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This article reviews the literature on non-profit volunteering to argue that the concept of ‘work calling’ is critical to broadening our understanding of volunteer motivation and retention. As an emerging concept, work calling is generally used to explain how individuals satisfy their calling by doing meaningful work. This concept is introduced to the issue of volunteer motivation and retention to detail why volunteers decide to join non-profit organisations and then willingly stay longer. Current theories explain volunteer motivation and retention by focusing on individual factors (commitment and job satisfaction) and organisational factors (management practices, volunteer tasks and organisational reputation). This article integrates work calling with these theories and thus contributes two important insights: (a) volunteers may choose to engage in meaningful work and, therefore, experience self-satisfaction and meaningful life by volunteering; and (b) work calling improves current theories of volunteering motivation and retention at both the individual and organisational levels.

The compact linear accelerator for research and applications (CLARA) is an ultrabright electron beam test facility being developed at STFC Daresbury Laboratory. The ultimate aim of CLARA is to test advanced free electron laser (FEL) schemes that can later be implemented on existing and future short-wavelength FELs. In addition, CLARA is a unique facility to provide a high-quality electron beam to test novel concepts and ideas in a wide range of disciplines and to function as a technology demonstrator for a future United Kingdom x-ray FEL facility. CLARA is being built in three phases; the first phase, or front end (FE), comprises an S-band rf photoinjector, a linac, and an S-bend merging with the existing versatile electron linear accelerator beam line; the second phase will complete the acceleration to full beam energy of 250 MeV and also incorporate a separate beam line for use of electrons at 250 MeV; and the third phase will include the FEL section. The CLARA FE was commissioned during 2018, and the facility was later made available for user experiments. Significant advancements have been made in developing high-level software and a simulation framework for start-to-end simulations. The high-level software has been successfully used for unmanned rf conditioning and for characterization of the electron beam. This paper describes the design of the CLARA FE, performance of technical systems, high-level software developments, preliminary results of measured beam parameters, and plans for improvements and upgrades. © 2020 authors. Published by the American Physical Society.

Heeding calls to generate a creative synthesis between business history and organisation studies, this article analyses the emergence, institutionalisation and digitalisation of record pooling practices through the lens of institutional work. By developing an ‘analytically structured history’, this article contributes to the field of business history by demonstrating the value of practice and boundary work as organising categories. Practice and boundary work capture the continuous, recursive relations between structure and agency when constructing narrative explanations. It also contributes to neo-institutionalist history by demonstrating the embeddedness of institutional work – the everyday motivations and actions to revise practices and boundaries are shown to be intimately shaped by the conditions and affordances of historically-situated technologies.

How does the articulation of a business idea take place? Despite the extent of research on opportunities, there is still a lack of insight into the experience of opportunity pursuit. Opportunity research identifies a gap in understanding the transition between imagined and real structures, from individual aspirations to social structures. Adopting a practice perspective to the pursuit of opportunities implies the individual mind is no longer the sole setting of opportunity pursuit. Instead, we prioritise the practices and underlying activities which drive opportunity pursuit. Taking an enterprise development program as the site of our study, we conduct a video ethnography to observe a group of nascent entrepreneurs as they develop their business ideas. Our study identifies key practices that emerged as participants developed their business idea. The relational, aesthetic and sociomaterial dimensions of these practices implies an alternative perspective to the prevailing individualistic and cognitive impression of how opportunities are pursued.

PurposeEntrepreneurship research in the context of developing countries has typically investigated the ways in which culture, politics or economic institutions prohibit or enable entrepreneurial activities using macro-level surveys and deductive designs. In contrast, the purpose of this paper is to take a micro-institutional perspective to study these three institutions influencing entrepreneurial activities in such a context.Design/methodology/approachThe analysis is based on inductive, qualitative field data from a challenging institutional environment, Tanzania. This includes two focus groups, one with experts and one with entrepreneurs; and 24 individual interviews with entrepreneurs.FindingsEntrepreneurial activities in Tanzania are not constrained only by bureaucracy and arbitrary enforcement, access to capital, competition and consumer spending, but also by language barriers, negative media portrayals and gender disparity. In their favour, recent trade policy, opening up of borders and changing gender relations, has led to more opportunities, but just as important are traditional festivals, marital gift-giving and familial support. Entrepreneurs respond to institutional constraints in many creative ways, including undertaking entrepreneurial strategies, developing inner strength, joining associations, giving back to communities and skilfully managing relations with authorities.Originality/valueThe fine-grained discussion of the findings of this study specifically contributes to theory by illustrating the constraining and enabling role of under-represented institutions, such as festivals and marriages, as well as entrepreneurial creative responses that define everyday entrepreneurial life in a developing country.

