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Background: Low-risk gestational trophoblastic neoplasia are currently receiving monochemotherapy as first-line therapy. In the case of a resistance, a second-line monochemotherapy or polychemotherapy is proposed. As an alternative to these toxic and historic chemotherapy agents, the efficacy of the anti-PD-L1 monoclonal antibody (avelumab) was assessed in the TROPHIMMUN phase II trial Cohort A. Avelumab yielded a 53% cure rate with an acceptable tolerance profile, including normal further pregnancy and delivery. Beyond the blockade of PD-1/PD-L1 interactions, avelumab effect could rely on the induction of antibody-dependent cell-mediated cytotoxicity mediated by FcγR3A-expressing natural killer cells., Objective: This translational study aimed at testing whether antibody-dependent cell-mediated cytotoxicity is involved in avelumab efficacy on gestational trophoblastic neoplasia and if FcγR3A affinity polymorphism could help predicting the response to avelumab in gestational trophoblastic neoplasia., Study Design: The expression of PD-L1 by the tumor and the phenotype of natural killer cells infiltrating gestational trophoblastic neoplasia were verified by performing transcriptomic and proteomic analyses. Then, JEG-3 choriocarcinoma cells were cocultured with human natural killer cells in the presence and absence of avelumab. The impact of FcγR3A functional polymorphism was assessed on the activation status of natural killer cells and the viability of JEG-3 choriocarcinoma cells. Finally, the data from TROPHIMMUN trial were re-analyzed to determine the impact of the FcγR3A polymorphism of patients on their response to avelumab., Results: We confirmed that FcγR3A+ natural killer cells infiltrated PD-L1-expressing gestational trophoblastic neoplasia. In vitro, avelumab-coated JEG-3 choriocarcinoma cells induced natural killer cell activation, which promoted the destruction of JEG-3 cells. Natural killer cell activation was abolished when the Fc portion of avelumab was removed, demonstrating the importance of Fcγ receptor in this process. Using this model of antibody-dependent cell-mediated cytotoxicity, we demonstrated that high-affinity FcγR3A polymorphism on natural killer cells was associated with better in vitro response to avelumab. In line with this result, patients from the TROPHIMMUN trial homozygous for the high-affinity FcγR3A polymorphism had better clinical response to avelumab., Conclusion: Our work demonstrates that antibody-dependent cell-mediated cytotoxicity contributes to the therapeutic effect of avelumab in gestational trophoblastic neoplasia and that the individual patient response is impacted by the FcγR3A polymorphism. The FcγR3A polymorphism could be used as a biomarker to identify patients diagnosed with monochemoresistant gestational trophoblastic neoplasia who are most likely to respond to avelumab., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: De novo donor-specific antibody (dnDSA) is a strong biomarker associated with the development of antibody-mediated rejection (AMR) and graft loss after kidney transplantation. This procedure is expensive; however, systematic annual screening was recommended by some national organ transplant agencies or societies even though its clinical utility was not clearly established., Methods: To address this question, we retrospectively assessed the incidence of dnDSA according to the test justification (clinically indicated or systematic) in a cohort of low-immunological risk patients, defined by being nonhuman leukocyte antigen (non-HLA)-sensitized and having no previous kidney transplants., Results: A total of 1072 patients, for whom 4611 anti-HLA tests were performed, were included in the study. During the follow-up period of 8 (interquartile range, IQR: 5-11) years, 77 recipients developed dnDSA (prevalence of 7.2%). Thirty-five of these dnDSAs (45.5%) were detected during the first year posttransplantation. In 95% of patients with dnDSA, an immunizing event was identified in their medical records. dnDSA was detected in 46 of 4267 systematic screening tests (1.08%) performed. Active and chronic AMR were frequently observed in biopsies performed after systematic DSA testing (17.9% and 15.4%, respectively)., Conclusion: Our results suggest that the detection by systematic screening of dnDSA in low-immunological risk kidney transplant patients without sensitizing events is a rare event, especially after 1 year. Moreover, in real life, systematic annual screening for dnDSA, seems having a limited impact to detect AMR at an earlier stage compared to patients in whom dnDSA was detected after a clinically indicated test., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Background: Aspirin and platelet P2Y 12 inhibitors, such as ticagrelor, suboptimally inhibit microvascular thrombosis during ST-elevation myocardial infarction. Glycoprotein (GP) IIb/IIIa inhibitors may further inhibit this but cause excessive bleeding., Objectives: We investigated whether combination of glenzocimab, a GPVI inhibitor, with aspirin and ticagrelor provides additional antithrombotic effects, as GPVI has a critical role in atherothrombosis but minimal involvement in hemostasis., Methods: We investigated the effects of glenzocimab (monoclonal antibody Fab fragment) using blood from healthy donors