Summary
Background
Tralokinumab, a fully human monoclonal antibody, specifically neutralizes interleukin‐13, a key cytokine driving peripheral inflammation in atopic dermatitis (AD). In phase II ...studies, tralokinumab combined with topical corticosteroids provided early and sustained improvements in AD signs and symptoms.
Objectives
To evaluate the efficacy and safety of tralokinumab monotherapy in adults with moderate‐to‐severe AD who had an inadequate response to topical treatments.
Methods
In two 52‐week, randomized, double‐blind, placebo‐controlled, phase III trials, ECZTRA 1 and ECZTRA 2, adults with moderate‐to‐severe AD were randomized (3 : 1) to subcutaneous tralokinumab 300 mg every 2 weeks (Q2W) or placebo. Primary endpoints were Investigator’s Global Assessment (IGA) score of 0 or 1 at week 16 and ≥ 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16. Patients achieving an IGA score of 0 or 1 and/or EASI 75 with tralokinumab at week 16 were rerandomized to tralokinumab Q2W or every 4 weeks or placebo, for 36 weeks. The trials were registered with ClinicalTrials.gov: NCT03131648 and NCT03160885.
Results
At week 16, more patients who received tralokinumab vs. placebo achieved an IGA score of 0 or 1: 15·8% vs. 7·1% in ECZTRA 1 difference 8·6%, 95% confidence interval (CI) 4·1–13·1; P = 0·002 and 22·2% vs. 10·9% in ECZTRA 2 (11·1%, 95% CI 5·8–16·4; P < 0·001) and EASI 75: 25·0% vs. 12·7% (12·1%, 95% CI 6·5–17·7; P < 0·001) and 33·2% vs. 11·4% (21·6%, 95% CI 15·8–27·3; P < 0·001). Early improvements in pruritus, sleep interference, Dermatology Life Quality Index, SCORing Atopic Dermatitis and Patient‐Oriented Eczema Measure were observed from the first postbaseline measurements. The majority of week 16 tralokinumab responders maintained response at week 52 with continued tralokinumab treatment without any rescue medication (including topical corticosteroids). Adverse events were reported in 76·4% and 61·5% of patients receiving tralokinumab in ECZTRA 1 and ECZTRA 2, respectively, and in 77·0% and 66·0% of patients receiving placebo in ECZTRA 1 and ECZTRA 2, respectively, in the 16‐week initial period.
Conclusions
Tralokinumab monotherapy was superior to placebo at 16 weeks of treatment and was well tolerated up to 52 weeks of treatment.
What is already known about this topic?
Atopic dermatitis (AD) is a chronic interleukin (IL)‐13‐mediated disease.
There is a need for safe and effective long‐term treatment options for AD.
Tralokinumab is a fully human monoclonal antibody that binds specifically to IL‐13 with high affinity, thereby preventing receptor interaction and subsequent downstream signalling.
Tralokinumab combined with topical corticosteroids showed early and sustained efficacy and safety in a 12‐week, phase IIb trial in moderate‐to‐severe AD.
What does this study add?
These are the first pivotal phase III trials demonstrating that by specifically targeting IL‐13 alone, patients can achieve significant improvements in AD signs and symptoms and quality of life, and maintain these improvements over time without the requirement for topical corticosteroids.
These trials provide evidence that tralokinumab offers a long‐term, well‐tolerated treatment option for patients with moderate‐to‐severe AD.
Linked Comment: Morra and Drucker. Br J Dermatol 2021; 184:386–387.
Plain language summary available online
ABSTRACT The Rosetta probe, orbiting Jupiter-family comet 67P/Churyumov-Gerasimenko, has been detecting individual dust particles of mass larger than 10−10 kg by means of the GIADA dust collector and ...the OSIRIS Wide Angle Camera and Narrow Angle Camera since 2014 August and will continue until 2016 September. Detections of single dust particles allow us to estimate the anisotropic dust flux from 67P, infer the dust loss rate and size distribution at the surface of the sunlit nucleus, and see whether the dust size distribution of 67P evolves in time. The velocity of the Rosetta orbiter, relative to 67P, is much lower than the dust velocity measured by GIADA, thus dust counts when GIADA is nadir-pointing will directly provide the dust flux. In OSIRIS observations, the dust flux is derived from the measurement of the dust space density close to the spacecraft. Under the assumption of radial expansion of the dust, observations in the nadir direction provide the distance of the particles by measuring their trail length, with a parallax baseline determined by the motion of the spacecraft. The dust size distribution at sizes >1 mm observed by OSIRIS is consistent with a differential power index of −4, which was derived from models of 67P's trail. At sizes <1 mm, the size distribution observed by GIADA shows a strong time evolution, with a differential power index drifting from −2 beyond 2 au to −3.7 at perihelion, in agreement with the evolution derived from coma and tail models based on ground-based data. The refractory-to-water mass ratio of the nucleus is close to six during the entire inbound orbit and at perihelion.