Entrepreneurship is widely recognized to play a crucial role in transitioning societies towards sustainability, yet sustainable ventures often have difficulty in attracting talented management employees that are necessary to scale their sustainable opportunities. This study examined 19 qualitative interviews with three interview groups (human resource managers of sustainable ventures, recently hired employees at sustainable ventures, and management professionals looking for employment opportunities) to explain the impediments of attracting management talent and what competitive advantages sustainable ventures may have in the labour market. We discuss how these findings have theoretical and practical implications for scholars and sustainable entrepreneurs by drawing out a number of ways that sustainable ventures may attract management professionals.

It is well known that bereavement presents major challenges of adjustment to the individuals so affected, but what is much less well recognized is the major challenges bereavement can present to organizations in general and their managers and human resources professionals in particular. This article explores the significance of death for the workplace and argues that organization that fail to give adequate attention to such matters will be poorly placed when it comes to promoting workplace well-being.

Mullins (1996) makes the important point that: We live in an organisational world. Organisations of one form or another are a necessary part of our society and serve many important needs … Organisations play a major and continuing role in the lives of us all, especially with the growth of large-scale business organisations and the divorce of ownership from management. It is important, therefore, to understand how organisations function and the pervasive influences which they exercise over the behaviour of people. (p. 4)

Non-small cell lung cancer (NSCLC) molecular profiling is a key factor in treatment selection. Although, patients with NSCLC tumors harboring EGFR or ALK mutations can benefit from personalized therapies, there are currently no approved targeted therapies for KRAS mutant tumors which occur in 25% to 30% of patients with NSCLC. The constitutive activation of the MAPK pathway in these tumors provides a rationale for targeting effectors such as MEK1/2 (MEK) or ERK1/2 (ERK). Inhibitor of MEK kinase have been tested clinically in KRAS-mutant NSCLC but results have been disappointing, possibly because compensatory signaling such as the reactivation of ERK is triggered following the inhibition of MEK, leading to cancer cell survival. Therefore, targeting ERK directly represents an attractive therapeutic approach. As previously described, we have developed a novel, potent and selective ERK inhibitor identified by fragment-based drug discovery which has potent activity in vitro and in vivo. Here, we demonstrate the activity of this lead compound in KRAS-mutant NSCLC models. Our novel ERK inhibitor was tested in a panel of 440 human cancer cell lines of which the KRAS NSCLC population was identified as particularly sensitive. 62% of the KRAS-mutant NSCLC cell lines tested, exhibited antiproliferative IC50s ranging from 1 nM to 500 nM. This lead compound also inhibited ERK downstream signaling in KRAS NSCLC models both in vitro and in vivo. Indeed, the phosphorylation level of the ERK substrate, RSK, was strongly decreased in HCC-44 and Calu-6 xenograft tumors 2h after oral administration of the lead compound at 50 mg/kg. Levels of pRSK remained below those of untreated tumors for up to 16h in HCC-44 tumors and 24h in Calu-6 tumors. We also confirmed that, the ERK inhibitor conferred a decrease in phosphorylation of ERK itself in both models. The inhibition of ERK signaling corresponded to significant anti-tumor activity in these models with a daily oral administration of 50 mg/kg compound leading to significant tumor regression in subcutaneous models of HCC-44 (18.3% T/C) and Calu-6 (8.9% T/C) xenograft tumors. This work demonstrates the in vitro and in vivo activity of a novel, highly potent, selective ERK inhibitor in models of KRAS-mutant NSCLC. These data support the further optimisation of this series of compounds for clinical development. Citation Format: Aurelie Courtin, Luke Bevan, Tom Heightman, Birikiti Kidane, Justyna Kucia-Tran, John Lyons, Sandra Muench, Alpesh Shah, Lukas Stanczuk, Neil Thompson, Nicola Wallis, Nicola Wilsher, Joanne Munck. A novel ERK1/2 inhibitor has potent activity in KRAS-mutant non-small cell lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5781.

