Tolerance induction through early feeding to prevent food allergy in infants with eczema (TEFFA): rationale, study design, and methods of a randomized controlled trial

BACKGROUND: Up to 8% of all children in industrialized countries suffer from food allergies, whereas children with atopic eczema are affected considerably more frequently. In addition, the type and starting time of weaning foods seem to influence the development of food allergies. However, data from interventional studies on weaning are controversial. The aim of this randomized-controlled clinical trial is to investigate, whether an early introduction of hen's egg (HE), cow's milk (CM), peanut (PN), and hazelnut (HN) in children with atopic eczema can reduce the risk for developing food allergies in the first year of life. METHODS: This is a protocol for a randomized, placebo controlled, double blind, single-center clinical trial. One hundred fifty infants with atopic eczema at 4-8 months of age will be randomized in a 2:1 manner into an active group that will receive rusk-like biscuit powder with HE, CM, PN, and HN (initially approximately 2 mg of each food protein) for 6-8 months or a placebo group, whose participants will receive the same rusk-like biscuit powder without HE, CM, PN, and HN on a daily basis. During the interventional period, the amount of allergens in the study product will be increased three times, each after 6 weeks. All study participants who are sensitized to HE, CM, PN, or HN at the end of the interventional period will undergo an oral food challenge to the respective food in a further visit. Primary endpoint is IgE-mediated food allergy to at least one of the four foods (HE, CM, PN or HN) after 6-8 months of intervention (i.e., at around 1 year of age). Secondary endpoints include multiple food allergies, severity of eczema, wheezing, and sensitization levels against food allergens. DISCUSSION: This clinical trial will assess whether an early introduction of allergenic foods into the diet of children with atopic eczema can prevent the development of food allergies. This trial will contribute to update food allergy prevention guidelines. TRIAL REGISTRATION: German Clinical Trials Register DRKS00016770 . Registered on 09 January 2020

Therapeutic effect of all-trans-retinoic acid (at-RA) on an autoimmune nephritis experimental model: role of the VLA-4 integrin

BACKGROUND: Mercuric chloride (HgCl(2)) induces an autoimmune nephritis in the Brown Norway (BN) rats characterized by anti-glomerular basement membrane antibodies (anti-GBM Ab) deposition, proteinuria and a severe interstitial nephritis, all evident at day 13 of the disease. We assessed the effects of all-trans retinoic acid (at-RA) in this experimental model. At-RA is a vitamin A metabolite which has shown beneficial effects on several nephropathies, even though no clear targets for at-RA were provided. METHODS: We separated animals in four different experimental groups (HgCl(2), HgCl(2)+at-RA, at-RA and vehicle). From each animal we collected, at days 0 and 13, numerous biological samples: urine, to measure proteinuria by colorimetry; blood to determine VLA-4 expression by flow citometry; renal tissue to study the expression of VCAM-1 by Western blot, the presence of cellular infiltrates by immunohistochemistry, the IgG deposition by immunofluorescence, and the cytokines expression by RT-PCR. Additionally, adhesion assays to VCAM-1 were performed using K562 α4 transfectant cells. ANOVA tests were used for statistical significance estimation. RESULTS: We found that at-RA significantly decreased the serum levels of anti-GBM and consequently its deposition along the glomerular membrane. At-RA markedly reduced proteinuria as well as the number of cellular infiltrates in the renal interstitium, the levels of TNF-α and IL-1β cytokines and VCAM-1 expression in renal tissue. Moreover, we reported here for the first time in an in vivo model that at-RA reduced, to basal levels, the expression of VLA-4 (α4β1) integrin induced by mercury on peripheral blood leukocytes (PBLs). In addition, using K562 α4 stable transfectant cells, we found that at-RA inhibited VLA-4 dependent cell adhesion to VCAM-1. CONCLUSION: Here we demonstrate a therapeutic effect of at-RA on an autoimmune experimental nephritis model in rats. We report a significant reduction of the VLA-4 integrin expression on PBLs as well as the inhibition of the VLA4/VCAM1-dependent leukocyte adhesion by at-RA treatment. Thereby we point out the VLA-4 integrin as a target for at-RA in vivo

Tolerance induction through non-avoidance to prevent persistent food allergy (TINA) in children and adults with peanut or tree nut allergy: rationale, study design and methods of a randomized controlled trial and observational cohort study

