'Frenzied law making': overcriminalization by numbers

The New Labour government was accused of frenzied law making, creating a criminal offence for every day spent in office. The current government, responding to these concerns, has introduced a ‘gateway’ mechanism to halt the tide of criminalization. New research suggests that the accusations levelled against the last government badly underestimated the reality: criminal offences were—and despite the gateway mechanism, are still—created at a far greater rate than one a day. But what does this actually mean? This paper reviews the available evidence on the extent of the criminal law, including recent research by the author and others, noting the characteristics of new criminal offences, which are typically directed towards the regulation of particular activities rather than the general public, but frequently potentially carry severe maximum penalties and should not be wrongly dismissed as trivial and/or regulatory. While acknowledging the significant rate at which criminal offences are committed, it casts doubt on the common assumption that this is something which has increased substantially in recent years. It explores how the vast quantity of criminal offences on the statute book can be reconciled with the doctrinal treatment of criminal law as a somewhat narrower topic, and concludes by analysing the extent to which critiques made of criminalization in modern practice, particularly in relation to the claims made about the New Labour government, are borne out by the available evidence

The potential role and application of PARP inhibitors in cancer treatment

Background: Since many anti-cancer agents act by inflicting DNA damage on tumour cells, there is increasing interest in the use of inhibitors of DNA repair to increase the cytotoxicity of these agents. Poly(ADP-ribose) polymerase (PARP) is an abundant nuclear enzyme that binds to sites of DNA damage and promotes repair by modifying a number of key proteins. Potent and specific inhibitors of PARP are available; these have been shown to increase the cytotoxicity of a range of anti-cancer agents including temozolomide, irinotecan and radiation. Sources of data: Data from laboratory studies on human tumour cell lines, pre-clinical studies including tumour xenograft models and early phase clinical testing in human subjects are discussed. Areas of agreement: Pre-clinical and early clinical testing indicates that PARP inhibitors are extremely well tolerated. As single agents they have activity against BRCA1- and BRCA2-deficient cancers, and in combination they increase the cytotoxic effects of certain chemotherapy agents. Areas of controversy: In order for PARP inhibitors to improve outcomes for patients, their sensitizing effects must be tumour specific. Early clinical data indicate that systemic toxicity may be exacerbated, so future trials must address this issue. The mechanism of action of PARP inhibitors in combination with cytotoxic agents is also uncertain. Growing points: Among BRCA-deficient cancers, mechanisms of inherent and acquired resistance to PARP inhibitors are under investigation. Combining these agents with radiotherapy appears promising but designing clinical trials to test the efficacy and toxicity of this combination is problematic. Areas timely for developing research: A particularly promising role for PARP inhibitors in the treatment of malignant brain tumours is outlined

Structuralism as a Response to Skepticism

Cartesian arguments for global skepticism about the external world start from the premise that we cannot know that we are not in a Cartesian scenario such as an evil-demon scenario, and infer that because most of our empirical beliefs are false in such a scenario, these beliefs do not constitute knowledge. Veridicalist responses to global skepticism respond that arguments fail because in Cartesian scenarios, many or most of our empirical beliefs are true. Some veridicalist responses have been motivated using verificationism, externalism, and coherentism. I argue that a more powerful veridicalist response to global skepticism can be motivated by structuralism, on which physical entities are understood as those that play a certain structural role. I develop the structuralist response and address objections

A general framework for quantifying the effects of DNA repair inhibitors on radiation sensitivity as a function of dose

Purpose. Current methods for quantifying effects of DNA repair modifiers on radiation sensitivity assume a constant effect independent of the radiation dose received. The aim of this study was to develop and evaluate a modelling strategy by which radiation dose dependent effects of DNA repair inhibitors on clonogenic survival might be identified and their significance assessed. Methods. An indicator model that allowed quantification of the Sensitiser Effect on Radiation response as a function of Dose (SERD) was developed. This model was fitted to clonogenic survival data derived from human tumour and rodent fibroblast cell lines irradiated in the presence and absence of chemical inhibitors of poly(ADP-ribose) polymerase (PARP) activity. Results. PARP inhibition affected radiation response in a cell cycle and radiation dose dependent manner, and was also associated with significant radiation-independent effects on clonogenic survival. Application of the SERD method enabled identification of components of the radiation response that were significantly affected by PARP inhibition and indicated the magnitude of the effects on each component. Conclusion. The proposed approach improves on current methods of analysing effects of DNA repair modification on radiation response. Furthermore, it may be generalised to account for other parameters such as proliferation or dose rate to enable its use in the context of fractionated or continuous radiation exposures