DAISY: picking synthetic lethals from cancer genomes.

A better understanding of genetic interactions in cancer might help identify new therapeutic approaches that exploit the concept of synthetic lethality. Ruppin and colleagues have developed a new computational method, DAISY, that predicts such interactions and potentially facilitates the delineation and validation of comprehensive genetic interaction networks

An RNA interference screen for identifying downstream effectors of the p53 and pRB tumour suppressor pathways involved in senescence

Background: Cellular senescence is an irreversible cell cycle arrest that normal cells undergo in response to progressive shortening of telomeres, changes in telomeric structure, oncogene activation or oxidative stress and acts as an important tumour suppressor mechanism.Results: To identify the downstream effectors of the p53-p21 and p16-pRB tumour suppressor pathways crucial for mediating entry into senescence, we have carried out a loss-of-function RNA interference screen in conditionally immortalised human fibroblasts that can be induced to rapidly undergo senescence, whereas in primary cultures senescence is stochastic and occurs asynchronously. These cells are immortal but undergo a rapid irreversible arrest upon activation of the p53-p21 and p16-pRB pathways that can be readily bypassed upon their inactivation. The primary screen identified 112 known genes including p53 and another 29 shRNAmirs targetting as yet unidentified loci. Comparison of these known targets with genes known to be up-regulated upon senescence in these cells, by micro-array expression profiling, identified 4 common genes TMEM9B, ATXN10, LAYN and LTBP2/3. Direct silencing of these common genes, using lentiviral shRNAmirs, bypassed senescence in the conditionally immortalised cells.Conclusion: The senescence bypass screen identified TMEM9B, ATXN10, LAYN and LTBP2/3 as novel downstream effectors of the p53-p21 and p16-pRB tumour suppressor pathways. Although none of them has previously been linked to cellular senescence, TMEM9B has been suggested to be an upstream activator of NF-kappa B signalling which has been found to have a causal role in promoting senescence. Future studies will focus on determining on how many of the other primary hits also have a casual role in senescence and what is the mechanism of action

PARP inhibitor combination therapy.

In 2014, olaparib (Lynparza) became the first PARP (Poly(ADP-ribose) polymerase) inhibitor to be approved for the treatment of cancer. When used as single agents, PARP inhibitors can selectively target tumour cells with BRCA1 or BRCA2 tumour suppressor gene mutations through synthetic lethality. However, PARP inhibition also shows considerable promise when used together with other therapeutic agents. Here, we summarise both the pre-clinical and clinical evidence for the utility of such combinations and discuss the future prospects and challenges for PARP inhibitor combinatorial therapies

Self-branding and content creation strategies on Instagram: A case study of foodie influencers

The purpose of this study is to better understand the processes and procedures adopted by micro-influencers to create ‘Instagrammable’ content. It is based on 17 in-depth interviews with foodie micro-influencers based in London and Barcelona. Interview data was complemented with participant observation in restaurants or cafes. This paper makes three original contributions. Firstly, the study expands the understanding of the concept of ‘instagrammability’ by approaching it from the perspective of influencers creating content to satisfy and/or growan audience. Secondly, it illustrates how two dominant factors drive influencers content creation process: the self/audience focus content branding orientation. The the audience-focus content development process varied drastically, with some influencers being very conscious of responding to their audiences’ needs whereas others maintained first and foremost a very strong self-focus’. However, even for the influencers who were the most responsive to their audiences perceived wishes, a sense of self-focus was maintained as an anchor point in all developed content, often linked to a passion for a certain type of food. Thirdly, this paper maps and describes the behind-the-scenes content creation process adopted by micro-influencers, including four stages (1)Content Planning,(2)Media Gathering, (3)Editing,and (4)Publishing, which was followed by an engagement phase.This study offers a timely contribution to better comprehending the content creation cycle adopted by micro-influencers by using foodie influencers as a case study

Managing brand presence through social media: the case of UK football clubs

Purpose – The purpose of this paper is to contribute knowledge on the issues and benefits associated with managing brand presence and relationships through social media. UK football clubs are big businesses, with committed communities of fans, so are an ideal context from which to develop an understanding of the issues and challenges facing organisations as they seek to protect and promote their brand online. Design/methodology/approach – Due to the emergent nature of social media, and the criticality of the relationships between clubs and their fans, an exploratory study using a multiple case study approach was used to gather rich insights into the phenomenon. Findings – Clubs agreed that further development of social media strategies had potential to deliver interaction and engagement, community growth and belonging, traffic flow to official web sites and commercial gain. However, in developing their social media strategies they had two key concerns. The first concern was the control of the brand presence and image in social media, and how to respond to the opportunities that social media present to fans to impact on the brand. The second concern was how to strike an appropriate balance between strategies that deliver short-term revenue, and those that build longer term brand loyalty. Originality/value – This research is the first to offer insights into the issues facing organisations when developing their social media strategy