Objective: To pilot a brief cognitive behavioral therapy-based intervention designed to enhance client empowerment and the therapeutic alliance with the aim of reducing clozapine discontinuation. Design: Randomized controlled trial with two conditions: therapy (Alliance Enhancement Therapy [AET]) and control (psychoeducation alone). Assess ments took place at: baseline, twelve weeks and twenty-four weeks (follow-up). The primary outcomes were levels of empowerment, alliance with the clinical team and clozapine discontinuation. Secondary outcomes included insight and other clinical measures. Methods: Treatment-resistant patients who had a diagnosis of schizophrenia, had been registered for clozapine in the previous month and who consented, were independently randomized to active versus control therapy. Results: Thirty-nine patients entered the study. Both groups improved on the main measures with no differential effects of AET intervention. However, patients who attended for more than five sessions showed a differen tial enhancement of working alliance. Conclusions: Although the active therapy showed no general improvement, it did provide some added value over psychoeducation alone when patients attended several sessions. Effective methods of reducing clozapine discontinuation and engaging patients in psychosocial interventions are needed.

We have witnessed in recent times an increasing emphasis on the need to identify outcomes. This paper explores the significance of this development and relates it to previous work on the subject, notably the long-standing concept of systematic practice. Possible objections to the use of systematic practice (and therefore, by extension, outcome-focused practice) are identified and addressed. Some key implications for practice are identified. The paper seeks to distance outcome-focused practice from the problems associated with managerialism.

Objectives. The authors investigated the effects of cigarette smoking on midlife cognitive performance. Methods. Multiple regression was used to test the association between cigarette smoking and changes in cognitive test scores among male and female members of the British 1946 birth cohort aged between 43 and 53 years. Results. Smoking was associated with faster declines in verbal memory and with slower visual search speeds. These effects were largely accounted for by individuals who smoked more than 20 cigarettes per day and were independent of sex, socioeconomic status, previous (adolescent) cognitive ability, and a range of health indicators. Conclusions. The present results show that heavy smoking is associated with cognitive impairment and decline in midlife. Smokers who survive into later life may be at risk of clinically significant cognitive declines.

• Summary: This article explores models and strategies for developing empowering forms of social work practice with older people. • Findings: Social work with older people has strong roots in a predominantly medical model in which the primary objective is to ensure that care is provided. While social work with other client groups has made major steps forward in developing less medicalized approaches, the work undertaken with older people has seen far less progress. This article examines the differences between a care model and an empowerment model, identifies some of the barriers standing in the way of movement from one to the other and considers ways of responding to such barriers. • Applications: The authors identify strategies for developing empowering forms of practice.

We show that the combination of a scanning near field optical microscope and an infra-red free electron laser yields chemical images with sub-cellular spatial resolution that have the potential to provide a diagnostic for oesophageal adenocarcinoma.

The considerable number of major disasters in the last decade have had a significant impact on very many children. Some have been victims, some bereaved, others just generally anxious and frightened by their proximity to, or awareness of such disasters. Additionally, many personal disasters-accidents, illness, family breakdown, and, of course, child abuse-befall children and their caregivers, producing a traumatic, crisis-torn existence for large numbers of children, a proportion of whom will come to the attention of the caring professions. One dimension relatively unexplored in the growing literature on the subject of disaster work is that of the existential or “ontological”. A number of existentialist concepts can help us piece together a picture of this missing dimension. This article explores some of these key concepts to show their applicability to this complex and demanding area of health and social welfare practice. To explore the basic questions of ontology I shall draw on existentialist ...

