Acquired differential regulation of caspase-8 in cisplatin-resistant non-small-cell lung cancer

Failure to efficiently induce apoptosis contributes to cisplatin resistance in non-small-cell lung cancer (NSCLC). Although BCL-2-associated X protein (BAX) and BCL-2 antagonist killer (BAK) are critical regulators of the mitochondrial apoptosis pathway, their requirement has not been robustly established in relation to cisplatin. Here, we show that cisplatin can efficiently bypass mitochondrial apoptosis block caused by loss of BAX and BAK, via activation of the extrinsic death receptor pathway in some model cell lines. Apoptosis resistance following cisplatin can only be observed when both extrinsic and intrinsic pathways are blocked, consistent with redundancy between mitochondrial and death receptor pathways in cisplatin-induced apoptosis. In H460 NSCLC cells, caspase-8 cleavage was shown to be induced by cisplatin and is dependent on death receptor 4, death receptor 5, Fas-associated protein with death domain, acid sphingomyelinase and ceramide synthesis. In contrast, cisplatin-resistant cells fail to activate caspase-8 via this pathway despite conserving sensitivity to death ligand-driven activation. Accordingly, caspase-8 activation block acquired during cisplatin resistance, can be bypassed by death receptor agonism.

Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer

Non-small cell lung carcinoma remains by far the leading cause of cancer-related deaths worldwide. Overexpression of FLIP, which blocks the extrinsic apoptotic pathway by inhibiting caspase-8 activation, has been identified in various cancers. We investigated FLIP and procaspase-8 expression in NSCLC and the effect of HDAC inhibitors on FLIP expression, activation of caspase-8 and drug resistance in NSCLC and normal lung cell line models. Immunohistochemical analysis of cytoplasmic and nuclear FLIP and procaspase-8 protein expression was carried out using a novel digital pathology approach. Both FLIP and procaspase-8 were found to be significantly overexpressed in tumours, and importantly, high cytoplasmic expression of FLIP significantly correlated with shorter overall survival. Treatment with HDAC inhibitors targeting HDAC1-3 downregulated FLIP expression predominantly via post-transcriptional mechanisms, and this resulted in death receptor- and caspase-8-dependent apoptosis in NSCLC cells, but not normal lung cells. In addition, HDAC inhibitors synergized with TRAIL and cisplatin in NSCLC cells in a FLIP- and caspase-8-dependent manner. Thus, FLIP and procaspase-8 are overexpressed in NSCLC, and high cytoplasmic FLIP expression is indicative of poor prognosis. Targeting high FLIP expression using HDAC1-3 selective inhibitors such as entinostat to exploit high procaspase-8 expression in NSCLC has promising therapeutic potential, particularly when used in combination with TRAIL receptor-targeted agents.

Long non coding RNAs (lncRNAs) are dysregulated in Malignant Pleural Mesothelioma (MPM)

Malignant Pleural Mesothelioma (MPM) is an aggressive cancer that is often diagnosed at an advanced stage and is characterized by a long latency period (20-40 years between initial exposure and diagnosis) and prior exposure to asbestos. Currently accurate diagnosis of MPM is difficult due to the lack of sensitive biomarkers and despite minor improvements in treatment, median survival rates do not exceed 12 months. Accumulating evidence suggests that aberrant expression of long non-coding RNAs (lncRNAs) play an important functional role in cancer biology. LncRNAs are a class of recently discovered non-protein coding RNAs >200 nucleotides in length with a role in regulating transcription. Here we used NCode long noncoding microarrays to identify differentially expressed lncRNAs potentially involved in MPM pathogenesis. High priority candidate lncRNAs were selected on the basis of statistical (P<0.05) and biological significance (>3-fold difference). Expression levels of 9 candidate lncRNAs were technically validated using RT-qPCR, and biologically validated in three independent test sets: (1) 57 archived MPM tissues obtained from extrapleural pneumonectomy patients, (2) 15 cryopreserved MPM and 3 benign pleura, and (3) an extended panel of 10 MPM cell lines. RT-qPCR analysis demonstrated consistent up-regulation of these lncRNAs in independent datasets. ROC curve analysis showed that two candidates were able to separate benign pleura and MPM with high sensitivity and specificity, and were associated with nodal metastases and survival following induction chemotherapy. These results suggest that lncRNAs have potential to serve as biomarkers in MPM.

