The application of 'omics' to pulmonary arterial hypertension

Recent genome-wide analyses of rare and common sequence variations have brought greater clarity to the genetic architecture of pulmonary arterial hypertension and implicated novel genes in disease development. Transcriptional signatures have been reported in whole lung tissue, pulmonary vascular cells and peripheral circulating cells. High-throughput platforms for plasma proteomics and metabolomics have identified novel biomarkers associated with clinical outcomes and provided molecular instruments for risk assessment. There are methodological challenges to integrating these datasets, coupled to statistical power limitations inherent to the study of a rare disease, but the expectation is that this strategy will reveal novel druggable targets and biomarkers that will open the way to personalised medicine. Here we review the current state-of-the-art and future promise of "omics" in the field of translational medicine in pulmonary arterial hypertension

Recent advances in pulmonary arterial hypertension [version 1; referees: 2 approved]

Pulmonary arterial hypertension (PAH) is a rare disorder with a high mortality rate. Treatment options have improved in the last 20 years, but patients still die prematurely of right heart failure. Though rare, it is heterogeneous at the genetic and molecular level, and understanding and exploiting this is key to the development of more effective treatments. BMPR2 , encoding bone morphogenetic receptor type 2, is the most commonly affected gene in both familial and non-familial PAH, but rare mutations have been identified in other genes. Transcriptomic, proteomic, and metabolomic studies looking for endophenotypes are under way. There is no shortage of candidate new drug targets for PAH, but the selection and prioritisation of these are challenges for the research community

Trends in health complaints from 2002 to 2010 in 34 countries and their association with health behaviours and social context factors at individual and macro-level

Publisher Copyright: © 2015 The Author. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.Background: This article describes trends and stability over time in health complaints in adolescents from 2002 to 2010 and investigates associations between health complaints, behavioural and social contextual factors at individual level and economic factors at macro-level. Methods: Comprising N = 510 876 11-, 13- and 15-year-old children and adolescents in Europe, North America and Israel, data came from three survey cycles of the international Health Behaviour in School-aged Children (HBSC) study. Age- and gender-adjusted trends in health complaints were examined in each country by means of linear regression. By using the country as the random effects variable, we tested to what extent individual and contextual variables were associated with health complaints. Results: Significant associations are stronger for individual level determinants (e.g. being bullied, smoking) than for determinants at macro-level (e.g. GDP, Gini), as can be seen by the small effect sizes (less than 5% for different trends). Health complaints are fairly stable over time in most countries, and no clear international trend in health complaints can be observed between 2002 and 2010. The most prominent stable determinants were being female, being bullied, school pressure and smoking. Conclusion: Factors associated with health complaints are more related to the proximal environment than to distal macro-level factors. This points towards intensifying targeted interventions, (e.g. for bullying) and also targeting specific risk groups. The comparably small effect size at country-level indicates that country-level factors have an impact on health and should not be ignored.publishersversionPeer reviewe

An FPGA-based track finder for the L1 trigger of the CMS experiment at the high luminosity LHC

A new tracking system is under development for operation in the CMS experiment at the High Luminosity LHC. It includes an outer tracker which will construct stubs, built by correlating clusters in two closely spaced sensor layers for the rejection of hits from low transverse momentum tracks, and transmit them off-detector at 40 MHz. If tracker data is to contribute to keeping the Level-1 trigger rate at around 750 kHz under increased luminosity, a crucial component of the upgrade will be the ability to identify tracks with transverse momentum above 3 GeV/c by building tracks out of stubs. A concept for an FPGA-based track finder using a fully time-multiplexed architecture is presented, where track candidates are identified using a projective binning algorithm based on the Hough Transform. A hardware system based on the MP7 MicroTCA processing card has been assembled, demonstrating a realistic slice of the track finder in order to help gauge the performance and requirements for a full system. This paper outlines the system architecture and algorithms employed, highlighting some of the first results from the hardware demonstrator and discusses the prospects and performance of the completed track finder

Emulation of a prototype FPGA track finder for the CMS Phase-2 upgrade with the CIDAF emulation framework

The CMS collaboration is preparing a major upgrade of its detector, so it can operate during the high luminosity run of the LHC from 2026. The upgraded tracker electronics will reconstruct the trajectories of charged particles within a latency of a few microseconds, so that they can be used by the level-1 trigger. An emulation framework, CIDAF, has been developed to provide a reference for a proposed FPGA-based implementation of this track finder, which employs a Time-Multiplexed (TM) technique for data processing.The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Unions Seventh Framework Programme FP7/2007- 2013/ under REA grant agreement n [317446] INFIERI “Intelligent Fast Interconnected and Efficient Devices for Frontier Exploitation in Research and Industry”. This work was supported in part by the the UK Science and Technology Facilities Council, we gratefully acknowledge their support

Prolactin receptor is a negative prognostic factor in patients with squamous cell carcinoma of the head and neck

Background: The influence of human prolactin (hPRL) on the development of breast and other types of cancer is well established. Little information, however, exists on the effects of hPRL on squamous cell carcinomas of the head and neck (SCCHNs). Methods: In this study, we evaluated prolactin receptor (PRLR) expression in SCCHN cell lines and assessed by immunohistochemistry the expression in 89 patients with SCCHNs. The PRLR expression was correlated with clinicopathological characteristics as well as clinical outcome. The effect of hPRL treatment on tumour cell growth was evaluated in vitro. Results: Immunoreactivity for PRLR was observed in 85 out of 89 (95%) tumours. Multivariate COX regression analysis confirmed high levels of PRLR expression (>25% of tumour cells) to be an independent prognostic factor with respect to overall survival (HR=3.70, 95% CI: 1.14–12.01; P=0.029) and disease-free survival (P=0.017). Growth of PRLR-positive cancer cells increased in response to hPRL treatment. Conclusion: Our data indicate that hPRL is an important growth factor for SCCHN. Because of PRLR expression in a vast majority of tumour specimens and its negative impact on overall survival, the receptor represents a novel prognosticator and a promising drug target for patients with SCCHNs

Prolactin Receptor in Primary Hyperparathyroidism – Expression, Functionality and Clinical Correlations

<div><h3>Background</h3><p>Primary hyperparathyroidism (PHPT) is an endocrine disorder most commonly affecting women, suggesting a role for female hormones and/or their receptors in parathyroid adenomas. We here investigated the prolactin receptor (PRLr) which is associated with tumours of the breast and other organs.</p> <h3>Methodology/Principal Findings</h3><p>PRLr expression was investigated in a panel of 37 patients with sporadic parathyroid tumours and its functionality in cultured parathyroid tumour cells. In comparison with other tissues and breast cancer cells, high levels of prolactin receptor gene (<em>PRLR</em>) transcripts were demonstrated in parathyroid tissues. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours, PRLr immunoreactivity was observed in the cytoplasm (in all cases, n = 36), cytoplasmic granulae (n = 16), the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim (n = 28), PRLr was uniformly expressed in the cytoplasm and granulae. In <em>in vitro</em> studies of short-term cultured human parathyroid tumour cells, prolactin stimulation was associated with significant transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signalling pathways as documented by gene expression profiling. Moreover, <em>PRLR</em> gene expression in parathyroid tumours was inversely correlated with the patients’ plasma calcium levels.</p> <h3>Conclusions</h3><p>We demonstrate that the prolactin receptor is highly abundant in human parathyroid tissues and that PRLr isoforms expression and PRLr subcellular localisation are altered in parathyroid tumours. Responsiveness of PRLr to physiological levels of prolactin was observed in the form of increased PTH secretion and altered gene transcription with significant increase of RIG-I like receptor, JAK-STAT and Type II interferon signalling pathways. These data suggest a role of the prolactin receptor in parathyroid adenomas.</p> </div

Search for Resonant Production of High-Mass Photon Pairs in Proton-Proton Collisions at root s=8 and 13 TeV

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