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  • 1.
    Abramsson-Zetterberg, L
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Genetics.
    Ascorbic acid is not clastogenic and does not modify the effect of extended low-dose-rate gamma-irradiation in mouse bone marrow1996In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 70, no 1, p. 77-81Article in journal (Refereed)
    Abstract [en]

    Ascorbic acid was given to CBA mice in drinking water (5%) a week before and during 35-day exposure to gamma-radiation from 137 Cs at a very low dose-rate (44 mGy/day). The frequency of micronucleated normochromatic erythrocytes (fMNCE) in peripheral blood was monitored by repeated sampling during the exposure. The analyses were made with flow cytometry giving a high resolution because of the large number of cells analysed, about 10(6) for each dose group and sampling occasion. Ascorbic acid in the drinking water did not modify the increase of fMNCE in the gamma-irradiated groups of mice, nor did ascorbic acid influence the fMNCE in the non-irradiated groups of mice.

  • 2.
    Buratovic, Sonja
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Sundell-Bergman, Synnöve
    Department of Soil and Environment, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Developmental effects of fractionated low-dose exposure to gamma radiation on behaviour and susceptibility of the cholinergic system in mice2016In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 92, no 7, p. 371-379Article in journal (Refereed)
    Abstract [en]

    Purpose: To investigate whether neonatal exposure to fractionated external gamma radiation and co-exposure to radiation and nicotine can affect/exacerbate developmental neurotoxic effects, including altered behavior/cognitive function and the susceptibility of the cholinergic system in adult male mice. Materials and methods: Neonatal male Naval Medical Research Institute (NMRI) mice were irradiated with one 200 mGy fraction/day and/or exposed to nicotine (66 μg/kg b.w.) twice daily on postnatal day (PND) 10, 10–11, 10–12 or 10–13 (nicotine only). At 2 months of age the animals were tested for spontaneous behavior in a novel home environment, habituation capacity and nicotine-induced behavior. Results: Fractionated irradiation and co-exposure to radiation and nicotine on three consecutive days disrupted behavior and habituation and altered susceptibility of the cholinergic system. All observed effects were significantly more pronounced in mice co-exposed to both radiation and nicotine. Conclusions: The fractionated irradiation regime affects behavior/cognitive function in a similar manner as has previously been observed for single-dose exposures. Neonatal co-exposure to radiation and nicotine, during a critical period of brain development in general and cholinergic system development in particular, enhance these behavioral defects suggesting that the cholinergic system can be a target system for this type of developmental neurotoxic effects.

  • 3. Elmroth, K.
    et al.
    Nygren, J.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Hultborn, R.
    Chromatin- and temperature-dependent modulation of radiation-induceddouble-strand breaks2003In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 79, no 10, p. 809-16Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To investigate the influence of chromatin organization and scavenging capacity in relation to irradiation temperature on the induction of double-strand breaks (DSB) in structures derived from human diploid fibroblasts. MATERIALS AND METHODS: Agarose plugs with different chromatin structures (intact cells+/-wortmannin, permeabilized cells with condensed chromatin, nucleoids and DNA) were prepared and irradiated with X-rays at 2 or 37 degrees C and lysed using two different lysis protocols (new ice-cold lysis or standard lysis at 37 degrees C). Induction of DSB was determined by constant-field gel electrophoresis. RESULTS: The dose-modifying factor (DMF(temp)) for irradiation at 37 compared with 2 degrees C was 0.92 in intact cells (i.e. more DSB induced at 2 degrees C), but gradually increased to 1.5 in permeabilized cells, 2.2 in nucleoids and 2.6 in naked DNA, suggesting a role of chromatin organization for temperature modulation of DNA damage. In addition, DMF(temp) was influenced by the presence of 0.1 M DMSO or 30 mM glutathione, but not by post-irradiation temperature. CONCLUSION: The protective effect of low temperature was correlated to the indirect effects of ionizing radiation and was not dependent on post-irradiation temperature. Reasons for a dose modifying factor <1 in intact cells are discussed.

  • 4. Fernandez-Varea, Jose M.
    et al.
    Gonzalez-Munoz, Gloria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Galassi, Mariel E.
    Wiklund, Kristin
    Lind, Bengt K.
    Ahnesjö, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Tilly, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Limitations (and merits) of PENELOPE as a track-structure code2012In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 88, no 1-2, p. 66-70Article in journal (Refereed)
    Abstract [en]

    Purpose: To outline the limitations of PENELOPE (acronym of PENetration and Energy LOss of Positrons and Electrons) as a track-structure code, and to comment on modifications that enable its fruitful use in certain microdosimetry and nanodosimetry applications. Methods: Attention is paid to the way in which inelastic collisions of electrons are modelled and to the ensuing implications for microdosimetry analysis. Results: Inelastic mean free paths and collision stopping powers calculated with PENELOPE and two well-known optical-data models are compared. An ad hoc modification of PENELOPE is summarized where ionization and excitation of liquid water by electron impact is simulated using tables of realistic differential and total cross sections. Conclusions: PENELOPE can be employed advantageously in some track-structure applications provided that the default model for inelastic interactions of electrons is replaced by suitable tables of differential and total cross sections.

