New Cases and Mutations in SEC23B Gene Causing Congenital Dyserythropoietic Anemia Type II

Hereditary anemias; Ineffective erythropoiesis; Rare blood diseaseAnèmies hereditàries; Eritropoesi ineficaç; Malaltia rara de la sangAnemias hereditarias; Eritropoyesis ineficaz; Enfermedad rara de la sangreCongenital dyserythropoietic anemia type II (CDA II) is an inherited autosomal recessive blood disorder which belongs to the wide group of ineffective erythropoiesis conditions. It is characterized by mild to severe normocytic anemia, jaundice, and splenomegaly owing to the hemolytic component. This often leads to liver iron overload and gallstones. CDA II is caused by biallelic mutations in the SEC23B gene. In this study, we report 9 new CDA II cases and identify 16 pathogenic variants, 6 of which are novel. The newly reported variants in SEC23B include three missenses (p.Thr445Arg, p.Tyr579Cys, and p.Arg701His), one frameshift (p.Asp693GlyfsTer2), and two splicing variants (c.1512-2A>G, and the complex intronic variant c.1512-3delinsTT linked to c.1512-16_1512-7delACTCTGGAAT in the same allele). Computational analyses of the missense variants indicated a loss of key residue interactions within the beta sheet and the helical and gelsolin domains, respectively. Analysis of SEC23B protein levels done in patient-derived lymphoblastoid cell lines (LCLs) showed a significant decrease in SEC23B protein expression, in the absence of SEC23A compensation. Reduced SEC23B mRNA expression was only detected in two probands carrying nonsense and frameshift variants; the remaining patients showed either higher gene expression levels or no expression changes at all. The skipping of exons 13 and 14 in the newly reported complex variant c.1512-3delinsTT/c.1512-16_1512-7delACTCTGGAAT results in a shorter protein isoform, as assessed by RT-PCR followed by Sanger sequencing. In this work, we summarize a comprehensive spectrum of SEC23B variants, describe nine new CDA II cases accounting for six previously unreported variants, and discuss innovative therapeutic approaches for CDA II.This work was supported by NEOTEC grant SNEO-20191246 from Spanish CDTI to C.T., RETOS COLABORACION grant RTC2019-007074-1 from: MCIN/AEI/10.13039/501100011033 from Spanish Ministry of Science and Innovation (MICINN) to C.T. and M.S.; ARETHA grant PID2021-122436OB-I00 funded by MCIN/AEI/10.13039/501100011033 to M.S.; RTI-2018-101735-B-I100 from MCIN/AEI/10.13039/501100011033/ERDF “A way to make Europe” from the Spanish Ministry of Science and Innovation (MICINN) to M.S. M.M.M. is supported by a Marie Curie Fellowship from the European Commission under Horizon 2020 Framework Program Project: 894737. G.H. is supported by funds provided by the APU and ADISCON patient associations. L.R.-C. holds an FI-AGAUR predoctoral fellowship (2020FI-B00038) from Generalitat de Catalunya. X.F.-C. is partially supported by funds provided by the grant RTI-2018-101735-B-I100 from MCIN/AEI/10.13039/501100011033/ERDF “A way to make Europe”. V.V. was supported by funds provided by APU and ADISCON patient associations and UIC postdoctoral scholarship; she is currently supported by funds provided by RETOS COLABORACION grant RTC2019-007074-1 from MCIN/AEI/10.13039/501100011033 from Spanish Ministry of Science and Innovation (MICINN)

High frequency of low-count monoclonal B-cell lymphocytosis in hospitalized COVID-19 patients

