ORGAN SPECIFIC VASCULAR RESPONSE TO FIBROSIS AFFECTS BREAST CANCER METASTATIC ORGANOTROPISM

The solid tumor microenvironment, pre-metastatic niche, and fibrotic environment are known to have significant biochemical and biomechanical similarities to the fibrotic environment. All have significantly increased levels of factors such as TGFβ, HIF1α, TNFα, PDGF, VEGF, FGF, interleukins and other growth factors that are known to be pro-tumorigenic. Clinical and basic science research has shown that fibrosis presents an environment that favors tumor growth, such as hepatocellular carcinoma being commonly preceded by liver cirrhosis, or bleomycin induced lung fibrosis enhancing pulmonary metastasis in mouse models of breast cancer. In addition to the evidence indicating that fibrosis enhances primary tumor growth and metastasis it is also well characterized that primary tumor metastasis has specific organotropism, for example breast cancer commonly spreads to the lungs, brain, bone, liver and lymph nodes. However, whether non-organtropic fibrosis can redirect metastasis to the damaged organ has not been investigated. To elucidate the fibrotic effect on tumor organotropism we induced fibrosis in the organotropic lungs and in the non-organotropic kidney of two mouse models of breast cancer, the 4T1 murine cancer cell line model and the genetic MMTV-Pymt model, both of which are known to metastasize. Using histopathology, microarrays, gene expression by polymerase chain reaction, ELISA, chemokine array, and in vitro experiments we demonstrate that despite the pro-tumorigenic environment, kidney fibrosis does not redirect metastasis to the non-organotropic damaged organ. However, mice with kidney fibrosis had increased metastasis to their lungs. Furthermore, we found that kidney fibrosis increases the circulating levels of the pro-angiogenic factor Angiopoietin 2 that increased vascular permeability of the lungs, but not the kidneys. In fact, while fibrotic lungs showed decreased expression of endothelial tight gap junction protein Claudin-5, the fibrotic kidneys had an elevated expression of Claudin-5. Our findings suggest that despite the similarities between fibrosis, the tumor microenvironment and the pre-metastatic niche, that while it can enhance tropic metastatic disease, it cannot redirect organotropism indicating that other factors must be involved in directing organotropism. Here we report that tumor organotropism may be a result of organ specific vascular responses to excess circulating factors and increased fibrotic factors. These findings indicate that organotropism is directly related to and as a result of organ specific vascular alterations

Taking Prudence Seriously

Philosophers have long theorized about which things make people’s lives go well, and why, and the extent to which morality and self-interest can be reconciled. Yet little time has been spent on meta-prudential questions, questions about prudential discourse. This is surprising given that prudence is, prima facie, a normative form of discourse and, as such, cries out for further investigation. Chapter 4 takes up two major meta-prudential questions. It first examines whether there is a set of prudential reasons, generated by evaluative prudential properties, and defends the view that evaluative well-being facts generate agent-relative reasons for the relevant agent. It also investigates whether prudential discourse is normative. It is proposed that prudential discourse is normative by arguing that prudential judgements are normative judgements. The case for this is presented by analogy with moral discourse by showing that the features of moral judgements that metaethicists appeal to when articulating, explaining, and justifying the claim that moral judgements are normative are also possessed by prudential judgements. Various objections to the analogy are also considered

"Anything can happen" : narrative ambiguity and musical intertextuality in THE HOLIDAY

Romantic comedies are not renowned for intricate storytelling and have rarely been deemed worthy of the sustained scholarly attention of analytic ‘close readings’. What applies to the genre as a whole applies no less to its music, which has yet to be discovered by film musicology as a field of enquiry. But genre films such as romcoms can be highly self-conscious and self-reflexive, and can show a playfulness in their use of cinematic techniques that may be as much fun for the analyst as for the audience

The benefits of applying wound-bed preparation into practice

Original article can be found at: http://www.journalofwoundcare.com/ Copyright MA HealthcarePeer reviewe

'Does he look like a Paki?' an exploration of 'whiteness', positionality and reflexivity in inter-racial sports research1851)

This article reflects on fieldwork with white and British Asian cricketers which explored the construction, maintenance and contestation of racialised identities in the sport of cricket. It addresses my experiences of gaining access to and working alongside both communities, particularly as I negotiated insecurities over the suitability of my own identity(ies), the normalisation of ‘whiteness’ and the constant awareness of my insider and outsiderness within different contexts. I draw on personal experiences and fieldnotes to argue that one’s insider or outsider status is never certain; rather it is filled with dissonance and ambiguity, is an ongoing performance and is always in a state of flux. I provide evidence to show how white researchers (of sport) are, at times, culpable of reinforcing dominant racial discourses rather than challenging them. I conclude by arguing that if sociologists of sport are to establish a methodological framework for researching ‘race’ and its intersections, more scholars need to engage with the relationships between self and other and the self-as-other; more freely exploring the nature of reflexivity, and how doing reflexivity presents opportunities to connect with people across (and in spite of) cultural divides