SSMs forsknings dagar 24-25 oktober 2013 Centrum för Strålskyddsforskning, Forskning med fokus på effekter av låga doser, låga dosrater och olika strålkvalitéer Andrzej Wojcik, Siamak Haghdoost and Mats Harms-Ringdahl Centrum för Strålskyddsforskning Stockholms universitet
Centrum för strålskyddsforskning CRPR Stockholms universitet www.crpr-su.se
Styrelse CRPR Eva Forssell-Aronsson, professor ordf. Avd för radiofysik, Sahlgrenska universitetssjukhuset, GU Clare Bradshaw, docent Systemekologi SU Andrzej Wojcik, professor Hooshang Nikjoo, professor Eva Simic Forskningschef Föreståndare CRPR SU Med. Strålningsfysik KI Strålsäkerhetsmyndigheten 2013-10-30 / CRPR Stockholms universitet
Seniora forskare Clare Bradshaw, docent Systemekologi SU Hooshang Nikjoo, professor Med. Strålningsfysik KI Andrzej Wojcik, professor MBW SU Dag Jenssen, professor MBW SU Thomas Helleday, professor SciLifeLab KI Siamak Haghdoost, Docent MBW SU Ulf Rannug, professor, professor MBW SU Mats Harms-Ringdahl, professor MBW SU 2013-10-30 / CRPR Stockholms universitet
Strålningsbiologiska verksamheten vid CRPR SU Andrzej Wojcik, Siamak Haghdoost and Mats Harms-Ringdahl Genotoxiska effekter av låga doser, låga dosrater och olika strålkvalitéer (+UVA). Individuell strålkänslighet, mekanismer och diagnostiska verktyg Effekter av låga doser och dosrater på modelsystem för vasculära sjukdomar och kognitiv funktion 2013-10-30 / CRPR Stockholm University
Low dose risk extrapolation Epidemiological data (excess cancers) (above background)
Low dose risk extrapolation Strålkvalité Individuell känslighet Epidemiological data (excess cancers) Non-cancer diseases (above background)
Who is exposed to mixed beams of radiation? People living in areas of high natural background radiation α + ɣ Astronauts n + p + ɣ Cancer patients treated by high energy intensity modulated radiotherapy (IMRT) n + ɣ Boron Neutron Capture Therapy n th 7 Li 0.84 MeV 1 H + 1 n = ɣ + 2.20 MeV 14 N + 1 n = 14 C + 1 p + 0.58 MeV 1.47 MeV 10 B gamma 0.48 MeV 4 He(alpha)
Alpha exposure facility at the Centre for Radiation Protection Research The alpha source - 50 MBq 241 Am The mixed beam irradiation incubator with the X-ray source underneath Images taken with a ZnS:Ag phosporous sheet
Experiments on the effects of combined exposure to alpha particles and X-rays 1. Micronuclei in human peripheral blood lymphocytes 2. Chromosomal aberrations in human peripheral blood lymphocytes 3. Gamma H2AX-foci in VH10 human fibroblasts Micronuclei Aberrations Repair foci Staaf et al Genome Integr. 2012 Wojcik et al J Radiol Prot. 2012 Staaf et al Radiat Prot Dosimetry. 2012 Staaf et al Mutat Res. 2013
Micronuclei in human peripheral blood lymphocytes Lymphocytes of one donor, 3 independent repeats observed predicted Conclusion: the frequency of micronuclei in lymphocytes exposed to mixed beams is significantly higher than expected based on the assumption of additivity
1995 2013-10-30 / CRPR Stockholm University
Low dose rate chronic exposure Facility 1.4-4.2 mgy/h 2013-10-30 / CRPR Stockholm University Low dose rate facility at CRPR, Stockholm University, Helmholtz, Münich, Germany
Radiation induced changes in protein expression profiles in CHO cells in response to gamma or alpha exposure. 2013-10-30
Radiation induced changes in protein expression profiles in CHO cells in response to gamma or alpha exposure. Wild type CHO cells (AA8) Gamma from 137 Cs (0.43 Gy/min) Alpha from 214 Po Analysis 3 hour post irradiation PDQuest analysis 2 fold Identification MALDI-ToF. 2013-10-30 Bajinskis et al 2012
Proteins selected from multivariate analysis Protein expression i hamster celler Unique patterns for doses as well as for radiation quality
UVA induces an intracellular stress response that leads to increased levels or reactive oxygen species and damage on the nucleotide pool that leads to mutations. Reduction of 8-oxodGTP in the nucleotide pool by hmth1 leads to reduction in mutations in the human lymphoblastoid cell line TK6 exposed to UVA Fotouhi A. et al Mutation Research 2011 Analysis of mutant frequencies and mutation spectra in hmth1 knockdown TK6 cells exposed to UV radiation Fotouhi A. et al Mutation Research 2013 October 2013-10-30 / CRPR Stockholm University
Individuell strålkänslighet 2013-10-30 / CRPR Stockholm University
Individuell strålkänslighet Burnet et al, Int. J. Cancer, 1998, 79, 606 2013-10-30 / CRPR Stockholm University
Individuell strålkänslighet Burnet et al, Int. J. Cancer, 1998, 79, 606 2013-10-30 / CRPR Stockholm University
8-oxo-dG as a biomarker for individual sensitivity 2914 breast cancer patients classified according to their acute skin reactions (Radiumhemmet och Karolinska institutet)
Can 8-oxo-dG be used as a predictor for individual radiosensitivity? Haghdoost et al 2001. Int.J. Radiation Oncology Biol. Phys. 8-oxo-dG in urine of patients undegoing radiotherpy Acute advers skin reactions Minor acute skin reactions
Relative increase in 8-oxo-dG in serum from blood samples exposed to 5 or 2000 mgy Skiöld et al 2012
Non sensitiv Sensitive 2013-10-30 Skiöld et al 2012
Proteinexpression som biomarkör för strålkänslighet Radiosensitive patients (8) Radioresistant patients (9) 2013-10-30 / CRPR Stockholm University Differentially regulated proteins in response to radiation in pooled whole blood from the two groups.
Radiosensitive patients Radioresistant patients
Summary: Individual sensitivity 8-oxo-dG i serum eller urin har en diagnostisk potential Ett antal proteiner har identifierats som skiljer mellan strålkänslig och icke strålkänsliga patienter Genom att kombinera 8-oxo-dG med proteinexpression har vi förhoppningen att kunna identifiera patienter som har hög strålkänslighet och kunna individualisera strålterapin. Parallellt pågår studier av genetiska skillnader mellan de olika grupperna (polymorfisms).
Effekter av låga doser och dosrater på modelsystem för vaskulära sjukdomar och kognitiv funktion 2013-10-30 / CRPR Stockholm University
Radiation induced effects on neuronal differentiation. Neurite formation in SH-Sy5Y neuroblastoma cell line of human origin (retinoic acid) Astrocyte differentiation (Glial fibrillary acidic protein (GFAP)) in murine derived v-myc immortalized neural stem cells 5 mgy/h 30 mgy Post irradiation Differentiation Protein expression 6 h 6 days Bajinskis et al Radiation Research 2011
Effects of low dose chronic exposure (5 mgy/h) on neuronal differentiation SH-SY5Y is a neuronal cell line of human origin
Effects of γ-radiation (5 mgy/h) on Glial fibrillary acidic protein (GFAP) expression in C17.2 cells.. Day 1 Day 6 Control 10 mgy 30 mgy
Differentiation Differentiation suppressed by low doses and dose rates Effects on protein expression for individual proteins different for human and murine cells. In common were effects on cell cycle proliferation, neuronal development, neuronal function and apoptosis.
Modelsystem för vaskulära sjukdomar Studier på primära endotelialceller (HUVEC) 2013-10-30 / CRPR Stockholm University
Sampling times C: n=4 1.4 mgy/h: n=3 2.4 mgy/h: n=3 4.1 mgy/h: n=3
Strålningsinducerad senescence Quantitative proteomic analysis reveals induction of premature senescence in human umbilical vein endothelial cells exposed to chronic low-dose rate gamma radiation Yentrapalli R., et al Proteomics. 2013 Apr;13(7):1096-107 The PI3K/Akt/mTOR pathway is implicated in the premature senescence of primary human endothelial cells exposed to chronic radiation Yentrapalli R., et al. PLoS One. 2013 Aug 1;8(8) Transcriptomic profiling suggests a role for IGFBP5 in premature senescence of endothelial cells after chronic low dose rate irradiation. Rombouts C., et al mansucript 2013-10-30 / CRPR Stockholm University
Denna forskning har stötts av: SSI/SSM Euroatom (RiscRad, DoReMi, EpiRadBio, RadSens) Security (MultiBioDos) Cancerfonden 2013-10-30 / CRPR Stockholm University
Karl Ainars Traimat Marina Asal Andrzej Siamak 2013-10-30 / CRPR Stockholm University Elina Sara Sara Alice Marta
Institute of Radiation Biology (ISB) Radiation Proteomics Helmholtz-Munich Dr. Soile Tapio Dr. Omid Dr. Yentrapalli Ramesh