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An Antarctic biopile using a composite liner (high-density polyethylene geomembrane (GMB) over a geosynthetic clay liner (GCL)) was constructed on a coarse granular subgrade to contain hydrocarbon-contaminated soil and leachate. The soil was remediated after 4 years and the biopile was decommissioned. The liner was exhumed to assess the properties and performance of the GMB and GCL. There was no significant change in the GMB index properties. Although cobbles and coarse gravel of the subgrade had left indentations in the GMB, implying tensile strains that could impact long-term performance, there were no holes. There was significant variability in the hydration of the GCL (from 10% to 220%) and in the underlying subgrade soil water content (from 5% to 30%). This reflects the complexity of the subgrade and groundwater flow in the Antarctic environment. The exhumed GCL specimens had low hydraulic conductivity (1 * [10.sup.-11] to 7 * [10.sup.-11] m/s) at 13 kPa. Soil samples from below the composite liner showed no detectable hydrocarbons and confirmed no migration through the barrier. It is concluded that the composite barrier contained the leachate and biopile soil over the 4 years in service in the extreme Antarctic conditions. Key words: geosynthetic clay liner, hydration, geomembrane, cold region engineering, field case. Une biopile antarctique utilisant un revetement composite (geomembrane de polyethylene haute densite (GMB) recouvrant un revetement d'argile geosynthetique (GCL)) a ete construit sur un sol de fondation granulaire grossier afin de contenir un sol et du lixiviat contamines par des hydrocarbures. Le sol a ete assaini apres 4 ans et le biopile a ete mis hors service. La doublure a ete exhumee pour evaluer les proprietes et les performances du GMB et du GCL. Il n'y a pas eu de changement significatif dans les proprietes de l'indice GMB. Bien que les galets et le gravier grossier du sol de fondation aient laisse des empreintes dans le GMB, impliquant des deformations susceptibles de nuire a la performance a long terme, il n'ya pas eu de trous. Il y avait une variabilite significative dans l'hydratation de la GCL (de 10 a 220 %) et dans la teneur en eau sous-jacente du sol de fondation (de 5 a 30 %). Cela reflete la complexite du sol de fondation et de l'ecoulement des eaux souterraines dans l'environnement antarctique. Les echantillons de GCL exhumes avaient une faible conductivite hydraulique (1 * [10.sup.-11] a 7 * [10.sup.-11] m/s) a 13 kPa. Les echantillons de sol sous la membrane composite ne montraient aucun hydrocarbure detectable et ne confirmaient aucune migration a travers la barriere. Il est conclu que la barriere composite contenait le sol de lixiviat et de biopile pendant les 4 annees de service dans les conditions extremes de l'Antarctique. [Traduit par la Redaction] Mots-cles: doublure d'argile geosynthetique, hydration, geomembrane, ingenierie des regions froides, cas de terrain., 1. Introduction Soils in Antarctica, whilst limited in distribution, are important sources of biodiversity and are crucial to the terrestrial ecosystem. Fuel spills and hydrocarbon-contaminated soils are present across many [...]

Herein, we report the synthesis, photophysical characterization and validation of iridium(iii)-polypyridine complexes functionalized for click chemistry and bioorthogonal chemistry, as well as their versatile applications as probes in bioimaging studies exploiting metabolic labeling. The designed dyes are conjugated to chemical reporters in a specific manner within cells by CuAAC ligation and display attractive photophysical properties in the UV-visible range. They are indeed highly photostable and emit in the far-red to near-IR region with long lifetimes and large Stokes shifts. We demonstrate that they can be efficiently used to monitor nascent intracellular sialylated glycoconjugates in bioorthogonal MOE studies with a varied panel of optical and non-optical techniques, namely conventional UV-vis laser scanning confocal microscopy (for routine purposes), UV-vis time-resolved luminescence imaging (for specificity and facilitated multiplexing with nano-environment sensitivity), synchrotron radiation based X-ray fluorescence nanoimaging (for high resolution, elemental mapping and quantification in situ ) and inductively coupled plasma mass spectrometry (for routine quantification on cell populations with high statistical confidence). The synthesized Ir(iii) complexes were utilized in single labeling experiments, as well as in dual click-labeling experiments utilizing two distinct monosaccharide reporters relevant to the same metabolic pathway., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Successful implementation of Safe and Sustainable by Design (SSbD) and grouping approaches requires simple, reliable, and cost-effective assays to facilitate hazard screening at early stages of product development. Especially for nanomaterials (NMs), which exist in many different forms, efficient hazard screening is of utmost importance. Oxidative potential (OP), which is the ability of a substance to induce reactive oxygen species (ROS), is an important indicator of the potential to induce oxidative damage and oxidative stress. A frequently used assay to measure OP of NMs is the ferric reducing ability of serum (FRAS) assay. Although the widely used cuvette-based FRAS protocol is considered a robust assay, its low throughput makes the screening of multiple materials challenging. Here, we adapt the original cuvette-based FRAS assay protocol, into a 96-well format and thereby improve its user-friendliness, simplicity, and screening capacity. The adapted protocol allows for the screening of multiple NMs per plate, and multiple plates per day, where the original protocol allows for the screening of one NM dose-range per day. When comparing the two protocols, the adapted protocol showed slightly decreased assay precision as compared to the original protocol. The results obtained with the adapted protocol were compared using eight reference NMs in an interlaboratory study and showed acceptably low intra- and interlaboratory variation. We conclude that the adapted FRAS assay protocol is suitable to be used for hazard screening to facilitate SSbD and grouping approaches.

