Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

SummaryWe report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

The Somatic Genomic Landscape of Glioblastoma

We describe the landscape of somatic genomic alterations based on multi-dimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer

Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin

Recent genomic analyses of pathologically-defined tumor types identify “within-a-tissue” disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head & neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multi-platform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All datasets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies

Hållplatsen som offentlig miljö - En fallstudie av busshållplatser i Malmö

Syftet med detta examensarbete är att förstå vad som ligger till grund för dagens utformning av busshållplatser och vilka möjligheter det finns för att bygga attraktiva busshållplatser. För att kunna göra det är det viktigt att förstå de inblandade aktörernas ansvarsfördelning och intressen. Metoden som har använts är kvalitativa intervjuer med trafikplanerare från Malmö Stad, Skånetrafiken och andra intressanta aktörer. De slutsatser som dragits är att hållplatser är ett komplext ämne och att det finns flera aspekter att ta hänsyn till både när det kommer till utformningen av hållplatser men också eftersom flera olika aktörer är delaktiga i processen. Det finns troligtvis inte en ultimat standardhållplats utan en välfungerande hållplats är en hållplats som är anpassad efter den plats som den befinner sig på. De största utmaningar som har identifierats är ytbristen i staden och att aktörerna delvis har olika målbilder. Den största möjligheten som har identifierats är att det finns en stor vilja och intresse från alla aktörer att samarbeta för att förbättra hållplatserna.The aim of this master thesis is to understand why bus stops are designed the way they are and what the possibilities are to build attractive bus stops. To do so it is also important to know which the invovled parties are and what role they play. The method for this study are qualtive interviews with transport planners from Malmö Stad and Skånetrafiken and other interesting parties. The study has shown that the bus stop is a complex subject and there are several aspects to have in consideration when it comes to the design of bus stops but, also because there are several different parties involved in the process. There is probably not one perfect design for all bus stop but, a well functional bus stop is a bus stop adapted to the site. Challengers that have been identified are the lack of area in the city and that the parties somewhat have different goals. A possibility that have been identified is that all parties express a will and interest to collaborate for improving the bus stops

Increasing influenza vaccination coverage in healthcare workers: a review on campaign strategies and their effect

PURPOSE: Increasing influenza vaccination coverage in healthcare workers is a challenge. Especially during the ongoing COVID-19 pandemic, high vaccination coverage should be attained. This review analyzed strategies to increase influenza vaccination coverage in healthcare workers. METHODS: A literature search using PubMed was conducted and 32 publications on influenza vaccination campaigns for healthcare workers were reviewed for key interventions and resulting vaccination coverage. RESULTS: Among key interventions analyzed, mandatory vaccination policies or multifaceted campaigns including a vaccinate-or-wear-a-mask policy as well as mandatory declination reached vaccination coverage in healthcare workers of over 90%. Although campaigns solely based on education and promotion or on-site-vaccination did not regularly exceed an absolute vaccination coverage of 40%, a substantial relative increase in vaccination coverage was reached by implementation of these strategies. CONCLUSION: Mandatory vaccination policies are effective measures to achieve high overall vaccination coverage. In clinics where policies are infeasible, multifaceted campaigns comprising on-site vaccination, vaccination stands and educational and promotional campaigns as well as incentives should be implemented. Lessons learned from influenza campaigns could be implemented in future SARS-CoV-2 vaccination campaigns

Delayed Cutaneous Hypersensitivity Reaction to Vaxzevria (ChAdOx1-S) Vaccine against SARS-CoV-2

Recently, an increasing number of cases with delayed cutaneous reaction after immunization with mRNA-based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported. This adverse reaction, which is considered a delayed-type or T cell-mediated hypersensitivity reaction, has been described for the Moderna (mRNA-1273) and Comirnaty (Pfizer/BioNTech, BNT162b2) vaccines. We describe a delayed large local cutaneous reaction in a patient who received the viral vector vaccine Vaxzevria (ChAdOx1-S, AstraZeneca). The time course and clinical symptoms of delayed skin reaction after mRNA vaccines have a similar pattern that we recognized in our patient after Vaxzevria vaccination. This phenomenon has not been described in the Vaxzevria clinical trials and is to our knowledge the first report of this adverse reaction to a vector-based SARS-CoV-2 vaccine. With this, we hope to raise awareness about delayed injection site reactions that also occur after viral vector vaccines and to encourage additional reporting and patient education regarding the cutaneous reactions after coronavirus disease 2019 (COVID-19) vaccination

Increasing influenza vaccination coverage in healthcare workers: a review on campaign strategies and their effect

Purpose Increasing influenza vaccination coverage in healthcare workers is a challenge. Especially during the ongoing COVID-19 pandemic, high vaccination coverage should be attained. This review analyzed strategies to increase influenza vaccination coverage in healthcare workers. Methods A literature search using PubMed was conducted and 32 publications on influenza vaccination campaigns for healthcare workers were reviewed for key interventions and resulting vaccination coverage. Results Among key interventions analyzed, mandatory vaccination policies or multifaceted campaigns including a vaccinate-or-wear-a-mask policy as well as mandatory declination reached vaccination coverage in healthcare workers of over 90%. Although campaigns solely based on education and promotion or on-site-vaccination did not regularly exceed an absolute vaccination coverage of 40%, a substantial relative increase in vaccination coverage was reached by implementation of these strategies. Conclusion Mandatory vaccination policies are effective measures to achieve high overall vaccination coverage. In clinics where policies are infeasible, multifaceted campaigns comprising on-site vaccination, vaccination stands and educational and promotional campaigns as well as incentives should be implemented. Lessons learned from influenza campaigns could be implemented in future SARS-CoV-2 vaccination campaigns