BACKGROUND: Peanuts (PN) and tree nuts (TN) are among the most frequent elicitors of food allergy and can lead to life-threatening reactions. The current advice for allergic patients is to strictly avoid the offending food independently of their individual threshold level, whereas sensitized patients without allergic symptoms should frequently consume the food to avoid (re-)development of food allergy. The aim of this trial is to investigate (I) whether the consumption of low allergen amounts below the individual threshold may support natural tolerance development and (II) to what extent regular allergen consumption in sensitized but tolerant subjects prevents the (re-)development of PN or TN allergy. METHODS: The TINA trial consisting of (part I) a randomized, controlled, open, parallel group, single-center, superiority trial (RCT), and (part II) a prospective observational exploratory cohort study. Children and adults (age 1-67 years) with suspected or known primary PN and/or TN allergy will undergo an oral food challenge (OFC) to determine their clinical reactivity and individual threshold. In the RCT, 120 PN or TN allergic patients who tolerate ≥100 mg of food protein will be randomized (1:1 ratio) to consumption of products with low amounts of PN or TN on a regular basis or strict avoidance for 1 year. The consumption group will start with 1/100 of their individual threshold, increasing the protein amount to 1/50 and 1/10 after 4 and 8 months, respectively. The primary endpoint is the clinical tolerance to PN or TN after 1 year assessed by OFC. In the cohort study, 120 subjects sensitized to PN and/or TN but tolerant are advised to regularly consume the food and observed for 1 year. The primary endpoint is the maintenance of clinical tolerance to PN and/or TN after 1 year assessed by challenging with the former tolerated cumulative dose. DISCUSSION: This clinical trial will help to determine the impact of allergen consumption versus avoidance on natural tolerance development and whether the current dietary advice for PN or TN allergic patients with higher threshold levels is still valid. Trial registration: German Clinical Trials Register; ID: DRKS00016764 (RCT), DRKS00020467 (cohort study). Registered on 15 January 2020, http://www.drks.de

An interdisciplinary approach to characterize peanut-allergic patients - first data from the FOOD@ consortium

BACKGROUND: Peanut allergy is a frequent cause of food allergy and potentially life-threatening. Within this interdisciplinary research approach, we aim to unravel the complex mechanisms of peanut allergy. As a first step were applied in an exploratory manner the analysis of peanut allergic versus non-allergic controls. METHODS: Biosamples were studied regarding DNA methylation signatures, gut microbiome, adaptive and innate immune cell populations, soluble signaling molecules and allergen-reactive antibody specificities. We applied a scalable systems medicine computational workflow to the assembled data. RESULTS: We identified combined cellular and soluble biomarker signatures that stratify donors into peanut-allergic and non-allergic with high specificity. DNA methylation profiling revealed various genes of interest and stool microbiota differences in bacteria abundances. CONCLUSION: By extending our findings to a larger set of patients (e.g., children vs. adults), we will establish predictors for food allergy and tolerance and translate these as for example, indicators for interventional studies

Superoutburst of CR Bootis: Estimation of mass ratio of a typical AMCVn star by stage A superhumps

© The Author 2016.We report on two superoutbursts of the AMCVn-type object CR Boo in 2014 April-March and 2015 May-June. A precursor outburst accompanied both of these superoutbursts. During the rising branch of the main superoutburst in 2014, we detected growing superhumps (stage A superhumps) whose period was 0.017669(24) d. Assuming that this period reflects the dynamical precession rate at the radius of the 3:1 resonance, we could estimate the mass ratio (q = M2/M1) of 0.101(4) by using the stage A superhump period and the orbital period of 0.0170290(6) d. This mass ratio is consistent with that expected from the theoretical evolutionary model of AMCVn-type objects. The detection of precursor outbursts and stage A superhumps is the second case in AMCVn-type objects. There are two interpretations of the outbursts of AMCVn-type objects. One is a dwarf nova (DN) outbursts analogy, which suggets that the outbursts are caused by thermal and tidal instabilities. Another is the VY Scl-type variation, which suggests that the outbursts are caused by the variation of the mass-transfer rate of the secondary. This detection of the superhump variations strongly supports the former interpretation

Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation

Naturally occurring regulatory T (Treg) cells, which specifically express the transcription factor forkhead box P3 (Foxp3), are engaged in the maintenance of immunological self-tolerance and homeostasis. By transcriptional start site cluster analysis, we assessed here how genome-wide patterns of DNA methylation or Foxp3 binding sites were associated with Treg-specific gene expression. We found that Treg-specific DNA hypomethylated regions were closely associated with Treg up-regulated transcriptional start site clusters, whereas Foxp3 binding regions had no significant correlation with either up- or down-regulated clusters in nonactivated Treg cells. However, in activated Treg cells, Foxp3 binding regions showed a strong correlation with down-regulated clusters. In accordance with these findings, the above two features of activation-dependent gene regulation in Treg cells tend to occur at different locations in the genome. The results collectively indicate that Treg-specific DNA hypomethylation is instrumental in gene up-regulation in steady state Treg cells, whereas Foxp3 down-regulates the expression of its target genes in activated Treg cells. Thus, the two events seem to play distinct but complementary roles in Treg-specific gene expression

Survey of period variations of superhumps in SU UMa-type dwarf novae. VIII. The eighth year (2015-2016)

