Yttria and Ceria Doped Zirconia Thin Films Grown by Pulsed Laser Deposition

The Yttria stabilized Zirconia (YSZ) is a standard electrolyte for solid oxide fuel cells (SOFCs), which are potential candidates for next generation portable and mobile power sources. YSZ electrolyte thin films having a cubic single phase allow reducing the SOFC operating temperature without diminishing the electrochemical power density. Films of 8 mol % Yttria stabilized Zirconia (8YSZ) and films with addition of 4 weight % Ceria (8YSZ + 4CeO2) were grown by pulsed laser deposition (PLD) technique using 8YSZ and 8YSZ + 4CeO2 targets and a Nd-YAG laser (355 nm). Films have been deposited on Soda-Calcia-Silica glass and Si(100) substrates at room temperature. The morphology and structural characteristics of the samples have been studied by means of X-ray diffraction and scanning electron microscopy. Films of a cubic-YSZ single phase with thickness in the range of 1-3 µm were grown on different substrates.Fil: Saporiti, F.. Universidad de Buenos Aires. Facultad de Ingeniería. Departamento de Ingeniería Mecánica. Grupo de Materiales Avanzados; Argentina;Fil: Juarez, R. E.. Universidad de Buenos Aires. Facultad de Ingeniería. Departamento de Ingeniería Mecánica. Grupo de Materiales Avanzados; Argentina;Fil: Audebert, Fernando Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Tecnologías y Ciencias de la Ingeniería; Argentina; Universidad de Buenos Aires. Facultad de Ingeniería. Departamento de Ingeniería Mecánica. Grupo de Materiales Avanzados; Argentina;Fil: Boudard, M.. Centre National de la Recherche Scientifique. Laboratoire des Matériaux et du Génie Physique; Francia

SLC6A14, a Pivotal Actor on Cancer Stage: When Function Meets Structure

SLC6A14 (ATB0,+) is a sodium- and chloride-dependent neutral and dibasic amino acid transporter that regulates the distribution of amino acids across cell membranes. The transporter is overexpressed in many human cancers characterized by an increased demand for amino acids; as such, it was recently acknowledged as a novel target for cancer therapy. The knowledge on the molecular mechanism of SLC6A14 transport is still limited, but some elegant studies on related transporters report the involvement of the 12 transmembrane \u3b1-helices in the transport mechanism, and describe structural rearrangements mediated by electrostatic interactions with some pivotal gating residues. In the present work, we constructed a SLC6A14 model in outward-facing conformation via homology modeling and used molecular dynamics simulations to predict amino acid residues critical for substrate recognition and translocation. We docked the proteinogenic amino acids and other known substrates in the SLC6A14 binding site to study both gating regions and the exposed residues involved in transport. Interestingly, some of these residues correspond to those previously identified in other LeuT-fold transporters; however, we could also identify a novel relevant residue with such function. For the first time, by combined approaches of molecular docking and molecular dynamics simulations, we highlight the potential role of these residues in neutral amino acid transport. This novel information unravels new aspects of the human SLC6A14 structure-function relationship and may have important outcomes for cancer treatment through the design of novel inhibitors of SLC6A14-mediated transport

Surface Plasmon Resonance as a Tool for Ligand Binding Investigation of Engineered GPR17 Receptor, a G Protein Coupled Receptor Involved in Myelination

The aim of this study was to investigate the potential of surface plasmon resonance (SPR) spectroscopy for the measurement of real-time ligand-binding affinities and kinetic parameters for GPR17, a G protein-coupled receptor (GPCR) of major interest in medicinal chemistry as potential target in demyelinating diseases. The receptor was directly captured, in a single-step, from solubilized membrane extracts on the sensor chip through a covalently bound anti-6x-His-antibody and retained its ligand binding activity for over 24h. Furthermore, our experimental setup made possible, after a mild regeneration step, to remove the bound receptor without damaging the antibody, and thus to reuse many times the same chip. Two engineered variants of GPR17, designed for crystallographic studies, were expressed in insect cells, extracted from crude membranes and analyzed for their binding with two high affinity ligands: the antagonist Cangrelor and the agonist Asinex 1. The calculated kinetic parameters and binding constants of ligands were in good agreement with those reported from activity assays and highlighted a possible functional role of the N-terminal residues of the receptor in ligand recognition and binding. Validation of SPR results was obtained by docking and molecular dynamics of GPR17-ligands interactions and by functional in vitro studies. The latter allowed us to confirm that Asinex 1 behaves as GPR17 receptor agonist, inhibits forskolin-stimulated adenylyl cyclase pathway and promotes oligodendrocyte precursor cell maturation and myelinating ability

