PO-099 Targeting the mitogen activated protein kinase ERK5 in human melanoma

Introduction Melanoma is the most aggressive skin cancer with a poor prognosis in advanced stages. Available treatments for melanoma are unsatisfactory, because rapidly lead to an acquired resistance in the majority of cases. Therefore, there is urgent need to identify novel possible targets involved in melanoma growth. ERK5/BMK1 is a member of the Mitogen-Activated Protein Kinases (MAPK) family and regulates cell functions critical for tumour development. Indeed, several studies reported a direct involvement of ERK5 in several types of cancer including prostate and breast cancer and hepatocellular carcinoma. However, no data have been reported about a possible role of ERK5 in melanoma. Material and methods Cell lines and patient-derived primary melanoma cells (wild type B-RAF: SSM2c and M26c; BRAFV600E: A375, SK-Mel-5, SK-Mel-28, 501-Mel, expressing; NRASQ61R: SK-Mel-2; MeWo) have been used for in vitro and in vivo experiments. HEK293T cells were used for protein overexpression. ERK5 inhibition was achieved using ERK5 and MEK5 inhibitors or lentiviral vectors encoding shRNA specific for ERK5. BRAF inhibition was achieved using Vemurafenib, a BRAFV600E inhibitor. Results and discussions In silico data analysis indicated that components of the ERK5 pathway are upregulated in up to 47% melanoma patients. Accordingly, we found that ERK5 is consistently expressed and active in commercial and patients derived melanoma cell lines. On that basis, we investigated the role of ERK5 in melanoma cell growth. In vitro , pharmacological or genetic inhibition of ERK5 decreased the number of viable cells in several melanoma cell lines. Moreover, xenografts performed using LV-shERK5-transduced A375 or SSM2c cells showed a reduced tumour growth when compared to those transduced with control LV-shC. We also found that oncogenic BRAF positively regulates expression, phosphorylation and nuclear localization of exogenous and endogenous ERK5. Accordingly, combined pharmacological inhibition of BRAFV600E and MEK5 is required to decrease nuclear ERK5, that is critical for the regulation of cell proliferation. Furthermore, the combination of MEK5 or ERK5 inhibitors with vemurafenib is more effective than single treatments in reducing 2D colony formation and growth of BRAFV600E melanoma cells and xenografts. Conclusion Our results identify ERK5 as a critical regulator of melanoma growth in vitro and in vivo , and point toward the possibility of targeting ERK5, alone or in combination with BRAF-MEK1/2 inhibitors, for the treatment of melanoma

Effect of the Orbital Level Difference in Doped Spin-1 Chains

Doping of a two-orbital chain with mobile S=1/2 Fermions and strong Hund's rule couplings stabilizing the S=1 spins strongly depends on the presence of a level difference among these orbitals. By DMRG methods we find a finite spin gap upon doping and dominant pairing correlations without level-difference, whereas the presence of a level difference leads to dominant charge density wave (CDW) correlations with gapless spin-excitations. The string correlation function also shows qualitative differences between the two models.Comment: 4 pages, 4 figure

Rethinking the social impacts of the arts

The paper presents a critical discussion of the current debate over the social impacts of the arts in the UK. It argues that the accepted understanding of the terms of the debate is rooted in a number of assumptions and beliefs that are rarely questioned. The paper goes on to present the interim findings of a three‐year research project, which aims to rethink the social impact of the arts, with a view to determining how these impacts might be better understood. The desirability of a historical approach is articulated, and a classification of the claims made within the Western intellectual tradition for what the arts “do” to people is presented and discussed

Size Dependence In The Disordered Kondo Problem

We study here the role randomly-placed non-magnetic scatterers play on the Kondo effect. We show that spin relaxation effects (with time $\tau_s^o$)in the vertex corrections to the Kondo self-energy lead to an exact cancellation of the singular temperature dependence arising from the diffusion poles. For a thin film of thickness $L$ and a mean-free path $\ell$, disorder provides a correction to the Kondo resistivity of the form $\tau_s^o/(k_FL\ell^2)\ln T$ that explains both the disorder and sample-size depression of the Kondo effect observed by Blachly and Giordano (PRB {\bf 51}, 12537 (1995)).Comment: 11 pages, LaTeX, 2 Postscript figure

