PP2A methylesterase PME-1 suppresses anoikis and is associated with therapy relapse of PTEN-deficient prostate cancers

While organ-confined prostate cancer (PCa) is mostly therapeutically manageable, metastatic progression of PCa remains an unmet clinical challenge. Resistance to anoikis, a form of cell death initiated by cell detachment from the surrounding extracellular matrix, is one of the cellular processes critical for PCa progression towards aggressive disease. Therefore, further understanding of anoikis regulation in PCa might provide therapeutic opportunities. Here, we discover that PCa tumors with concomitant inhibition of two tumor suppressor phosphatases, PP2A and PTEN, are particularly aggressive, having less than 50% 5-year secondary-therapy-free patient survival. Functionally, overexpression of PME-1, a methylesterase for the catalytic PP2A-C subunit, inhibits anoikis in PTEN-deficient PCa cells. In vivo, PME-1 inhibition increased apoptosis in in ovo PCa tumor xenografts, and attenuated PCa cell survival in zebrafish circulation. Molecularly, PME-1-deficient PC3 cells display increased trimethylation at lysines 9 and 27 of histone H3 (H3K9me3 and H3K27me3), a phenotype known to correlate with increased apoptosis sensitivity. In summary, our results demonstrate that PME-1 supports anoikis resistance in PTEN-deficient PCa cells. Clinically, these results identify PME-1 as a candidate biomarker for a subset of particularly aggressive PTEN-deficient PCa

European Position Paper on Rhinosinusitis and Nasal Polyps 2020

The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise. The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included.Peer reviewe

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

Negotiating culture in a cosmopolitan capital: Urban style and the Tanzanian state in colonial and postcolonial Dar es Salaam.

This dissertation is a study of political contests over culture and the meanings of style in the burgeoning capital city of late-colonial and postcolonial Tanzania. Focusing in particular on the public controversies, scandals and struggles generated by the banning of transnational cultural forms such as the mini-skirt, soul music, 'Afro' hairstyles and beauty contests in the heady years of President Nyerere's ujamaa socialism, I situate these debates in several, overlapping contexts: debates over colonial interventions in culture from the 1930s through the 1950s; the postcolonial state's construction of national culture in the 1960s and 1970s; urban social struggles of the period around gender, wealth and generation; and finally, specific and bounded cosmopolitan networks of knowledge, power and style along which Dar es Salaam was a nodal point. Tracing the roots of these postcolonial debates back to colonial attempts to define 'African culture' and control urban 'undesirables,' I argue that 'national culture' facilitated attempts on the part of the postcolonial political elite to demarcate an independent Tanzania from its colonial past, even as it pursued policies strikingly similar to those of its colonial predecessor. But the heated debates surrounding the campaigns against 'decadence' that gripped Dar es Salaam in the late 1960s and 1970s not only saw official notions of 'national culture,' and citizenship strongly contested, they also spilled beyond the question of 'national culture' to become touch points for the articulation of anxieties and struggles over a wide range of urban social concerns: the changing nature of public space in a rapidly expanding Dar es Salaam, women's work and mobility in the city, the state's increasing control of paths to resources and power, and crises of masculinity and youth in an era of urban joblessness. In suggesting that Tanzania's national cultural project as well as the 'foreign' practices it targeted were embedded in competing cosmopolitan networks---along which traveled not only the influences of music, fashion and the events of '68, but also those of Mao, modernization theory and Third World Marxisms---my work argues that a complex international frame is crucial to understanding urban cultural politics in postcolonial contexts.Ph.D.African historyBlack studiesSocial SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/123871/2/3106089.pd

The EBRAINS Hodgkin-Huxley Neuron Builder: An online resource for building data-driven neuron models

International audienceIn the last decades, brain modeling has been established as a fundamental tool for understanding neural mechanisms and information processing in individual cells and circuits at different scales of observation. Building data-driven brain models requires the availability of experimental data and analysis tools as well as neural simulation environments and, often, large scale computing facilities. All these components are rarely found in a comprehensive framework and usually require ad hoc programming. To address this, we developed the EBRAINS Hodgkin-Huxley Neuron Builder (HHNB), a web resource for building single cell neural models via the extraction of activity features from electrophysiological traces, the optimization of the model parameters via a genetic algorithm executed on high performance computing facilities and the simulation of the optimized model in an interactive framework. Thanks to its inherent characteristics, the HHNB facilitates the data-driven model building workflow and its reproducibility, hence fostering a collaborative approach to brain modeling

PP2A methylesterase PME-1 suppresses anoikis and is associated with therapy relapse of PTEN-deficient prostate cancers

Peer reviewe