Prognostic factors facilitating multiple food allergies and atopiv march occurrence in children with Non-IgE mediated gastrointestinal Food Allergy: results of two years follow up of the NIGEFA project

Objectives and Study: Non-IgE mediated gastrointestinal food allergies (non-IgE-GIFA) are an increasing problem in pediatric gastroenterology clinical practice. These conditions include food protein-induced: enterocolitis syndrome (FPIES), enteropathy (FPE), allergic proctocolitis (FPIAP), and motility disorders (FPIMD). The NIGEFA project is focused on the investigation of main clinical features, prognostic factors (presence atopic dermatitis (AD), multiple food allergies, diagnostic delay, and familial history of allergy), and natural history (atopic march (AM) prevalence and timing of immune tolerance acquisition). Methods: Prospective observational study evaluating children with non-IgE-GIFA diagnosed according to standard criteria observed at a tertiary center for pediatric gastroenterology and allergy (both sexes, aged <36 m, follow up 12 m after diagnosis). Main anamnestic, demographic, and clinical data were collected from all enrolled patients. Immune tolerance acquisition was evaluated by the result of oral food challenge. Results: A total of 100 patients were enrolled: 58% male, mean age at diagnosis (SD) 8.5(8.8) m. Non-IgE-GIFA conditions were: FPE (44%), FPIES (11%), FPIAP (18%), FPIMD (27%). Mean diagnostic delay was 5.3 (7.4) m. Multiple non-IgE-GIFA were observed in 47% at baseline. Familial history of allergy was observed in 64% of subjects. Presence of AD before the onset of non-IgE-GIFA was observed in 40% of subjects. The overall rate of immune tolerance acquisition at 12 m was 27%, with a higher rate in FPIAP (44%) compared with FPIMD (29.6%), FPE (22.7%) and FPIES (9.1%) subjects (p<0.05). The rate of immune tolerance acquisition at 12 m was significantly lower in children with familial history of allergy (-48%, estimated risk ratio (RR)0.52 (95% CI 0.28 to 0.99, p<0.05)) and in those with multiple non-IgE-GIFA (-61%, RR at 12 m 0.39 (95% CI 0.18 to 0.85, p<0.05)). At 12 m follow up, the rate of subjects presenting AM was 24% with no difference among the 4 disease groups. The occurrence of AM was significantly higher in subjects with multiple (38%) vs. mono non-IgE-GIFA (11%) (p<.001) at baseline, with an estimated RR of 3.38 (95% CI 1.47 to 7.81, p<0.01) at 12 m. Moreover, for every 1-month of diagnostic delay there was an increase of 1.04 RR(95% CI 1.01 to 1.07) of AM occurrence at 12 m. No associations with other potential predictors (sex, familial allergy risk, AD before the onset of GIFA, type of non-IgE-GIFA) were found. Conclusions: These data shed lights on prognostic factors and natural history of non-IgE-GIFA suggesting the importance of early diagnosis in preventing the occurrence of AM occurrence in these patients. Contac

Tolerogenic Effect Elicited by Protein Fraction Derived From Different Formulas for Dietary Treatment of Cow’s Milk Allergy in Human Cells

Several formulas are available for the dietary treatment of cow’s milk allergy (CMA). Clinical data suggest potentially different effect on immune tolerance elicited by these formulas. We aimed to comparatively evaluate the tolerogenic effect elicited by the protein fraction of different formulas available for the dietary treatment of CMA. Five formulas were compared: extensively hydrolyzed whey formula (EHWF), extensively hydrolyzed casein formula (EHCF), hydrolyzed rice formula (HRF), soy formula (SF), and amino acid-based formula (AAF). The formulas were reconstituted in water according to the manufacturer’s instructions and subjected to an in vitro infant gut simulated digestion using a sequential gastric and duodenal static model. Protein fraction was then purified and used for the experiments on non-immune and immune components of tolerance network in human enterocytes and in peripheral mononuclear blood cells (PBMCs). We assessed epithelial layer permeability and tight junction proteins (occludin and zonula occludens-1, ZO-1), mucin 5AC, IL-33, and thymic stromal lymphopoietin (TSLP) in human enterocytes. In addition, Th1/Th2 cytokine response and Tregs activation were investigated in PBMCs from IgE-mediated CMA infants. EHCF-derived protein fraction positively modulated the expression of gut barrier components (mucin 5AC, occludin and ZO-1) in human enterocytes, while SF was able to stimulate the expression of occludin only. EHWF and HRF protein fractions elicited a significant increase in TSLP production, while IL-33 release was significantly increased by HRF and SF protein fractions in human enterocytes. Only EHCF-derived protein fraction elicited an increase of the tolerogenic cytokines production (IL-10, IFN-γ) and of activated CD4+FoxP3+ Treg number, through NFAT, AP1, and Nf-Kb1 pathway. The effect paralleled with an up-regulation of FoxP3 demethylation rate. Protein fraction from all the study formulas was unable to induce Th2 cytokines production. The results suggest a different regulatory action on tolerogenic mechanisms elicited by protein fraction from different formulas commonly used for CMA management. EHCF-derived protein fraction was able to elicit tolerogenic effect through at least in part an epigenetic modulation of FoxP3 gene. These results could explain the different clinical effects observed on immune tolerance acquisition in CMA patients and on allergy prevention in children at risk for atopy observed using EHCF

The Action Mechanism of the Myc Inhibitor Termed Omomyc May Give Clues on How to Target Myc for Cancer Therapy

