Histone Acetylation-Mediated Regulation of the Hippo Pathway

The Hippo pathway is a signaling cascade recently found to play a key role in tumorigenesis therefore understanding the mechanisms that regulate it should open new opportunities for cancer treatment. Available data indicate that this pathway is controlled by signals from cell-cell junctions however the potential role of nuclear regulation has not yet been described. Here we set out to verify this possibility and define putative mechanism(s) by which it might occur. By using a luciferase reporter of the Hippo pathway, we measured the effects of different nuclear targeting drugs and found that chromatin-modifying agents, and to a lesser extent certain DNA damaging drugs, strongly induced activity of the reporter. This effect was not mediated by upstream core components (i.e. Mst, Lats) of the Hippo pathway, but through enhanced levels of the Hippo transducer TAZ. Investigation of the underlying mechanism led to the finding that cancer cell exposure to histone deacetylase inhibitors induced secretion of growth factors and cytokines, which in turn activate Akt and inhibit the GSK3 beta associated protein degradation complex in drug-affected as well as in their neighboring cells. Consequently, expression of EMT genes, cell migration and resistance to therapy were induced. These processes were suppressed by using pyrvinium, a recently described small molecule activator of the GSK 3 beta associated degradation complex. Overall, these findings shed light on a previously unrecognized phenomenon by which certain anti-cancer agents may paradoxically promote tumor progression by facilitating stabilization of the Hippo transducer TAZ and inducing cancer cell migration and resistance to therapy. Pharmacological targeting of the GSK3 beta associated degradation complex may thus represent a unique approach to treat cancer. © 2013 Basu et al

Blockade of T-cell activation by dithiocarbamates involves novel mechanisms of inhibition of nuclear factor of activated T cells.

Dithiocarbamates (DTCs) have recently been reported as powerful inhibitors of NF-kappaB activation in a number of cell types. Given the role of this transcription factor in the regulation of gene expression in the inflammatory response, NF-kappaB inhibitors have been suggested as potential therapeutic drugs for inflammatory diseases. We show here that DTCs inhibited both interleukin 2 (IL-2) synthesis and membrane expression of antigens which are induced during T-cell activation. This inhibition, which occurred with a parallel activation of c-Jun transactivating functions and expression, was reflected by transfection experiments at the IL-2 promoter level, and involved not only the inhibition of NF-kappaB-driven reporter activation but also that of nuclear factor of activated T cells (NFAT). Accordingly, electrophoretic mobility shift assays (EMSAs) indicated that pyrrolidine DTC (PDTC) prevented NF-kappaB, and NFAT DNA-binding activity in T cells stimulated with either phorbol myristate acetate plus ionophore or antibodies against the CD3-T-cell receptor complex and simultaneously activated the binding of AP-1. Furthermore, PDTC differentially targeted both NFATp and NFATc family members, inhibiting the transactivation functions of NFATp and mRNA induction of NFATc. Strikingly, Western blotting and immunocytochemical experiments indicated that PDTC promoted a transient and rapid shuttling of NFATp and NFATc, leading to their accelerated export from the nucleus of activated T cells. We propose that the activation of an NFAT kinase by PDTC could be responsible for the rapid shuttling of the NFAT, therefore transiently converting the sustained transactivation of this transcription factor that occurs during lymphocyte activation, and show that c-Jun NH2-terminal kinase (JNK) can act by directly phosphorylating NFATp. In addition, the combined inhibitory effects on NFAT and NF-KB support a potential use of DTCs as immunosuppressants

Cornish identities and migration: a multi-scalar approach

The definitive version is available at www.blackwell-synergy.com. 24 month embargo by the publisher. Article will be released July 2009.In this article we argue that theories of transnationalism have value in exploring the historical context of migration and that historical contexts help to shape such theoretical conceptualizations. Historians of migration have now begun to engage more directly with the literature of transnationalism, focusing on the networks that linked settler and home communities. Here we add to this by examining a nineteenth-century migrant community from a British region through the lens of transnationalism, applying the concept to the case of the Cornish, whose economic specialization produced culturally distinct Cornish communities on the mining frontiers of North America, Australia and South Africa. In doing so, we bring together the issues of scale and time. We review the multiple levels of the Cornish transnational space of the late nineteenth century, which exhibited aspects of both core transnationalism and translocalism. This waned, but in the later twentieth century, a renewed interest in a transnational Cornish identity re-emerged, articulating with changing identity claims in Cornwall itself. To capture better the experience of the Cornish over these two very different phases of transnationalism we identify another subset of transnationalism - that of transregionalism.Leverhulme Trus

Lateral adhesion drives reintegration of misplaced cells into epithelial monolayers.

