Evidence and Policy in Aid-Dependent Settings

This chapter examines how the political dynamics of aid relationships can affect the use of evidence within health policymaking. Empirical examples from Cambodia, Ethiopia and Ghana illustrate how relationships between national governments and donor agencies influence the ways in which evidence is generated, selected, or utilised to inform policymaking. We particularly consider how relationships with donors influence the underlying systems and processes of evidence use. We find a number of issues affecting which bodies or forms of evidence are taken to be policy relevant, including: levels of local technical capacity to utilise or synthesise evidence; differing stakeholder framing of issues; and the influence of non-state actors on sector-wide systems of agenda setting. The chapter also reflects on some of the key governance implications of these arrangements in which global actors promote forms of evidence use – often under a banner of technical efficiency – with limited consideration for local representation or accountability

Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis

FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers1–5. However, the role and the molecular mechanisms by which FAT1 mutations control tumour initiation and progression are poorly understood. Here, using mouse models of skin squamous cell carcinoma and lung tumours, we found that deletion of Fat1 accelerates tumour initiation and malignant progression and promotes a hybrid epithelial-to-mesenchymal transition (EMT) phenotype. We also found this hybrid EMT state in FAT1-mutated human squamous cell carcinomas. Skin squamous cell carcinomas in which Fat1 was deleted presented increased tumour stemness and spontaneous metastasis. We performed transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies, which revealed that loss of function of FAT1 activates a CAMK2–CD44–SRC axis that promotes YAP1 nuclear translocation and ZEB1 expression that stimulates the mesenchymal state. This loss of function also inactivates EZH2, promoting SOX2 expression, which sustains the epithelial state. Our comprehensive analysis identified drug resistance and vulnerabilities in FAT1-deficient tumours, which have important implications for cancer therapy. Our studies reveal that, in mouse and human squamous cell carcinoma, loss of function of FAT1 promotes tumour initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state

Generation of an integrated transcription map of the BRCA2 region on chromosome 13q12-q13

An integrated approach involving physical mapping, identifcation of transcribed sequences, and computational analysis of genomic sequence was used to generate a detailed transcription map of the 1.0-Mb region containing the breast cancer susceptibility locus BRCA2 on chromosome 13q12–q13. This region is included in the genetic interval bounded by D13S1444 and D13S310. Retrieved sequences from exon amplif-cation or hybrid selection procedures were grouped into physical intervals and subsequently grouped into transcription units by clone overlap. Overlap was established by direct hybridization, cDNA library screening, PCR cDNA linking (island hopping), and/ or sequence alignment. Extensive genomic sequencing was performed in an effort to understand transcription unit organization. In total, approximately 500 kb of genomic sequence was completed. The transcription units were further characterized by hybridization to RNA from a series of human tissues. Evidence for seven genes, two putative pseudogenes, and nine additional putative transcription units was obtained. One of the transcription units was recently identifed as BRCA2 but all others are novel genes of unknown function as only limited alignment to sequences in public databases was observed. One large gene with a transcript size of 10.7 kb showed signifcant similarity to a gene predicted by the Caenorhabditis elegans genome and the Saccharomyces cerevisiae genome sequencing efforts, while another contained a motif sequence similar to the human 2*, 3* cyclic nucleotide 3* phosphodies-terase gene. Several retrieved transcribed sequences were not aligned into transcription units because no corresponding cDNAs were obtained when screening libraries or because of a lack of defnitive evidence for splicing signals or putative coding sequence based on computational analysis. However, the presence of additional genes in the BRCA2 interval is suggested as groups of putative exons and hybrid selected clones that were transcribed in consistent orientations could be localized to common physical intervals. q 1996 Academic Press, Inc

Urbanization and mortality in Britain, c. 1800-50.

In the long-running debate over standards of living during the industrial revolution, pessimists have identified deteriorating health conditions in towns as undermining the positive effects of rising real incomes on the 'biological standard of living'. This article reviews long-run historical relationships between urbanization and epidemiological trends in England, and then addresses the specific question: did mortality rise especially in rapidly growing industrial and manufacturing towns in the period c. 1830-50? Using comparative data for British, European, and American cities and selected rural populations, this study finds good evidence for widespread increases in mortality in the second quarter of the nineteenth century. However, this phenomenon was not confined to 'new' or industrial towns. Instead, mortality rose in the 1830s especially among young children (aged one to four years) in a wide range of populations and environments. This pattern of heightened mortality extended between c. 1830 and c. 1870, and coincided with a well-established rise and decline in scarlet fever virulence and mortality. The evidence presented here therefore supports claims that mortality worsened for young children in the middle decades of the nineteenth century, but also indicates that this phenomenon was more geographically ubiquitous, less severe, and less chronologically concentrated than previously argued.Leverhulme Trust (award RPG-2012-803) Wellcome Trust (award no. 103322

Mechanisms of stretch-mediated skin expansion at single-cell resolution.

The ability of the skin to grow in response to stretching has been exploited in reconstructive surgery1. Although the response of epidermal cells to stretching has been studied in vitro2,3, it remains unclear how mechanical forces affect their behaviour in vivo. Here we develop a mouse model in which the consequences of stretching on skin epidermis can be studied at single-cell resolution. Using a multidisciplinary approach that combines clonal analysis with quantitative modelling and single-cell RNA sequencing, we show that stretching induces skin expansion by creating a transient bias in the renewal activity of epidermal stem cells, while a second subpopulation of basal progenitors remains committed to differentiation. Transcriptional and chromatin profiling identifies how cell states and gene-regulatory networks are modulated by stretching. Using pharmacological inhibitors and mouse mutants, we define the step-by-step mechanisms that control stretch-mediated tissue expansion at single-cell resolution in vivo.Wellcome Trust Royal Societ