There is a growing literature on the subject of workplace well-being, covering a wide range of workplace problems. However, two sets of issues that have received relatively little attention are those of loss and grief and the related subject of trauma. For example, MacDonald (2005), a book published by the Chartered Institute of Personnel and Development, the leading human resource organization in the United Kingdom, makes no reference at all to such matters.

For many people the topic of sickness absence is quite straightforward: people on sick leave fall into one of two categories, those who are ‘genuinely’ ill and who deserve support and those who are ‘malingering’ who deserve contempt, if not actual punishment. The reality of the situation is far more complex than this. In this chapter, we shall see that what constitutes ‘sickness’ or ‘illness’ is subject to debate and competing theoretical understandings, especially when mental illness is the topic under consideration. We shall also see that the reasons for sickness absence are many and varied, and that there are various factors involved at various levels. I shall therefore be arguing that simple solutions are unlikely to work and may actually prove counterproductive. A much more sophisticated understanding is called for, one that connects with the wider field of workplace well-being and the emerging knowledge base about such matters.

The proposed 4GLS is a suite of temporally synchronised accelerator based light sources, including a low-Q cavity free electron laser operating in the energy range 3 - 10 eV (the VUV-FEL), a seeded XUV-FEL designed to operate in the range 8 - 100 eV, an infra-red cavity FEL (the IR-FEL), as well as spontaneous radiation sources. The output from these sources is summarized. With respect to radiation damage, the two main areas of concern are the high average power from the VUV-FEL and the high peak power from the XUV-FEL. The suitability of different materials for the cavity mirror for the VUV-FEL and beamline optics is investigated. Beamline design strategies to militate against radiation damage are described and an example of a high throughput beamline in the XUV-FEL is given. The need for accurate optical constants in the VUV region, as well as damage threshold measurements, is highlighted and we outline a program of experimental measurements to be undertaken in the near future.

Background: Kinase inhibitors have been used successfully in the clinic, but relapse is common due to the emergence of resistance. Inhibition of HSP90 leads to the depletion of oncogenic ‘client’ proteins and the simultaneous inhibition of many signalling pathways. As such, the use of HSP90 inhibitors to overcome resistance has been widely investigated. Onalespib (AT13387) is a potent, second generation HSP90 inhibitor, which has been studied in many preclinical models of kinase inhibitor resistance. Recent findings indicate that an upfront combination of onalespib and either vemurafenib or crizotinib, in models of mutant BRAF melanoma or ALK-translocated non-small cell lung cancer (NSCLC), can delay the emergence of resistance to these therapies. Here we have extended this work to a combination of onalespib and erlotinib in an EGFR-driven NSCLC model. Methods: Mice bearing HCC827 tumor xenografts were dosed with either 12.5 mg/kg erlotinib po qd, or a combination of 12.5 mg/kg erlotinib and 55 mg/kg onalespib ip qw for 52 weeks. Results: Initially both the erlotinib single-agent and onalespib/erlotinib combination treatments significantly inhibited tumor growth of the EGFR-driven NSCLC HCC827 xenograft model; all tumors in the monotherapy and combination groups regressed rapidly and achieved complete response (CR) (median times to CR were 79 and 56 days for monotherapy and combination treatments respectively). However, after 20 weeks of continuous treatment, tumor relapse was observed in one of the xenografts dosed with erlotinib only and this was followed by regrowth of a further 2 tumors in this group over the 52-week study period, with these tumors reaching 50% of the original tumor volumes by 26 and 46 weeks. Of the remaining tumors, 5 out of 6 were detectable at the end of the study. In comparison, tumor growth remained inhibited in the group treated with the erlotinib/onalespib combination; no tumors were observed to regrow over the course of the study and none (of 9) were palpable when treatments were terminated. This suggests that while treatment with monotherapy erlotinib in this model leads to relapse, as seen in the clinic, combination treatment with onalespib can delay the emergence of resistance. Conclusions: These data demonstrate that an upfront combination of onalespib and erlotinib can delay the emergence of resistance in an EGFR-driven xenograft model, suggesting there is therapeutic potential for an upfront erlotinib/onalespib combination in the clinic. Onalespib is currently being tested in a Phase 2 clinical trial in combination with crizotinib in ALK-positive NSCLC. The preclinical data presented here, alongside our previous data on combinations of onalespib with vemurafenib or crizotinib, suggest that the concept of using an HSP90 inhibitor combination upfront in the clinic to delay resistance could be extended to further targeted therapies. Citation Format: Aurélie Courtin, Tomoko Smyth, Keisha Hearn, John Lyons, Neil Thompson, Nicola G. Wallis. The HSP90 inhibitor, onalespib (AT13387), delays the emergence of resistance to erlotinib in an EGFR-driven xenograft model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2688. doi:10.1158/1538-7445.AM2015-2688

4GLS is a suite of accelerator-based light sources planned to provide state-of-the-art radiation in the low energy photon regime. Superconducting energy recovery linac (ERL) technology will be utilised in combination with a variety of free electron lasers (IR to XUV), undulators and bending magnets. The 4GLS undulators will generate spontaneous high flux, high brightness radiation, of variable polarisation from 3 - 800 eV, optimised in the lower harmonics up to about 200 eV. Viable radiation at energies up to several keV may be provided from multipole wiggler magnet radiation. The ERL technology of 4GLS will allow shorter bunches and higher peak photon fluxes than possible from storage ring sources. It will also give users the added bonuses of pulse structure flexibility and effectively an infinite beam lifetime. VUV and XUV FELs will be used to generate short pulses (in the fs regime) of extreme ultraviolet light that is broadly tuneable and more than a million times more intense than the equivalent spontaneous undulator radiation. A strong feature of the scientific programme planned for 4GLS is dynamics experiments in a wide range of fields. Pump probe experiments will allow the study of chemical reactions and short-lived intermediates on the timescale of bond breaking and bond making, even for very dilute species. The high intensity of the FEL radiation will allow very high resolution in imaging applications. Funding for the first three years of the 4GLS project was announced by the UK Government in April 2003. This includes the research and development work necessary to produce a design study report, with the construction of an ERL-prototype. Additional funds have recently been awarded that will enable a study of the production of ultra-short pulsed X-rays from the ERL-prototype via Thomson scattering. It is anticipated that the full 4GLS facility will be available to users in 2011.

Background: Although Epidermal Growth Factor Receptor (EGFR)-driven non-small cell lung cancer (NSCLC) can be successfully treated with EGFR inhibitors such as erlotinib, relapse is common due to the development of resistance. Methods to improve response and delay resistance are therefore of value. Inhibition of the chaperone, HSP90, leads to the depletion of many client proteins, including EGFR, and has the capacity to simultaneously affect many signalling pathways, offering an alternative strategy for targeting EGFR-driven disease. AT13387 is a potent, second generation HSP90 inhibitor currently being tested in Phase II clinical trials. Here we investigated the effects of combining AT13387 and erlotinib in models of EGFR-driven NSCLC. Results: AT13387 single-agent treatment was effective in EGFR-driven NSCLC xenograft models, significantly inhibiting tumor growth of both HCC827 and NCI-H1650 xenograft tumors when dosed once weekly (see table). As expected, treatment with erlotinib caused significant tumor regression in all HCC827 tumors, but was less effective in the NCI-H1650 model; its PTEN status conferring a reduction in sensitivity. However, combination of AT13387 with erlotinib led to a further enhancement of tumor growth inhibition over either of the monotherapies in both of these models. All HCC827 tumors treated with the combination regressed further (by at least 80%), and regression was also now observed in all NCI-H1650 tumors. These data demonstrate that combination with AT13387 has the potential to increase response, despite the differing initial sensitivities to erlotinib of these models. The combination was well tolerated. Effects of AT13387 and erlotinib on EGFR-driven xenograftsCell lineGenetic BackgroundT/C(Median RTV, treated / control)AT1338755 mg/kg ip 1qwErlotinib12.5 mg/kg po qdCombinationHCC827(Day 32)EGFR Del E746_A75026%17%(47% regression)6%(84% regression)NCI-H1650(Day 31)EGFR Del E746_A750/PTEN del35%36%6%(50% regression) Conclusions: AT13387 was shown to improve response when combined with erlotinib in EGFR-driven xenograft models. These data suggest that there is therapeutic potential in an upfront combination of an HSP90 inhibitor, such as AT13387, with erlotinib and support clinical investigation of such a combination. Citation Format: Tomoko Smyth, Jon Lewis, Keisha Hearn, Neil Thompson, John Lyons, Nicola G. Wallis. The HSP90 inhibitor, AT13387, combined with erlotinib improves response in EGFR-driven xenograft models of NSCLC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1794. doi:10.1158/1538-7445.AM2014-1794