Oxide-perovskites designed for automotive catalysts contain multiple metal elements whose presence is crucial to achieving the targeted performance. They are highly stable in exhaust operating conditions; however, little is known about their stability under physiological conditions. As some of the metallic components are hazardous to humans and the environment, perovskite benefits in cleaner air must be balanced with risks in a Safe and Sustainable Design (SSbD) approach. New approach methodologies (NAMs), including in chemico and in silico methods, were used for testing hazards and benefits, including catalytic activity and tolerance for temporary excess of oxygen under dynamic driving conditions. The composition and surface properties of six different lanthanum-based oxide-perovskites compromised their stability under lung physiological conditions, influencing the oxidative damage of the particles and the bioacessibility of leaching metals. We found consistent biotransformation of the oxide-perovskite materials at pH 4.5. The leached lanthanum ions, but not other metals, respeciated into lanthanum phosphate nanoparticles, which increased the overall oxidative damage in additive synergy. The NAM results in the presented SSbD approach were challenged by in vivo studies in rats and mice, which confirmed multicomponent clearance from lungs into urine and supported the comparative ranking of effects against well-characterized spinel materials. Among the perovskites, the version with reduced nickel content and doped with palladium offered the best SSbD balance, despite not improving the conventional benchmark catalytic performance and related sustainability benefits. Redesign by industry may be necessary to better fulfill all SSbD dimensions.

Jumping translocations (JT) are rare cytogenetic abnormalities associated with progression in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Typically, a tri-tetra-somic 1q chromosome is translocated to two or more recipient chromosomes. In multiple myeloma JT were shown to originate after DNA demethylation and decondensation. Using epigenomics, we investigated sequential samples in an SRSF2-mutated MDS and AML cohort with normal karyotype at diagnosis and 1qJT at disease evolution after 5'-azacytidine (AZA). 1qJT breakpoints fell within repetitive DNA at both 1q12 and the translocation partners, namely acrocentrics n. 14, 15, 21, and 22, chromosome 16, and chromosome Y. The global methylome at diagnosis showed hypermethylation at 61% of the differentially methylated regions (DMRs), followed by hypomethylation at 80% of DMRs under AZA, mostly affecting pathways related to immune system, chromatin organization, chromosome condensation, telomere maintenance, rRNA, and DNA repair. At disease evolution, a shift toward hypermethylation, intronic enhancers enrichment and epigenetic involvement of the PI3K/AKT and MAPK signaling emerged. In particular, AKT1 phosphorylation behaved as a hallmark of the progression. Overall, we provided new insights on the characterization of 1qJT in SRSF2-mutated myeloid neoplasms and first showed that epigenetics is a powerful tool to investigate the molecular landscape of repetitive DNA rearrangements., (© 2024 The Author(s). Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)

Making research data findable, accessible, interoperable and reusable (FAIR) is typically hampered by a lack of skills in technical aspects of data management by data generators and a lack of resources. We developed a Template Wizard for researchers to easily create templates suitable for consistently capturing data and metadata from their experiments. The templates are easy to use and enable the compilation of machine-readable metadata to accompany data generation and align them to existing community standards and databases, such as eNanoMapper, streamlining the adoption of the FAIR principles. These templates are citable objects and are available as online tools. The Template Wizard is designed to be user friendly and facilitates using and reusing existing templates for new projects or project extensions. The wizard is accompanied by an online template validator, which allows self-evaluation of the template (to ensure mapping to the data schema and machine readability of the captured data) and transformation by an open-source parser into machine-readable formats, compliant with the FAIR principles. The templates are based on extensive collective experience in nanosafety data collection and include over 60 harmonized data entry templates for physicochemical characterization and hazard assessment (cell viability, genotoxicity, environmental organism dose-response tests, omics), as well as exposure and release studies. The templates are generalizable across fields and have already been extended and adapted for microplastics and advanced materials research. The harmonized templates improve the reliability of interlaboratory comparisons, data reuse and meta-analyses and can facilitate the safety evaluation and regulation process for (nano) materials., (© 2024. Springer Nature Limited.)

