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Abstract Antibody engineering can tailor the design and activities of therapeutic antibodies for better efficiency or other advantageous clinical properties. Here we report the development of ISB 1442, a fully human bispecific antibody designed to re-establish synthetic immunity in CD38+ hematological malignancies. ISB 1442 consists of two anti-CD38 arms targeting two distinct epitopes that preferentially drive binding to tumor cells and enable avidity-induced blocking of proximal CD47 receptors on the same cell while preventing on-target off-tumor binding on healthy cells. The Fc portion of ISB 1442 is engineered to enhance complement dependent cytotoxicity, antibody dependent cell cytotoxicity and antibody dependent cell phagocytosis. ISB 1442 thus represents a CD47-BsAb combining biparatopic targeting of a tumor associated antigen with engineered enhancement of antibody effector function to overcome potential resistance mechanisms that hamper treatment of myeloma with monospecific anti-CD38 antibodies. ISB 1442 is currently in a Phase I clinical trial in relapsed refractory multiple myeloma.

The association between endometriosis and autoimmune diseases is well known, however no acquired platelet function defect has been described so far. We describe the case of two patients with endometriosis associated with an antiplatelet glycoprotein VI (anti-GPVI) antibody. The two women with deep pelvic endometriosis associated with secondary infertility presented a mild bleeding tendency, a deficient platelet aggregation response to collagen, convulxin or CRP and a severe GPVI deficiency. Immunoblot revealed a combined FcRγ deficiency but no indication of GPVI cleavage. In the first case, platelet count was normal and an anti-GPVI IgG was detected in plasma. A first corticosteroids administration normalized in vitro platelet functions but further administrations were unsuccessful. Three IVF attempts failed. Conservative laparoscopic surgery was carried out after antifibrinolytic treatment without bleeding. The second case presented with a history of moderate thrombocytopenia and a weak anti-GPVI in the context of infertility and autoimmune disease, the Sjögren syndrome resolved after corticosteroids and hydroxychloroquine treatment. Acquired GPVI deficiencies are rare. It would be useful to determine whether the association with endometriosis is coincidental or not by more systematic investigations. It does not seem that in these patients, GPVI deficiency is associated with an increased risk of bleeding.

Abstract Growing evidence suggests that the origins of the panzootic amphibian pathogens Batrachochytrium dendrobatidis (Bd) and Batrachochytrium salamandrivorans (Bsal) are in Asia. In Taiwan, an island hotspot of high amphibian diversity, no amphibian mass mortality events linked to Bd or Bsal have been reported. We conducted a multi-year study across this subtropical island, sampling 2517 individuals from 30 species at 34 field sites, between 2010 and 2017, and including 171 museum samples collected between 1981 and 2009. We analyzed the skin microbiome of 153 samples (6 species) from 2017 in order to assess any association between the amphibian skin microbiome and the probability of infection amongst different host species. We did not detect Bsal in our samples, but found widespread infection by Bd across central and northern Taiwan, both taxonomically and spatially. Museum samples show that Bd has been present in Taiwan since at least 1990. Host species, geography (elevation), climatic conditions and microbial richness were all associated with the prevalence of infection. Host life-history traits, skin microbiome composition and phylogeny were associated with lower prevalence of infection for high altitude species. Overall, we observed low prevalence and burden of infection in host populations, suggesting that Bd is enzootic in Taiwan where it causes subclinical infections. While amphibian species in Taiwan are currently threatened by habitat loss, our study indicates that Bd is in an endemic equilibrium with the populations and species we investigated. However, ongoing surveillance of the infection is warranted, as changing environmental conditions may disturb the currently stable equilibrium.