The toxicity of mycotoxins is well recognized in mammals, but their effects on fish have received less attention. Moreover, in the last years several studies have reported that some mycotoxins may ...act as endocrine disruptors. The aim of this study was to determine the cytotoxic effects and endocrine activities of three mycotoxins: beauvericin, deoxynivalenol and ochratoxin-A. Cytotoxicity in two fish hepatoma and one mammalian hepatoma cell lines was determined by the AlamarBlue, Neutral Red Uptake and CFDA-AM assays. For the assessment of androgenic, estrogenic and thyroidal agonistic/antagonistic effects three cell lines stably expressing luciferase as reporter gene under the control of hormone receptors were used. Results showed that both fish and mammalian cell lines were very sensitive to the mycotoxins tested. OTA was the least toxic mycotoxin and DON and BEA showed similar acute toxicity. None of the three mycotoxins tested presented agonistic effects at the receptors studied, but all of them showed strong antagonistic effect at the thyroid receptor. BEA showed a weak antagonistic effect at the androgen receptor and OTA produced a biphasic dose-response curve at the estrogen receptor. The data obtained in this work are of high interest for aquaculture industries and for regulators.
•Beauvericin (BEA), deoxynivalenol (DON) and ochratoxin A (OTA) are similarly toxic to fish and mammalian cell lines.•BEA, DON and OTA present antagonistic effect at the thyroid hormone receptor, DON and BEA at very low concentrations.•BEA seems to exert a weak antagonistic effect at the androgen receptor.•OTA is an estrogen receptor antagonist, but an agonist at concentrations which produce a very low cytotoxicity.
Context. During the period between 15 September 2014 and 4 February 2015, the Rosetta spacecraft accomplished the circular orbit phase around the nucleus of comet 67P/Churyumov-Gerasimenko (67P). The ...Grain Impact Analyzer and Dust Accumulator (GIADA) onboard Rosetta monitored the 67P coma dust environment for the entire period. Aims. We aim to describe the dust spatial distribution in the coma of comet 67P by means of in situ measurements. We determine dynamical and physical properties of cometary dust particles to support the study of the production process and dust environment modification. Methods. We analyzed GIADA data with respect to the observation geometry and heliocentric distance to describe the coma dust spatial distribution of 67P, to monitor its activity, and to retrieve information on active areas present on its nucleus. We combined GIADA detection information with calibration activity to distinguish different types of particles that populate the coma of 67P: compact particles and fluffy porous aggregates. By means of particle dynamical parameters measured by GIADA, we studied the dust acceleration region. Results. GIADA was able to distinguish different types of particles populating the coma of 67P: compact particles and fluffy porous aggregates. Most of the compact particle detections occurred at latitudes and longitudes where the spacecraft was in view of the comet’s neck region of the nucleus, the so-called Hapi region. This resulted in an oscillation of the compact particle abundance with respect to the spacecraft position and a global increase as the comet moved from 3.36 to 2.43 AU heliocentric distance. The speed of these particles, having masses from 10-10 to 10-7 kg, ranged from 0.3 to 12.2 m s-1. The variation of particle mass and speed distribution with respect to the distance from the nucleus gave indications of the dust acceleration region. The influence of solar radiation pressure on micron and submicron particles was studied. The integrated dust mass flux collected from the Sun direction, that is, particles reflected by solar radiation pressure, was three times higher than the flux coming directly from the comet nucleus. The awakening 67P comet shows a strong dust flux anisotropy, confirming what was suggested by on-ground dust coma observations performed in 2008.
Context.
Point source (PS) detection is an important issue for future cosmic microwave background (CMB) experiments since they are one of the main contaminants to the recovery of CMB signal on small ...scales. Improving its multi-frequency detection would allow us to take into account valuable information otherwise neglected when extracting PS using a channel-by-channel approach.
Aims.
We aim to develop an artificial intelligence method based on fully convolutional neural networks to detect PS in multi-frequency realistic simulations and compare its performance against one of the most popular multi-frequency PS detection methods, the matrix filters. The frequencies used in our analysis are 143, 217, and 353 GHz, and we imposed a Galactic cut of 30°.
Methods.
We produced multi-frequency realistic simulations of the sky by adding contaminating signals to the PS maps as the CMB, the cosmic infrared background, the Galactic thermal emission, the thermal Sunyaev-Zel’dovich effect, and the instrumental and PS shot noises. These simulations were used to train two neural networks called flat and spectral MultiPoSeIDoNs. The first one considers PS with a flat spectrum, and the second one is more realistic and general because it takes into account the spectral behaviour of the PS. Then, we compared the performance on reliability, completeness, and flux density estimation accuracy for both MultiPoSeIDoNs and the matrix filters.