  • 5.
    Gustafsson, Ann-Sofie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Hartman, Torbjörn
    Uppsala University, The Svedberg Laboratory.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Formation and repair of clustered damaged DNA sites in high LET irradiated cells2015In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 91, no 10, p. 820-826Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Radiation with high linear energy transfer (LET) produces clustering of DNA double-strand breaks (DSB) as well as non-DSB lesions. Heat-labile sites (HLS) are non-DSB lesions in irradiated cells that may convert into DSB at elevated temperature during preparation of naked DNA for electrophoretic assays and here we studied the initial formation and repair of these clustered damaged sites after irradiation with high LET ions.

    MATERIALS AND METHODS: Induction and repair of DSB were studied in normal human skin fibroblast (GM5758) after irradiation with accelerated carbon and nitrogen ions at an LET of 125 eV/nm. DNA fragmentation was analyzed by pulsed-field gel electrophoresis (PFGE) and by varying the lysis condition we could differentiate between prompt DSB and heat-released DSB.

    RESULTS: Before repair (t = 0 h), the 125 eV/nm ions produced a significant fraction of heat-released DSB, which appeared clustered on DNA fragments with sizes of 1 Mbp or less. These heat-released DSB increased the total number of DSB by 30-40%. This increase is similar to what has been found in low-LET irradiated cells, suggesting that the relative biological effectiveness (RBE) for DSB induction will not be largely affected by the lysis temperature. After 1-2 hours repair, a large fraction of DSB was still unrejoined but there was essentially no heat-released DSB present.

    CONCLUSIONS: These results suggest that high LET radiation, as low LET gamma radiation, induces a significant fraction of heat-labile sites which can be converted into DSB, and these heat-released DSB may affect both induction yields and estimates of repair.

  • 6.
    Kullberg, Erika Bohl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Wei, Qichun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Capala, Jacek
    NCI / NIH USA.
    Giusti, Valerio
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Gedda, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    EGF-receptor targeted liposomes with boronated acridine: growth inhibition of cultured glioma cells after neutron irradiation2005In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 81, no 8, p. 621-629Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To study survival of cultured U-343MGaCl 2:6 glioma cells after incubation with boron-containing liposomes targeting the epidermal growth factor receptor following neutron irradiation. MATERIALS AND METHODS: Epidermal growth factor-tagged liposomes were loaded with water-soluble boronated acridine developed for boron neutron capture therapy, (BNCT). Cellular uptake and distribution were studied. Further, cells were placed at 3 cm depth in a phantom and exposed to an epithermal neutron beam to study clonogenic cell survival. RESULTS: The cellular uptake of boron reached 90 ppm and it was determined by subcellular fractionation that most of the cell-associated boron was located outside of the nucleus. For clonogenic survival, the cells were incubated with epidermal growth factor receptor-targeted liposomes for 4 hours resulting in a cellular concentration of 55 ppm boron (11 ppm 10B). At a fluence of 3 x 10(12) neutrons/cm2 the cell killing effect of the boron-containing epidermal growth factor-liposomes was about ten times higher than for neutrons only. Furthermore, theoretical calculation of the survival by enriched compound (55 ppm 10B), using the parameters from non-enriched compound (11 ppm 10B), shows that the killing effect in this case would be approximately five orders of magnitude higher than for neutrons only. CONCLUSION: The results in this study show that epidermal growth factor-receptor targeted liposomes are suitable as tumor-cell delivery agents of boron for BNCT and support further studies to demonstrate their effectiveness in vivo.

  • 7. Meijer, Annelie E.
    et al.
    Jernberg, A. R-M.
    Heiden, T.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Persson, L. M.
    Tilly, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Lind, B. K.
    Edgren, M. R.
    Dose and time dependent apoptotic response in a human melanoma cell line exposed to accelerated boron ions at four different LET2005In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 81, no 4, p. 261-72Article in journal (Refereed)
    Abstract [en]

