Deciphering predictive factors for choice of thrombopoietin receptor agonist, treatment free responses, and thrombotic events in immune thrombocytopenia

Malalties hematològiques; Trastorns immunològicsEnfermedades hematológicas; Trastornos inmunológicosHaematological diseases; Immunological disordersVery few data exist on when a particular thrombopoietin-receptor agonist (TPO-RA) is favored in clinical practice for the treatment of patients with immune thrombocytopenia (ITP), about novel risk factors for vascular events (VE) with these drugs, nor about predictive factors for therapy free responses (TFR). We conducted an observational, retrospective, long-term follow-up multicenter study from November 2016 to January 2018 of 121 adult ITP patients initiating TPO-RA between January 2012 to December 2014. Data reflected that a platelet count ≤25 × 109/l at the time when the TPO-RA was initiated was associated with a 2.8 higher probability of receiving romiplostim vs. eltrombopag (P = 0.010). VE on TPO-RA was related to previous neoplasia in patients over 65 years (50% vs. 2.2%, P < 0.001), and to previous splenectomy in younger patients (100% vs. 33%, P = 0.001). Receiving romiplostim as first TPO-RA with no subsequent TPO-RA switching was associated with a 50% likelihood of TFR after 2.9 years of therapy (3.3 years in chronic ITP patients). These real-world data help deciphering some areas of uncertainty, and offer insight into some of the most relevant challenges of ITP which may help clinicians make appropriate treatment decisions in the management of adult ITP patients with TPO-RA

Biological effeects of new hydraulic materials on human periodontal ligament stem cells

Abstract: Background: The aim of this study was: to evaluate the biological properties of new hydraulic materials: Bio-C Repair and Bio-C Sealer. Methods: Periodontal ligament stem cells were exposed to several dilutions of Bio-C Repair and Bio-C Sealer. The ion release profile and pH were determined. Metabolic activity, cell migration and cell survival were assessed using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), wound-healing assays and Annexin assays, respectively. Cells were cultured in direct contact with the surface of each material. These were then analyzed via scanning electron microscopy (SEM) and energy dispersive X-ray (EDX). Statistical differences were assessed using a two-way ANOVA (α < 0.05). Results: Similar pH was observed in these cements. Bio-C Sealer released significantly more Ca and Si ions (p < 0.05) in comparison with Bio-C Repair. Undiluted Bio-C Sealer induced a significant reduction on cellular viability, cell survival and cell migration when compared to the control (p < 0.05). Moreover, SEM showed abundant cells adhered on Bio-C Repair and a moderate number of cells attached on Bio-C Sealer. Finally, EDX analysis identified higher percentages of Ca and O in the case of Bio-C repair than with Bio-C sealer, while other elements such as Zr and Si were more abundant in Bio-C sealer. Conclusions: Bio-C Repair displayed higher cell viability, cell adhesion and migration rates than Bio-C Sealer

TOMATO AGAMOUS1 and ARLEQUIN/TOMATO AGAMOUS-LIKE1 MADS-box genes have redundant and divergent functions required for tomato reproductive development

