New molecular targets in radiotherapy: DNA damage signalling and repair in targeted and non-targeted cells

Ionising radiation plays a key role in therapy due to its ability to directly induce DNA damage, in particular DNA double-strand breaks leading to cell death. Cells have multiple repair pathways which attempt to maintain genomic stability. DNA repair proteins have become key targets for therapy, using small molecule inhibitors, in combination with radiation and or chemotherapeutic agents as a means of enhancing cell killing. Significant advances in our understanding of the response of cells to radiation exposures has come from the observation of non-targeted effects where cells respond via mechanisms other than those which are a direct consequence of energy-dependent DNA damage. Typical of these is bystander signalling where cells respond to the fact that their neighbours have been irradiated. Bystander cells show a DNA damage response which is distinct from directly irradiated cells. In bystander cells, ATM- and Rad3-related (ATR) protein kinase-dependent signalling in response to stalled replication forks is an early event in the DNA damage response. The ATM protein kinase is activated downstream of ATR in bystander cells. This offers the potential for differential approaches for the modulation of bystander and direct effects with repair inhibitors which may impact on the response of tumours and on the protection of normal tissues during radiotherapy. (C) 2009 Elsevier B.V. All rights reserved.

Juxtaposition and Non-Motion: Varese Bridges Modernism and Electroacoustic Music

Edgard Vare` se’s Poe` me e´ lectronique can be viewed as a bridge between early twentieth-century modernism and electroacoustic music. This connection to early modernism is most clearly seen in its use of musical juxtaposition, a favoured technique of early modernist composers, especially those active in Paris. Juxtaposition and non-motion are considered here, particularly in relationship to Smalley’s exposition of spectromorphology (Smalley 1986), which in its preoccupation with motion omits any significant consideration of non-motion. Juxtaposition and non-motion have an important history within twentieth-century music, and as an early classic of electroacoustic music, Poe` me e´ lectronique is a particularly striking example of a composition that is rich in juxtapositions similar to those found in passages of early modernist music. Examining Poe` me e´ lectronique through the lens of juxtaposition and non-motion reveals how the organisation of its juxtaposed sounds encourages the experience of sound structure suspended time.