Herein, a Safe-and-Sustainable-by-Design (SSbD) screening strategy on four different inorganic aerogel mats and two conventional mineral wools for ranking purposes is demonstrated. Given that they do not consist of particles, the release is first simulated, addressing three occupational exposure scenarios, realistic for their intended use as building insulators. No exposure to consumers nor to the environment is foreseen in the use phase, however, aerosols may be released during mat installation, posing an inhalation risk for workers. All four aerogel mats release more respirable dust than the benchmark materials and 60% thereof deposits in the alveolar region according to modelling tools. The collected aerogel dust allows for subsequent screening of hazard implications via two abiotic assays: 1) surface reactivity in human blood serum; 2) biodissolution kinetics in lung simulant fluids. Both aerogels and conventional insulators show similar surface reactivity. Differences in biodissolution are influenced by the specifically designed organic and inorganic structural modifications. Aerogel mats are better-performing insulators (2-fold lower thermal conductivity than the benchmark) However, this work demonstrates how investment decisions can be balanced with safety and sustainability aspects. Concepts of analogy and similarity thus support easily accessible methods to companies for safe and economically viable innovation with advanced materials., (© 2024 Wiley‐VCH GmbH.)

The treatment of Parkinson's disease (PD) has not been consistently modified for more than 60 years. L-DOPA, the blood-brain barrier permeable precursor prodrug of dopamine, is to date the only effective therapy on the market. However, it is well known that prolonged treatment with L-DOPA leads to several side effects, which may affect the patient's life expectancy (i.e., the wearing-off phenomenon, on-off fluctuations, and dyskinesia). For this reason, modifications, and supplements to L-DOPA treatment have been and are being studied, which, however, have not yet resulted in a valid alternative to the cornerstone drug. This review aims to summarize the main formulations currently in use for PD treatment, explaining advantages and disadvantages for each class. The attention will be focused on the promising prodrug concept, aimed at finding a suitable L-DOPA substitute with improved pharmacokinetic behavior. In this respect, new potential candidates which show interesting properties for the intended scope, the so-called dicarba-closo-dodecaboranes(12) (carboranes), will be discussed. Carboranes are inorganic molecular icosahedral boron-carbon clusters with 12 vertices and 20 deltahedral faces. They have been extensively studied for applications in medicine as potential pharmacophores, reagents in boron neutron capture therapy (BNCT) and radiotherapy. Here, we discuss them as inorganic scaffolds for dopamine delivery at the central nervous system (CNS) level., Competing Interests: Declaration of Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

GATA2 is a transcription factor with key roles in hematopoiesis. Germline GATA2 gene variants have been associated with several inherited and acquired hematologic disorders, including myelodysplastic syndromes. Among the spectrum of GATA2 deficiency- associated manifestations thrombosis has been reported in 25% of patients, but the mechanisms are unknown. GATA2 was shown to be involved in endothelial nitric oxide synthase (eNOS) regulation and vascular development. We assessed eNOS expression and angiogenesis in patients with GATA2 deficiency. Platelets and blood outgrowth endothelial cells (BOEC) from GATA2 variant carriers showed impaired NO production and reduction of eNOS mRNA and protein expression and of eNOS activity. GATA2 binding to the eNOS gene was impaired in BOEC from GATA2-deficient patients, differently from control BOEC. GATA2 deficiency BOEC showed also defective angiogenesis, which was completely restored by treatment with the NO-donor Snitroso- N-acetylpenicillamine (SNAP). Atorvastatin, but not resveratrol, largely restored eNOS expression, NO biosynthesis and neoangiogenesis in GATA2-deficient BOEC by a mechanism involving increased expression of the eNOS transcription factor AP-1/c-JUN, replacing GATA2 when the latter is inactive. Our results unravel a possible thrombogenic mechanism of GATA2 mutations, definitely establish the regulation of eNOS by GATA2 in endothelial cells and show that endothelial angiogenesis is strictly dependent on the eNOS/NO axis. Given the ability of atorvastatin to restore NO production and angiogenesis by GATA2-deficient endothelial cells, the preventive effect of atorvastatin on thrombotic events and possibly on other clinical manifestations of the syndrome related to deranged angiogenesis should be explored in patients with GATA2 deficiency in an ad hoc designed clinical trial.

