Background
Cow's milk allergy (CMA) is one of the most common food allergies in children. Epigenetic mechanisms have been suggested to play a role in CMA pathogenesis. We have shown that DNA ...methylation of Th1/Th2 cytokine genes and FoxP3 affects CMA disease course. Preliminary evidence suggests that also the miRNome could be implicated in the pathogenesis of allergy. Main study outcome was to comparatively evaluate miRNome in children with CMA and in healthy controls.
Methods
Peripheral blood mononuclear cells were obtained from children aged 4‐18 months: 10 CMA patients, 9 CMA patients who outgrew CMA, and 11 healthy controls. Small RNA libraries were sequenced using a next‐generation sequencing‐based approach. Functional assessment of IL‐4 expression was also performed.
Results
Among the miRNAs differently expressed, 2 were upregulated and 14 were downregulated in children with active CMA compared to healthy controls. miR‐193a‐5p resulted the most downregulated miRNA in children with active CMA compared to healthy controls. The predicted targets of miR‐193a‐5p resulted upregulated in CMA patients compared to healthy controls. Peripheral blood CD4+ T cells transfected with a miR193a‐5 inhibitor showed a significant upregulation of IL‐4 mRNA and its protein expression. Children who outgrew CMA showed miRNA‐193a‐5p level, and its related targets expression, similar to that observed in healthy controls.
Conclusions
Our results suggest that miR‐193a‐5p is a post‐transcriptional regulator of IL‐4 expression and could have a role in IgE‐mediated CMA. This miRNA could be a novel diagnostic and therapeutic target for this common form of food allergy in childhood.
The potential to accurately quantify epidermal growth factor receptor (EGFR) mutations in plasma from non–small-cell lung cancer patients would enable more rapid and more frequent analyses to assess ...disease status; however, the utility of such analyses for clinical purposes has only recently started to explore.
Plasma samples were obtained from 69 patients with EGFR-mutated tumors and 21 negative control cases. EGFR mutations in plasma were analyzed by a standardized allele-specific polymerase chain reaction (PCR) test and ultra-deep next-generation sequencing (NGS). A semiquantitative index (SQI) was derived from dilutions of known EGFR mutation copy numbers. Clinical responses were evaluated by Response Evaluation Criteria in Solid Tumors 1.1 criteria and expressed as percent tumor shrinkage.
The sensitivity and specificity of the PCR test and NGS assay in plasma versus tissue were 72% versus 100% and 74% versus 100%, respectively. Quantitative indices by the PCR test and NGS were significantly correlated (p < 0.001). EGFR testing at baseline and serially at 4 to 60 days during tyrosine kinase inhibitor therapy revealed a progressive decrease in SQI, starting from day 4, in 95% of cases. The rate of SQI decrease correlated with percent tumor shrinkage at 2 months (p < 0.0001); at 14 days, it was more than 50% in 70% of patients (rapid responders). In two patients with slow response, an early increase in the circulating levels of the T790M mutation was observed. No early T790M mutations were seen in plasma samples of rapid responders.
Quantification of EGFR mutations from plasma with a standardized PCR test is feasible. To our knowledge, this is the first study showing a strong correlation between the EGFR SQI in the first days of treatment and clinical response with relevant implications for patient management.
ABSTRACT We present results from γ-ray observations of the Coma cluster incorporating six years of Fermi-LAT data and the newly released "Pass 8" event-level analysis. Our analysis of the region ...reveals low-significance residual structures within the virial radius of the cluster that are too faint for a detailed investigation with the current data. Using a likelihood approach that is free of assumptions on the spectral shape we derive upper limits on the γ-ray flux that is expected from energetic particle interactions in the cluster. We also consider a benchmark spatial and spectral template motivated by models in which the observed radio halo is mostly emission by secondary electrons. In this case, the median expected and observed upper limits for the flux above 100 are 1.7 × 10−9 ph cm−2 s−1 and 5.2 × 10−9 ph cm−2 s−1 respectively (the latter corresponds to residual emission at the level of 1.8 ). These bounds are comparable to or higher than predicted levels of hadronic gamma-ray emission in cosmic-ray (CR) models with or without reacceleration of secondary electrons, although direct comparisons are sensitive to assumptions regarding the origin and propagation mode of CRs and magnetic field properties. The minimal expected γ-ray flux from radio and star-forming galaxies within the Coma cluster is roughly an order of magnitude below the median sensitivity of our analysis.
The High-energy Particle Detector (HEPD) on board the China Seismo-Electromagnetic Satellite (CSES-01)-launched on 2018 February 2-is a light and compact payload suitable for measuring electrons ...(3-100 MeV), protons (30-250 MeV), and light nuclei (up to a few hundreds of MeV). The Sun-synchronous orbit and large acceptance allow HEPD to measure cosmic-ray particles near the 65° latitude limit for a fair amount of time per day. In this work, three semiannual galactic hydrogen energy spectra between ∼40 and 250 MeV are presented, including a comparison with theoretical spectra from HelMod, a 2D Monte Carlo model developed to simulate the solar modulation of cosmic rays throughout the heliosphere. To our knowledge, these are the first hydrogen energy spectra below 250 MeV measured at 1 au between 2018 and 2020.
