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

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

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

Self-esteem and women with disabilities

This study examines the sense of self of women with physical disabilities in terms of self-esteem, self-cognition (perceptions of how others see them), and social isolation. It was hypothesized that these variables mediate the relation of precursor variables (age, education, severity of disability, and childhood experiences, including overprotection, familial affection, and school environment) and outcomes (intimacy, employment, and health promoting behaviors). Data were gathered from a sample of 881 community-dwelling women in the USA, 475 with a variety of mild to severe physical disabilities, and 406 without disabilities. Correlation analyses indicated that the women with disabilities had significantly lower self-cognition and self-esteem, and greater social isolation than the women without disabilities, as well as significantly less education, more overprotection during childhood, poorer quality of intimate relationships, and lower rates of salaried employment. Path analysis indicated that each of the sense of self mediators was significantly related to the outcome of intimacy, that both social isolation and self-esteem were significantly related to health promoting behaviors, and that only self-esteem was significantly related to employment. Respondents who were older, less disabled, less educated, less over-protected, and had more affection shown in the home tended to feel that others saw them more positively. Women with positive school environments, less over-protection, and more affection in the home experienced less social isolation; age, education, and disability severity were not significantly related to social isolation. Older respondents with less disability, a more positive school environment, less over-protection, and more affection in the home tended to have greater self-esteem; education was not significantly related to self-esteem. Older respondents tended to report less intimacy. Younger, more educated, and less disabled respondents were significantly more likely to be employed. More highly educated respondents reported engaging in more health promoting behaviors.Physical disability Self-esteem Women USA