and patients with acute coronary syndrome treated with aspirin and ticagrelor. Platelets were stimulated with multiple agonists, including atherosclerotic plaque, from patients undergoing carotid endarterectomy., Results: Aspirin and ticagrelor partially inhibited atherosclerotic plaque-induced platelet aggregation by 48% compared with control (34 ± 3 vs 65 ± 4 U; P < .001). Plaque-induced platelet aggregation, adhesion, secretion, and activation were critically dependent on GPVI activation. Glenzocimab alone reduced plaque-induced aggregation by 75% compared with control (16 ± 4 vs 65 ± 4 U; P < .001) and by >95% when combined with aspirin and ticagrelor (3 ± 1 vs 65 ± 4 U; P < .001). Glenzocimab reduced platelet aggregation, adhesion, and thrombin generation when added to blood of aspirin- and ticagrelor-treated patients with acute coronary syndrome. Glenzocimab shared several antithrombotic effects with the GPIIb/IIIa inhibitor eptifibatide with less effect on general hemostasis assessed by rotational thromboelastometry. In a murine intravital model of ST-elevation myocardial infarction, genetic depletion of GPVI reduced microvascular thrombosis., Conclusion: Addition of glenzocimab to aspirin and ticagrelor enhances platelet inhibition via multiple mechanisms of atherothrombosis. Compared with a GPIIb/IIIa inhibitor, glenzocimab shares multiple antithrombotic effects, with less inhibition of mechanisms involved in general hemostasis., Competing Interests: Declaration of competing interests P.L.R.N. reports institutional research grants from Novartis, Rigel Pharmaceuticals, Principia Biopharma, Acticor Biotech, and honoraria from Bayer, Grifols, and Takeda. P.K. receives research support for basic, translational, and clinical research projects from the European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), German Centre for Cardiovascular Research, and several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies in the past, but not in the last 3 years. P.K. is listed as an inventor on 2 patents held by the University of Birmingham (Atrial Fibrillation Therapy WO 2015140571 and Markers for Atrial Fibrillation WO 2016012783). M.J.-P. is the founder of Acticor Biotech and scientific adviser of the company. S.P.W. reports institutional research grants from Acticor Biotech, Novartis, Rigel Pharmaceuticals, and Principia Biopharma. M.R.T. declares institutional research grants from Acticor Biotech, Novartis, Rigel Pharmaceuticals, and Principia Biopharma. M.R.T. declares consultancy fees from Cytosorbents. F.O.A., M.H.H., D.P.K., J.P., P.B., O.H., P.H., A.S., N.K., A.T., and P.H.M. have no competing interests to disclose., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

With the rising popularity of endovascular aortic repair (EVAR) for aortic aneurysms and dissections, there is a crucial need for investigating the delayed appearance of post-EVAR complications such as stent-graft kinking, fracture and migration respectively. These complications have been noted to be influenced by the radial stiffness and bending flexibility attributes of stent-grafts. Auxetic designs with negative Poisson's ratio offer interesting advantages such as enhanced fracture toughness, superior indentation resistance and adaptive stiffness in response to intricate morphology for stenting applications over conventional stent designs. The objective of this study is to propose different auxetic stent candidates and to compare their mechanical performance with two conventional stent candidates for endovascular applications using numerical simulation through crimp/crushing tests for their radial stiffness and three-point bending/kinking tests for their flexibility, respectively. The results demonstrate that the novel hybrid auxetic designs (CRE and CSTAR) possess the best trade-off between radial stiffness and bending flexibility characteristics among all candidates for stent-graft applications., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Stephane Avril is a cofounder of Predisurge SAS, France., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The most common method to study the mechanical behavior of soft tissue is to test animal specimens, which should be prepared as soon as possible after the death to avoid biological deterioration effects such as rigor mortis. Freezing and cryo-preservation could allow extending the time between procurement and implantation. From a mechanical perspective, tissue preservation could influence mechanical testing results. Therefore, this study focuses on the influence of cryo-preserved samples on their mechanical behavior, especially at the rupture. In order to analyze this aspect, two tests were performed on the porcine abdominal wall. A tensile test to study the elastic behavior of samples and the tensile strength until rupture. A peeling test to more finely investigate the cohesion between muscle fibers. No statistical difference could be observed following tensile test. However, peeling tests between cryo-preserved and control samples showed a clear statistical difference with a p-value of 0.0097 for G p . Indeed, energy release rate was higher for the Cryo-preserve group than the Control group with G p  = 0.36 ± 0.07 N/mm vs 0.26 ± 0.10 N/mm. This difference suggests that the characterization of rupture energies for muscular tissue should be done