Background
Allergen immunotherapy (AIT) is an effective treatment for allergic rhinoconjunctivitis (AR) with or without asthma. It is important to note that due to the complex interaction between ...patient, allergy triggers, symptomatology and vaccines used for AIT, some patients do not respond optimally to the treatment. Furthermore, there are no validated or generally accepted candidate biomarkers that are predictive of the clinical response to AIT. Clinical management of patients receiving AIT and efficacy in randomised controlled trials for drug development could be enhanced by predictive biomarkers.
Method
The EAACI taskforce reviewed all candidate biomarkers used in clinical trials of AR patients with/without asthma in a literature review. Biomarkers were grouped into seven domains: (i) IgE (total IgE, specific IgE and sIgE/Total IgE ratio), (ii) IgG‐subclasses (sIgG1, sIgG4 including SIgE/IgG4 ratio), (iii) Serum inhibitory activity for IgE (IgE‐FAB and IgE‐BF), (iv) Basophil activation, (v) Cytokines and Chemokines, (vi) Cellular markers (T regulatory cells, B regulatory cells and dendritic cells) and (vii) In vivo biomarkers (including provocation tests?).
Results
All biomarkers were reviewed in the light of their potential advantages as well as their respective drawbacks. Unmet needs and specific recommendations on all seven domains were addressed.
Conclusions
It is recommended to explore the use of allergen‐specific IgG4 as a biomarker for compliance. sIgE/tIgE and IgE‐FAB are considered as potential surrogate candidate biomarkers. Cytokine/chemokines and cellular reponses provided insight into the mechanisms of AIT. More studies for confirmation and interpretation of the possible association with the clinical response to AIT are needed.
Many of the results in modern astrophysics rest on the notion that the initial mass function (IMF) is universal. Our observations of a sample of H I selected galaxies in the light of Ha and the ...far-ultraviolet (FUV) challenge this result. The extinction-corrected flux ratio F Ha/f FUV from these two tracers of star formation shows strong correlations with the surface brightness in Ha and the R band: low surface brightness (LSB) galaxies have lower F Ha/f FUV ratios compared to high surface brightness galaxies as well as compared to expectations from equilibrium models of constant star formation rate (SFR) using commonly favored IMF parameters. Weaker but significant correlations of F Ha/f FUV with luminosity, rotational velocity, and dynamical mass as well as a systematic trend with morphology, are found. The correlated variations of F Ha/f FUV with other global parameters are thus part of the larger family of galaxy scaling relations. The F Ha/f FUV correlations cannot be due to residual extinction correction errors, while systematic variations in the star formation history (SFH) cannot explain the trends with both Ha and R surface brightness nor with other global properties. The possibility that LSB galaxies have a higher escape fraction of ionizing photons seems inconsistent with their high gas fraction, and observations of color-magnitude diagrams (CMDs) of a few systems which indicate a real deficit of O stars. The most plausible explanation for the correlations is the systematic variations of the upper mass limit and/or the slope g which define the upper end of the IMF. We outline a scenario of pressure driving the correlations by setting the efficiency of the formation of the dense star clusters where the highest mass stars preferentially form. Our results imply that the SFR measured in a galaxy is highly sensitive to the tracer used in the measurement. A nonuniversal IMF would also call into question the interpretation of metal abundance patterns in dwarf galaxies as well as SFHs derived from CMDs.
A taskforce comprised of an expert group of 21 rheumatologists, radiologists and methodologists from 11 countries developed evidence-based recommendations on the use of imaging in the clinical ...management of both axial and peripheral spondyloarthritis (SpA). Twelve key questions on the role of imaging in SpA were generated using a process of discussion and consensus. Imaging modalities included conventional radiography, ultrasound, magnetic resonance imaging, computed tomography (CT), positron emission tomography, single photon emission CT, dual-emission x-ray absorptiometry and scintigraphy. Experts applied research evidence obtained from systematic literature reviews using MEDLINE and EMBASE to develop a set of 10 recommendations. The strength of recommendations (SOR) was assessed by taskforce members using a visual analogue scale. A total of 7550 references were identified in the search process, from which 158 studies were included in the systematic review. Ten recommendations were produced using research-based evidence and expert opinion encompassing the role of imaging in making a diagnosis of axial SpA or peripheral SpA, monitoring inflammation and damage, predicting outcome, response to treatment, and detecting spinal fractures and osteoporosis. The SOR for each recommendation was generally very high (range 8.9-9.5). These are the first recommendations which encompass the entire spectrum of SpA and evaluate the full role of all commonly used imaging modalities. We aimed to produce recommendations that are practical and valuable in daily practice for rheumatologists, radiologists and general practitioners.
