On the active deformations of hybrid specimens

Purpose – The purpose of this study concerns numerical studies and experimental validation of the mechanical behavior of hybrid specimens. These kinds of composite specimens are made up of thin carbon and glass substrates on which some Macro Fiber Composite ® (MFC) piezoelectric patches are glued. A proper design and manufacturing of the hybrid specimens as well as testing activities have been performed. The research activity has been carried out under the FutureWings project, funded by the European Commission within the 7th Framework. Design/methodology/approach – The paper describes the basic assumptions made to define specimen geometries and to carry out experimental tests. Finite element (FE) results and experimental data (laser technique measurements) have been compared: it shows very good agreement for the displacements’ distribution along the specimens. Findings – Within the objectives of the project, the study of passive and active deformation characteristics of the hybrid composite material has provided reference technical data and has allowed for the correct adaptation of the FE models. More in particular, using the hybrid specimens, both the bending deformations and the torsion deformations have been studied. Practical implications – The deformation capability of the hybrid specimens will be used in the development of prototypical three-dimensional structures, that, through the electrical control of the MFC patches, will be able to change the curvature of their cross section or will be able to change the angle of torsion along their longitudinal axis. Originality/value – The design of nonstandard specimens and the tests executed represent a novelty in the field of structures using piezoelectric actuators. The numerical and experimental data of the present research constitute a small step forward in the field of smart materials technology

Assessment of genetic diversity among seed transfer zones for multiple grassland plant species across Germany

Species diversity and intraspecific genetic diversity play a critical role in conservation and restoration of grassland ecosystems. To maintain regional adaptations of native wild plants, seeds for restoration projects are produced regionally. The delineation of regions is organised by seed transfer zones (STZs). Generalised STZs that apply uniformly to many species have been established in several European countries. Ideally, generalised STZs should be based on comprehensive data of intraspecific genetic and phenotypic diversity for a larger number of species. However, such underlying data is missing. The project RegioDiv aims to fill this gap and generate empirical data on genetic variation of multiple grassland plant species across Germany. Here we describe the driving principles and main methods of the project. A total of 33 species were collected at an average density of ∼1 sample/1000 km2 across the 22 existing STZs, and a total of 11,976 samples were genotyped with SNP markers. The analysis of genetic population structure included cluster analysis and analyses of isolation-by-distance and isolation-by-environment. An exemplary within-species analysis for Agrostis capillaris, a widespread grass, revealed five intraspecific genetic clusters, distributed in spatially coherent ranges that did not fully match the STZs. Most of the STZs differed genetically following a pattern of isolation-by-distance and isolation-by-environment. In an across-species analysis, genetic differentiation was affected by mating system and ploidy. Outcrossed and polyploid species were less differentiated than self-compatible and diploid species. However, genetic differentiation did not significantly differ between grasses and herbs, highlighting the variability among species within these groups. The dataset of the RegioDiv project will advance both basic and applied research on genetic variation of grassland plant species. The results will allow the assessment of the current German STZ system and guide potential improvements

Alterations of cohesin complex genes in acute myeloid leukemia: differential co-mutations, clinical presentation and impact on outcome

Functional perturbations of the cohesin complex with subsequent changes in chromatin structure and replication are reported in a multitude of cancers including acute myeloid leukemia (AML). Mutations of its STAG2 subunit may predict unfavorable risk as recognized by the 2022 European Leukemia Net recommendations, but the underlying evidence is limited by small sample sizes and conflicting observations regarding clinical outcomes, as well as scarce information on other cohesion complex subunits. We retrospectively analyzed data from a multi-center cohort of 1615 intensively treated AML patients and identified distinct co-mutational patters for mutations of STAG2 , which were associated with normal karyotypes (NK) and concomitant mutations in IDH2 , RUNX1, BCOR, ASXL1 , and SRSF2 . Mutated RAD21 was associated with NK, mutated EZH2, KRAS, CBL , and NPM1 . Patients harboring mutated STAG2 were older and presented with decreased white blood cell, bone marrow and peripheral blood blast counts. Overall, neither mutated STAG2, RAD21, SMC1A nor SMC3 displayed any significant, independent effect on clinical outcomes defined as complete remission, event-free, relapse-free or overall survival. However, we found almost complete mutual exclusivity of genetic alterations of individual cohesin subunits. This mutual exclusivity may be the basis for therapeutic strategies via synthetic lethality in cohesin mutated AML