The process of Chirped Pulse Amplification (CPA) as presently implemented on the VULCAN glass laser is capable of delivering 30 J to target with pulselengths in the sub- picosecond regime. Results from various experiments have shown that intensities of 1018 - 1019 W cm-2 have been achieved on target enabling users to carry out important new experiments in X-ray laser research, laser fusion, basic plasma physics and particle acceleration. An EPSRC (Engineering and Physical Sciences Research Council) facility upgrade grant has been awarded to increase the current operational level of 35 TW, to over 200 TW. This upgrade forms Phase I of a two phase upgrade to raise the performance of VULCAN to the Petawatt level. This paper details the design of the upgraded system and describes a new interaction chamber which takes full advantage of the availability of synchronous kJ multi-beam long pulse operation on VULCAN with the CPA capabilities.© (1997) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Melanoma is a highly aggressive malignancy with an exceptional ability to develop resistance and no curative therapy is available for patients with metastatic disease. Inhibitor of apoptosis proteins (IAP) play a key role in preventing cell death by apoptosis. In normal cell, IAPs are highly regulated by endogenous antagonists (e.g. SMAC) but in melanoma cell lines and in patient samples expression levels of IAPs are generally high and depleting IAPs by siRNA tended to reduce cell viability, with XIAP reduction being the most efficient [1]. Small molecule IAP antagonists have the ability to switch IAP-controlled pro-survival pathways towards apoptosis and cell death. Recent evidence suggests that a true dual antagonist of both cIAP1 and XIAP will promote an effective apoptotic response through generation of death-inducing ripoptosome complexes, with resultant caspase activation [2, 3]. We have used our fragment-based drug discovery technology PyramidTM to derive a non-peptidomimetic IAP antagonist, AT-IAP, which does not have an alanine warhead and has nanomolar cellular potency for both XIAP and cIAP1. Initial pharmacokinetic and pharmacodynamic modeling of AT-IAP in mice bearing the MDA-MB-231 cell line indicated that daily oral dosing of AT-IAP at 30 mg/kg ensures high concentrations of compound in tumor and plasma over a 24 h period with resultant inhibition of both XIAP and cIAP1 and induction of apoptosis markers (cleaved PARP and cleaved caspase-3). In this paper, we describe the characterization of AT-IAP in melanoma models. An in vitro cell line proliferation screen demonstrated that 36% of melanoma cell lines exhibited enhanced sensitivity to AT-IAP, which was improved on addition of exogenous 1 ng/ml TNF-α (92% of cell lines were sensitive to AT-IAP + TNF-α). Sensitivity of melanoma cells to AT-IAP has also been confirmed in a panel of 20 primary melanoma tumors in colony formation assays set up in the presence and absence of added TNF-α. Finally, a set of biomarkers has been identified and used to predict single agent activity of AT-IAP in a range of melanoma cell line and patient derived xenograft models. [1] Engesaeter et al., Cancer Biology & Therapy, 2011, 12 (1), 47 [2] Ndubaku et al., ACS Chem Biol., 2009, 4 (7), 557 [3] Meier, P., Nat Rev. Cancer, 2010, 10 (8), 561 Citation Format: Gianni Chessari, Ahn Maria, Ildiko Buck, Elisabetta Chiarparin, Joe Coyle, James Day, Martyn Frederickson, Charlotte Griffiths-Jones, Keisha Hearn, Steven Howard, Tom Heightman, Petra Hillmann, Aman Iqbal, Christopher N. Johnson, Jon Lewis, Vanessa Martins, Joanne Munck, Mike Reader, Lee Page, Anna Hopkins, Alessia Millemaggi, Caroline Richardson, Gordon Saxty, Tomoko Smyth, Emiliano Tamanini, Neil Thompson, George Ward, Glyn Williams, Pamela Williams, Nicola Wilsher, Alison Woolford. AT-IAP, a dual cIAP1 and XIAP antagonist with oral antitumor activity in melanoma models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2944. doi:10.1158/1538-7445.AM2013-2944

