Fulfilling Lives: Supporting people with multiple needs, Evaluation Report, Year 1

This report is prepared for the Big Lottery Fund (the Fund) by the national evaluationteam and provides emerging findings and lessons learned from the first year of thenational evaluation of the Fulfilling Lives: Supporting people with multiple needsinitiative hereafter referred to as Fulfilling Lives (multiple needs).The national evaluation has been designed to determine the degree to which the initiativeis successfully achieving its aims and how they are being achieved. The evaluation will beboth formative and summative in nature, in that, it will inform the ongoing design and delivery of Fulfilling Lives (multiple needs) and its component projects as well as assessoverall achievements and value for money to inform future decision and policy making.Within this context, the evaluation has a number of objectives:— To track and assess the achievements of the initiative and to estimate the extent to whichthese are attributable to the projects and interventions delivered.— To calculate the costs of the projects and the corresponding value of benefits to theexchequer and wider society. This will enable an assessment of value for money of theprogramme and for individual interventions.— To identify what interventions and approaches work well, for which people, families andcommunities and in which circumstances and contexts.— To assess the extent to which the Big Lottery Fund's principles are incorporated into projectdesign and delivery and to determine the degree to which these principles affect successfuldelivery and outcomes.— To explore project implementation, understand problems faced and to facilitate theidentification of solutions and lessons learned

Historical flash floods in England:new regional chronologies and database

There is increasing interest in past occurrences of flooding from intense rainfall, commonly referred to as “flash flooding,” and the associated socioeconomic consequences. Historical information can help us to place recent events in context and to understand the effect of low frequency climate variability on changing flash flood frequencies. Previous studies have focussed on fluvial flooding to reconstruct the temporal and spatial patterns of past events. Here, we provide an online flood chronology for the north and south‐west of England for flash floods, including both surface water and fluvial flooding, with coverage from ~1700 to ~2013 (http://ceg-fepsys.ncl.ac.uk/fc). The primary source of documentary material is local newspaper reports, which often give detailed descriptions of impacts. This provides a new resource to inform communities and first responders of flood risks, especially those from rapid rise in water level whose severity may be greater than those of accompanying peak flow. Examples are provided of historical flash floods that exemplify how the chronologies can help to place recent floods in the context of the preinstrumental record for: (a) more robust estimates of event return period, (b) identification of catchment or settlement susceptibility to flash flood events, and (c) characterisation of events in ungauged catchments

HES5 silencing is an early and recurrent change in prostate tumourigenesis.

Prostate cancer is the most common cancer in men, resulting in over 10 000 deaths/year in the UK. Sequencing and copy number analysis of primary tumours has revealed heterogeneity within tumours and an absence of recurrent founder mutations, consistent with non-genetic disease initiating events. Using methylation profiling in a series of multi-focal prostate tumours, we identify promoter methylation of the transcription factor HES5 as an early event in prostate tumourigenesis. We confirm that this epigenetic alteration occurs in 86-97% of cases in two independent prostate cancer cohorts (n=49 and n=39 tumour-normal pairs). Treatment of prostate cancer cells with the demethylating agent 5-aza-2'-deoxycytidine increased HES5 expression and downregulated its transcriptional target HES6, consistent with functional silencing of the HES5 gene in prostate cancer. Finally, we identify and test a transcriptional module involving the AR, ERG, HES1 and HES6 and propose a model for the impact of HES5 silencing on tumourigenesis as a starting point for future functional studies.The authors are grateful to study volunteers for their participation and staff at the Welcome Trust Clinical Research Facility, Addenbrooke’s Clinical Research Centre, Cambridge. They also thank the NIHR Cambridge Biomedical Research Centre, the DOH HTA (ProtecT grant), and the NCRI/MRC (ProMPT grant) for help with the bio-repository, The University of Cambridge, Hutchison Whampoa Limited and Cancer Research UK for funding. They are grateful to the CRUK Cambridge Institute Genomics and Bioinformatics Core Facilities. Cross-validation of HES5 methylation includes the use of data generated by the TCGA Research Network.This is the final version of the article. It was originally published in the Endocrine-Related Cancer, April 1, 2015 22 131-144 doi: 10.1530/ERC-14-0454

The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer.

The androgen receptor (AR) is the dominant growth factor in prostate cancer (PCa). Therefore, understanding how ARs regulate the human transcriptome is of paramount importance. The early effects of castration on human PCa have not previously been studied 27 patients medically castrated with degarelix 7 d before radical prostatectomy. We used mass spectrometry, immunohistochemistry, and gene expression array (validated by reverse transcription-polymerase chain reaction) to compare resected tumour with matched, controlled, untreated PCa tissue. All patients had levels of serum androgen, with reduced levels of intraprostatic androgen at prostatectomy. We observed differential expression of known androgen-regulated genes (TMPRSS2, KLK3, CAMKK2, FKBP5). We identified 749 genes downregulated and 908 genes upregulated following castration. AR regulation of α-methylacyl-CoA racemase expression and three other genes (FAM129A, RAB27A, and KIAA0101) was confirmed. Upregulation of oestrogen receptor 1 (ESR1) expression was observed in malignant epithelia and was associated with differential expression of ESR1-regulated genes and correlated with proliferation (Ki-67 expression).We thank CRUK, The NIHR, The Academy of Medical Sciences(RG:63397) and the National Cancer Research Prostate Cancer: Mechanisms of Progression and Treatment (ProMPT) collaborative (G0500966/75466), Hutchison Whampoa Limited, the Human Research Tissue Bank (Addenbrooke’s Hospital, supported by the NIHR Cambridge BRC), and Cancer Research UK

Developing observational methods to drive future hydrological science: can we make a start as a community?

Hydrology is still, and for good reasons, an inexact science, even if evolving hydrological understanding has provided a basis for improved water management for at least the last three millennia. The limitations of that understanding have, however, become much more apparent and important in the last century as the pressures of increasing populations, and the anthropogenic impacts on catchment forcing and responses, have intensified. At the same time, the sophistication of hydrological analyses and models has been developing rapidly, often driven more by the availability of computational power and geographical data sets than any real increases in understanding of hydrological processes. This sophistication has created an illusion of real progress but a case can be made that we are still rather muddling along, limited by the significant uncertainties in hydrological observations, knowledge of catchment characteristics and related gaps in conceptual understanding, particularly of the sub-surface. These knowledge gaps are illustrated by the fact that for many catchments we cannot close the water balance without significant uncertainty, uncertainty that is often neglected in evaluating models for practical applications