Abstract Background The fungal pathogen Batrachochytrium dendrobatidis (Bd) threatens amphibian biodiversity and ecosystem stability worldwide. Amphibian skin microbial community structure has been linked to the clinical outcome of Bd infections, yet its overall functional importance is poorly understood. Methods Microbiome taxonomic and functional profiles were assessed using high-throughput bacterial 16S rRNA and fungal ITS2 gene sequencing, bacterial shotgun metagenomics and skin mucosal metabolomics. We sampled 56 wild midwife toads (Alytes obstetricans) from montane populations exhibiting Bd epizootic or enzootic disease dynamics. In addition, to assess whether disease-specific microbiome profiles were linked to microbe-mediated protection or Bd-induced perturbation, we performed a laboratory Bd challenge experiment whereby 40 young adult A. obstetricans were exposed to Bd or a control sham infection. We measured temporal changes in the microbiome as well as functional profiles of Bd-exposed and control animals at peak infection. Results Microbiome community structure and function differed in wild populations based on infection history and in experimental control versus Bd-exposed animals. Bd exposure in the laboratory resulted in dynamic changes in microbiome community structure and functional differences, with infection clearance in all but one infected animal. Sphingobacterium, Stenotrophomonas and an unclassified Commamonadaceae were associated with wild epizootic dynamics and also had reduced abundance in laboratory Bd-exposed animals that cleared infection, indicating a negative association with Bd resistance. This was further supported by microbe-metabolite integration which identified functionally relevant taxa driving disease outcome, of which Sphingobacterium and Bd were most influential in wild epizootic dynamics. The strong correlation between microbial taxonomic community composition and skin metabolome in the laboratory and field is inconsistent with microbial functional redundancy, indicating that differences in microbial taxonomy drive functional variation. Shotgun metagenomic analyses support these findings, with similar disease-associated patterns in beta diversity. Analysis of differentially abundant bacterial genes and pathways indicated that bacterial environmental sensing and Bd resource competition are likely to be important in driving infection outcomes. Conclusions Bd infection drives altered microbiome taxonomic and functional profiles across laboratory and field environments. Our application of multi-omics analyses in experimental and field settings robustly predicts Bd disease dynamics and identifies novel candidate biomarkers of infection. Video Abstract

Immediate reocclusion after mechanical thrombectomy (MT) for acute ischemic stroke (AIS) is a rare but devastating condition associated with poor functional outcome. The aim of this study was to gain insights into the mechanisms underlying immediate reocclusion, and to evaluate the efficacy and safety of the glycoprotein IIb/IIIa antagonist abciximab, for its treatment. Clinical data were collected from April 2015 to April 2019 in a monocentric prospective registry of AIS patients treated by MT. All patients with immediate reocclusion were retrospectively selected and subdivided into 2 groups according to abciximab treatment status. In vitro, the separate and combined effects of abciximab and alteplase on clot formation in whole blood under flow conditions were further investigated in microfluidic chambers. From 929 MT-treated patients, 21 had post-MT immediate reocclusion. Abciximab treatment in reocclusion patients (n = 10) led to higher rate of final recanalization (p

Microbial assemblages naturally living on the skin are an integral part of immunity. In amphibians, this skin microbiota may hold a mitigation solution against the fungal pathogen Batrachochytrium dendrobatidis (Bd), which causes the panzootic disease chytridiomycosis. We used 16S rRNA gene metabarcoding to test the adaptive microbiome hypothesis. We compared the community composition, richness, and putative Bd‐inhibitory function of the skin microbiome of three amphibian host species in the Pyrenees, as well as three species in Taiwan, in both Bd‐positive and negative mountain populations. In both geographical regions, the amphibian host species played a decisive role in shaping the microbial assemblage and putative anti‐Bd properties. In the Pyrenees, the species most susceptible to chytridiomycosis, Alytes obstetricans, had the lowest relative abundances of putative protective bacteria. In Bd‐positive and negative sites, individuals had different skin microbiomes, with all anuran species showing increased relative abundances of potential anti‐Bd bacteria, while the Taiwanese caudata Hynobius sonani showed the opposite pattern. Our results suggest that, in response to exposure to the pathogen, the skin microbiota shifted to a defensive state with increased anti‐Bd function, which may contribute to promoting disease resistance, as proposed by the adaptive microbiome hypothesis. [ABSTRACT FROM AUTHOR]

