SSMs forsknings dagar oktober 2013

Transkript

1 SSMs forsknings dagar 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

2 Centrum för strålskyddsforskning CRPR Stockholms universitet

3 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 / CRPR Stockholms universitet

4 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 / CRPR Stockholms universitet

5 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 / CRPR Stockholm University

6 Low dose risk extrapolation Epidemiological data (excess cancers) (above background)

7 Low dose risk extrapolation Strålkvalité Individuell känslighet Epidemiological data (excess cancers) Non-cancer diseases (above background)

8 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 MeV 14 N + 1 n = 14 C + 1 p MeV 1.47 MeV 10 B gamma 0.48 MeV 4 He(alpha)

9 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

10 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 Wojcik et al J Radiol Prot Staaf et al Radiat Prot Dosimetry Staaf et al Mutat Res. 2013

11 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

12 / CRPR Stockholm University

13 Low dose rate chronic exposure Facility mgy/h / CRPR Stockholm University Low dose rate facility at CRPR, Stockholm University, Helmholtz, Münich, Germany

14 Radiation induced changes in protein expression profiles in CHO cells in response to gamma or alpha exposure

15 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 Bajinskis et al 2012

16 Proteins selected from multivariate analysis Protein expression i hamster celler Unique patterns for doses as well as for radiation quality

17 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 / CRPR Stockholm University

18 Individuell strålkänslighet / CRPR Stockholm University

19 Individuell strålkänslighet Burnet et al, Int. J. Cancer, 1998, 79, / CRPR Stockholm University

20 Individuell strålkänslighet Burnet et al, Int. J. Cancer, 1998, 79, / CRPR Stockholm University

21 8-oxo-dG as a biomarker for individual sensitivity 2914 breast cancer patients classified according to their acute skin reactions (Radiumhemmet och Karolinska institutet)

22 Can 8-oxo-dG be used as a predictor for individual radiosensitivity? Haghdoost et al Int.J. Radiation Oncology Biol. Phys. 8-oxo-dG in urine of patients undegoing radiotherpy Acute advers skin reactions Minor acute skin reactions

23 Relative increase in 8-oxo-dG in serum from blood samples exposed to 5 or 2000 mgy Skiöld et al 2012

24 Non sensitiv Sensitive Skiöld et al 2012

25 Proteinexpression som biomarkör för strålkänslighet Radiosensitive patients (8) Radioresistant patients (9) / CRPR Stockholm University Differentially regulated proteins in response to radiation in pooled whole blood from the two groups.

26 Radiosensitive patients Radioresistant patients

27 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).

28 Effekter av låga doser och dosrater på modelsystem för vaskulära sjukdomar och kognitiv funktion / CRPR Stockholm University

29 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

30 Effects of low dose chronic exposure (5 mgy/h) on neuronal differentiation SH-SY5Y is a neuronal cell line of human origin

31 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

32 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.

33 Modelsystem för vaskulära sjukdomar Studier på primära endotelialceller (HUVEC) / CRPR Stockholm University

34 Sampling times C: n=4 1.4 mgy/h: n=3 2.4 mgy/h: n=3 4.1 mgy/h: n=3

35 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 Apr;13(7): 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 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 / CRPR Stockholm University

36 Denna forskning har stötts av: SSI/SSM Euroatom (RiscRad, DoReMi, EpiRadBio, RadSens) Security (MultiBioDos) Cancerfonden / CRPR Stockholm University

37 Karl Ainars Traimat Marina Asal Andrzej Siamak / CRPR Stockholm University Elina Sara Sara Alice Marta

38 Institute of Radiation Biology (ISB) Radiation Proteomics Helmholtz-Munich Dr. Soile Tapio Dr. Omid Dr. Yentrapalli Ramesh