Context. The consortium of the Spectro-Polarimetric High-contrast Exoplanet REsearch installed at the Very Large Telescope (SPHERE/VLT) has been operating its guaranteed observation time (260 nights ...over five years) since February 2015. The main part of this time (200 nights) is dedicated to the detection and characterization of young and giant exoplanets on wide orbits. Aims. The large amount of data must be uniformly processed so that accurate and homogeneous measurements of photometry and astrometry can be obtained for any source in the field. Methods. To complement the European Southern Observatory pipeline, the SPHERE consortium developed a dedicated piece of software to process the data. First, the software corrects for instrumental artifacts. Then, it uses the speckle calibration tool (SpeCal) to minimize the stellar light halo that prevents us from detecting faint sources like exoplanets or circumstellar disks. SpeCal is meant to extract the astrometry and photometry of detected point-like sources (exoplanets, brown dwarfs, or background sources). SpeCal was intensively tested to ensure the consistency of all reduced images (cADI, Loci, TLoci, PCA, and others) for any SPHERE observing strategy (ADI, SDI, ASDI as well as the accuracy of the astrometry and photometry of detected point-like sources. Results. SpeCal is robust, user friendly, and efficient at detecting and characterizing point-like sources in high contrast images. It is used to process all SPHERE data systematically, and its outputs have been used for most of the SPHERE consortium papers to date. SpeCal is also a useful framework to compare different algorithms using various sets of data (different observing modes and conditions). Finally, our tests show that the extracted astrometry and photometry are accurate and not biased.
Emactuzumab is a monoclonal antibody against the colony-stimulating factor-1 receptor and targets tumor-associated macrophages (TAMs). This study assessed the safety, clinical activity, ...pharmacokinetics (PK) and pharmacodynamics (PD) of emactuzumab, as monotherapy and in combination with paclitaxel, in patients with advanced solid tumors.
This open-label, phase Ia/b study comprised two parts (dose escalation and dose expansion), each containing two arms (emactuzumab, every 2 or 3weeks, as monotherapy or in combination with paclitaxel 80mg/m2 weekly). The dose-escalation part explored the maximum tolerated dose and optimal biological dose (OBD). The dose-expansion part extended the safety assessment and investigated the objective response rate. A PK/PD analysis of serial blood, skin and tumor biopsies was used to explore proof of mechanism and confirm the OBD.
No maximum tolerated dose was reached in either study arm, and the safety profile of emactuzumab alone and in combination does not appear to preclude its use. No patients receiving emactuzumab monotherapy showed an objective response; the objective response rate for emactuzumab in combination with paclitaxel was 7% across all doses. Skin macrophages rather than peripheral blood monocytes or circulating colony-stimulating factor-1 were identified as an optimal surrogate PD marker to select the OBD. Emactuzumab treatment alone and in combination with paclitaxel resulted in a plateau of immunosuppressive TAM reduction at the OBD of 1000mg administered every 2weeks.
Emactuzumab showed specific reduction of immunosuppressive TAMs at the OBD in both treatment arms but did not result in clinically relevant antitumor activity alone or in combination with paclitaxel. (ClinicalTrials.gov Identifier: NCT01494688)
Abstract X-linked juvenile retinoschisis (XLRS) is a retinal degenerative disorder caused by mutations in the RS1 gene encoding a protein termed retinoschisin. The disease is an excellent candidate ...for gene replacement therapy as the majority of mutations have been shown to lead to a complete deficiency of the secreted protein in the retinal structures. In this work, we have studied the ability of non-viral vectors based on solid lipid nanoparticles (SLN) to induce the expression of retinoschisin in photoreceptors (PR) after intravitreal administration to Rs1h-deficient mice. We designed two vectors prepared with SLN, protamine, and dextran (DX) or hyaluronic acid (HA), bearing a plasmid containing the human RS1 gene under the control of the murin opsin promoter (mOPS). In vitro, the nanocarriers were able to induce the expression of retinoschisin in a PR cell line. After injection into the murine vitreous, the formulation prepared with HA induced a higher transfection level in PR than the formulation prepared with DX. Moreover, the level of retinoschisin in the inner nuclear layer (INL), where bipolar cells are located, was also higher. Two weeks after vitreal administration into Rs1h-deficient mice, both formulations showed significant improvement of the retinal structure by inducing a decrease of cavities and PR loss, and an increase of retinal and outer nuclear layer (ONL) thickness. HA-SLN resulted in a significant higher increase in the thickness of both retina and ONL, which can be explained by the higher transfection level of PR. In conclusion, we have shown the structural improvement of the retina of Rs1h-deficient mice with PR specific expression of the RS1 gene driven by the specific promoter mOPS, after successful delivery via SLN-based non-viral vectors.
Previous studies demonstrated the relevance of focal lesions (FL) in whole-body magnetic resonance imaging (wb-MRI) at the initial workup of patients with smoldering multiple myeloma (SMM). The aim ...of this study was to assess the effects of longitudinal wb-MRIs on progression into multiple myeloma (MM). Sixty-three patients with SMM were analyzed who received at least two wb-MRIs for follow-up before progression into MM. Radiological progressive disease (MRI-PD) was defined as detection of new FL or increase in diameter of existing FL and a novel or progressive diffuse infiltration. Radiological stable disease (MRI-SD) was defined by no change compared with the prior MRI. Patients were followed-up every 3-6 months, including a serological and clinical evaluation. One Hundred and eighty-two wb-MRIs were analyzed. MRI-PD occurred in 31 patients (49%), and 25 (40%) patients developed MM. MRI-PD was highly significantly associated with progression into MM, regardless of findings at the initial MRI. In multivariate analysis, MRI-PD remained a risk factor, independent of relevant baseline parameters like serum monoclonal protein or ⩾95% aberrant plasma cells in the bone marrow. Patients with MRI-SD had no higher risk of progression, even when FL were present at the initial MRI. Therefore, MRI is suitable for the follow-up of patients with SMM.
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