Differential expression of mTOR signalling components in drug resistance in ovarian cancer

This article has been made available through the Brunel Open Access Publishing Fund and is available from the specified link - Copyright @ 2010 The International Institute of Anticancer Research.Background/Aim: A limitation to successful cancer chemotherapy treatments is the acquisition of drug resistance. In advanced-stage ovarian cancer, the mammalian target of rapamycin (mTOR) pathway is upregulated, and inhibition of this pathway increases chemosensitivity in ovarian carcinoma cell lines. In this study, the expression of DEPTOR, mTOR, RICTOR, RAPTOR and S6 kinases were investigated in SKOV-3 and PEO1 parental and the paclitaxel-resistant (TaxR) SKOV-3TaxR and PEO1TaxR cell lines. Materials and Methods: RT-PCR, immunofluorescent analysis and Western blotting were carried out. Results: Quantitative RT-PCR revealed significant up-regulation of DEPTOR in both paclitaxel-resistant cell lines. SKOV-3TaxR exhibited down-regulation of RICTOR, RAPTOR and mTOR, whereas PEO1-TaxR showed down-regulation of RAPTOR and up-regulation of RICTOR and mTOR. Semi-quantitative RT-PCR analysis revealed marked changes in the expression of p70S6K splice variants mRNA in PEO1TaxR. Moreover, the phosphorylation status of p70S6K at Ser371 appears to be cell-type specific. Conclusion: We hypothesize that mTOR signalling may play a role in mediating paclitaxel resistance in ovarian cancer

Infrastructure investment - the emergent PPP equity market

Increasingly governments are looking to private sector actors to invest in infrastructure projects. An emergent mechanism for such investment is the market in PPP equity. This is an aspect of PPPs that has to date had little empirical attention. This paper reports on the size and scope of the market in PPP equity sales within the UK. In the process, the nature of PPP projects and the existing rationales for the policy are critiqued. The paper concludes by laying out a number of potential research agendas focused on PPP equity sales including a call for reassessing theoretical perspectives

Shimura varieties in the Torelli locus via Galois coverings of elliptic curves

We study Shimura subvarieties of $\mathsf{A}_g$ obtained from families of Galois coverings $f: C \rightarrow C'$ where $C'$ is a smooth complex projective curve of genus $g' \geq 1$ and $g= g(C)$. We give the complete list of all such families that satisfy a simple sufficient condition that ensures that the closure of the image of the family via the Torelli map yields a Shimura subvariety of $\mathsf{A}_g$ for $g' =1,2$ and for all $g \geq 2,4$ and for $g' > 2$ and $g \leq 9$. In a previous work of the first and second author together with A. Ghigi [FGP] similar computations were done in the case $g'=0$. Here we find 6 families of Galois coverings, all with $g' = 1$ and $g=2,3,4$ and we show that these are the only families with $g'=1$ satisfying this sufficient condition. We show that among these examples two families yield new Shimura subvarieties of $\mathsf{A}_g$, while the other examples arise from certain Shimura subvarieties of $\mathsf{A}_g$ already obtained as families of Galois coverings of $\mathbb{P}^1$ in [FGP]. Finally we prove that if a family satisfies this sufficient condition with $g'\geq 1$, then $g \leq 6g'+1$.Comment: 18 pages, to appear in Geometriae Dedicat

Forecasting scenarios for UK household expenditure and associated GHG emissions : Outlook to 2030

Peer reviewedPreprin

Assessing the feasibility, acceptability and potential effectiveness of Dignity Therapy for people with advanced cancer referred to a hospital-based palliative care team: Study protocol

<p>Abstract</p> <p>Background</p> <p>Loss of dignity for people with advanced cancer is associated with high levels of psychological and spiritual distress and the loss of the will to live. Dignity Therapy is a brief psychotherapy, which has been developed to help promote dignity and reduce distress. It comprises a recorded interview, which is transcribed, edited then returned to the patient, who can bequeath it to people of their choosing. Piloting in Canada, Australia and the USA, has suggested that Dignity Therapy is beneficial to people with advanced cancer and their families. The aims of this study are to assess the feasibility, acceptability and potential effectiveness of Dignity Therapy to reduce psychological and spiritual distress in people with advanced cancer who have been referred to hospital-based palliative care teams in the UK, and to pilot the methods for a Phase III RCT.</p> <p>Design</p> <p>A randomised controlled open-label trial. Forty patients with advanced cancer are randomly allocated to one of two groups: (i) Intervention (Dignity Therapy offered in addition to any standard care), and (ii) Control group (standard care). Recipients of the 'generativity' documents are asked their views on taking part in the study and the therapy. Both quantitative and qualitative outcomes are assessed in face-to-face interviews at baseline and at approximately one and four weeks after the intervention (equivalent in the control group). The primary outcome is patients' sense of dignity (potential effectiveness) assessed by the Patient Dignity Inventory. Secondary outcomes for patients include distress, hopefulness and quality of life. In view of the relatively small sample size, quantitative analyses are mainly descriptive. The qualitative analysis uses the Framework method.</p> <p>Discussion</p> <p>Dignity Therapy is brief, can be delivered at the bedside and may help both patients and their families. This detailed exploratory research shows if it is feasible to offer Dignity Therapy to patients with advanced cancer, many of whom are likely to be in the terminal stage of their illness, whether it is acceptable to them and their families, if it is likely to be effective, and determine whether a Phase III RCT is desirable.</p> <p>Trial registration</p> <p>Current Controlled Clinical Trials: ISRCTN29868352</p