In addition to the words we speak, we give very powerful messages through non-verbal communication. Our body language adds an extra layer of communication, an additional set of signals above and beyond the verbal messages given. An important aspect of interaction skills in people work, then, is the ability to send and receive non-verbal signals appropriately. It is for this reason that this chapter explores some of the key issues relating to non-verbal communication — so that we can better understand, and use, this important dimension of human interaction.

Continuous professional development (CPD) is increasingly being recognised as an important part of working life. It is a concept that acknowledges the danger of getting stuck in a rut and failing to learn and develop. CPD is an essential element of modern management, based on principles of human resource management (Beardwell and Holden, 1994) which sees the staff of an organisation as its most important resource. This is closely linked to the Investors in People initiative in which employing organisations can receive accreditation for their commitment to staff development. The use of personal portfolios to chart personal and professional development is also becoming more popular. Increasingly, then, the value of CPD is being appreciated, although there sadly remain very many organisations who have yet to make a commitment to staff development. They remain oblivious to the problems that such an unenlightened approach can cause.

As university involvement in “technology transfer” and entrepreneurship has grown, concerns have been raised about the impact of academic patenting on academic science. Murray and Stern (2007) sugg...

Background: Mutations in BRAF are found in approximately 50% of melanomas. Vemurafenib, the selective mutant BRAF inhibitor, is an effective treatment in this disease but is limited by the onset of resistance. A number of mechanisms of resistance to RAF inhibitors have been described, including alternative mechanisms for activating the MEK-ERK and AKT pathways. HSP90 inhibitors affect clients in both these pathways and so it has been suggested that HSP90 inhibition is a potential mechanism for overcoming resistance to RAF inhibitors in melanoma. Results: AT13387 is a fragment-derived, potent HSP90 inhibitor, which is currently being evaluated in clinical trials. AT13387 inhibited cell proliferation in a range of melanoma cell lines, including cell lines with different mechanisms of resistance to vemurafenib (See Table). AT13387 treatment of melanoma cell lines resulted in the induction of HSP70, a marker of HSP90 inhibition, and depletion of HSP90 client proteins including BRAF and AKT. The levels of phospho-ERK, phospho-AKT and phospho-S6 were also depleted in both vemurafenib-sensitive (A375) and vemurafenib-resistant (A2058) lines indicating that the MEK-ERK and AKT signaling pathways were both inhibited. This demonstrates that vemurafenib resistance mediated by upregulation of the AKT pathway can be overcome by HSP90 inhibition. In vivo, AT13387 significantly inhibited growth of an A375 melanoma xenograft. Client proteins, including BRAF, CRAF and AKT were depleted in xenograft tissue and the MEK-ERK and AKT signaling pathways were again inhibited. Conclusions: These results demonstrate the activity of AT13387 in both vemurafenib-sensitive and -resistant models and show that HSP90 inhibition results in downregulation of signaling pathways that may be activated as a result of resistance to RAF inhibitors. These data support further clinical evaluation of AT13387 in melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2772. doi:1538-7445.AM2012-2772

This is the first of two chapters which address wider organisational aspects of social work stress. Chapter 6 explores those aspects that are largely related to the ways in which social work agencies are organised and managed — the factors that can be improved if the political will to bring about change exists or can be generated. The focus of this chapter, by contrast, is on those aspects of social work that cannot be changed — the factors that are intrinsic to the nature of the social work enterprise.