Low-count monoclonal B-cell lymphocytosis (MBLlo, <500 clonal B-cells/μL) is a highly prevalent condition in the general population (4% to 16% of otherwise healthy adults), which increases significantly with age.1-7 In most cases, clonal B-cells share phenotypic and cytogenetic features with chronic lymphocytic leukemia (CLL), but only a small fraction (≈1.8%) progresses to high-count MBL (MBLhi; ≥500 and <5000 clonal B-cells/μL)3 in the medium-term.8 However, previous reports showed that MBLlo subjects had an increased risk of severe infections in association with a (predominantly) secondary antibody deficiency,8-10 suggesting that MBLlo might be a risk marker for developing more severe infections.This work was supported by the Instituto de Salud Carlos III (Ministerio de Ciencia e Innovación, Madrid, Spain, and FONDOS FEDER (a way to build Europe) grants CB16/12/00400 (CIBERONC), COV20/00386, and PI17/00399; the Consejería de Educación and the Gerencia Regional de Salud, Consejería de Sanidad from Junta de Castilla y León (Valladolid, Spain) grants SA109P20 and GRS-COVID-33/A/20; the European Regional Development Fund (INTERREG POCTEP Spain-Portugal) grant 0639-IDIAL-NET-3-3; and the CRUK (United Kingdom), Fundación AECC (Spain), and Associazione Italiana per la Ricerca Sul Cancro (Italy) “Early Cancer Research Initiative Network on MBL (ECRINM3)” ACCELERATOR award. G.O.-A. is supported by a grant from the Consejería de Educación, Junta de Castilla y León (Valladolid, Spain); B.F.-H. was supported by grant 0639-IDIAL-NET-3-3.Peer reviewe

B-cell regeneration profile and minimal residual disease status in bone marrow of treated multiple myeloma patients

Simple Summary B-cell regeneration during therapy has been associated with the outcome of multiple myeloma (MM) patients. However, the effects of therapy and hemodilution in bone marrow (BM) B-cell recovery have not been systematically evaluated. Here, we show that hemodilution is present in a significant fraction of MM BM samples, leading to lower total B-cell, B-cell precursor (BCP), and normal plasma cell (nPC) counts. Among MM BM samples, decreased percentages (vs. healthy donors) of BCP, transitional/naive B-cell (TBC/NBC) and nPC populations were observed at diagnosis. BM BCP, but not TBC/NBC, increased after induction therapy. At day+100 post-autolo-gous stem cell transplantation, a greater increase in BCP with recovered TBC/NBC numbers but persistently low memory B-cell and nPC counts were found. At the end of therapy, complete response (CR) BM samples showed higher CD19(-) nPC counts vs. non-CR specimens with no clear association between BM B-cell regeneration profiles and patient outcomes. B-cell regeneration during therapy has been considered as a strong prognostic factor in multiple myeloma (MM). However, the effects of therapy and hemodilution in bone marrow (BM) B-cell recovery have not been systematically evaluated during follow-up. MM (n = 177) and adult (>= 50y) healthy donor (HD; n = 14) BM samples were studied by next-generation flow (NGF) to simultaneously assess measurable residual disease (MRD) and residual normal B-cell populations. BM hemodilution was detected in 41 out of 177 (23%) patient samples, leading to lower total B-cell, B-cell precursor (BCP) and normal plasma cell (nPC) counts. Among MM BM, decreased percentages (vs. HD) of BCP, transitional/naive B-cell (TBC/NBC) and nPC populations were observed at diagnosis. BM BCP increased after induction therapy, whereas TBC/NBC counts remained abnormally low. At day+100 postautologous stem cell transplantation, a greater increase in BCP with recovered TBC/NBC cell numbers but persistently low memory B-cell and nPC counts were found. At the end of therapy, complete response (CR) BM samples showed higher CD19(-) nPC counts vs. non-CR specimens. MRD positivity was associated with higher BCP and nPC percentages. Hemodilution showed a negative impact on BM B-cell distribution. Different BM B-cell regeneration profiles are present in MM at diagnosis and after therapy with no significant association with patient outcome

Assessment of flesh browning diversity in apple germplasm collections phenotyped by image analysis

