Nutrición parenteral domiciliaria en España, 2019: informe del Grupo de Nutrición Artificial Domiciliaria y Ambulatoria NADYA

RESUMEN Objetivo: comunicar los datos de nutrición parenteral domiciliaria (NPD) obtenidos del registro del grupo NADYA-SENPE (www.nadyasenpe.com) del año 2019. Material y métodos: análisis descriptivo de los datos recogidos de pacientes adultos y pediátricos con NPD en el registro NADYA-SENPE desde el 1 de enero al 31 de diciembre de 2019. Resultados: se registraron 283 pacientes (51,9 %, mujeres), 31 niños y 252 adultos procedentes de 47 hospitales españoles, lo que representa una tasa de prevalencia de 6,01 pacientes/millón de habitantes/año 2019. El diagnóstico más frecuente en los adultos fue “oncológico paliativo” y “otros” (21,0 %). En los niños fue la enfermedad de Hirschsprung junto a la enterocolitis necrotizante, las alteraciones de la motilidad intestinal y la pseudoobstrucción intestinal crónica, con 4 casos cada uno (12,9 %). El primer motivo de indicación fue el síndrome del intestino corto tanto en los niños (51,6 %) como en los adultos (37,3 %). El tipo de catéter más utilizado fue el tunelizado tanto en los niños (75,9 %) como en los adultos (40,8 %). Finalizaron 68 episodios, todos en adultos: la causa más frecuente fue el fallecimiento (54,4 %). Pasaron a la vía oral el 38,2 %. Conclusiones: el número de centros y profesionales colaboradores con el registro NADYA va incrementándose. Se mantienen estables las principales indicaciones y los motivos de finalización de la NPD

Systematic Collaborative Reanalysis of Genomic Data Improves Diagnostic Yield in Neurologic Rare Diseases

Altres ajuts: Generalitat de Catalunya, Departament de Salut; Generalitat de Catalunya, Departament d'Empresa i Coneixement i CERCA Program; Ministerio de Ciencia e Innovación; Instituto Nacional de Bioinformática; ELIXIR Implementation Studies (CNAG-CRG); Centro de Investigaciones Biomédicas en Red de Enfermedades Raras; Centro de Excelencia Severo Ochoa; European Regional Development Fund (FEDER).Many patients experiencing a rare disease remain undiagnosed even after genomic testing. Reanalysis of existing genomic data has shown to increase diagnostic yield, although there are few systematic and comprehensive reanalysis efforts that enable collaborative interpretation and future reinterpretation. The Undiagnosed Rare Disease Program of Catalonia project collated previously inconclusive good quality genomic data (panels, exomes, and genomes) and standardized phenotypic profiles from 323 families (543 individuals) with a neurologic rare disease. The data were reanalyzed systematically to identify relatedness, runs of homozygosity, consanguinity, single-nucleotide variants, insertions and deletions, and copy number variants. Data were shared and collaboratively interpreted within the consortium through a customized Genome-Phenome Analysis Platform, which also enables future data reinterpretation. Reanalysis of existing genomic data provided a diagnosis for 20.7% of the patients, including 1.8% diagnosed after the generation of additional genomic data to identify a second pathogenic heterozygous variant. Diagnostic rate was significantly higher for family-based exome/genome reanalysis compared with singleton panels. Most new diagnoses were attributable to recent gene-disease associations (50.8%), additional or improved bioinformatic analysis (19.7%), and standardized phenotyping data integrated within the Undiagnosed Rare Disease Program of Catalonia Genome-Phenome Analysis Platform functionalities (18%)

Tomar la palabra (II). Intertextualidad e intermedialidad como herramientas pedagógicas para la enseñanza de la literatura y otros discursos

Este proyecto explora las relaciones entre obras literarias y literatura y otras artes (música, pintura, fotografía, cine, etc.) como medio para desarrollar la competencia lectora y expresiva y estimular el disfrute literario en ámbito universitario

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2

Nutrición parenteral domiciliaria en España 2018. Informe del Grupo de Nutrición Artificial Domiciliaria y Ambulatoria NADYA

