Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Private space and teenage culture : age, 'zones' and identity

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Left Behind, Left Unsaid: Absences On Young People's Facebook Timelines

Since its launch in 2004, Facebook has promoted an ethos of sharing and connecting with friends. From Facebook’s motto to “connect and share with people in your life” to its recent “Friendaversary” that invites users to celebrate friendships mediated on the site, Facebook operates on a logic of sharing. While there is considerable work on sharing practices, what is less well-understood is dis-use, or the absence of disclosures. In other words, what is left unsaid on Facebook? In this paper we draw on data from the Facebook Timelines project to explore the multi-dimensional notion of ‘absence’ as it plays out on Facebook: obvious gaps, disclosures that were erased, and significant events (deaths, break-ups, failures) deemed inappropriate for Facebook. In this study we interviewed 34 people in their twenties who had been using Facebook for more than five years, in both Tasmania (Australia) and Liverpool (UK). During our interviews, we ‘scrolled back’ with our participants over their years of disclosures. This paper will be divided into three parts to cover three themes in the data: evolving social media literacies, imagined audiences, and absence on social media as a safety mechanism. We argue our findings contribute towards Light's (2014) theorisation of 'disconnective practice'

Characterisation and validation of Mel38; A multi-tissue microRNA signature of cutaneous melanoma.

BACKGROUND:Histopathologic examination of melanocytic neoplasms can be challenging and subjective, with no specific circulating or tissue-based biomarkers currently available. Recently, a circulating 38-microRNA profile of melanoma (Mel38) was described. In this study, Mel38 expression and its impact on downstream mRNA regulation in solid tissue is examined. METHODS:Mel38 was applied to archival, clinically-annotated, solid-tissue genomic datasets representing benign naevi, primary and metastatic melanoma. Statistical analysis of the signature in relation to disease status, patient outcome and molecular pathways was performed. RESULTS:Mel38 is able to stratify genomic data from solid tissue biopsies on the basis of disease status and differences in melanoma-specific survival. Experimentally-verified messenger-RNA targets of Mel38 also exhibit prognostic expression patterns and represent key molecular pathways and events in melanoma development and progression. CONCLUSION:The Mel38 microRNA profile may have diagnostic and prognostic utility in solid tissue as well as being a robust circulating biomarker of melanoma

Constructing, deconstructing and negotiating the boundaries of digital cultures

The focus of this special issue is upon notions, and experiences of, the erosion and blurring of the boundaries constructed between work, play, the public and private as related to digital media. We seek to increase knowledge regarding the contemporary experiences and potential reshaping of the boundaries and structures of existing social organisation, and the altering of the ways in which people learn to experience life. We know that even as access to digital technologies continues to vary based on age, gender, nationality, residence, ethnicity, work, and other key aspects of society, it is clear the presence and uses of these digital technologies are increasingly important features of contemporary life..

Subcultures, popular music and social change

Style-based subcultures, scenes and tribes have pulsated through the history of social, economic and political change. From 1940s zoot-suiters and hepcats; through 1950s rock ’n’ rollers, beatniks and Teddy boys; 1960s surfers, rudeboys, mods, hippies and bikers; 1970s skinheads, soul boys, rastas, glam rockers, funksters and punks; on to the heavy metal, hip-hop, casual, goth, rave, hipster and clubber styles of the 1980s, 90s, noughties and beyond; distinctive blends of fashion and music have become a defining feature of the cultural landscape. Research into these phenomena has traversed the social sciences and humanities, and Subcultures, Popular Music and Social Change assembles important theoretical interventions and empirical studies from this rich, interdisciplinary field. Featuring contributions from major scholars and new researchers, the book explores the historical and cultural significance of subcultural styles and their related music genres. Particular attention is given to the relation between subcultures and their historical context, the place of subcultures within patterns of cultural and political change, and their meaning for participants, confederates and opponents. As well as Anglo-American developments, the book considers experiences across a variety of global sites and locales, giving reference to issues such as class, ethnicity, gender, sexuality, creativity, commerce, identity, resistance and deviance