without having frozen the samples, even with a cryopreservative agent. These results could also indicate that even if the rupture mode is the same between mechanical tests, a different rupture direction could imply different mechanical preservations for soft tissues. This study could help to understand the difficult mechanical preservation of soft tissues, especially on the rupture behavior. Future studies on skeletal muscles will be necessary to compare our results, especially in peeling., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Skin irritation is a common phenomenon that becomes a real concern when caused by the use of medical devices. Because the materials used for the design of these devices are usually carefully selected for chemical compatibility with the skin, it is reasonable to assume that the irritations result from the mechanical interaction between the devices and the skin. The aim of this work was to develop a new device to study both the shear strains in the layers of the skin, using Digital Image Correlation (DIC), and the friction behaviour of ex vivo skin interacting with objects. Pig skin samples with various surface preparations were tested in friction experiments involving different contacting materials encountered in the conception of medical devices. The measure of the static and dynamic coefficients of friction as well as the length of adhesion has highlighted the great influence of skin surface conditioning on friction properties. Strain maps obtained through DIC provided insights into the impact of friction and adhesion effects on shear strain distribution in the skin as a function of depth beneath its surface., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The risk of venous thromboembolism (VTE) during warm autoimmune hemolytic anemia (wAIHA) is apparent in several published series. Unlike proximate disorders (autoimmune thrombocytopenia, non-immune hemolytic diseases) little is known about the presentation and risk factors for VTE in this setting., Objective: To determine the frequency, presentation and risk factors for VTE associated with wAIHA., Methods: We performed a single center retrospective study of adult patients (>18years) followed for wAIHA between 2009 and 2013. VTE risk factors were systematically assessed. The characteristics of patients with or without VTE were compared. VTE presentation and precipitating factors were analyzed. The Padua VTE risk score was calculated in each case., Results: Forty patients were included. wAIHA was idiopathic in 24 patients (60%). Twelve patients (30%) had Evans syndrome. Mean lowest hemoglobin level was 6.6g/dl [3.7-11.5]. Eight patients (20%) presented VTE after the appearance of wAIHA, at a mean age of 52.5years. All patients had pulmonary embolus, associated with a deep venous thrombosis in 4 cases. At the time of VTE 7/8 patients had frank hemolysis (median hemoglobin level: 7g/dL) and 6/8 were outpatients with a low Padua VTE risk score. The frequency of usual VTE risk factor was similar in cases and controls. By contrast, lowest hemoglobin level was significantly lower in patients that experienced VTE (5.3 vs 7.2g/dL, p=0.016). During the first episode of wAIHA, patients with concurrent VTE had a more pronounced anemia (5.3 vs 7.4g/dL, p=0.026). At the time of VTE, anemia was more severe when no other precipitating factor was present (6 vs 8.9g.dL, p=0.04)., Conclusion: In our cohort, 20% of patients with wAIHA presented VTE. The vast majority of VTE occurred during severe hemolytic flares and were not attributable to usual VTE risk factors. VTE prophylaxis is advisable in any patient admitted for wAIHA, irrespective of Padua VTE risk score. Prophylaxis also seems reasonable for outpatients with marked hemolysis., (Copyright © 2015. Published by Elsevier B.V.)

Autoimmune lymphoproliferative syndrome (ALPS) caused by impaired FAS-mediated apoptosis of lymphocytes is characterized by lymphoproliferation, autoimmunity, but also an increased risk of invasive bacterial infection, notably following splenectomy. We surveyed a cohort of 100 ALPS patients (including 33 splenectomized) and found that 12 (10 splenectomized) had experienced 23 invasive bacterial infections mainly caused by Streptococcus pneumoniae. This vulnerability was associated with evidence of defective B-cell function characterized by low serum immunoglobulin (Ig) M, low IgM antibody production in response to S pneumoniae following nonconjugated immunization, and low blood memory B-cells counts (including marginal zone [MZ] B-cell counts). This immunodeficiency strongly correlated with intensity of lymphoproliferation. Spleen sections from 9 ALPS patients revealed double-negative T-cell (DN-T) infiltration of the MZ, which was depleted of B cells. MZ in ALPS patients contained an abnormally thick layer of MAdCAM-1((+)) stromal cells and an excess of DN-Ts. DN-Ts were shown to express MAdCAM-1 ligand, the α4β7 integrin. These observations suggest that accumulating DN-Ts are trapped within stromal cell meshwork and interfere with correct localization of MZ B cells. Similar observations were made in spleens of fas-deficient mice. Our data revealed an unexpected mechanism by which ALPS results in anti-polysaccharide IgM antibody production-specific defect. Splenectomy should be avoided., (© 2014 by The American Society of Hematology.)