Search

Despite tremendous efforts from the scientific community, pancreatic ductal adenocarcinoma (PDAC) is still a deadly disease and will soon become the second cause of death by cancer worldwide1. When surgery is not possible, therapeutic options are few and ineffective2. Patients are most often treated with Folfirinox or gemcitabine chemotherapy, that extends survival in weeks to months. Cytidine deaminase (CDA) catalyzes the irreversible hydrolytic deamination of cytidine and deoxycytidine to uridine and deoxyuridine to fuel RNA and DNA synthesis3. CDA also deaminates and neutralizes deoxycytidine-based therapies, and as such, has been identified as a major contributor of tumor chemoresistance, especially to gemcitabine in PDAC3. We previously identified that CDA is elevated in PDAC tumors at diagnosis and that CDA exerts an unexpected role on DNA replication that can be exploited for therapeutic intervention4. Very recently, CDA was associated with cellular metabolism5. Here, we show that CDA promotes mitochondrial biogenesis and oxidative phosphorylation independently of its deaminase activity. This uncloaks novel therapeutic vulnerabilities in primary cancer cells that overexpress this protein. This study shines a new light on the tumoral potential of CDA in PDAC.

This project explores the business practices and cultural place of independent bookshops in Scotland. The research examines the connections that independent bookshops have with their various stakeholders, and investigates the support and policy change bookshops require in order to survive and prosper. The research finds a wealth of expertise and business acumen across Scottish independent booksellers, uniquely driven by a commitment to literacy, community and a love of books. A strong contribution to communities, welfare and social capital is identified. Policy recommendations are made, which recognise the cultural and community contributions made by bookshops, as well as proposing that bookshops be at the centre of policy planning around the regeneration of high streets.

Malgré une attention académique considérable au rôle de la famille des soignants avec la population générale, peu de recherches ont été menées avec les familles autochtones. Cette étude qualitative vise à combler cette lacune en se concentrant sur l'expérience des soignants Metis, fournir des soins aux adultes Metis plus âges. Des groupes de discussions et des entrevues ont été menés avec des aidants familiaux Metis (n - 79), aînés Metis (n - 11), et soignants officiels (n - 8). Bien qu'il existe de parallèles considérables dans les expériences des soins identifiés dans cette étude sur les Metis avec celles déjà documentées dans la littérature, il existe néanmoins des différences importantes pour la prestation des soins culturellement adaptés aux aînés Metis.Despite considerable academic attention to the role of family caregivers within the general population, little research has been conducted with Indigenous families. This qualitative study aims to fill that gap by focusing on the experiences of Metis caregivers providing care for older Metis adults. Focus groups and interviews were conducted with Metis family caregivers (n = 79), Metis Elders (n = 11) and formal caregivers (n = 8). Although there are considerable parallels in the caregiving experiences identified in this Metis study with those already documented in the literature, there are nonetheless important differences for providing culturally responsive care to Metis seniors.Malgri tot li zitchud ki lon fayt dan li zikol ipi li universiti powr l’rol di famiyl caregiver dan la populasyon general, il a paw gro d’itchud ki la iti fayt powr li famiyl Michif. L’ichud y va emplyr l’ispaws par konsantri a li ziksperians di Mitchif caregivers ki sa ayd a li plu vyu Michif. Li growp di djiskusyon ipi li interviews itay kondwi avek li caregivers di famiyl Michif (n = 79), li vyu Michif (n = 11), ipi li caregiver formal (n = 8). Mem ki la enmas di shos pareyl dan l’experyans di caregivers indentchifyi dan li leson di Michif avek suslaw dija ikri dan la literachur, il a kanmem tot li djiferens importan powr prodjwir li swin adapti a la kulture powr li vyu Michif.

International audience; The recycling activity of cytidine deaminase (CDA) within the pyrimidine salvage pathway is essential to DNA and RNA synthesis. As such, CDA deficiency can lead to replicative stress, notably in Bloom syndrome. Alternatively, CDA also can deaminate cytidine and deoxycytidine analog-based therapies, such as gemcitabine. Thus, CDA overexpression is often associated with lower systemic, chemotherapy-related, adverse effects but also with resistance to treatment. Considering the increasing interest of CDA in cancer chemoresistance, the aims of this review are to describe CDA structure, regulation of expression, and activity, and to report the therapeutic strategies based on CDA expression that recently emerged for tumor treatment.