Enzymatic flesh browning (EB) is one of the major problems affecting the quality and limiting the shelf life of minimally processed fruit. Traditionally, EB has been measured objectively using colourimeters. However, colourimeters are not suitable for phenotyping large quantities of fruit samples as they measure just one small area of a sample at a time, which hampers the acquisition of representative measurements and renders them time-consuming and costly. Previous research has shown that image analysis of digital photographs could be a viable alternative to obtain colour information of the entire surface of samples for large scale phenotyping, but to date there are no references for its practical application. The aim of this work was to assess the diversity in EB in a large set of cultivars phenotyped using digital photographs and a high-throughput analytical system based on image analysis developed by our team. A set of 143 cultivars from 104 genotypes, including modern references (16 cultivars) and traditional Spanish cultivars from UPNA (67 cultivars) and CITA (60 cultivars) germplasm collections was analysed in 2020 and 2021. The traditional cultivars were part of the core collection, which optimizes the representativeness of the genetic variation of apples preserved in Spanish collections. EB was evaluated in 10 fruits per cultivar and photographed at regular intervals from just after cutting to one hour later. A wide range of EB intensities was observed, with up to 20-fold differences between cultivars, which could be classified into five levels using two indices. The time at which EB was evaluated (30 or 60 min after slicing) had little influence on the classification. Traditional cultivars with low or very low EB were found to be comparable to those of references with less EB. The results show the potential of traditional germplasm to diversify the varietal offer and introduce new traits in apple breeding.This research has been funded by INIA project RTA2015-00052-C02-00 and project PID2019-108081RR-C22 (APPLECUT) funded by MCIN/ AEI /10.13039/501100011033

New Cases and Mutations in <i>SEC23B</i> Gene Causing Congenital Dyserythropoietic Anemia Type II

Congenital dyserythropoietic anemia type II (CDA II) is an inherited autosomal recessive blood disorder which belongs to the wide group of ineffective erythropoiesis conditions. It is characterized by mild to severe normocytic anemia, jaundice, and splenomegaly owing to the hemolytic component. This often leads to liver iron overload and gallstones. CDA II is caused by biallelic mutations in the SEC23B gene. In this study, we report 9 new CDA II cases and identify 16 pathogenic variants, 6 of which are novel. The newly reported variants in SEC23B include three missenses (p.Thr445Arg, p.Tyr579Cys, and p.Arg701His), one frameshift (p.Asp693GlyfsTer2), and two splicing variants (c.1512-2A>G, and the complex intronic variant c.1512-3delinsTT linked to c.1512-16_1512-7delACTCTGGAAT in the same allele). Computational analyses of the missense variants indicated a loss of key residue interactions within the beta sheet and the helical and gelsolin domains, respectively. Analysis of SEC23B protein levels done in patient-derived lymphoblastoid cell lines (LCLs) showed a significant decrease in SEC23B protein expression, in the absence of SEC23A compensation. Reduced SEC23B mRNA expression was only detected in two probands carrying nonsense and frameshift variants; the remaining patients showed either higher gene expression levels or no expression changes at all. The skipping of exons 13 and 14 in the newly reported complex variant c.1512-3delinsTT/c.1512-16_1512-7delACTCTGGAAT results in a shorter protein isoform, as assessed by RT-PCR followed by Sanger sequencing. In this work, we summarize a comprehensive spectrum of SEC23B variants, describe nine new CDA II cases accounting for six previously unreported variants, and discuss innovative therapeutic approaches for CDA II

Didáctica de las ciencias sociales para Educación Infantil

Resumen basado en el de la publicaciónSe presenta un manual adecuado a los nuevos planes de estudio de Maestro Educación Infantil. Su diseño y elaboración responde a una doble necesidad: por un lado, debido al cambio de los currículos escolares de Educación Infantil a partir de 2007-2008, se hace necesaria una actualización de los manuales universitarios orientados a la formación de futuros maestros. Por otro lado, este hecho coincide con un cambio en los planes de estudio en la Universidad española, ya que de una diplomatura de tres cursos, se ha pasado a un grado de cuatro años a la par que las especialidades se reducen a dos. Para dar respuesta a tan perentoria necesidad nace esta obra, fruto de la reflexión de trece experimentados profesores pertenecientes al CEIP de Ateca (Zaragoza) y a nueve universidades distintas. Se muestran ejemplos y actividades que permiten aplicar los conceptos y teorías a la realidad diaria de las aulas de infantil.AragónBiblioteca de Educación del Ministerio de Educación, Cultura y Deporte; Calle San Agustín, 5 - 3 planta; 28014 Madrid; Tel. +34917748000; [email protected]

Treatments for multi-system inflammatory syndrome in children - discharge, fever, and second-line therapies.