‘With a little help from my friends’: exploring mutual engagement and authenticity within foodie influencers’ communities of practice

The aim of this paper is to analyze the dynamics of mutual engagement within the foodie influencer communities of practice created via Instagram. The study is based on 20 in-depth interviews with foodie Instagrammers. Findings demonstrate that unlike other communities of practice, rather than competing among themselves, foodies learn from each other, exchange tips, help those starting out in the field and attend events together. Close collaboration also leads to the formation of strong friendship bonds. However, findings show that whilst authenticity of content is deemed important, elements of influencer engagement are artificially orchestrated within their own community of practice. These findings have implications for marketing professionals in terms of evaluating influencersʻ engagement authenticity and the selection criteria they consider with regard to targeting appropriate and specific influencers to work with

Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity.

Based on a series of basic, preclinical and clinical studies, the Poly (ADP-ribose) Polymerase 1 (PARP1) inhibitor, olaparib, has recently been approved for use in ovarian cancer patients with BRCA1 or BRCA2 mutations. By identifying novel predictive biomarkers of tumour cell sensitivity to olaparib, it is possible that the utility of PARP inhibitors could be extended beyond this patient subgroup. Many of the known genetic determinants of PARP inhibitor response have key roles in DNA damage response (DDR) pathways. Although protein ubiquitylation is known to play an important role in regulating the DDR, the exact mechanisms by which this occurs are not fully understood. Using two parallel RNA interference-based screening approaches, we identified the E3 ubiquitin ligase, CBLC, as a candidate biomarker of response to olaparib. We validated this observation by demonstrating that silencing of CBLC causes increased sensitivity to olaparib in breast cancer cell line models and that defective homologous recombination (HR) DNA repair is the likely cause. This data provides an example of how defects in the ubiquitin machinery have the potential to influence the response of tumour cells to PARP inhibitors

The cylindromatosis gene product, CYLD, interacts with MIB2 to regulate notch signalling.

CYLD, an ubiquitin hydrolase, has an expanding repertoire of regulatory roles in cell signalling and is dysregulated in a number of cancers. To dissect CYLD function we used a proteomics approach to identify CYLD interacting proteins and identified MIB2, an ubiquitin ligase enzyme involved in Notch signalling, as a protein which interacts with CYLD. Coexpression of CYLD and MIB2 resulted in stabilisation of MIB2 protein levels and was associated with reduced levels of JAG2, a ligand implicated in Notch signalling. Conversely, gene silencing of CYLD using siRNA, resulted in increased JAG2 expression and upregulation of Notch signalling. We investigated Notch pathway activity in skin tumours from patients with germline mutations in CYLD and found that JAG2 protein levels and Notch target genes were upregulated. In particular, RUNX1 was overexpressed in CYLD defective tumour cells. Finally, primary cell cultures of CYLD defective tumours demonstrated reduced viability when exposed to γ-secretase inhibitors that pharmacologically target Notch signalling. Taken together these data indicate an oncogenic dependency on Notch signalling and suggest potential novel therapeutic approaches for patients with CYLD defective tumours

The cylindromatosis gene product, CYLD, interacts with MIB2 to regulate notch signalling.

CYLD, an ubiquitin hydrolase, has an expanding repertoire of regulatory roles in cell signalling and is dysregulated in a number of cancers. To dissect CYLD function we used a proteomics approach to identify CYLD interacting proteins and identified MIB2, an ubiquitin ligase enzyme involved in Notch signalling, as a protein which interacts with CYLD. Coexpression of CYLD and MIB2 resulted in stabilisation of MIB2 protein levels and was associated with reduced levels of JAG2, a ligand implicated in Notch signalling. Conversely, gene silencing of CYLD using siRNA, resulted in increased JAG2 expression and upregulation of Notch signalling. We investigated Notch pathway activity in skin tumours from patients with germline mutations in CYLD and found that JAG2 protein levels and Notch target genes were upregulated. In particular, RUNX1 was overexpressed in CYLD defective tumour cells. Finally, primary cell cultures of CYLD defective tumours demonstrated reduced viability when exposed to γ-secretase inhibitors that pharmacologically target Notch signalling. Taken together these data indicate an oncogenic dependency on Notch signalling and suggest potential novel therapeutic approaches for patients with CYLD defective tumours