This article offers an analysis of the impact of professional social-media engagement upon authors. Authors primarily use Facebook, Twitter and there is growing use of Pinterest. Authors use social-media platforms primarily for marketing, publicity and making contact with readers. They tend to adopt a multi-layered approach to self-presentation and the lines between their ‘public’ and ‘private’ identities are blurred. The research reveals a limited author-reader community, but a much stronger online author–author community, founded upon practical support and encouragement. There are implications for the publishing industry as authors believe their publishers lack social-media expertise. The commercial benefits of maintaining a social-media presence are unclear for many authors.

Purpose To meet stated waste reduction goals, the UK government via Defra (Department for environment, farming and rural affairs) is attempting to reduce household mainstream waste. One approach is to encourage children in environmentally-friendly behaviour. We take this as a starting point to document the environmental content of dedicated childrens channels, and to consider whether television could act as an ecological socialising agent for waste reduction behaviour. Approach Our content analysis of four childrens television channels over 168 hours recorded the extent to which the waste hierarchy (reduce, reuse and recycling behaviour) was included in all forms of broadcast output: programmes, advertisements, trailers, sponsorship and idents. Outcomes We found 6,921 instances of waste activity, distributed across 666 broadcasts which included eleven identifiable materials, such as plastic and cardboard. Whilst reuse behaviour was well represented (5,751), instances of reduction (406) and recycling were relatively infrequent (275) and there were 489 instances of materials being placed in refuse bins. Contribution By placing childrens television on the environmental agenda, we raise the possibility of channels examining their own broadcast material to assess its environmental content, and how that content is distributed across the waste hierarchy and in relation to broadcast output. Further research Our case study was based on four channels and within the specific context of waste. There are many more channels (e.g. available on cable/satellite) and more environmental behaviours that can be examined with a view to meeting other targets “ for example those connected to climate change such as travel, domestic energy consumption, and food choices, all of which are included on childrens television. The response of the intended audience to the environmental content can be assessed.

Based upon empirical research, and using a range of methods, this paper examines the behaviour and experiences of consumers in online bookselling settings and offers comparison between online and offline (traditional) bookselling. The research finds that while the convenience of online bookshops is important, the key factors enticing consumers online are a combination of breadth of range, ease of access to obscure titles, as well as ‘personalised’ recommendations and customer reviews. The research is of value to the book trade, highlighting consumer responses to widely adopted online marketing approaches. The research also contributes to scholarly knowledge in the fields of consumer behaviour, e-marketing and e-commerce in online bookselling, as well as providing findings which can be tested in other online settings, informing future theoretical research.

Purpose – This research theoretically conceptualises the notion of “third place” within the setting of chain bookshops. The widespread adoption of coffee franchises and comfortable seating has developed the bookshop as a leisurely setting. Underpinning the discussion in current retail marketing theory, the research aims to explore how the understanding of “third place” has changed with the passage of time and to examine whether chain bookshops can be called third places. Design/methodology/approach – The methodological approach is largely qualitative, drawing upon interviews with bookshop managers with regard to their strategic aims, and using focus groups to discuss consumers' bookshop experiences. The research also draws upon quantitative data, i.e. face-to-face questionnaires and online surveys. Findings – The research concludes that while consumer experience of chain bookshops is positive, they cannot be called a “third place” due to the lack of conversation therein. Nevertheless, an important caveat exists – the presence of an integral coffee shop encourages socialising among bookshop customers. Research limitations/implications – The project's scope is limited to chain bookshops in the UK. Future work might look at third place or restorative provision in other retail settings or over a wider geographic spread. Practical implications – The research has important implications and recommendations for managers of retail sites regarding the potential restorative qualities of bookshops, coffee shops and other retail environments. Originality/value – This empirical research enhances scholarly understanding of the bookshop as a restorative space, highlighting an important advantage which traditional retailers have over internet retailers.