Scarce evidence exists about the best treatment for multi-system inflammatory syndrome (MIS-C). We analyzed the effects of steroids, intravenous immunoglobulin (IVIG), and their combination on the probability of discharge over time, the probability of switching to second-line treatment over time, and the persistence of fever 2 days after treatment. We did a retrospective study to investigate the effect of different treatments on children with MIS-C from 1 March 2020 to 1 June 2021. We estimated the time-to-event probability using a Cox model weighted by propensity score to balance the baseline characteristics. Thirty of 132 (22.7%) patients were initially treated with steroids alone, 29/132 (21.9%) with IVIG alone, and 73/132 (55%) with IVIG plus steroids. The probability of early discharge was higher with IVIG than with IVIG plus steroids (hazard ratio [HR] 1.65, 95% CI 1.11-2.45, p = 0.013), but with a higher probability of needing second-line therapy compared to IVIG plus steroids (HR 3.05, 95% CI 1.12-8.25, p = 0.028). Patients on IVIG had a higher likelihood of persistent fever than patients on steroids (odds ratio [OR] 4.23, 95% CI 1.43-13.5, p = 0.011) or on IVIG plus steroids (OR 4.4, 95% CI 2.05-9.82, p

Basophil-lineage commitment in acute promyelocytic leukemia predicts for severe bleeding after starting therapy.

Severe hemorrhagic events occur in a significant fraction of acute promyelocytic leukemia patients, either at presentation and/or early after starting therapy, leading to treatment failure and early deaths. However, identification of independent predictors for high-risk of severe bleeding at diagnosis, remains a challenge. Here, we investigated the immunophenotype of bone marrow leukemic cells from 109 newly diagnosed acute promyelocytic leukemia patients, particularly focusing on the identification of basophil-related features, and their potential association with severe bleeding episodes and patient overall survival.From all phenotypes investigated on leukemic cells, expression of the CD203c and/or CD22 basophil-associated markers showed the strongest association with the occurrence and severity of bleeding (p ≤ 0.007); moreover, aberrant expression of CD7, coexpression of CD34+/CD7+ and lack of CD71 was also more frequently found among patients with (mild and severe) bleeding at baseline and/or after starting treatment (p ≤ 0.009). Multivariate analysis showed that CD203c expression (hazard ratio: 26.4; p = 0.003) and older age (hazard ratio: 5.4; p = 0.03) were the best independent predictors for cumulative incidence of severe bleeding after starting therapy. In addition, CD203c expression on leukemic cells (hazard ratio: 4.4; p = 0.01), low fibrinogen levels (hazard ratio: 8.8; p = 0.001), older age (hazard ratio: 9.0; p = 0.002), and high leukocyte count (hazard ratio: 5.6; p = 0.02) were the most informative independent predictors for overall survival.In summary, our results show that the presence of basophil-associated phenotypic characteristics on leukemic cells from acute promyelocytic leukemia patients at diagnosis is a powerful independent predictor for severe bleeding and overall survival, which might contribute in the future to (early) risk-adapted therapy decisions

III Premio Nacional de Educación para el Desarrollo "Vicente Ferrer" 2011 : buenas prácticas

La Agencia Española de Cooperación Internacional para el Desarrollo (AECID) junto con el Ministerio de Educación convoca anualmente los premios de educación para el desarrollo que están dirigidos a todos los centros docentes españoles sostenidos con fondos públicos que impartan educación infantil, educación primaria, educación secundaria obligatoria, bachillerato y formación profesional. Se recogen las buenas prácticas de los docentes premiados en esta segunda edición. Docentes que en el ejercicio de su función educadora han convertido el proceso educativo en un proceso dinámico e interactivo que permite al alumnado desarrollar un conocimiento crítico de nuestro mundo. Profesores y profesoras que han estimulado la participación del alumnado en la construcción de estructuras sociales más justas y solidarias, y han promovido actuaciones basadas en el principio de la corresponsabilidad de todos los actores implicados.ES