[EN] Within the tomato MADS-box gene family, TOMATO AGAMOUS1 (TAG1) and ARLEQUIN/TOMATO AGAMOUS LIKE1 (hereafter referred to as TAGL1) are, respectively, members of the euAG and PLE lineages of the AGAMOUS clade. They perform crucial functions specifying stamen and carpel development in the flower and controlling late fruit development. To gain insight into the roles of TAG1 and TAGL1 genes and to better understand their functional redundancy and diversification, we characterized single and double RNAi silencing lines of these genes and analyzed expression profiles of regulatory genes involved in reproductive development. Double RNAi lines did show cell abnormalities in stamens and carpels and produced extremely small fruit-like organs displaying some sepaloid features. Expression analyses indicated that TAG1 and TAGL1 act together to repress fourth whorl sepal development, most likely through the MACROCALYX gene. Results also proved that TAG1 and TAGL1 have diversified their functions in fruit development: while TAG1 controls placenta and seed formation, TAGL1 participates in cuticle development and lignin biosynthesis inhibition. It is noteworthy that both TAG1 and double RNAi plants lacked seed development due to abnormalities in pollen formation. This seedless phenotype was not associated with changes in the expression of B-class stamen identity genes Tomato MADS-box 6 and Tomato PISTILLATA observed in silencing lines, suggesting that other regulatory factors should participate in pollen formation. Taken together, results here reported support the idea that both redundant and divergent functions of TAG1 and TAGL1 genes are needed to control tomato reproductive development.This work was supported by the Spanish Ministry of Economy and Competitiveness (Grant Numbers AGL2012-40150-C03-01, AGL2012-40150-C03-02 and AGL2015-64991-C3-1-R); and the European Commission through the JAE-Doc Program of the Spanish National Research Council (CSIC) (Grant Number AGL2012-40150-C03-01 to B.P.).Giménez Caminero, ME.; Castañeda, L.; Pineda Chaza, BJ.; Pan, IL.; Moreno Ferrero, V.; Angosto, T.; Lozano, R. (2016). TOMATO AGAMOUS1 and ARLEQUIN/TOMATO AGAMOUS-LIKE1 MADS-box genes have redundant and divergent functions required for tomato reproductive development. Plant Molecular Biology. 91(4-5):513-531. https://doi.org/10.1007/s11103-016-0485-4S513531914-

Extracellular NK histones promote immune cell anti-tumor activity by inducing cell clusters through binding to CD138 receptor.

BACKGROUND: Natural killer (NK) cells are important anti-tumor cells of our innate immune system. Their anti-cancer activity is mediated through interaction of a wide array of activating and inhibitory receptors with their ligands on tumor cells. After activation, NK cells also secrete a variety of pro-inflammatory molecules that contribute to the final immune response by modulating other innate and adaptive immune cells. In this regard, external proteins from NK cell secretome and the mechanisms by which they mediate these responses are poorly defined. METHODS: TRANS-stable-isotope labeling of amino acids in cell culture (TRANS-SILAC) combined with proteomic was undertaken to identify early materials transferred between cord blood-derived NK cells (CB-NK) and multiple myeloma (MM) cells. Further in vitro and in vivo studies with knock-down of histones and CD138, overexpression of histones and addition of exogenous histones were undertaken to confirm TRANS-SILAC results and to determine functional roles of this material transferred. RESULTS: We describe a novel mechanism by which histones are actively released by NK cells early after contact with MM cells. We show that extracellular histones bind to the heparan sulfate proteoglycan CD138 on the surface of MM cells to promote the creation of immune-tumor cell clusters bringing immune and MM cells into close proximity, and thus facilitating not only NK but also T lymphocyte anti-MM activity. CONCLUSION: This study demonstrates a novel immunoregulatory role of NK cells against MM cells mediated by histones, and an additional role of NK cells modulating T lymphocytes activity that will open up new avenues to design future immunotherapy clinical strategies

PROPUESTAS METODOLÓGICAS PARA LA MATEMÁTICA SUPERIOR A DISTANCIA EN CONTABILIDAD Y FINANZAS

In the present work, the results of the application of the research methods that support the design of a methodological alternative that contributes to the improvement of the teaching-learning process of Higher Mathematics I in the distance modality in the career of Accounting are presented. Finance; in the Municipal University Center of Jagüey Grande, Matanzas, Cuba; academic courses 2019, 2020 and 2021; aimed at preparing the teacher to take on this challenge. The theoretical-methodological foundations are addressed, in correspondence with the preparation of teachers to face this challenge. A flexible alteEn el presente trabajo se presentan los resultados de la aplicación de los métodos de investigación que respaldan el diseño de propuestas como alternativa metodológica que contribuya al perfeccionamiento del proceso de enseñanza-aprendizaje de la Matemática Superior I en la modalidad a distancia en la carrera de Contabilidad y Finanzas; en el Centro Universitario Municipal de Jagüey Grande, Matanzas, Cuba; cursos académico 2019,2020 y 2021; orientada a la preparación del profesor para asumir este reto. Se abordan los fundamentos teórico-metodológicos, en correspondencia con la preparación de docentes para enfrentar este reto. Se proponen alternativas flexibles, que pueden ser enriquecidas por la creatividad de los docentes