Mutated IKZF1 is an independent marker of adverse risk in acute myeloid leukemia

Genetic lesions of IKZF1 are frequent events and well-established markers of adverse risk in acute lymphoblastic leukemia. However, their function in the pathophysiology and impact on patient outcome in acute myeloid leukemia (AML) remains elusive. In a multicenter cohort of 1606 newly diagnosed and intensively treated adult AML patients, we found IKZF1 alterations in 45 cases with a mutational hotspot at N159S. AML with mutated IKZF1 was associated with alterations in RUNX1 , GATA2 , KRAS , KIT , SF3B1 , and ETV6 , while alterations of NPM1 , TET2 , FLT3 -ITD, and normal karyotypes were less frequent. The clinical phenotype of IKZF1 -mutated AML was dominated by anemia and thrombocytopenia. In both univariable and multivariable analyses adjusting for age, de novo and secondary AML, and ELN2022 risk categories, we found mutated IKZF1 to be an independent marker of adverse risk regarding complete remission rate, event-free, relapse-free, and overall survival. The deleterious effects of mutated IKZF1 also prevailed in patients who underwent allogeneic hematopoietic stem cell transplantation ( n  = 519) in both univariable and multivariable models. These dismal outcomes are only partially explained by the hotspot mutation N159S. Our findings suggest a role for IKZF1 mutation status in AML risk modeling

Real-world multicentre cohort study on choices and effectiveness of immunotherapies in NMOSD and MOGAD

Background: Recurrent attacks in neuromyelitis optica spectrum disorders (NMOSDs) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) can lead to severe disability. We aimed to analyse the real-world use of immunotherapies in patients with NMOSD and MOGAD, focusing on changes in treatment strategies, effects on attack rates (ARR) and risk factors for attacks. Methods: This longitudinal registry-based cohort study included 493 patients (320 with aquaporin-4 immunoglobulin G (AQP4-IgG) seropositive NMOSD (65%), 44 with AQP4-IgG seronegative NMOSD (9%) and 129 MOGAD (26%)) with 1247 treatments from 19 German and one Austrian centre from the registry of the neuromyelitis optica study group (NEMOS). We analysed unadjusted ARR and implemented survival analyses and Cox proportional hazard regression to assess efficiency and risk factors for subsequent attacks over time. Results: Rituximab and azathioprine are the most widely used immunotherapies in NMOSD as well as in MOGAD, with changes in distribution over the last decade. Immunotherapy demonstrated significant therapeutic effects in NMOSD but less pronounced effects in MOGAD. Risk factors for attacks included younger age and prior attacks under the same therapy. Efficacy varied among the different immunotherapies, with azathioprine, rituximab and eculizumab showing significant risk reductions in AQP4-IgG seropositive NMOSD. Conclusions: This study provides insights into the evolving treatment landscape and effectiveness of immunotherapies in NMOSD and MOGAD. Established off-label therapies continue to play an important role, especially for patients with stable disease, with emerging evidence supporting newly approved therapies. Future studies are needed to refine treatment algorithms and address the ongoing uncertainties in MOGAD management

Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial

PURPOSE: This randomized, open -label trial compared the efficacy and safety of adjuvant nabpaclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430). METHODS: We assigned 866 treatment -naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m(2)) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28 -day cycles. The primary end point was independently assessed disease -free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS: Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nabpaclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 (nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P =.18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P=.02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P =.045). At a 16 -month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 (nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P =.0232). At the 5 -year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P =.0091). Eighty-six percent (nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade >= 3 treatment -emergent adverse events. Two patients per study arm died of treatment -emergent adverse events. CONCLUSION: The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine