The Emerging Role of PARP Inhibitors in the Treatment of Epithelial Ovarian Cancer

Poly(ADP-ribose) polymerase-1 (PARP-1) is an important novel target in cancer therapy. This enzyme is essential in the repair of single-stranded breaks in DNA via the base excision repair pathway. Drugs which inhibit PARP are emerging as a promising new class of anticancer agents particularly effective against tumors which have lost homologous recombination (HR) through loss of functional BRCA1 and BRCA2. PARP inhibitors potentially represent a major breakthrough for patients with hereditary BRCA-associated cancers. Furthermore their role in sporadic epithelial ovarian cancer is emerging with identification of additional subpopulations of women who may benefit a priority. This paper will summarize the mechanism of action of PARP inhibition and its role in the treatment of BRCA1- and 2-associated cancers. We will then expand on the broader relevance and future directions for PARP inhibition in the clinical setting

Spatial variation of hydroclimate in north-eastern North America during the last millennium

Climatic expressions of the Medieval Climate Anomaly (MCA) and the Little Ice Age (LIA) vary regionally, with reconstructions often depicting complex spatial patterns of temperature and precipitation change. The characterisation of these spatial patterns helps advance understanding of hydroclimate variability and associated responses of human and natural systems to climate change. Many regions, including north-eastern North America, still lack well-resolved records of past hydrological change. Here, we reconstruct hydroclimatic change over the past millennium using testate amoeba-inferred peatland water table depth reconstructions obtained from fifteen peatlands across Maine, Nova Scotia, Newfoundland and Québec. Spatial comparisons of reconstructed water table depths reveal complex hydroclimatic patterns that varied over the last millennium. The records suggest a spatially divergent pattern across the region during the Medieval Climate Anomaly and the Little Ice Age. Southern peatlands were wetter during the Medieval Climate Anomaly, whilst northern and more continental sites were drier. There is no evidence at the multi-decadal sampling resolution of this study to indicate that Medieval mega-droughts recorded in the west and continental interior of North America extended to these peatlands in the north-east of the continent. Reconstructed Little Ice Age hydroclimate change was spatially variable rather than displaying a clear directional shift or latitudinal trends, which may relate to local temporary permafrost aggradation in northern sites, and reconstructed characteristics of some dry periods during the Little Ice Age are comparable with those reconstructed during the Medieval Climate Anomaly. The spatial hydroclimatic trends identified here suggest that over the last millennium, peatland moisture balance in north-eastern North America has been influenced by changes in the Polar Jet Stream, storm activities and sea surface temperatures in the North Atlantic as well as internal peatland dynamics

Capability in the digital: institutional media management and its dis/contents

This paper explores how social media spaces are occupied, utilized and negotiated by the British Military in relation to the Ministry of Defence’s concerns and conceptualizations of risk. It draws on data from the DUN Project to investigate the content and form of social media about defence through the lens of ‘capability’, a term that captures and describes the meaning behind multiple representations of the military institution. But ‘capability’ is also a term that we hijack and extend here, not only in relation to the dominant presence of ‘capability’ as a representational trope and the extent to which it is revealing of a particular management of social media spaces, but also in relation to what our research reveals for the wider digital media landscape and ‘capable’ digital methods. What emerges from our analysis is the existence of powerful, successful and critically long-standing media and reputation management strategies occurring within the techno-economic online structures where the exercising of ‘control’ over the individual – as opposed to the technology – is highly effective. These findings raise critical questions regarding the extent to which ‘control’ and management of social media – both within and beyond the defence sector – may be determined as much by cultural, social, institutional and political influence and infrastructure as the technological economies. At a key moment in social media analysis, then, when attention is turning to the affordances, criticisms and possibilities of data, our research is a pertinent reminder that we should not forget the active management of content that is being similarly, if not equally, effective

HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma

CONTEXT: ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. OBJECTIVES: To establish an evidence-based guideline for HER2 testing in patients with GEA, to formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. DESIGN: The College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology convened an expert panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. RESULTS: The panel is proposing 11 recommendations with strong agreement from the open-comment participants. RECOMMENDATIONS: The panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and a HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. CONCLUSIONS: This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results

HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology

-ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the as

Integrative analyses identify modulators of response to neoadjuvant aromatase inhibitors in patients with early breast cancer

Introduction Aromatase inhibitors (AIs) are a vital component of estrogen receptor positive (ER+) breast cancer treatment. De novo and acquired resistance, however, is common. The aims of this study were to relate patterns of copy number aberrations to molecular and proliferative response to AIs, to study differences in the patterns of copy number aberrations between breast cancer samples pre- and post-AI neoadjuvant therapy, and to identify putative biomarkers for resistance to neoadjuvant AI therapy using an integrative analysis approach. Methods Samples from 84 patients derived from two neoadjuvant AI therapy trials were subjected to copy number profiling by microarray-based comparative genomic hybridisation (aCGH, n = 84), gene expression profiling (n = 47), matched pre- and post-AI aCGH (n = 19 pairs) and Ki67-based AI-response analysis (n = 39). Results Integrative analysis of these datasets identified a set of nine genes that, when amplified, were associated with a poor response to AIs, and were significantly overexpressed when amplified, including CHKA, LRP5 and SAPS3. Functional validation in vitro, using cell lines with and without amplification of these genes (SUM44, MDA-MB134-VI, T47D and MCF7) and a model of acquired AI-resistance (MCF7-LTED) identified CHKA as a gene that when amplified modulates estrogen receptor (ER)-driven proliferation, ER/estrogen response element (ERE) transactivation, expression of ER-regulated genes and phosphorylation of V-AKT murine thymoma viral oncogene homolog 1 (AKT1). Conclusions These data provide a rationale for investigation of the role of CHKA in further models of de novo and acquired resistance to AIs, and provide proof of concept that integrative genomic analyses can identify biologically relevant modulators of AI response

A REPORT BY THE ALL - PARTY PARLIAMENTARY GROUP ON A FIT AND HEALTHY CHILDHOOD THE IMPACT OF SOCIAL AND ECONOMIC INEQUALITIES ON CHILDREN’S HEALTH

A child born into circumstances of social and economic inequality in the 21st century United Kingdom will start life with one hand tied behind their back. Nowhere is the disparity of experience more marked than in that of health and this, in turn, impacts the entire life course. In the same way that priority is given to securing the national infrastructure, prioritising the health of children from all areas and in all circumstances from the outset would therefore seem to be prudent rather than profligate. Yet as this Report demonstrates,successive Governments have skimped rather thansaved; failedto build upon existing policy and played a costly policy game of ‘catching up later’ instead of deploying the early ntervention me asures that are cheaper andmore effective in the long term