Increased Th17-Related Cytokine Serum Levels in Patients With Multiple Polyps of Unexplained Origin

OBJECTIVES: Most patients with multiple colonic polyps do not have a known genetic or hereditary origin. Our aim was to analyze the presence of inflammatory cytokines and levels of glucose, insulin, and C-reactive protein (CRP) in patients with multiple colonic polyps. METHODS: Eighty-three patients with 10 or more adenomatous or serrated polyps and 53 control people with normal colonoscopy were included. Smoking habits were registered, and glucose, CRP, and basal insulin in the serum/blood were measured. Quantification of IL-2, IL-4, IL-6, IL-10, IL-11, IL-17A, and IL-23 cytokine levels in the serum was performed by a high-sensitivity enzyme-linked immunosorbent assay. RESULTS: Smoking and diabetes were more prevalent in those with colonic polyps than in the control people (67% vs 16%, P = 0.001; 11% vs 2%, P = 0.048). In addition, the cytokine serum levels were higher, i.e., IL-2 (P = 0.001), IL-4 (P = 0.001), IL-6 (P = 0.001), IL-17A (P = 0.001), IL-23 (P = 0.014), and CRP (P = 0.003). Adjusting for sex, smoking, and diabetes in a multivariate analysis, IL-2, IL-4, IL-6, IL-17A, and IL-23 remained independently elevated in cases with multiple polyps. DISCUSSION: These results indicate that immune responses mediated by Th17 cells may be involved in the pathogenesis of multiple colonic polyps

Oncogenic driver mutations predict outcome in a cohort of head and neck squamous cell carcinoma (HNSCC) patients within a clinical trial

234 diagnostic formalin-fixed paraffin-embedded (FFPE) blocks from homogeneously treated patients with locally advanced head and neck squamous cell carcinoma (HNSCC) within a multicentre phase III clinical trial were characterised. The mutational spectrum was examined by next generation sequencing in the 26 most frequent oncogenic drivers in cancer and correlated with treatment response and survival. Human papillomavirus (HPV) status was measured by p16INK4a immunohistochemistry in oropharyngeal tumours. Clinicopathological features and response to treatment were measured and compared with the sequencing results. The results indicated TP53 as the most mutated gene in locally advanced HNSCC. HPV-positive oropharyngeal tumours were less mutated than HPV-negative tumours in TP53 (p < 0.01). Mutational and HPV status influences patient survival, being mutated or HPV-negative tumours associated with poor overall survival (p < 0.05). No association was found between mutations and clinicopathological features. This study confirmed and expanded previously published genomic characterization data in HNSCC. Survival analysis showed that non-mutated HNSCC tumours associated with better prognosis and lack of mutations can be identified as an important biomarker in HNSCC. Frequent alterations in PI3K pathway in HPV-positive HNSCC could define a promising pathway for pharmacological intervention in this group of tumours

Anti-tumour necrosis factor discontinuation in inflammatory bowel disease patients in remission: study protocol of a prospective, multicentre, randomized clinical trial

Background: Patients with inflammatory bowel disease who achieve remission with anti-tumour necrosis factor (anti-TNF) drugs may have treatment withdrawn due to safety concerns and cost considerations, but there is a lack of prospective, controlled data investigating this strategy. The primary study aim is to compare the rates of clinical remission at 1?year in patients who discontinue anti-TNF treatment versus those who continue treatment. Methods: This is an ongoing, prospective, double-blind, multicentre, randomized, placebo-controlled study in patients with Crohn?s disease or ulcerative colitis who have achieved clinical remission for ?6?months with an anti-TNF treatment and an immunosuppressant. Patients are being randomized 1:1 to discontinue anti-TNF therapy or continue therapy. Randomization stratifies patients by the type of inflammatory bowel disease and drug (infliximab versus adalimumab) at study inclusion. The primary endpoint of the study is sustained clinical remission at 1?year. Other endpoints include endoscopic and radiological activity, patient-reported outcomes (quality of life, work productivity), safety and predictive factors for relapse. The required sample size is 194 patients. In addition to the main analysis (discontinuation versus continuation), subanalyses will include stratification by type of inflammatory bowel disease, phenotype and previous treatment. Biological samples will be obtained to identify factors predictive of relapse after treatment withdrawal. Results: Enrolment began in 2016, and the study is expected to end in 2020. Conclusions: This study will contribute prospective, controlled data on outcomes and predictors of relapse in patients with inflammatory bowel disease after withdrawal of anti-TNF agents following achievement of clinical remission. Clinical trial reference number: EudraCT 2015-001410-1

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project

INTRODUCTION: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. METHODS: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. RESULTS: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. DISCUSSION: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series

Real Wage Responsiveness to Unemployment in Spain: Asymmetries Along the Business Cycle

We estimate real wage cyclicality in the period compressed between 1987 and 2013 using a large administrative dataset of workers in Spain. Real wages are weakly procyclical in Spain and focusing on differences in different phases of the business cycle, we find that differences across expansions and recessions are significant, with an even lower real wage cyclicality in recessions. Furthermore, higher levels of unemployment do not translate into additional real wages adjustments when the economy is contracting, while lower levels of unemployment during expansions have incremental effects on wage elasticity. This general result holds after accounting for differences in tenure, type of contract and age categories. Nevertheless, wages of newly-hired workers are the most sensitive to the business cycle and exhibit the lowest asymmetric pattern between expansions and recessions. At the other end, wages of workers with more than six years of tenure can be characterized as the most protected against economic downturns. The same is true for fixed-term vs. permanent workers, as well as for young vs. older workers

Planck 2013 results. III. LFI systematic uncertainties

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Planck intermediate results. XIX. An overview of the polarized thermal emission from Galactic dust

This paper presents an overview of the polarized sky as seen by Planck HFI at 353GHz, which is the most sensitive Planck channel for dust polarization. We construct and analyse maps of dust polarization fraction and polarization angle at 1 degrees resolution, taking into account noise bias and possible systematic effects. The sensitivity of the Planck HFI polarization measurements allows for the first time a mapping of Galactic dust polarized emission on large scales, including low column density regions. We find that the maximum observed dust polarization fraction is high (p(max) = 19.8%), in particular in some regions of moderate hydrogen column density (N-H <2 x 10(21) cm(-2)). The polarization fraction displays a large scatter at NH below a few 10(21) cm(-2). There is a general decrease in the dust polarization fraction with increasing column density above N-H similar or equal to 1 x 10(21) cm(-2) and in particular a sharp drop above N-H similar or equal to 1.5 x 10(22) cm(-2). We characterize the spatial structure of the polarization angle using the angle dispersion function. We find that the polarization angle is ordered over extended areas of several square degrees, separated by filamentary structures of high angle dispersion function. These appear as interfaces where the sky projection of the magnetic field changes abruptly without variations in the column density. The polarization fraction is found to be anti-correlated with the dispersion of polarization angles. These results suggest that, at the resolution of 1 degrees, depolarization is due mainly to fluctuations in the magnetic field orientation along the line of sight, rather than to the loss of grain alignment in shielded regions. We also compare the polarization of thermal dust emission with that of synchrotron measured with Planck, low-frequency radio data, and Faraday rotation measurements toward extragalactic sources. These components bear resemblance along the Galactic plane and in some regions such as the Fan and North Polar Spur regions. The poor match observed in other regions shows, however, that dust, cosmic-ray electrons, and thermal electrons generally sample different parts of the line of sight.Peer reviewe

Planck intermediate results. XXI. Comparison of polarized thermal emission from Galactic dust at 353 GHz with interstellar polarization in the visible

The Planck survey provides unprecedented full-sky coverage of the submillimetre polarized emission from Galactic dust. In addition to the information on the direction of the Galactic magnetic field, this also brings new constraints on the properties of dust. The dust grains that emit the radiation seen by Planck in the submillimetre also extinguish and polarize starlight in the visible. Comparison of the polarization of the emission and of the interstellar polarization on selected lines of sight probed by stars provides unique new diagnostics of the emission and light scattering properties of dust, and therefore of the important dust model parameters, composition, size, and shape. Using ancillary catalogues of interstellar polarization and extinction of starlight, we obtain the degree of polarization, p(V), and the optical depth in the V band to the star, tau(V). Toward these stars we measure the submillimetre polarized intensity, P-S, and total intensity, I-S,I- in the Planck 353 GHz channel. We compare the column density measure in the visible, E(B - V), with that inferred from the Planck product map of the submillimetre dust optical depth and compare the polarization direction (position angle) in the visible with that in the submillimetre. For those lines of sight through the di ff use interstellar medium with comparable values of the estimated column density and polarization directions close to orthogonal, we correlate properties in the submillimetre and visible to find two ratios, R-S/V = (P-S/I-S) = (p(V)/tau(V)) and R-P/p = P-S/p(V), the latter focusing directly on the polarization properties of the aligned grain population alone. We find R-S/V = 4.2, with statistical and systematic uncertainties 0.2 and 0.3, respectively, and R-P/p = 5.4 MJy sr(-1), with uncertainties 0.2 and 0.3 MJy sr(-1), respectively. Our estimate of R-S/V is compatible with predictions based on a range of polarizing dust models that have been developed for the di ff use interstellar medium. This estimate provides new empirical validation of many of the common underlying assumptions of the models, but is not yet very discriminating among them. However, our estimate of R-P/p is not compatible with predictions, which are too low by a factor of about 2.5. This more discriminating diagnostic, R-P/p, indicates that changes to the optical properties in the models of the aligned grain population are required. These new diagnostics, together with the spectral dependence in the submillimetre from Planck, will be important for constraining and understanding the full complexity of the grain models, and for interpreting the Planck thermal dust polarization and refinement of the separation of this contamination of the cosmic microwave background.Peer reviewe

Planck 2013 results. XXVI. Background geometry and topology of the Universe

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