2. Yet another one

4. In other words… … based on what you will hear on the bystander effect , this may well be my last attendance at CERRO!

9. … violations appeared Genomic instability (1992) Time Violation Space Violation Bystander effect (1992) time

10. I. Bystander effect: cells do talk to each other (1992) gap junctions -mediated signals Medium-mediated signals Influenced by both phenotype and micro-environment

12. Radiation-induced genetic damage. Old Paradigm An IR-induced mutation is carried on to the entire progeny

14. II. Genomic Instability Gene mutation Chromosomal aberration Cell death Mitotic failure-aneuploidy Micronuclei

15. Genomic Instability and 2 nd cancers? … As nearly one in 10 cancer diagnoses are second (or higher) malignancies, it is important to understand the contribution of radiotherapy to second cancer induction and pursue well-coordinated efforts to determine the role of induced genomic instability

16. Phenomenological Inter-relations HRS/IRR (‘91) Adaptive Response (‘84) Genomic Instability (‘92) Bystander effect (‘92)

17. Phenomenological Inter-relations HRS/IRR Adaptive Response Genomic Instability Bystander effect Oxidative metabolism

18. Phenomenological Inter-relations HRS/IRR Adaptive Response Genomic Instability Bystander effect

19. Bystander as Adaptive Ed Azzam Roger Howell Pinto, Azzam & Howell, Radiat Prot Dosim 2006 Howell et al, Radiat Prot Dosim 2006 Pinto & Howell, Biotechniques 2007 Pinto, Azzam & Howell, in prep .

20. Phenomenological Inter-relations HRS/IRR Adaptive Response Genomic Instability Bystander effect

21. Bystander-mediated Genomic instability ... 35 y.o. Male. Nuclear power plant accident. Total body neutron dose of 5.4 Gy, plus 8.5–13 Gy γ rays. B lood stem cell transplant from his sister ( HLA identity ). Good initial recovery. Chromosomal damage was then observed in the offspring of the donor (sister) cells, hinting at a bystander effect . Decesased 82 days after the accident due to multi-organ failure .

23. Waiting for some convincing evidence

24. In vivo oncogenic bystander

25. Even if…how relevant? Age at first radiotherapy treatment Late Adulthood Pediatric / Young Adult not so relevant Time to develop a secondary cancer

27. Thank you