© The Author 2016.Continuing the project described by Kato et al. (2009, PASJ, 61, S395), we collected times of superhump maxima for 128 SUUMa-type dwarf novae observed mainly during the 2015-2016 season and characterized these objects. The data have improved the distribution of orbital periods, the relation between the orbital period and the variation of superhumps, and the relation between period variations and the rebrightening type in WZSge-type objects. Coupled with new measurements of mass ratios using growing stages of superhumps, we now have a clearer and statistically greatly improved evolutionary path near the terminal stage of evolution of cataclysmic variables. Three objects (V452 Cas, KK Tel, and ASASSN-15cl) appear to have slowly growing superhumps, which is proposed to reflect the slow growth of the 3 : 1 resonance near the stability border. ASASSN-15sl, ASASSN-15ux, SDSSJ074859.55+312512.6, and CRTS J200331.3-284941 are newly identified eclipsing SUUMa-type (or WZ Sge-type) dwarf novae. ASASSN- 15cy has a short (0.050 d) superhump period and appears to belong to EI Psc-type objects with compact secondaries having an evolved core. ASASSN-15gn, ASASSN- 15hn, ASASSN-15kh, and ASASSN-16bu are candidate period bouncers with superhump periods longer than 0.06 d. We have newly obtained superhump periods for 79 objects and 13 orbital periods, including periods from early superhumps. In order that future observations will be more astrophysically beneficial and rewarding to observers, we propose guidelines on how to organize observations of various superoutbursts

Reciprocal priming between receptor tyrosine kinases at recycling endosomes orchestrates cellular signalling outputs

From Wiley via Jisc Publications RouterHistory: received 2020-10-29, rev-recd 2021-04-27, accepted 2021-04-28, pub-electronic 2021-06-04Article version: VoRPublication status: PublishedFunder: Wellcome Trust; Grant(s): 107636/Z/15/Z, 210002/Z/17/ZFunder: UKRI | Biotechnology and Biological Sciences Research Council (BBSRC); Id: http://dx.doi.org/10.13039/501100000268; Grant(s): BB/R015864/1, BB/M011208/1Funder: UKRI | Medical Research Council (MRC); Id: http://dx.doi.org/10.13039/501100000265; Grant(s): MR/T016043/1Funder: Cancer Research UK (CRUK); Id: http://dx.doi.org/10.13039/501100000289; Grant(s): A27445Funder: NIHR Manchester Biomedical Research Centre; Grant(s): IS‐BRC‐1215‐20007Funder: Breast Cancer Now; Grant(s): MAN‐Q2‐Y4/5Abstract: Integration of signalling downstream of individual receptor tyrosine kinases (RTKs) is crucial to fine‐tune cellular homeostasis during development and in pathological conditions, including breast cancer. However, how signalling integration is regulated and whether the endocytic fate of single receptors controls such signalling integration remains poorly elucidated. Combining quantitative phosphoproteomics and targeted assays, we generated a detailed picture of recycling‐dependent fibroblast growth factor (FGF) signalling in breast cancer cells, with a focus on distinct FGF receptors (FGFRs). We discovered reciprocal priming between FGFRs and epidermal growth factor (EGF) receptor (EGFR) that is coordinated at recycling endosomes. FGFR recycling ligands induce EGFR phosphorylation on threonine 693. This phosphorylation event alters both FGFR and EGFR trafficking and primes FGFR‐mediated proliferation but not cell invasion. In turn, FGFR signalling primes EGF‐mediated outputs via EGFR threonine 693 phosphorylation. This reciprocal priming between distinct families of RTKs from recycling endosomes exemplifies a novel signalling integration hub where recycling endosomes orchestrate cellular behaviour. Therefore, targeting reciprocal priming over individual receptors may improve personalized therapies in breast and other cancers

Survey of period variations of superhumps in SU UMa-type dwarf novae. VII. the seventh year (2014-2015)

© The Author 2015. Published by Oxford University Press on behalf of the Astronomical Society of Japan. All rights reserved. Continuing the project described by Kato et al. (2009, PASJ, 61, S395), we collected times of superhump maxima for 102 SU UMa-type dwarf novae, observed mainly during the 2014-2015 season, and characterized these objects. Our project has greatly improved the statistics of the distribution of orbital periods, which is a good approximation of the distribution of cataclysmic variables at the terminal evolutionary stage, and has confirmed the presence of a period minimum at a period of 0.053 d and a period spike just above this period. The number density monotonically decreased toward the longer period and there was no strong indication of a period gap. We detected possible negative superhumps in Z Cha. It is possible that normal outbursts are also suppressed by the presence of a disk tilt in this system. There was no indication of enhanced orbital humps just preceding the superoutburst, and this result favors the thermal-tidal disk instability as the origin of superoutbursts. We detected superhumps in three AM CVn-type dwarf novae. Our observations and recent other detections suggest that 8% of objects showing dwarf nova-type outbursts are AM CVn-type objects. AM CVn-type objects and EI Psc-type objects may be more abundant than previously recognized. OT J213806, a WZ Sge-type object, exhibited remarkably different features between the 2010 and 2014 superoutbursts. Although the 2014 superoutburst was much fainter, the plateau phase was shorter than the 2010 one, and the course of the rebrightening phase was similar. This object indicates that the O - C diagrams of superhumps can indeed be variable, at least in WZ Sge-type objects. Four deeply eclipsing SU UMa-type dwarf novae (ASASSN-13cx, ASASSN-14ag, ASASSN-15bu, and NSV 4618) were identified. We studied long-term trends in supercycles in MM Hya and CY UMa and found systematic variations of supercycles of ∼20%