The China Seismo-Electromagnetic Satellite (CSES) aims to monitor electromagnetic, particle, and plasma perturbations in the iono-magnetosphere and inner Van Allen radiation belts originated by ...electromagnetic sources external and internal to the geomagnetic cavity, cosmic rays, and solar events. In particular, the objective of the space mission is to investigate lithosphere-atmosphere-ionosphere coupling mechanisms (including the effects of lightning, earthquakes, volcanoes, and artificial electromagnetic emissions) that induce perturbations of the top side of the ionosphere and lower boundary of the radiation belts. To this purpose, the mission has been conceived to take advantage of a multi-instrument payload comprising nine detectors for the measurement of electromagnetic field components, plasma parameters, and energetic particles, as well as X-ray flux. The Italian team participating in the CSES mission has built one of these devices, the High-Energy Particle Detector (HEPD), for high-precision observations of electrons, protons, and light nuclei. During its trip along the orbit, and thanks to the large set of detectors operated on board, CSES completely monitors the Earth, acting as an excellent instrument for space weather. The satellite was launched on 2018 February 2, with an expected life span of 5 yr. This article describes the CSES mission with a particular focus on the HEPD apparatus and its in-flight performance.
We present the detections of 18 solar flares detected in high-energy gamma-rays (above 100 MeV) with the Fermi Large Area Telescope (LAT) during its first 4 yr of operation. This work suggests that ...particle acceleration up to very high energies in solar flares is more common than previously thought, occurring even in modest flares, and for longer durations. We then describe the detailed temporal, spatial, and spectral characteristics of the first two long-lasting events; the 2011 March 7 flare, a moderate (M3.7) impulsive flare followed by slowly varying gamma-ray emission over 13 hr, and the 2011 June 7 M2.5 flare. We compare the Fermi LAT data with X-ray and proton data measurements from GOES and RHESSI. We argue that the gamma-rays are more likely produced through pion decay than electron bremsstrahlung, and we find that flic energy spectrum of the proton distribution softens during the extended emission of the 2011 March 7 flare.
ABSTRACT Galaxy clusters are one of the prime sites to search for dark matter (DM) annihilation signals. Depending on the substructure of the DM halo of a galaxy cluster and the cross sections for DM ...annihilation channels, these signals might be detectable by the latest generation of γ-ray telescopes. Here we use three years of Fermi-Large Area Telescope data, which are the most suitable for searching for very extended emission in the vicinity of the nearby Virgo galaxy cluster. Our analysis reveals statistically significant extended emission which can be well characterized by a uniformly emitting disk profile with a radius of 3° that moreover is offset from the cluster center. We demonstrate that the significance of this extended emission strongly depends on the adopted interstellar emission model (IEM) and is most likely an artifact of our incomplete description of the IEM in this region. We also search for and find new point source candidates in the region. We then derive conservative upper limits on the velocity-averaged DM pair annihilation cross section from Virgo. We take into account the potential γ-ray flux enhancement due to DM sub-halos and its complex morphology as a merging cluster. For DM annihilating into assuming a conservative sub-halo model setup, we find limits that are between 1 and 1.5 orders of magnitude above the expectation from the thermal cross section for mDM 100 GeV. In a more optimistic scenario, we exclude for mDM 40 GeV for the same channel. Finally, we derive upper limits on the γ-ray-flux produced by hadronic cosmic-ray interactions in the inter cluster medium. We find that the volume-averaged cosmic-ray-to-thermal pressure ratio is less than ∼6%.
We implemented a novel technique to perform the collective spectral analysis of sets of multiple gamma-ray point sources using the data collected by the Large Area Telescope onboard the Fermi ...satellite. The energy spectra of the sources are reconstructed starting from the photon counts and without assuming any spectral model for both the sources and the background. In case of faint sources, upper limits on their fluxes are evaluated with a Bayesian approach. This analysis technique is very useful when several sources with similar spectral features are studied, such as sources of gamma rays from annihilation of dark matter particles. We present the results obtained by applying this analysis to a sample of dwarf spheroidal galaxies and to the Milky Way dark matter halo. The analysis of dwarf spheroidal galaxies yields upper limits on the product of the dark matter pair annihilation cross section and the relative velocity of annihilating particles that are well below those predicted by the canonical thermal relic scenario in a mass range from a few GeV to a few tens of GeV for some annihilation channels.
The EURTAC trial demonstrated that the tyrosine kinase inhibitor (TKI) erlotinib was superior to chemotherapy as first-line therapy for advanced non-small cell lung cancers (NSCLC) that harbor EGFR ...activating mutations in a predominantly Caucasian population. Based on EURTAC and several Asian trials, anti-EGFR TKIs are standard of care for EGFR mutation-positive NSCLC. We sought to validate a rapid multiplex EGFR mutation assay as a companion diagnostic assay to select patients for this therapy. Samples from the EURTAC trial were prospectively screened for EGFR mutations using a combination of laboratory-developed tests (LDTs), and tested retrospectively with the cobas EGFR mutation test (EGFR PCR test). The EGFR PCR test results were compared to the original LDT results and to Sanger sequencing, using a subset of specimens from patients screened for the trial. Residual tissue was available from 487 (47%) of the 1044 patients screened for the trial. The EGFR PCR test showed high concordance with LDT results with a 96.3% overall agreement. The clinical outcome of patients who were EGFR-mutation detected by the EGFR PCR test was very similar to the entire EURTAC cohort. The concordance between the EGFR PCR test and Sanger sequencing was 90.6%. In 78.9% of the discordant samples, the EGFR PCR test result was confirmed by a sensitive deep sequencing assay. This retrospective study demonstrates the clinical utility of the EGFR PCR test in the accurate selection of patients for anti-EGFR TKI therapy. The EGFR PCR test demonstrated improved performance relative to Sanger sequencing.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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