Boron-Doped Diamond Dual-Plate Deep-Microtrench Device for Generator-Collector Sulfide Sensing

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.A BDD-BDD dual-plate microtrench electrode with 6μm inter-electrode spacing is investigated using generator-collector electrochemistry and shown to give microtrench depth-dependent sulfide detection down to the μM levels. The effect of the microtrench depth is compared for a "shallow" 44 μm and a "deep" 180μm microtrench and linked to the reduction of oxygen to hydrogen peroxide which interferes with sulfide redox cycling. With a deeper microtrench and a fixed collector potential at -1.4V vs. SCE, two distinct redox cycling potential domains are observed at 0.0V vs. SCE (2-electron) and at 1.1V vs. SCE (6-electron).F. M. and A. J. G. thank EPSRC for financial support (EP/I028706/1)

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

Testing the feasibility of the Dignity Therapy interview: adaptation for the Danish culture

<p>Abstract</p> <p>Background</p> <p><b>'</b>Dignity Therapy' (DT) is a brief, flexible intervention, which allows patients to complete an interview and create a document regarding their life, identity and what they want to leave in writing for their loved ones. DT is based on the DT Question Protocol. Developed and tested in English speaking settings, DT has proven to be a feasible and effective way to enhance patient dignity, while diminishing suffering and depression. The aim of this study was to test the acceptability and feasibility of the DT Question Protocol among Danish health professionals and cancer patients, and to obtain preliminary estimates of patient uptake for DT. These results will be used to inform a larger evaluation study.</p> <p>Method</p> <p>Ten professionals were interviewed about their perception of DT and the Question Protocol. It was then tested with 20 patients at two palliative care sites and one gynecologic oncology department. Data was analyzed using content analysis techniques to evaluate the protocol for relevance, acceptability and comprehension. The interest and relevance of the intervention was also determined by examining the preliminary participation rate.</p> <p>Results</p> <p>Overall, DT was perceived to be comprehensible and relevant. Professionals highlighted six concerns that might warrant modification. These issues were examined using patient data. Some of their concerns overlapped with those raised by the professionals (e.g. <it>'unacceptable self-praise' </it>and '<it>interference with the lives of others'</it>). Tailoring DT to Danish culture required easily accommodated adjustments to the procedures and the DT Question Protocol. Some concerns expressed by health professionals may have reflected protectiveness toward the patients. While the intervention was relevant and manageable for patients admitted to palliative care, DT was less easily implemented at the gynecologic oncology department.</p> <p>Conclusion</p> <p>Based on patients' and professionals' reaction to the DT Question Protocol, and based on the preliminary proportion of participants accepting DT, the DT question protocol - with minor adaptations - appears to be a manageable, acceptable and relevant intervention for Danish patients admitted to palliative care.</p

Paying for free delivery: dependent self-employment as a measure of precarity in parcel delivery

This article explores supply chain pressures in parcel delivery and how the drive to contain costs to ‘preserve value in motion’, including the costs of failed delivery, underpins contractual differentiation. It focuses on owner-drivers and home couriers paid by delivery. It considers precarity through the lens of the labour process, while locating it within the supply chain, political economy and ‘instituted economic process’ that define it. Focus on the labour process shows how ‘self-employment’ is used to remove so-called ‘unproductive’ time from the remit of paid labour. Using Smith’s concept of double indeterminacy the article captures the dynamic relationship between those on standard and non-standard contracts and interdependency of effort power and mobility power. It exposes the apparent mobility and autonomy of dependent selfemployed drivers while suggesting that their presence, alongside the increased use of technology, reconfigures the work-effort bargain across contractual status

Regulation, governance and agglomeration: making links in city-region research

This paper provides an overview and synthesis of debates pertaining to the development of city-regions and their applicability to the UK space economy. The purpose is to make links to advance both interna- tional academic debates and realpolitik policy knowledge concerns. The paper, firstly, traces the multifari- ous and at times disconnected academic discussions around the concepts of regionalism, city-regionalism and localism in the UK. Secondly, it considers the contemporary academic debates on the city-region, focusing in particular on those applicable to the current UK policy context. Given that city-regions are increasingly seen as the principal (and often unquestioned) consolidating spatial scale for economic and social development, the paper, thirdly, probes on the silent and missing aspects of the prescribed city-re- gion approach, connecting and contributing in turn to concerns with building inclusive-growth