    The aim was to investigate and compare the influence of linear energy transfer (LET), dose and time on the induction of apoptosis in a human melanoma cell line exposed to accelerated light boron ((10)B) ions and photons. Cells were exposed in vitro to doses up to 6 Gy accelerated boron ions (40, 80, 125 and 160 eV nm(-1)) and up to 12 Gy photons (0.2 eV nm(-1)). The induction of apoptosis was measured up to 9 days after irradiation using morphological characterization of apoptotic cells and bodies. In parallel, measurements of cell-cycle distribution, monitored by DNA flow cytometry, and cell survival based on the clonogenic cell survival assay, were performed. In addition, the induction and repair of DNA double-strand breaks (DSB), using pulsed-field gel electrophoresis (PFGE) were studied. Accelerated boron ions induced a significant increase in apoptosis as compared with photons at all time points studied. At 1-5 h the percentage of radiation-induced apoptotic cells increased with both dose and LET. At the later time points (24-216 h) the apoptotic response was more complex and did not increase in a strictly LET-dependent manner. The early premitotic apoptotic cells disappeared at 24 h following exposure to the highest LET (160 eV nm(-1)). A postmitotic apoptotic response was seen after release of the dose-, time- and LET-dependent G2/M accumulations. The loss of clonogenic ability was dose- and LET-dependent and the fraction of un-rejoined DSB increased with increasing LET. Despite the LET-dependent clonogenic cell killing, it was not possible to measure quantitatively a LET-dependent apoptotic response. This was due to the different time course of appearance and disappearance of apoptotic cells.

  • 8. Olsson, P.
    et al.
    Black, M.
    Capala, J.
    Coderre, Jeffrey
    Hartman, T.
    Makar, Michael
    Malmquist, J.
    Pettersson, J.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry.
    Tilly, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sjöberg, S.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry.
    Carlsson, J.
    Uptake, toxicity and radiation effects of the boron compounds DAAC-1 and DAC-1 in cultured human glioma cells1998In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 73, no 1, p. 103-112Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To study the uptake, toxicity and radiation effects in vitro of a diol-amino acid-carborane (DAAC-1) and make comparisons with the previously studied diol-amine-carborane (DAC-1). MATERIALS AND METHODS: Toxicity and radiation effects were studied with clonogenic survival, uptake by measuring the cellular boron content and the subcellular distribution was investigated after organelle separation with centrifugation. The studied cell line was human glioma U343. RESULTS: DAAC-1 showed an accumulation of 1-1.5 times, compared with the culture medium, and was non-toxic up to 47 microg boron/ml. The accumulation of DAC-1 was about 90 times, but toxic effects were detectable already at the concentration 5 microg boron/ml. None of the compounds was localized in the cell nucleus. Following irradiation with thermal neutrons, DAC-1 was about 2.5 times more effective than DAAC-1 and about 4.9 times more effective than neutrons alone, at the survival level 0.2. The dose modifying factors, when compared with the neutron beam alone, were for both DAAC-1 and DAC-1 about 1.5 and about 5 when compared with 60Co-gamma-radiation. CONCLUSIONS: DAAC-1 was less toxic than DAC-1 but gave less accumulation of boron. Both substances gave significant boron-dependent cell inactivation when the test cells were exposed to thermal neutrons.

  • 9. Polischouk, A.G.
    et al.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Edgren, M.R.
    Lewensohn, R.
    Difference in the induction, but not in the repair, of X-ray- and nitrogen ion-induced DNA single-strand breaks as measured using human cell extracts2003In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 79, no 12, p. 965-71Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To compare the repair efficiency of X-ray (low linear energy transfer [LET]) and nitrogen ion (high LET)-induced single-strand breaks (SSB) in a human cell-free end-joining system. MATERIALS AND METHODS: SSB were introduced into a bacterial plasmid, pBR322, by X-rays (4 MeV photons) and nitrogen ions with an LET=125 keV micro m(-1). Repair efficiency was studied under incubation with the protein extracts from human squamous carcinoma cells, UT-SCC-5. RESULTS: A several fold higher dose of nitrogen ion radiation compared with X-ray radiation was needed to induce a similar loss of supercoiled plasmid DNA. There was no difference in the repair efficiency of SSB induced by these two types of radiation. CONCLUSION: The data indicate that X-rays at 25 Gy and nitroging ions at 100 Gy radiation doses, under condition of low scavenging capacity (10 mM Tris), induce SSB of similar complexity or, alternatively, differences in SSB complexity do not alter the repair rate.

  • 10.
    Tilly, Nina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Brahme, A.
    Carlsson, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Comparison of cell survival models for mixed LET radiation1999In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 75, no 2, p. 233-43Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Biophysical models for predicting survival for mixed LET radiations have been investigated by comparisons with experimental results from heavy ion irradiations. The aim was to choose a model for further theoretical studies on the effects of a variable RBE for protons. METHODS AND MATERIALS: Predicted survival curves by the Katz track-structure model, the linear quadratic model, LQ model, by Kellerer and Rossi and the lesion additivity model of Lam were compared to experimental survival curves for V79 cells that were irradiated with a mixture of nitrogen ions with an LET of either 78 or 165 keV/microm and 60Co gamma-rays. RESULTS: Results showed that all three models could predict survival within the uncertainty of the measurements for the different mixed radiation schedules used in this study. CONCLUSION: The choice of model could be made on other grounds, such as the type of model parameters and the availability of biological data for these parameters. Also, the possibility of including dose-rate effects and repair functions should be considered. For the purpose of carrying out theoretical studies on the effects of a variable RBE for protons, the LQ model was preferred.

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