Aberrant signaling in myeloproliferative neoplasms may arise from alterations in genes coding for signal transduction proteins or epigenetic regulators. Both mutated and normal cells cooperate, altering fragile balances in bone marrow niches and fueling persistent inflammation through paracrine or systemic signals. Despite the hopes placed in targeted therapies, myeloid proliferative neoplasms remain incurable diseases in patients not eligible for stem cell transplantation. Due to the emergence of drug resistance, patient management is often very difficult in the long term. Unexpected connections among signal transduction pathways highlighted in neoplastic cells suggest new strategies to overcome neoplastic cell adaptation.

Iron deficiency anemia is among the most frequent causes of disability. Intravenous iron is the quickest way to correct iron deficiency, bypassing the bottleneck of iron intestinal absorption, the only true mechanism of iron balance regulation in human body. Intravenous iron administration is suggested in patients who are refractory/intolerant to oral iron sulfate. However, the intravenous way of iron administration requires several precautions; as the in-hospital administration requires a resuscitation service, as imposed in Europe by the European Medicine Agency, it is very expensive and negatively affects patient's perceived quality of life. A new oral iron formulation, Sucrosomial iron, bypassing the normal way of absorption, seems to be cost-effective in correcting iron deficiency anemia at doses higher than those usually effective with other oral iron formulations. In this multicentric randomized study, we analyze the cost-effectiveness of intravenous sodium ferrigluconate vs oral Sucrosomial iron in patients with iron deficiency anemia refractory/intolerant to oral iron sulfate without other interfering factors on iron absorption., (© 2020. The Author(s).)

The last decade has been very important for the quantity of preclinical information obtained regarding chronic myeloproliferative neoplasms (MPNs) and the following will be dedicated to the translational implications of the new biological acquisitions. The overcoming of the mechanistic model of clonal evolution and the entry of chronic inflammation and dysimmunity into the new model are the elements on which to base a part of future therapeutic strategies. The innate immune system plays a major role in this context. Protagonists of the initiation and regulation of many pathological aspects, from cytokine storms to fibrosis, the NLRP3 and AIM2 inflammasomes guide and condition the natural history of the disease. For this reason, MPNs share many biological and clinical aspects with non-neoplastic diseases, such as autoimmune disorders. Finally, cardiovascular risk and disturbances in iron metabolism and myelopoiesis are also closely linked to the role of inflammasomes. Although targeted therapies are already being tested, an increase in knowledge on the subject is desirable and potentially translates into better care for patients with MPNs.

Indoleamine 2,3-dioxygenase 1 (IDO1) - the enzyme catalyzing the rate-limiting step of tryptophan catabolism along the kynurenine pathway - belongs to the class of inhibitory immune checkpoint molecules. Such regulators of the immune system are crucial for maintaining self-tolerance and thus, when properly working, preventing autoimmunity. A dysfunctional IDO1 has recently been associated with a specific single nucleotide polymorphism (SNP) and with the occurrence of autoimmune diabetes and multiple sclerosis. Many genetic alterations of IDO1 have been proposed being related with dysimmune disorders. However, the molecular and functional meaning of variations in IDO1 exomes as well as the promoter region remains a poorly explored field. In the present study, we identified a rare missense variant (rs751360195) at the IDO1 gene in a patient affected by coeliac disease, thyroiditis, and selective immunoglobulin A deficiency. Molecular and functional studies demonstrated that the substitution of lysine (K) at position 257 with a glutamic acid (E) results in an altered IDO1 protein that undergoes a rapid protein turnover. This genotype-to-phenotype relation is produced by peripheral blood mononuclear cells (PBMCs) of the patient bearing this variation and is associated with a specific phenotype (i.e., impaired tryptophan catabolism and defective mechanisms of immune tolerance). Thus decoding functional mutations of the IDO1 exome may provide clinically relevant information exploitable to personalize therapeutic interventions., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Thymoma is an uncommon slowly growing neoplasm. It usually presents with paraneoplastic syndromes including the immunodeficiency syndrome called Good syndrome and hematological disorders. Pure red cell aplasia is a well-recognized complication of thymoma, and aplastic anemia is very rare in association with GS. We report a case of GS in a heavily treated patient with stage IV thymoma associated with a pure red cell aplasia and an amegakaryocytic thrombocytopenia that evolved into an AA and provide an up-to-date review of the relevant literature. This is the first case of the association of GS and AA with the coexistence of a heavily treated stage IV thymoma. The fatal outcome was not related to the progression of the thymoma, but rather to the severe infectious complications. The combination of lymphopenia and hypogammaglobulinemia typical of GS, coupled to the neutropenia, caused by bone marrow failure, was the main predisposing factor for the unfavourable outcome., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Sofia Chiatamone Ranieri et al.)