Recent evidence points to Myc – a multifaceted bHLHZip transcription factor deregulated in the majority of human cancers – as a priority target for therapy. How to target Myc is less clear, given its involvement in a variety of key functions in healthy cells. Here we report on the action mechanism of the Myc interfering molecule termed Omomyc, which demonstrated astounding therapeutic efficacy in transgenic mouse cancer models in vivo. Omomyc action is different from the one that can be obtained by gene knockout or RNA interference, approaches designed to block all functions of a gene product. This molecule – instead – appears to cause an edge-specific perturbation that destroys some protein interactions of the Myc node and keeps others intact, with the result of reshaping the Myc transcriptome. Omomyc selectively targets Myc protein interactions: it binds c- and N-Myc, Max and Miz-1, but does not bind Mad or select HLH proteins. Specifically, it prevents Myc binding to promoter E-boxes and transactivation of target genes while retaining Miz-1 dependent binding to promoters and transrepression. This is accompanied by broad epigenetic changes such as decreased acetylation and increased methylation at H3 lysine 9. In the presence of Omomyc, the Myc interactome is channeled to repression and its activity appears to switch from a pro-oncogenic to a tumor suppressive one. Given the extraordinary therapeutic impact of Omomyc in animal models, these data suggest that successfully targeting Myc for cancer therapy might require a similar twofold action, in order to prevent Myc/Max binding to E-boxes and, at the same time, keep repressing genes that would be repressed by Myc

Weighing Neutrinos with Cosmic Neutral Hydrogen

We investigate the signatures left by massive neutrinos on the spatial distribution of neutral hydrogen (H I) in the post-reionization era by running hydrodynamic simulations that include massive neutrinos as additional collisionless particles. We find that halos in massive/massless neutrino cosmologies host a similar amount of neutral hydrogen, although for a fixed halo mass, on average, the H I mass increases with the sum of the neutrino masses. Our results show that H I is more strongly clustered in cosmologies with massive neutrinos, while its abundance, Omega(H I) (z), is lower. These effects arise mainly from the impact of massive neutrinos on cosmology: they suppress both the amplitude of the matter power spectrum on small scales and the abundance of dark matter halos. Modeling the H I distribution with hydrodynamic simulations at z > 3 and a simple analytic model at z < 3, we use the Fisher matrix formalism to conservatively forecast the constraints that Phase 1 of the Square Kilometre Array will place on the sum of neutrino masses, M-nu = Sigma m(nu). We find that with 10,000 hr of interferometric observations at 3 less than or similar to z less than or similar to 6 from a deep and narrow survey with SKA1-LOW, the sum of the neutrino masses can be measured with an error sigma(M-nu) less than or similar to 0.3 eV (95% CL). Similar constraints can be obtained with a wide and deep SKA1-MID survey at z less than or similar to 3, using the single-dish mode. By combining data from MID, LOW, and Planck, plus priors on cosmological parameters from a Stage IV spectroscopic galaxy survey, the sum of the neutrino masses can be determined with an error sigma(M-nu) similar or equal to 0.06 eV (95% CL)

Small Scattered Fragments Do Not a Dwarf Make: Biological and Archaeological Data Indicate that Prehistoric Inhabitants of Palau Were Normal Sized

Current archaeological evidence from Palau in western Micronesia indicates that the archipelago was settled around 3000–3300 BP by normal sized populations; contrary to recent claims, they did not succumb to insular dwarfism

Adenovirus-5-Vectored P. falciparum Vaccine Expressing CSP and AMA1. Part B: Safety, Immunogenicity and Protective Efficacy of the CSP Component

Background: A protective malaria vaccine will likely need to elicit both cell-mediated and antibody responses. As adenovirus vaccine vectors induce both these responses in humans, a Phase 1/2a clinical trial was conducted to evaluate the efficacy of an adenovirus serotype 5-vectored malaria vaccine against sporozoite challenge.\ud \ud Methodology/Principal Findings: NMRC-MV-Ad-PfC is an adenovirus vector encoding the Plasmodium falciparum 3D7 circumsporozoite protein (CSP). It is one component of a two-component vaccine NMRC-M3V-Ad-PfCA consisting of one adenovector encoding CSP and one encoding apical membrane antigen-1 (AMA1) that was evaluated for safety and immunogenicity in an earlier study (see companion paper, Sedegah et al). Fourteen Ad5 seropositive or negative adults received two doses of NMRC-MV-Ad-PfC sixteen weeks apart, at 1x1010 particle units per dose. The vaccine was safe and well tolerated. All volunteers developed positive ELISpot responses by 28 days after the first immunization (geometric mean 272 spot forming cells/million[sfc/m]) that declined during the following 16 weeks and increased after the second dose to levels that in most cases were less than the initial peak (geometric mean 119 sfc/m). CD8+ predominated over CD4+ responses, as in the first clinical trial. Antibody responses were poor and like ELISpot responses increased after the second immunization but did not exceed the initial peak. Pre-existing neutralizing antibodies (NAb) to Ad5 did not affect the immunogenicity of the first dose, but the fold increase in NAb induced by the first dose was significantly associated with poorer antibody responses after the second dose, while ELISpot responses remained unaffected. When challenged by the bite of P. falciparum-infected mosquitoes, two of 11 volunteers showed a delay in the time to patency compared to infectivity controls, but no volunteers were sterilely protected.\ud \ud Significance: The NMRC-MV-Ad-PfC vaccine expressing CSP was safe and well tolerated given as two doses, but did not provide sterile protection