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Quantification of R...
Quantification of Radiation Induced DNA Damage Response in Normal Skin Exposed in Clinical Settings
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- Simonsson, Martin, 1975- (författare)
- Uppsala universitet,Enheten för onkologi
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- Turesson, Ingela (preses)
- Uppsala universitet,Enheten för onkologi
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- Enblad, Gunilla (preses)
- Uppsala universitet,Enheten för onkologi
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- Olsen, Dag Rune (opponent)
- Universitetet i Bergen, Det matematisk-naturvitenskapelige fakultet
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(creator_code:org_t)
- ISBN 9789155479695
- Uppsala : Acta Universitatis Upsaliensis, 2011
- Engelska 51 s.
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Serie: Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 631
- Relaterad länk:
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- The structure, function and accessibility of epidermal skin provide aunique opportunity to study the DNA damage response (DDR) of a normaltissue. The in vivo response can be examined in detail, at a molecularlevel, and further associated to the structural changes, observed at atissue level. We collected an extensive skin biopsy material frompatients undergoing fractionated radiotherapy for 5 to 7 weeks. Several end-points inthe DDR pathways were examined before, during and after the treatment. Quantification of DNA double strand break (DSB) signalling focirevealed a hypersensitivity to doses below 0.3Gy. Furthermore, aconsiderable amount of foci persisted between fractions. The low dosehypersensitivity was observed throughout the treatment and was alsoobserved for several key parameters further downstream in the DDR-pathway, such as p21-associated checkpoint activation, apoptosisinduction and reduction in basal keratinocyte density (BKD).Furthermore, for dose fractions above 1.0 Gy, a distinct acceleration inDDR was observed half way into treatment. This was manifested as anaccelerated loss of basal keratinocytes, mirrored by a simultaneousincrease in DSBs and p21 expression. Quantifications of mitotic events revealed a pronounced suppression ofmitosis throughout the treatment which was clearly low dosehypersensitive. Thus, no evidence of accelerated repopulation could beobserved for fraction doses ranging from 0.05 to 2Gy. Our results suggest that the keratinocyte response primarily isdetermined by checkpoints, which leads to pre-mitotic cell elimination by permanent growth arrest and apoptosis. A comparison between the epidermal and dermal sub-compartments revealsa consistent up-regulation of the DDR response during treatment. Adifference was however observed in the recovery phase after treatment,where miR-34a and p21 remain up-regulated in dermis more persistentlythan in epidermis. Our observations suggest that the recovery phaseafter treatment can provide important clues to understand clinicalobservations such as the early and late effects observed in normaltissues during fractionated radiotherapy.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- DNA damage response
- low-dose hypersensitivity
- dose response
- normal tissue
- epidermis
- dermis
- keratinocyte
- fractionated radiotherapy
- DNA double strand break
- DSB
- foci
- gamma-H2AX
- 53BP1
- p21
- checkpoint
- apoptosis
- mitosis
- micro-RNA
- miR-34a
- Oncology
- Onkologi
- Oncology
- Onkologi
Publikations- och innehållstyp
- vet (ämneskategori)
- dok (ämneskategori)
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