When probabilistic seismic hazard climbs volcanoes: the Mt. Etna case, Italy – Part 2: Computational implementation and first results

Abstract. This paper describes the model implementation and presents results of a probabilistic seismic hazard assessment (PSHA) for the Mt. Etna volcanic region in Sicily, Italy, considering local volcano-tectonic earthquakes. Working in a volcanic region presents new challenges not typically faced in standard PSHA, which are broadly due to the nature of the local volcano-tectonic earthquakes, the cone shape of the volcano and the attenuation properties of seismic waves in the volcanic region. These have been accounted for through the development of a seismic source model that integrates data from different disciplines (historical and instrumental earthquake datasets, tectonic data, etc.; presented in Part 1, by Azzaro et al., 2017) and through the development and software implementation of original tools for the computation, such as a new ground-motion prediction equation and magnitude–scaling relationship specifically derived for this volcanic area, and the capability to account for the surficial topography in the hazard calculation, which influences source-to-site distances. Hazard calculations have been carried out after updating the most recent releases of two widely used PSHA software packages (CRISIS, as in Ordaz et al., 2013; the OpenQuake engine, as in Pagani et al., 2014). Results are computed for short- to mid-term exposure times (10 % probability of exceedance in 5 and 30 years, Poisson and time dependent) and spectral amplitudes of engineering interest. A preliminary exploration of the impact of site-specific response is also presented for the densely inhabited Etna's eastern flank, and the change in expected ground motion is finally commented on. These results do not account for M  >  6 regional seismogenic sources which control the hazard at long return periods. However, by focusing on the impact of M  <  6 local volcano-tectonic earthquakes, which dominate the hazard at the short- to mid-term exposure times considered in this study, we present a different viewpoint that, in our opinion, is relevant for retrofitting the existing buildings and for driving impending interventions of risk reduction

Earthquake source parameters and scaling relationships in Hungary (central Pannonian basin)

Abstract Fifty earthquakes that occurred in Hungary (central part of the Pannonian basin) with local magnitude ML ranging from 0.8 to 4.5 have been analyzed. The digital seismograms used in this study were recorded by six permanent broad-band stations and twenty short-period ones at hypocentral distances between 10 and 327 km. The displacement spectra for P- and SH-waves were analyzed according to Brune’s source model. Observed spectra were corrected for path-dependent attenuation effects using an independent regional estimate of the quality factor QS. To correct spectra for near-surface attenuation, the k parameterwas calculated, obtaining it fromwaveforms recorded at short epicentral distances. The values of the k parameter vary between 0.01 to 0.06 s with a mean of 0.03 s for P-waves and between 0.01 to 0.09 s with a mean of 0.04 s for SH-waves. After correction for attenuation effects, spectral parameters (corner frequency and low-frequency spectral level) were estimated by a grid search algorithm. The obtained seismic moments range from4.21×1011 to 3.41×1015 Nm (1.7≤Mw ≤4.3). The source radii are between 125 and 1343 m. Stress drop values vary between 0.14 and 32.4 bars with a logarithmic mean of 2.59 bars (1 bar = 105 Pa). From the results, a linear relationship between local andmomentmagnitudes has been established. The obtained scaling relations show slight evidence of self-similarity violation. However, due to the high scatter of our data, the existence of self-similarity cannot be excluded

The ARROWS project: Adapting and developing robotics technologies for underwater archaeology