PROPUESTAS METODOLÓGICAS PARA LA MATEMÁTICA SUPERIOR A DISTANCIA EN CONTABILIDAD Y FINANZAS

En el presente trabajo se presentan los resultados de la aplicación de los métodos de investigación que respaldan el diseño de propuestas como alternativa metodológica que contribuya al perfeccionamiento del proceso de enseñanza-aprendizaje de la Matemática Superior I en la modalidad a distancia en la carrera de Contabilidad y Finanzas; en el Centro Universitario Municipal de Jagüey Grande, Matanzas, Cuba; cursos académico 2019,2020 y 2021; orientada a la preparación del profesor para asumir este reto. Se abordan los fundamentos teórico-metodológicos, en correspondencia con la preparación de docentes para enfrentar este reto. Se proponen alternativas flexibles, que pueden ser enriquecidas por la creatividad de los docentes

Polymorphism analysis of the CTLA-4 gene in paracoccidioidomycosis patients

The CTLA-4 protein is expressed in activated T cells and plays an essential role in the immune response through its regulatory effect on T cell activation. Polymorphisms of the CTLA-4 gene have been correlated with autoimmune, neoplastic and infectious illnesses. This work aimed to verify possible associations between single nucleotide polymorphisms (SNPs) in CTLA-4, -318C/T in the promoter and +49A/G in exon 1 and paracoccidioidomycosis (PCM) caused by Paracoccidioides brasiliensis. For this purpose, 66 chronic form PCM patients and 76 healthy controls had their allele, genotype and haplotype frequencies determined. The genetic admixture structure of the patients and controls was evaluated to eliminate ancestral bias. The comparison of frequencies indicated no significant differences between patients and controls that could link the SNPs to PCM. Groups were admixture matched with no difference observed in population ancestry inference, indicating that the absence of association between CTLA-4 polymorphisms and PCM could not be attributed to ancestral bias. This study showed that there was no association between the CTLA-4 SNPs -318 and +49 and the resistance or susceptibility to PCM.22022

Prognostic stratification improvement by integrating ID1/ID3/IGJ gene expression signature and immunophenotypic profile in adult patients with B-ALL

Characteristics of pronostic groups according to EuroFlow immunophenotype. (TIFF 1364 kb

Elucidating the Mechanism of Action of the Attributed Immunomodulatory Role of Eltrombopag in Primary Immune Thrombocytopenia: An In Silico Approach

Intel·ligència artificial; Eltrombopag; Trombocitopènia immune primàriaInteligencia artificial; Eltrombopag; Trombocitopenia inmune primariaArtificial intelligence; Eltrombopag; Primary immune thrombocytopeniaEltrombopag is a thrombopoietin receptor (MPL) agonist approved for the treatment of primary immune thrombocytopenia (ITP). Recent evidence shows that some patients may sustain platelet counts following eltrombopag discontinuation. The systemic immunomodulatory response that resolves ITP in some patients could result from an increase in platelet mass, caused either by the direct action of eltrombopag on megakaryocytes through MPL stimulation, or potential MPL-independent actions on other cell types. To uncover the possible mechanisms of action of eltrombopag, in silico analyses were performed, including a systems biology-based approach, a therapeutic performance mapping system, and structural analyses. Through manual curation of the available bibliography, 56 key proteins were identified and integrated into the ITP interactome analysis. Mathematical models (94.92% mean accuracy) were obtained to elucidate potential MPL-dependent pathways in non-megakaryocytic cell subtypes. In addition to the effects on megakaryocytes and platelet numbers, the results were consistent with MPL-mediated effects on other cells, which could involve interferon-gamma, transforming growth factor-beta, peroxisome proliferator-activated receptor-gamma, and forkhead box protein P3 pathways. Structural analyses indicated that effects on three apoptosis-related proteins (BCL2L1, BCL2, BAX) from the Bcl-2 family may be off-target effects of eltrombopag. In conclusion, this study proposes new hypotheses regarding the immunomodulatory functions of eltrombopag in patients with ITP.This research was funded and promoted by Novartis, which contributed to setting up fundamental questions relevant for the study and reviewing the manuscript. However, the company did not have a role on study design, data collection, analysis, or interpretation