Donor Lymphocyte Infusions After Allogeneic Stem Cell Transplantation in Acute Leukemia: A Survey From the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

We conducted a retrospective multicenter study including pediatric and adult patients with acute leukemia (AL) who received donor lymphocyte infusions (DLIs) after allogeneic hematopoietic stem cell transplantation (HCT) between January 1, 2010 and December 31, 2015, in order to determine the efficacy and toxicity of the immune treatment. Two hundred fifty-two patients, median age 45.1 years (1.6\u201373.4), were enrolled from 34 Italian transplant centers. The underlying disease was acute myeloid leukemia in 180 cases (71%). Donors were HLA identical or 1 locus mismatched sibling (40%), unrelated (40%), or haploidentical (20%). The first DLI was administered at a median time of 258 days (55\u20133,784) after HCT. The main indication for DLI was leukemia relapse (73%), followed by mixed chimerism (17%), and pre-emptive/prophylactic use (10%). Ninety-six patients (38%) received one single infusion, whereas 65 (26%), 42 (17%), and 49 patients (19%) received 2, 3, or 654 infusions, respectively, with a median of 31 days between two subsequent DLIs. Forty percent of evaluable patients received no treatment before the first DLI, whereas radiotherapy, conventional chemotherapy or targeted treatments were administered in 3, 39, and 18%, respectively. In informative patients, a few severe adverse events were reported: grade III\u2013IV graft versus host disease (GVHD) (3%), grade III\u2013IV hematological toxicity (11%), and DLI-related mortality (9%). Forty-six patients (18%) received a second HCT after a median of 232 days (32\u20131,390) from the first DLI. With a median follow-up of 461 days (2\u20133,255) after the first DLI, 1-, 3-, and 5- year overall survival (OS) of the whole group from start of DLI treatment was 55, 39, and 33%, respectively. In multivariate analysis, older recipient age, and transplants from haploidentical donors significantly reduced OS, whereas DLI for mixed chimerism or as pre-emptive/prophylactic treatment compared to DLI for AL relapse and a schedule including more than one DLI significantly prolonged OS. This GITMO survey confirms that DLI administration in absence of overt hematological relapse and multiple infusions are associated with a favorable outcome in AL patients. DLI from haploidentical donors had a poor outcome and may represent an area of further investigation

The Impact of Graft CD3 Cell/Regulatory T Cell Ratio on Acute Graft-versus-Host Disease and Post-Transplantation Outcome: A Prospective Multicenter Study of Patients with Acute Leukemia Undergoing Allogeneic Peripheral Blood Stem Cell Transplantation

Although it is well known that tumor site- or bone marrow-infiltrating regulatory T cells (Tregs) might be correlated with worse outcomes in solid tumors and acute leukemias by promoting immune surveillance escape, their contribution to the immediate post-allogeneic transplantation phase by peripheral blood (PB) allografts remains unclear. Moreover, the Treg content in stem cells harvested from PB has been suggested to be correlated with acute graft versus-host-disease (aGVHD) and immunologic recovery after allogeneic PB stem cell transplantation (allo-PBSCT). This study aimed to investigate the impact of the graft content of Tregs, as graft CD3+/Tregs ratio (gCD3/TregsR), on acute GVHD and post-allo-PBSCT outcomes. We prospectively enrolled 94 consecutive patients at 9 Italian centers of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) with acute myelogenous (n = 71; 75%) or lymphoblastic (n = 23; 25%) leukemia in complete remission who underwent matched related donor (n = 35; 37%) or unrelated donor (n = 59; 63%) allo-PBSCT. The median graft CD3+ cell, Treg, and gCD3/TregsR values were 196 × 106/kg body weight (range, 17 to 666 × 106/kg), 3 × 106/kg (range, 0.1 to 35 × 106/kg), and 71 (range, 1 to 1883), respectively. The discriminatory power of the gCD3/TregsR value to predict grade ≥II aGVHD was assessed by estimating the area under the receiver operating characteristic (ROC) curve (AUC). Any grade and grade ≥II aGVHD occurred in 24 (26%) and 17 (18%) allo-PBSCT recipients, respectively. By ROC analysis, AUC (0.74; 95% confidence interval [CI], 0.608 to 0.866; P =.002) identified 70 as the optimal gCD3/TregsR cutoff value predicting the appearance of grade ≥II aGVHD with 76% sensitivity and 71% specificity. Patients were subdivided into a high (ROC curve value ≥70) gCD3/TregsR group (HR; n = 48) and a low (ROC curve value <70) gCD3/TregsR group (LR; n = 46). The incidence of grade II-IV aGVHD was lower in the LR group compared with the HR group (9% [4 of 46] versus 27% [13 of 48]) in both univariate analysis (odds ratio [OR], 4.8; 95% CI, 1.44 to 16.17; P =.015) and multivariate analysis (OR, 5.0; 95% CI, 1.34 to 18.93; P =.017), whereas no differences were documented taking into account aGVHD of any grade. The overall survival, disease-free survival, nonrelapse mortality, and relapse rates at 2 and 3 years were 61% and 54%, 62% and 55%, 15% and 23%, and 27% and 30%, respectively. Of note, gCD3/TregsR did not significantly correlate with relapse (P =.135). Taken together, our data from this prospective multicenter study confirm the value of Tregs in preventing aGVHD while maintaining the graft-versus-leukemia effect. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc

Severe fludarabine neurotoxicity after reduced intensity conditioning regimen to allogeneic hematopoietic stem cell transplantation: a case report

We present a case of severe, irreversible neurotoxicity in a 55-year-old-patient with myelofibrosis undergoing hematopoietic stem cell transplantation following a reduced intensity conditioning including fludarabine. The patient developed progressive sensory-motor, visual and consciousness disturbances, eventually leading to death. MRI imaging pattern was unique and attributable to fludarabine neurotoxicit

A trait-based framework for seagrass ecology: Trends and prospects

In the last three decades, quantitative approaches that rely on organism traits instead of taxonomy have advanced different fields of ecological research through establishing the mechanistic links between environmental drivers, functional traits, and ecosystem functions. A research subfield where trait-based approaches have been frequently used but poorly synthesized is the ecology of seagrasses; marine angiosperms that colonized the ocean 100M YA and today make up productive yet threatened coastal ecosystems globally. Here, we compiled a comprehensive trait-based response-effect framework (TBF) which builds on previous concepts and ideas, including the use of traits for the study of community assembly processes, from dispersal and response to abiotic and biotic factors, to ecosystem function and service provision. We then apply this framework to the global seagrass literature, using a systematic review to identify the strengths, gaps, and opportunities of the field. Seagrass trait research has mostly focused on the effect of environmental drivers on traits, i.e., “environmental filtering” (72%), whereas links between traits and functions are less common (26.9%). Despite the richness of trait-based data available, concepts related to TBFs are rare in the seagrass literature (15% of studies), including the relative importance of neutral and niche assembly processes, or the influence of trait dominance or complementarity in ecosystem function provision. These knowledge gaps indicate ample potential for further research, highlighting the need to understand the links between the unique traits of seagrasses and the ecosystem services they provide

Busulfan or Treosulfan Conditioning Platform for Allogeneic Stem Cell Transplantation in Patients Aged >60 y with Acute Myeloid Leukemia/Myelodysplastic Syndrome: A Subanalysis of the GITMO AlloEld Study

Background. The conditioning regimens with different alkylators at different doses can influence the outcome of allogeneic stem cell transplantation (SCT), but conclusive data are missing. Methods. With the aim to analyze real-life allogeneic SCTs performed in Italy between 2006 and 2017 in elderly patients (aged >60 y) with acute myeloid leukemia or myelodysplastic syndrome, we collected 780 first transplants data. For analysis purposes, patients were grouped according to the type of alkylator included in the conditioning (busulfan [BU]-based; n = 618; 79%; treosulfan [TREO]-based; n=162; 21%). Results. No significant differences were observed in nonrelapse mortality, cumulative incidence of relapse, and overall survival, although in the TREO-based group, we observed a greater proportion of elderly patients (P < 0.001); more active diseases at the time of SCT (P < 0.001); a higher prevalence of patients with either hematopoietic cell transplantation-comorbidity index ≥3 (P < 0.001) or a good Karnofsky performance status (P = 0.025); increased use of peripheral blood stem cells as graft sources (P < 0.001); and greater use of reduced intensity conditioning regimens (P = 0.013) and of haploidentical donors (P < 0.001). Moreover, the 2-y cumulative incidence of relapse with myeloablative doses of BU was significantly lower than that registered with reduced intensity conditioning (21% versus 31%; P = 0.0003). This was not observed in the TREO-based group. Conclusions. Despite a higher number of risk factors in the TREO group, no significant differences were observed in nonrelapse mortality, cumulative incidence of relapse, and overall survival according to the type of alkylator, suggesting that TREO has no advantage over BU in terms of efficacy and toxicity in acute myeloid leukemia and myelodysplastic syndrome