To be continued... fan fiction and the constructing of identity

This chapter contributes to the existing body of knowledge on fan fiction by reporting the findings from a quantitative and qualitative study on fan fiction in a Swedish context. The authors contextualize the fan fiction phenomenon as a part of a larger transformation of the media sphere and the society in general where media consumers’ role as collaborative cultural producers grows ever stronger. They explore what kind of stories inspire the writers and conclude that as in many other parts of the entertainment industry, fan fiction is dominated by a small number of international media brands. The authors show how fan fiction can play an important role in the development of adolescents’ literacies and identities and how their pastime works as a vehicle for personal growth.

Literacies on the Web : Co-Production of Literary Texts on Fan Fiction Sites

In this chapter the authors discuss and informal learning settings such as fan fiction sites and their relations to teaching and learning within formal learning settings. Young people today spend a lot of time with social media built on user generated content. These media are often characterized by participatory culture which offers a good environment for developing skills and identity work. In this chapter the authors problematize fan fiction sites as informal learning settings where the possibilities to learn are powerful and significant. They also discuss the learning processes connected to the development of literacies. Here the rhetoric principle of “imitatio” plays a vital part as well as the co-production of texts on the sites, strongly supported by the beta reader and the power of positive feedback. They also display that some fans, through the online publication of fan fiction, are able to develop their craft in a way which previously have been impossible.

Re-presenting the past : authenticity and the historical novel

This project involved writing Turrwan (great man), a novel set in Queensland in the nineteenth century, and an investigation into the way historical novels portray the past. Turrwan tells the story of Tom Petrie, who was six when he arrived with his family at the notorious Moreton Bay Penal Colony in 1837. The thesis examines historical fiction as a genre with particular focus on notions of historical authenticity. It analyses the complexities involved in a non-Indigenous person writing about the Australian Aboriginal people, and reflects on the process of researching, planning and writing a historical novel.

The mirror manoeuvre : telling the same story twice

The emerging field of ecopsychology is marked by two theoretical concerns which can be seen as mirror images of each other. One is the concern with what humans need, psychologically, from the non-human natural world (e.g. Wolsko & Lindberg 2013). The other is what nature needs from us (e.g. Swim 2013). Ecocriticism has been exploring these questions for at least two decades, but ecocritical theory examines ways of reading texts rather than ways of writing them (Bate 2000; Buell 2001; Garrard 2012). Undertaking theoretically-informed “creative manoeuvres”, and reflecting and reporting on the results, is one way for practice-led researchers in the field of creative writing to progress the knowledge claims of our discipline. This paper describes an ecowriting practice experiment based on the premise that specific techniques of narrative fiction writing can deepen reader engagement with ecopsychology’s twin concerns, and help motivate ecological action. Exploring this premise is time-critical given the current environmental crisis (Rust & Totton 2012), and emerging evidence that contemporary modes of representing the non-human natural world fail to elicit activist responses (Crompton & Kasser 2009; Joffe 2008). In the practice experiment reported here, a unique reading experience has been constructed such that the reader encounters from two different perspectives, through two different novels, a single story of humans benefiting from non-destructive interactions with non-human nature. This paper argues that the two novels create a complex and intense relationship between reader and story which generates specific psychological effects, and ultimately demands an activist response.

The role of Non-Government Organisations (NGOS) in practising editorial photography in a globalised media environment

The news media industry has changed dramatically into a global business with ever-increasing attention being devoted to entertainment and celebrity across the last 10–20 years. There has also been a growing reliance on images produced by citizens (citizen photojournalism), by media outlets and publishers. It is widely acknowledged that in tandem these changes have shrunk publication opportunities for professional photographers undertaking editorial projects. As a result, photographers are increasingly relying on non-government organisations (NGOs) to gain access to photographing issues and events in developing countries and to expand their economic and portfolio opportunities. This increase in photographers working for and alongside NGOs has given rise to a new genre of editorial photography which I call NGO Reportage. By way of a case study, an exploration of this new genre reveals important issues for photographers working with NGOs and examines the constructed narratives of images contained within these emerging practices.

"The Stratified Record upon Which We Set Our Feet" : The Spatial Turn and the Multilayering of History, Geography, and Geology

In Thomas Mann’s tetralogy of the 1930s and 1940s, Joseph and His Brothers, the narrator declares history is not only “that which has happened and that which goes on happening in time,” but it is also “the stratified record upon which we set our feet, the ground beneath us.” By opening up history to its spatial, geographical, and geological dimensions Mann both predicts and encapsulates the twentieth-century’s “spatial turn,” a critical shift that divested geography of its largely passive role as history’s “stage” and brought to the fore intersections between the humanities and the earth sciences. In this paper, I draw out the relationships between history, narrative, geography, and geology revealed by this spatial turn and the questions these pose for thinking about the disciplinary relationship between geography and the humanities. As Mann’s statement exemplifies, the spatial turn itself has often been captured most strikingly in fiction, and I would argue nowhere more so than in Graham Swift’s Waterland (1983) and Anne Michaels’s Fugitive Pieces (1996), both of which present space, place, and landscape as having a palpable influence on history and memory. The geographical/geological line that runs through both Waterland and Fugitive Pieces continues through Tim Robinson’s non-fictional, two-volume “topographical” history Stones of Aran. Robinson’s Stones of Aran—which is not history, not geography, and not literature, and yet is all three—constructs an imaginative geography that renders inseparable geography, geology, history, memory, and the act of writing.