ARchaeological RObot systems for the World's Seas (ARROWS) EU Project proposes to adapt and develop low-cost Autonomous Underwater Vehicle (AUV) technologies to significantly reduce the cost of archaeological operations, covering the full extent of archaeological campaign. ARROWS methodology is to identify the archaeologists requirements in all phases of the campaign and to propose related technological solutions. Starting from the necessities identified by archaeological project partners in collaboration with the Archaeology Advisory Group, a board composed of European archaeologists from outside ARROWS, the aim is the development of a heterogeneous team of cooperating AUVs capable of comply with a complete archaeological autonomous mission. Three new different AUVs have been designed in the framework of the project according to the archaeologists' indications: MARTA, characterized by a strong hardware modularity for ease of payload and propulsion systems configuration change; U-C AT, a turtle inspired bio-mimetic robot devoted to shipwreck penetration and A-Size AUV, a vehicle of small dimensions and weight easily deployable even by a single person. These three vehicles will cooperate within the project with AUVs already owned by ARROWS partners exploiting a distributed high-level control software based on the World Model Service (WMS), a storage system for the environment knowledge, updated in real-time through online payload data process, in the form of an ontology. The project includes also the development of a cleaning tool for well-known artifacts maintenance operations. The paper presents the current stage of the project that will lead to overall system final demonstrations, during Summer 2015, in two different scenarios, Sicily (Italy) and Baltic Sea (Estonia

The participation myth

Policy rhetoric around strategies to and the value of increasing participation in the arts has been well documented internationally over more than a decade. But in the UK, which is the focus for this article, targets to increase participation have been consistently missed and there remains a direct correlation between those taking part in cultural activity and their socio-economic status. The starting point for this article is to examine the barriers to increasing participation in the arts and question the way that such policy has been implemented within the English context, which may have relevance for policy making in other countries. What is demonstrated is that policy implementation is influenced by vested interest of those in receipt of funding and that a narrow range of voices, from a powerful cultural elite, are involved in the decision making in the arts. The article makes a case for widening the range of voices heard in decision making in order to support both artistic practice and public engagement

Institutional creativity and pathologies of potential space: The modern university

This paper proposes the applicability of object relations psychoanalytic conceptions of dialogue (Ogden, 1986, 1993) to thinking about relationships and relational structures and their governance in universities. It proposes that: the qualities of dialogic relations in creative institutions are the proper index of creative productivity; that is of, as examples, ’thinking’ (Evans, 2004), ’emotional learning’ (Salzberger-Wittenburg et al., 1983) or ’criticality’ (Barnett, 1997); contemporary institutions’ explicit preoccupation in assuring, monitoring and managing creative ’dialogue’ can, in practice, pervert creative processes and thoughtful symbolic productivity, thus inhibiting students’ development and the quality of ’thinking space’ for teaching and research. In this context the paper examines uncanny and perverse connections between Paulo Freire’s (1972) account of educational empowerment and dialogics (from his Pedagogy of the oppressed) to the consumerist (see, for example, Clarke & Vidler, 2005) rhetoric of student empowerment, as mediated by some strands of managerialism in contemporary higher education. The paper grounds its critique of current models of dialogue, feedback loops, audit and other mechanisms of accountability (Power, 1997; Strathern, 2000), in a close analysis of how creative thinking emerges. The paper discusses the failure to maintain a dialogic space in humanities and social science areas in particular, exploring psychoanalytic conceptions from Donald Winnicott (1971), Milner (1979), Thomas Ogden (1986) and Csikszentmihalyi (1997). Coleridge’s ideas about imagination as the movement of thought between subjective and objective modes are discussed in terms of both intra- and inter-subjective relational modes of ’dialogue’, which are seen as subject to pathology in the pathologically structured psychosocial environment. Current patterns of institutional governance, by micromanaging dialogic spaces, curtail the ’natural’ rhythms and temporalities of imagination by giving an over-emphasis to the moment of outcome, at the expense of holding the necessary vagaries of process in the institutional ’mind’. On the contrary, as this paper argues, creative thinking lies in sporadic emergences at the conjunction of object/(ive) outcome and through (thought) processes

A creative industries perspective on creativity and culture

The chapter considers changing definitions of creativity in relation to UK cultural policy and practice in the creative industries. Three perspectives are introduced, beginning with the notion of creativity as a product of individual creativity and talent, popularised by the UK government’s 1998 Creative Industries Mapping Document. This perspective is contrasted with an older model of creativity as a collective expression of shared values, as emphasised in earlier cultural industries policies of the 1970s and 1980s. Finally, the chapter considers contemporary views of creativity in the creative industries as participatory, user-generated, remixed and ‘democratized’. The chapter concludes that there is value in all three perspectives—the challenge for policy makers, managers and practitioners in the creative industries is connecting together individual self-expression with collective cultural values