Acquired deficiencies in platelet glycoprotein VI are rare and have not been found associated with other defects. Here we report the case of a 64-year old male patient presenting an immune GPVI deficiency associated to a mutation in the alpha-actinin gene and who has been treated with dual anti platelet therapy without bleeding. Introduction: Glycoprotein (GP) VI, a pluripotent receptor interacting with collagen and fibrin(ogen) is responsible for thrombus formation, growth and stability (). It is co-expressed with the Fc receptor γ (FcRγ) chain (). GPVI is not critical for haemostasis since subjects with a GPVI deficiency usually present low or even no bleeding tendency (, ). Acquired GPVI deficiency due to antibody-induced GPVI depletion is the most frequent finding. At least 10 patients have been described with an acquired GPVI deficiency, most often associated to immune thrombocytopenia, moderate bleeding and impaired collagen-induced platelet aggregation (). Several mechanisms leading to the GPVI deficiency are proposed including antibody-triggered GPVI internalization and/or shedding of the extracellular domain (, ). We report the case of a patient presenting an acquired GPVI deficiency different from those previously described: (i) he is male whereas all previous cases were female, (ii) he is heterozygous for a mutation in α (alpha)-actinin-1 gene and (iii) he was treated with dual antiplatelet therapy with no haemorrhagic manifestation.

This commentary reflects on the contributions by Egan, Delimatsis and Verghese that provide historical accounts of ETSI’s origin and its dynamic evolution and attempt to explain its resilience. In this commentary, we place focus on ETSI’s unique attributes and their dynamic evolution to arrive at a better understanding of its resilience during critical moments and over time. We identify three such key attributes, namely ETSI’s institutional set-up and openness, its standard-setting activities and flexibility and the ETSI IPR policy. The article illuminates their importance, also in ETSI’s interactions with the European Commission and how these traits originated, were activated and evolved during critical moments. Taken together, these contributions suggest that the governance reforms proposed by the EU risk undermining the attractiveness of open European ICT standardization, a key ingredient of ETSI’s very success in ICT matters. [ABSTRACT FROM AUTHOR]

Background: In extrinsically magnetoelectric materials made of two components, the direct magnetoelectric coupling arises from a mechanical strain transmission at the interface due to the shape change of the magnetostrictive component under an external magnetic field. Here, the size of the interface between the two components plays a crucial role. Therefore, the development of nanomaterials exhibiting large surface-to-volume ratios can help to respond to such a requirement. However, the magnetic nanoparticles (NPs) must be highly magnetostrictive and magnetically blocked at room temperature despite their nanometer-size. We describe here the use of the polyol process to synthesize cobalt ferrite (CoxFe3−xO4) nanoparticles with controlled size and composition and the study of the relationship between size and composition and the magnetic behavior.Methods: We used an improved synthesis of magnetostrictive CoxFe3−xO4 NPs based on the forced hydrolysis of metallic salts in a polyol solvent, varying the fraction x. Stoichiometric NPs (x = 1) are expected to be highly magnetostrictive while the sub-stoichiometric NPs (particularly for x ≈ 0.7) are expected to be less magnetostrictive but to present a higher magnetocrystalline anisotropy constant, as previously observed in bulk cobalt ferrites. To control the size of the NPs, in order to overcome the superparamagnetic limit, as well as their chemical composition, in order to get the desired magnetomechanic properties, we carried out the reactions for two nominal precursor contents (x = 1 and 0.67), using two different solvents, i.e., triethylene glycol (TriEG) and tetraethylene glycol (TetEG), and three different durations of refluxing (3, 6 and 15 h). The structure, microstructure and composition of the resulting NPs were then investigated by using X-ray diffraction (XRD), transmission electron microscopy (TEM) and X-ray fluorescence spectroscopy (XRF), respectively. The magnetic properties were also evaluated using standard magnetometry. To measure the magnetostrictive response of the particles, the particles were sintered to dense pellets on which strain gauges were bonded, measuring the size variation radially, as a function of a dc magnetic field.Findings: We found two samples, the first one being stoichiometric and magnetostrictive, and the second one being sub-stoichiometric and presenting a higher magnetization, that are appropriate to be used as ferromagnetic building blocks in nanostructured magnetoelectric materials, particularly materials based on polymers. We show that the polyol solvent and the reaction time are two key parameters to control the size and the magnetic properties of the resulting nanoparticles. We believe that these results provide relevant insights to the design of efficient magnetic and magnetostrictive nanoparticles that can be further functionalized by coupling agents, to be contacted with piezoelectric polymers.