Cartographic Strategies of Postmodernity : the Figure of the Map in Contemporary Theory and Fiction

The last fifty years have witnessed the growing pervasiveness of the figure of the map in critical, theoretical, and fictional discourse. References to mapping and cartography are endemic in poststructuralist theory, and, similarly, geographically and culturally diverse authors of twentieth-century fiction seem fixated upon mapping. While the map metaphor has been employed for centuries to highlight issues of textual representation and epistemology, the map metaphor itself has undergone a transformation in the postmodern era. This metamorphosis draws together poststructuralist conceptualizations of epistemology, textuality, cartography, and metaphor, and signals a shift away from modernist preoccupations with temporality and objectivity to a postmodern pragmatics of spatiality and subjectivity. Cartographic Strategies of Postmodernity charts this metamorphosis of cartographic metaphor, and argues that the ongoing reworking of the map metaphor renders it a formative and performative metaphor of postmodernity.

Feminist crime fiction : an examination of embodied feminist intentions in Denise Mina’s The Field of Blood (2005)

The writing of award winning tartan noir author, Denise Mina, “crime queen of Glasgow” has been identified with “explicitly feminist politics,” and Mina herself claims, as a feminist, she wants to use crime fiction to present a “narrative about very disempowered people becoming empowered.” This paper explores how Mina’s avowed stance on feminism plays out in her novel, The Field of Blood (2005), and examines whether her concerns are reflected in the embodied actions of her young protagonist, would-be investigative journalist, Paddy Meehan. It asks whether Mina has succeeded in working against entrenched patriarchal codes of crime fiction’s dominant narrative construction or whether her feminist intentions have been undermined by traditional stereotypical conventions of the genre.

Non-formal techniques for early assessment of design ideas for services

Designing systems for multiple stakeholders requires frequent collaboration with multiple stakeholders from the start. In many cases at least some stakeholders lack a professional habit of formal modeling. We report observations from student design teams as well as two case studies, respectively of a prototype for supporting creative communication to design objects, and of stakeholder-involvement in early design. In all observations and case studies we found that non-formal techniques supported strong collaboration resulting in deep understanding of early design ideas, of their value and of the feasibility of solutions.

Irregular readers : Arthur Conan Doyle’s “six dirty scoundrels”, boyhood and literacy in contemporary Sherlockian children’s literature

Young adult (YA) literature is a socialising genre that encourages young readers to take up particular ways of relating to historical or cultural materials. The first decade of the twenty-first century witnessed a boom in Sherlockian YA fiction using the Conan Doyle canon as a context and vocabulary for stories focused on the Baker Street Irregulars as figures of identification. This paper reads YA fiction’s deployment of Conan Doyle’s fictional universe as a strategy for negotiating anxieties of adolescent masculinity, particularly in relation to literacy and social agency.

Amateur Media : Social, Cultural and Legal Perspectives

The rise of Web 2.0 has pushed the amateur to the forefront of public discourse, public policy and media scholarship. Typically non-salaried, non-specialist and untrained in media production, amateur producers are now seen as key drivers of the creative economy. But how do the activities of citizen journalists, fan fiction writers and bedroom musicians connect with longer traditions of extra-institutional media production? This edited collection provides a much-needed interdisciplinary contextualisation of amateur media before and after Web 2.0. Surveying the institutional, economic and legal construction of the amateur media producer via a series of case studies, it features contributions from experts in the fields of law, economics and media studies based in the UK, Europe and Singapore. Each section of the book contains a detailed case study on a selected topic, followed by two further pieces providing additional analysis and commentary. Using an extraordinary array of case studies and examples, from YouTube to online games, from subtitling communities to reality TV, the book is neither a celebration of amateur production nor a denunciation of the demise of professional media industries. Rather, this book presents a critical dialogue across law and the humanities, exploring the dynamic tensions and interdependencies between amateur and professional creative production. This book will appeal to both academics and students of intellectual property and media law, as well as to scholars and students of economics, media, cultural and internet studies.