The unbalanced translocation dic(1;7)(q10;p10) in myelodysplastic syndromes (MDS) is originated by centromeric juxtaposition resulting into 1q trisomy and 7q monosomy. More than half of cases arise after chemo/radio-therapy. To date, given the absence of genes within the centromeric regions, no specific molecular events have been identified in this cytogenetic subgroup. We performed the first comprehensive genetic and epigenetic analysis of MDS with dic(1;7)(q10;p10) compared to normal controls and therapy-related myeloid neoplasms (t-MNs). RNA-seq showed a unique downregulated signature in dic(1;7) cases, affecting more than 80% of differentially expressed genes. As revealed by pathway and gene ontology analyses, downregulation of ATP-binding cassette (ABC) transporters and lipid-related genes and upregulation of p53 signaling were the most relevant biological features of dic(1;7). Epigenetic supervised analysis revealed hypermethylation at intronic enhancers in the dicentric subgroup, in which low expression levels of enhancer putative target genes accounted for around 35% of the downregulated signature. Enrichment of Krüppel-like transcription factor binding sites emerged at enhancers. Furthermore, a specific hypermethylated pattern on 1q was found to underlie the hypo-expression of more than 50% of 1q-deregulated genes, despite trisomy. In summary, dic(1;7) in MDS establishes a specific transcriptional program driven by a unique epigenomic signature.

Objective: The most typical cytogenetic aberration in myelodysplastic syndromes is del(5q), which, when isolated, is associated with refractory anaemia and good prognosis. Based on high rates of erythroid response and transfusion independence, Lenalidomide (LEN) became the standard treatment. This multi-centre study was designed to supplement Italian Registry data on LEN by addressing prescription, administration appropriateness, haematological and cytogenetic responses and disease evolution., Methods: MORE study was an observational, non-interventional, multi-centre, retrospective and prospective study. Cases were recruited from 45 Haematological Centres throughout Italy. Data were collected from the Italian National Registry for Lenalidomide administration and supplemented by a MORE data form., Results: Data from 190/213 patients were analysed. In all, 149 had been diagnosed by conventional cytogenetics (GROUP A) and 41 only by FISH (GROUP B). Overall erythroid response was obtained in 92.8% of cases. Overall cytogenetic remission was achieved in 22.6% of cases. Disease progression occurred in 15.6% of cases. Clonal cytogenetic evolution characterised progression to AML but not to higher risk MDS., Conclusions: Erythroid response to Lenalidomide was similar in MDS with isolated del(5q) and with del(5q) plus one anomaly. Progression to AML or higher risk MDS showed different cytogenetic features., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Detection of anti-transglutaminase, anti-endomysium and anti-gliadin antibodies is commonly used to screen celiac disease patients. Besides that in serum, these antibodies are detectable in culture supernatants of oral, duodenal and colonic biopsy samples, saliva, gut lavage fluid samples, and fecal supernatants. Our aim was to extend the intestinal antibody pattern in fecal supernatants from patients with celiac disease., Methods: The fecal supernatants obtained from 25 celiac disease patients and 12 healthy volunteers were used to determine IgA and IgG1 anti-endomysium by immunofluorescence analysis, IgA and IgG anti-transglutaminase, IgA and IgG anti-deamidated gliadin peptides, IgA/IgG anti-transglutaminase/deamidated gliadin peptides and IgA anti-actin by enzyme-linked immunosorbent assay., Results: IgA anti-endomysium were found in 11 of 25 (44.0%) celiac disease patients and in none of healthy volunteers (p=0.0066). The levels of IgA anti-transglutaminase, IgA anti-deamidated gliadin peptides, IgA/IgG anti-transglutaminase/deamidated gliadin peptides and IgA anti-actin determined in celiac disease patients were significantly higher (p=0.0005, p=0.0018, p=0.0061 and p=0.0477, respectively) than those measured in healthy volunteers. The ROC curve analysis showed a diagnostic significance in IgA anti-transglutaminase (AUC=0.862, p<0.0001), IgA anti-deamidated gliadin peptides (AUC=0.822, p<0.0001) and IgA/IgG anti-transglutaminase/deamidated gliadin peptides (AUC=0.783, p=0.0003) fecal tests., Conclusions: Our data extend the intestinal antibody pattern detectable in fecal supernatants, thus increasing the knowledge in the humoral immunity of celiac disease. Further studies are needed to better evaluate the role of fecal antibody tests in identifying celiac disease patients., (Copyright © 2015 Elsevier GmbH. All rights reserved.)