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inflammatory bowel disease who achieve remission with anti-tumour necrosis factor (anti-TNF) drugs may have treatment withdrawn due to safety concerns and cost considerations, but there is a lack of prospective, controlled data investigating this strategy.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

Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility : a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium

Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A > G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03-1.08; p value = 1.4 x 10(-6)). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 x 10(-3) and 7.0 x 10(-3), respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 x 10(-3), 4.5 x 10(-4) and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3, IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.Peer reviewe

Influence of magnetocrystalline anisotropy on the magnetization reversal mechanism in exchange bias Co CoO bilayers

We investigated the reversal mechanism in a Co CoO exchange bias bilayer with a pronounced magnetocrystalline anisotropy in the ferromagnet. The anisotropy, which is induced by the growth of a highly textured Co layer, imposes a distinct reversal mechanism along the magnetically easy and hard direction. It is shown that exchange bias can be induced along both directions, despite the magnetocrystalline anisotropy. The interplay between the magnetocrystalline anisotropy and exchange bias induces a different reversal mechanism for the subsequent reversals in the two crystallographic directions. Along the hard axis, the magnetization reverses according to the reversal mechanism observed before in polycrystalline exchange bias bilayers, i.e. domain wall nucleation and motion for the first reversal and coherent rotation for the subsequent ones. Along the easy axis, domain wall motion remains the dominant reversal mechanism and magnetization rotation has only a minor contributio

Enhancing Magneto Ionic Effects in Magnetic Nanostructured Films via Conformal Deposition of Nanolayers with Oxygen Acceptor Donor Capabilities

Effective manipulation of the magnetic properties of nanostructured metallic alloys, exhibiting intergrain porosity (i.e., channels) and conformally coated with insulating oxide nanolayers, with an electric field is demonstrated. Nanostructured Co–Pt films are grown by electrodeposition (ED) and subsequently coated with either AlOx or HfOx by atomic layer deposition (ALD) to promote magneto-ionic effects (i.e., voltage-driven ion migration) during electrolyte gating. Pronounced variations in coercivity (HC) and magnetic moment at saturation (mS) are found at room temperature after biasing the heterostructures. The application of a negative voltage results in a decrease of HC and an increase of mS, whereas the opposite trend is achieved for positive voltages. Although magneto-ionic phenomena are already observed in uncoated Co–Pt films (because of the inherent presence of oxygen), the ALD oxide nanocoatings serve to drastically enhance the magneto-ionic effects because of partially reversible oxygen migration, driven by voltage, across the interface between AlOx or HfOx and the nanostructured Co–Pt film. Co–Pt/HfOx heterostructures exhibit the most significant magneto-electric response at negative voltages, with an increase of mS up to 76% and a decrease of HC by 58%. The combination of a nanostructured magnetic alloy and a skinlike insulating oxide nanocoating is shown to be appealing to enhance magneto-ionic effects, potentially enabling electrolyte-gated magneto-ionic technology.Financial support by the European Research Council (SPIN-PORICS 2014-Consolidator Grant, agreement no. 648454), the Spanish Government (Project MAT2017-86357-C3-1-R, MAT2017-83169-R “Severo Ochoa” Programme for Centres of Excellence in R&D SEV-2015-0496 and associated FEDER), the Generalitat de Catalunya (2017-SGR-292 and 2017-SGR-1519), and the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 665919 is acknowledged. P.Y. acknowledges the Chinese Scholarship Council CSC fellowship (201606920073).Peer reviewe

Large Magnetoelectric Effects in Electrodeposited Nanoporous Microdisks Driven by Effective Surface Charging and Magneto Ionics

A synergetic approach to enhance magnetoelectric effects (i.e., control of magnetism with voltage) and improve energy efficiency in magnetically actuated devices is presented. The investigated material consists of an ordered array of Co–Pt microdisks, in which nanoporosity and partial oxidation are introduced during the synthetic procedure to synergetically boost the effects of electric field. The microdisks are grown by electrodeposition from an electrolyte containing an amphiphilic polymeric surfactant. The bath formulation is designed to favor the incorporation of oxygen in the form of cobalt oxide. A pronounced reduction of coercivity (88%) and a remarkable increase of Kerr signal amplitude (60%) are observed at room temperature upon subjecting the microdisks to negative voltages through an electrical double layer. These large voltage-induced changes in the magnetic properties of the microdisks are due to (i) the high surface-area-to-volume ratio with ultranarrow pore walls (sub-10 nm) that promote enhanced electric charge accumulation and (ii) magneto-ionic effects, where voltage-driven O^2– migration promotes a partial reduction of CoO to Co at room temperature. This simple and versatile procedure to fabricate patterned “nano-in-micro” magnetic motifs with adjustable voltage-driven magnetic properties is very appealing for energy-efficient magnetic recording systems and other magnetoelectronic devices