Results.
Using a flux detection limit of 60 mJy, MultiPoSeIDoN successfully recovered PS reaching the 90% completeness level at 58 mJy for the flat case, and at 79, 71, and 60 mJy for the spectral case at 143, 217, and 353 GHz, respectively. The matrix filters reach the 90% completeness level at 84, 79, and 123 mJy. To reduce the number of spurious sources, we used a safer 4
σ
flux density detection limit for the matrix filters, the same as was used in the
Planck
catalogues, obtaining the 90% of completeness level at 113, 92, and 398 mJy. In all cases, MultiPoSeIDoN obtains a much lower number of spurious sources with respect to the filtering method. The recovering of the flux density of the detections, attending to the results on photometry, is better for the neural networks, which have a relative error of 10% above 100 mJy for the three frequencies, while the filter obtains a 10% relative error above 150 mJy for 143 and 217 GHz, and above 200 mJy for 353 GHz.
Conclusions.
Based on the results, neural networks are the perfect candidates to substitute filtering methods to detect multi-frequency PS in future CMB experiments. Moreover, we show that a multi-frequency approach can detect sources with higher accuracy than single-frequency approaches also based on neural networks.
Apart from the overwhelming cases of allopolyploidization, the impact of speciation through homoploid hybridization is becoming more relevant than previously thought. Much less is known, however, ...about the impact of climate changes as a driven factor of speciation. To investigate these issues, we selected Festuca picoeuropeana, an hypothetical natural hybrid between the diploid species F. eskia and F. gautieri that occurs in two different mountain ranges (Cantabrian Mountains and Pyrenees) separated by more than 400 km. To unravel the outcomes of this mode of speciation and the impact of climate during speciation we used a multidisciplinary approach combining genome size and chromosome counts, data from an extensive nuclear genotypic analysis, plastid sequences and ecological niche models (ENM). Our results show that the same homoploid hybrid was originated independently in the two mountain ranges, being currently isolated from both parents and producing viable seeds. Parental species had the opportunity to contact as early as 21000 years ago although niche divergence occurs nowadays as result of a climate-driven shift. A high degree of niche divergence was observed between the hybrid and its parents and no recent introgression or backcrossed hybrids were detected, supporting the current presence of reproductive isolation barriers between these species.
Summary
Background
Peach is the most important fruit related to food allergy in the Mediterranean area. Pru p 3, its lipid transfer protein, has been described as the principal allergen responsible ...for cross‐reactivities with other foods and pollen and the severity of clinical symptoms. However, the involvement of other allergenic families cannot be ruled out. Thaumatin‐like proteins (TLPs) have been described as food allergen in several fruits, such as apple, cherry, kiwi and banana, and pollen.
Objective
To identify members of the TLP family in peach fruit and to characterize putative allergens.
Methods
Through two‐dimensional (2D) electrophoresis of peach extract and immunodetections with a pool of peach‐allergic patients, IgE‐binding spots were identified and the corresponding proteins purified and characterized as allergens by in vitro and in vivo assays.
Three isoforms, belonging to the TLP family, were purified by different chromatographic systems and characterized by N‐terminal amino acid sequences, molecular weight determination (MALDI) and enzymatic activity analysis (β‐1,3‐gluconase test and inhibition growth of fungi). In the same way, their IgE‐binding capacity and allergenic activity were tested by ELISA assays, basophil activation tests and skin prick tests (SPT).
Results
Two peach‐TLPs, Pru p 2.0101 and Pru p 2.0201, were identified as IgE‐binding spots by 2D electrophoresis. Another peach‐TLP, Pru p 2.0301, was cloned and produced as recombinant protein in a yeast system. The three isoforms were purified and characterized as TLPs by immunoblotting with anti‐chestnut TLP antibodies and anti‐plant N‐asparagine complex glycan (anti‐cross‐reactive carbohydrate determinant). All of them showed β‐1,3‐glucanase activity and inhibition of fungal growth. The three TLPs were recognized by around 50% of the sera from 31 patients analysed in ELISA experiments. All three gave a positive response to an SPT and/or in basophil activation experiments.
Conclusion
Three isoforms, belonging to the TLP family, were identified in peach as principal allergens. Their prevalence, observed in in vitro, ex vivo and in vivo analyses, suggests that they are important allergens and should therefore be included in the routine diagnosis of peach allergy, at least in the Mediterranean area.
Cite this as: A. Palacín, L. Tordesillas, P. Gamboa, R. Sanchez‐Monge, J. Cuesta‐Herranz, M. L. Sanz, D. Barber, G. Salcedo and A. Díaz‐Perales, Clinical & Experimental Allergy, 2010 (40) 1422–1430.
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