Cells in simple epithelia orient their mitotic spindles in the plane of the epithelium so that both daughter cells are born within the epithelial sheet. This is assumed to be important to maintain epithelial integrity and prevent hyperplasia, because misaligned divisions give rise to cells outside the epithelium. Here we test this assumption in three types of Drosophila epithelium; the cuboidal follicle epithelium, the columnar early embryonic ectoderm, and the pseudostratified neuroepithelium. Ectopic expression of Inscuteable in these tissues reorients mitotic spindles, resulting in one daughter cell being born outside the epithelial layer. Live imaging reveals that these misplaced cells reintegrate into the tissue. Reducing the levels of the lateral homophilic adhesion molecules Neuroglian or Fasciclin 2 disrupts reintegration, giving rise to extra-epithelial cells, whereas disruption of adherens junctions has no effect. Thus, the reinsertion of misplaced cells seems to be driven by lateral adhesion, which pulls cells born outside the epithelial layer back into it. Our findings reveal a robust mechanism that protects epithelia against the consequences of misoriented divisions.The authors are grateful to R. Nieuwburg, the St Johnston group, and other Gurdon Institute members for suggestions. We thank the Bloomington Stock Center, J. Knoblich, and the TRiP at Harvard Medical School (NIH/NIGMS R01-GM084947) for fly stocks. We thank N. Lowe for technical assistance. This work was supported by a Wellcome Trust Principal Fellowship to D.St.J. (080007), and by core support from the Wellcome Trust (092096) and Cancer Research UK (A14492). D.T.B. was supported by a Marie Curie Fellowship and the Wellcome Trust. H.E.L. was supported by a Herchel Smith Studentship.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ncb324

The role of valuation and bargaining in optimising transboundary watercourse treaty regimes

In the face of water scarcity, growing water demands, population increase, ecosystem degradation, climate change, and so on transboundary watercourse states inevitably have to make difficult decisions on how finite quantities of water are distributed. Such waters, and their associated ecosystem services, offer multiple benefits. Valuation and bargaining can play a key role in the sharing of these ecosystems services and their associated benefits across sovereign borders. Ecosystem services in transboundary watercourses essentially constitute a portfolio of assets. Whilst challenging, their commodification, which creates property rights, supports trading. Such trading offers a means by which to resolve conflicts over competing uses and allows states to optimise their ‘portfolios’. However, despite this potential, adoption of appropriate treaty frameworks that might facilitate a market-based approach to the discovery and allocation of water-related ecosystem services at the transboundary level remains both a challenge, and a topic worthy of further study. Drawing upon concepts in law and economics, this paper therefore seeks to advance the study of how treaty frameworks might be developed in a way that supports such a market-based approach to ecosystem services and transboundary waters

A review of the benefits and drawbacks to virtual field guides in today’s Geoscience higher education environment

Virtual Field Guides are a way for educators to tackle the growing issue of funding pressures in areas of higher education, such as geography. Virtual Field Guides are however underutilised and can offer students a different way of learning. Virtual Field Guides have many benefits to students, such as being more inclusive, building student skills and confidence in a controlled environment pre fieldtrip and can increase engagement in the topic studied. There are also benefits to the educator, such as reduced cost, more efficient students on fieldwork tasks and the ability to tailor and update their field guides to suit their needs. However there are drawbacks in the challenge of creation and their outcome as educational standalone tools. This paper reviews the literature around the benefits and draw backs to the creation and incorporation of virtual field guides in geoscience education. © 2017, The Author(s)

Impact of adverse events, treatment modifications, and dose intensity on survival among patients with advanced renal cell carcinoma treated with first‐line sunitinib: a medical chart review across ten centers in five European countries

Angiogenesis inhibitors have become standard of care for advanced and/or metastatic renal cell carcinoma (RCC), but data on the impact of adverse events (AEs) and treatment modifications associated with these agents are limited. Medical records were abstracted at 10 tertiary oncology centers in Europe for 291 patients ≥18 years old treated with sunitinib as first-line treatment for advanced RCC (no prior systemic treatment for advanced disease). Logistic regression models were estimated to compare dose intensity among patients who did and did not experience AEs during the landmark periods (18, 24, and 30 weeks). Cox proportional hazard models were used to explore the possible relationship of low-dose intensity (defined using thresholds of 0.7, 0.8, and 0.9) and treatment modifications during the landmark periods to survival. 64.4% to 67.9% of patients treated with sunitinib reported at least one AE of any grade, and approximately 10% of patients experienced at least one severe (grade 3 or 4) AE. Patients reporting severe AEs were statistically significantly more likely to have dose intensities below either 0.8 or 0.9. Dose intensity below 0.7 and dose discontinuation during all landmark periods were statistically significantly associated with shorter survival time. This study of advanced RCC patients treated with sunitinib in Europe found a significant relationship between AEs and dose intensity. It also found correlations between dose intensity and shorter survival, and between dose discontinuation and shorter survival. These results confirm the importance of tolerable treatment and maintaining dose intensity