed no changes in these genes. Thus, we investigated whether the Raf1, Mdm2, c-Myc, Cdc25a and Cdc25b proto-oncogenes, which are implicated in the ras or p53 or pRb pathways, are alternative oncogenic target genes. Analyses of gross genomic alterations by Southern blots failed to reveal rearrangement or amplification in any of the tumors examined. Frequent point mutations on the substrate binding domain of the Raf1 gene has been reported in 1-ethyl-1-nitrosourea (ENU)-induced murine lymphomas and lung tumors, along with a conspicuous lack of ras mutations [U. Naumann, I. Eisenmann-Tappe, U.R. Rapp, The role of raf kinases in development and growth of tumors, Recent Results Cancer Res., 143 (1997) 237–244]. To investigate whether Raf1 mutation is involved in our set of tumor especially those without ras mutations, the PCR-based single-strand conformation analyses (SSCA) and direct DNA sequencing were employed. No mutations but four genetic polymorphisms between C57BL/6 and C3H/He were found, with two of them reported as point mutations previously (op. cit.). The polymorphisms were utilized for allelic loss study of Raf1 locus. Losses of heterozygosity were found in six of 31 BD-induced lymphomas. These results indicate that genetic alterations of c-Myc, Cdc25, Raf1 and Mdm2 proto-oncogenes may not be involved in the development of ddC- and BD-induced lymphomas and the inactivation of tumor suppressor gene(s) located close to Raf1 gene might be important in the development of a subset of BD-induced lymphomas.
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| 17. |
- Nästegård, Emil, 1985
(author)
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Does Member State Law Make Article 35a of the EU Regulation on Credit Rating Agencies Redundant?
- 2015
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In: International and comparative corporate law journal. - : Elsevier BV. - 1388-7084. ; 11:2, s. 71-90
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Journal article (peer-reviewed)abstract
- The purpose of this paper is to analyze certain aspects of the CRAs’ civil liability under Article 35a of the EU Regulation on credit rating agencies. Central terms in Article 35a are dependent on the national private laws of the Member States. In that regard, this article discusses English law and Swedish law. (This paper was written before the adoption of The UK Credit Rating Agencies (Civil Liability) Regulations of 2013 (No. 1637) in July 2013. These Regulations are therefore not analyzed in this paper. They will be analyzed in my forthcoming dissertation.)
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