Replication Stress Drives Constitutive Activation of the DNA Damage Response and Radioresistance in Glioblastoma Stem-like Cells

Glioblastoma (GBM) is a lethal primary brain tumor characterized by treatment resistance and inevitable tumor recurrence, both of which are driven by a subpopulation of GBM cancer stem-like cells (GSC) with tumorigenic and self-renewal properties. Despite having broad implications for understanding GSC phenotype, the determinants of upregulated DNA damage response (DDR) and subsequent radiation resistance in GSC are unknown and represent a significant barrier to developing effective GBM treatments. In this study, we show that constitutive DDR activation and radiation resistance are driven by high levels of DNA replication stress (RS). CD133+ GSC exhibited reduced DNA replication velocity and a higher frequency of stalled replication forks than CD133- non-GSC in vitro; immunofluorescence studies confirmed these observations in a panel of orthotopic xenografts and human GBM specimens. Exposure of non-GSC to low-level exogenous RS generated radiation resistance in vitro, confirming RS as a novel determinant of radiation resistance in tumor cells. GSC exhibited DNA double strand breaks (DSB) which co-localized with 'replication factories' and RNA: DNA hybrids. GSC also demonstrated increased expression of long neural genes (>1Mbp) containing common fragile sites, supporting the hypothesis that replication/transcription collisions are the likely cause of RS in GSC. Targeting RS by combined inhibition of ATR and PARP (CAiPi) provided GSC-specific cytotoxicity and complete abrogation of GSC radiation resistance in vitro. These data identify RS as a cancer stem cell-specific target with significant clinical potential

Real world uptake, safety profile and outcomes of docetaxel in newly diagnosed metastatic prostate cancer

Objectives: To investigate the uptake, safety and efficacy of docetaxel chemotherapy in hormone-naïve metastatic prostate cancer (mPC) in the first year of use outside of a clinical trial. Subjects/patients and Methods: Patients in the West of Scotland Cancer Network (WoSCAN) with newly diagnosed mPC were identified from the regional multidisciplinary team (MDT) meetings and their treatment details were collected from electronic patient records. The rate of febrile neutropenia, hospitalisations, time to progression and overall survival were compared between those patients who received docetaxel and androgen deprivation therapy (ADT), or ADT alone using survival analysis. Results: Out of 270 eligible patients, 103 received docetaxel (38.1%). 35 patients (34%) were hospitalised and there were 17 episodes of febrile neutropenia (16.5%). Two patients (1.9%) died within 30 days of chemotherapy. Patients who received ADT alone had an increased risk of progression (HR 2.03, 95% CI (1.27, 3.25), log-rank test, p= 0.002) and had an increased risk of death (HR 5.88, 95% CI 2.52, 13.72, log-rank p=0.001) compared to the docetaxel group. The risk of febrile neutropenia was nine times greater if chemotherapy was started within three weeks of ADT initiation (95% CI (1.22,77.72) p= 0.032). Conclusion: Docetaxel chemotherapy in hormone-naïve mPC has significant toxicities, but has a similar effect on time to progression and overall survival as seen in randomised trials. Chemotherapy should be started 3 weeks or more after androgen deprivation

Academics, Cultural Workers and Critical Labour Studies

The aim of this paper is to locate academics within the sights of critical labour studies, and, in particular, the contemporary interest in cultural workers. Despite a growing literature about - and in response to - the transformation of the University there have been few attempts to study academics as workers. This paper argues that there are a number of parallels between academic work and the much more well-documented experiences of work in the cultural and creative industries. The paper examines the increasing experience of precariousness among academics, the intensification and extensification of work, and the new modes of surveillance in the academy and their affective impacts. The aim of the article is to build on the critical lexicon of studies of cultural labour in order to think about academic work as labour and to generate new ways of thinking about power, privilege and exploitation. It argues for the need for a psychosocial perspective that can understand the new labouring subjectivities in academia

Identifying the science and technology dimensions of emerging public policy issues through horizon scanning

Public policy requires public support, which in turn implies a need to enable the public not just to understand policy but also to be engaged in its development. Where complex science and technology issues are involved in policy making, this takes time, so it is important to identify emerging issues of this type and prepare engagement plans. In our horizon scanning exercise, we used a modified Delphi technique [1]. A wide group of people with interests in the science and policy interface (drawn from policy makers, policy adviser, practitioners, the private sector and academics) elicited a long list of emergent policy issues in which science and technology would feature strongly and which would also necessitate public engagement as policies are developed. This was then refined to a short list of top priorities for policy makers. Thirty issues were identified within broad areas of business and technology; energy and environment; government, politics and education; health, healthcare, population and aging; information, communication, infrastructure and transport; and public safety and national security.Public policy requires public support, which in turn implies a need to enable the public not just to understand policy but also to be engaged in its development. Where complex science and technology issues are involved in policy making, this takes time, so it is important to identify emerging issues of this type and prepare engagement plans. In our horizon scanning exercise, we used a modified Delphi technique [1]. A wide group of people with interests in the science and policy interface (drawn from policy makers, policy adviser, practitioners, the private sector and academics) elicited a long list of emergent policy issues in which science and technology would feature strongly and which would also necessitate public engagement as policies are developed. This was then refined to a short list of top priorities for policy makers. Thirty issues were identified within broad areas of business and technology; energy and environment; government, politics and education; health, healthcare, population and aging; information, communication, infrastructure and transport; and public safety and national security

Current challenges in software solutions for mass spectrometry-based quantitative proteomics

This work was in part supported by the PRIME-XS project, grant agreement number 262067, funded by the European Union seventh Framework Programme; The Netherlands Proteomics Centre, embedded in The Netherlands Genomics Initiative; The Netherlands Bioinformatics Centre; and the Centre for Biomedical Genetics (to S.C., B.B. and A.J.R.H); by NIH grants NCRR RR001614 and RR019934 (to the UCSF Mass Spectrometry Facility, director: A.L. Burlingame, P.B.); and by grants from the MRC, CR-UK, BBSRC and Barts and the London Charity (to P.C.