PurposeThe purpose of this paper is to identify current marketing initiatives undertaken by UK chain booksellers and analyses them in the context of established retailing and marketing theory. Thus, established scholarly theory is being examined in a novel research setting.Design/methodology/approachThe paper includes evidence and findings from semi‐structured, in‐depth interviews with various book trade experts working at different levels within the trade.FindingsFocusing on the strategies behind the chains' marketing techniques, the paper concentrates in particular upon the new emphasis by UK chains upon serving a wider clientele and their efforts to establish individual identities and be “community responsive”. This has resulted in a re‐emphasis both upon customer service and on the relationship between bookseller and customer. New developments in the facilities to be found in chain bookshops, such as coffee shops and the proliferation of sofas and browsing areas are analysed as to their contribution to bookshop “atmosphere”.Originality/valueThis research is both timely, responding to calls from the trade for research and original, given the dearth of research on the book trade. The findings are examined within the context of academic theory in related fields, such as retailing, marketing and consumer behaviour. As such, findings from this highly original research are relevant both for the trade and for the wider academic community regarding their application and consideration in other scholarly settings.

Le commerce du livre, bien que generalement considere comme a part parmi les autres types de commerce, commence a reconnaitre le role des strategies de marketing dans la recherche du developpement de marche. Face a un avenir incertain, le dilemme qui se pose pour les librairies consiste a tenter d'attirer une nouvelle tranche de lecteurs, tout en conservant sa fidele clientele.

Pancreatic cancer (PDAC) remains a deadly disease with no cure. In this dismal context, we demonstrated that non-viral gene therapy to sensitize cancer cells to chemotherapy was safe and feasible, and offers therapeutic benefit in patients (Thergap trial 2010-2012). However, alternative molecular pathways must be targeted to relieve resistance to treatment for best therapeutic benefit. We identified cytidine deaminase (CDA) that catalyzes the hydrolytic deamination of cytidine and deoxycytidine to uridine and deoxyuridine, as overexpressed (i) in cohorts of patients resisting to gemcitabine, (ii) in PDAC as compared to normal parenchyma, and (iii) in patients receiving gene therapy. Targeting CDA using genetic tools sensitizes cancer cells to chemotherapy both in vitro and in vivo, with very high efficacy in preclinical models of cancer. On the other hand, loss of CDA per se unexpectedly alters cell proliferation, cell cycle progression and tumor growth in vivo, when more than half of mice engrafted with CDA-null human pancreatic cancer cells remained free of tumors nor developed metastasis. Using a multi-omics approach, we found that both pyrimidine and purine levels are decreased, inducing replicative stress hallmarks in CDA-null cells, and TCA cycle is altered, strongly suggesting mitochondrial dysfunction, as we further demonstrate decreased mitochondrial ATP and down expression of key proteins of the mitochondrial OXPHOS complexes and β-oxidation. Consequently, mitochondrial ROS are elevated with major changes in the redox balance in PDAC cells. Remarkably, tumor cells retaliate using compensatory mechanisms resembling Pasteur effect with elevated lactate levels. These compensatory mechanisms served as secondary targets to (i) further strengthen the inhibition of cell proliferation and migration seen in CDA-null cells, and (ii) annihilate potential mechanisms of resistance to treatment. Taken together, our aforementioned results demonstrate for the first time that targeting CDA, an enzyme primarily thought to be restricted to the pyrimidine salvage pathway, strongly alters PDAC proliferation and tumor progression, via massive modification of cancer cell metabolism and alteration of cell cycle, in the absence of chemotherapy. To the best of our knowledge, the crosstalk between replicative and energetic pathways has been thus far totally underexplored in cancer. As specific inhibitors of CDA are underway, we postulate that PDAC rewiring following CDA targeting can be considered exploitable Achille’s eel or vulnerabilities for novel, DNA and metabolic-based, synthetic lethality strategies and the promise of targeted-approaches with high efficacy for PDAC therapy. Note: This abstract was not presented at the conference. Citation Format: Marion Gayral, Audrey Frances, Estelle Saland, Hubert Lulka, Naima Hanoun, Anthony Lemarié, Laetitia Ligat, Nathalie Saint-Laurent, Frédéric Lopez, Louis Buscail, Jean-Emmanuel Sarry, Pierre Cordelier.{Authors}. Characterization of novel molecular vulnerabilities provoking replicative and energetic stresses in pancreatic cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A23.

In this viewpoint article we seek to make the farming community aware of the increasing presence of organised criminals and crime within the farming community. In the past decade there has been a discernible rise in the level of organized criminality in rural areas especially in relation to farm crime across Britain and Europe. This has been reported in the media in many European States and is exacerbated by the financial crisis and by a lack of cooperation between member states and agencies.