Aim: To communicate home parenteral nutrition (HPN) data obtained from the HPN registry of the NADYA-SENPE group (www.nadya-senpe.  com) for the year 2018. Material and methods: Descriptive analysis of the data collected from adult and pediatric patients with HPN in the NADYA-SENPE group registry from January 1st, 2018 to December 31st, 2018.  Results: There were 278 patients from 45 Spanish hospitals (54.7% women), 23 children and 255 adults, which represent a prevalence rate of 5.95 patients/million inhabitants/year 2018. The most frequent diagnosis in adults was “palliative cancer” (22.0%), followed by “others”. In children it was Hirschsprung’s disease together with necrotizing enterocolitis, with four cases (17.4%). The first indication was short bowel syndrome in both children (60.9%) and adults (35.7%). The most frequently used type of catheter was tunneled in both children (81.0%) and adults (41.1%). Ending 75 episodes, the most frequent cause was death (52.0%) and change to oral feeding (33.3%). Conclusions: The number of centers and collaborating professionals in the registry of patients receiving HPN remains stable, as well as the main indications and reasons for termination of HPN.Objetivo: comunicar los datos de nutrición parenteral domiciliaria (NPD) obtenidos del registro del grupo NADYA-SENPE (www.nadyasenpe. com) del año 2018. Material y métodos: análisis descriptivo de los datos recogidos de pacientes adultos y pediátricos con NPD en el registro NADYA-SENPE del 1 de enero al 31 de diciembre de 2018. Resultados: se registraron 278 pacientes (54,7% mujeres), 23 niños y 255 adultos, procedentes de 45 hospitales españoles, lo que representa una tasa de prevalencia de 5,95 pacientes/millón de habitantes/año 2018. El diagnóstico más frecuente en adultos fue “oncológico paliativo” (22,0%), seguido de “otros”. En niños fue la enfermedad de Hirschsprung junto con la enterocolitis necrotizante, con cuatro casos (17,4%). El primer motivo de indicación fue síndrome de intestino corto tanto en niños (60,9%) como en adultos (35,7%). El tipo de catéter más utilizado fue el tunelizado tanto en niños (81,0%) como en adultos (41,1%). Finalizaron 75 episodios, la causa más frecuente fue el fallecimiento (52,0%) y el paso a vía oral (33,3%). Conclusiones: el número de centros y profesionales colaboradores en el registro de pacientes que reciben NPD se mantiene estable, así como las principales indicaciones y los motivos de finalización de la NPD

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification

Functional implication of the calmodulin-binding domain of the adaptor protein Grb7

Tesis doctoral inédita realizada en el Instituto de Investigaciones Biológicas 'Alberto Sols' y leída en la Universidad Autónoma de Madrid. Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 13 de Julio de 201

Functional implication of the calmodulin-binding domain of the adaptor proteína Grb7

Tutor de la Tesis Doctoral: Mario Vallejo.The growth factor receptor bound protein 7 (Grb7) gives name to a mammalian adaptor protein family that also includes Grb10 and Grb14. As an adaptor protein, Grb7 mediates signal transduction events initiated by tyrosine kinase receptors present in the plasma membrane or other cytosolic kinases through its Src homology 2 (SH2) domain. Our laboratory previously described the presence of a calmodulin (CaM)‐binding domain (CaM‐BD) located in the proximal region of the pleckstrin homology (PH) domain of Grb7 and described that Grb7 was able to bind CaM in a Ca2+‐dependent manner both in vitro and in living cells. In this Thesis, we first described that the other Grb7 family members, Grb10 and Grb14, are also CaM‐binding proteins (CaM‐BP). To investigate the role that CaM plays in Grb7 functionality, we generated a deletion mutant lacking the CaM‐BD named Grb7Δ. We report the differential behavior in vitro and in vivo of cells expressing Grb7Δ, as compared to those expressing either its wild type counterpart or cells lacking expression of this adaptor protein. Our results showed that deletion of the CaM‐BD resulted in a lower cell migration rate, impaired cell adhesion ability to the extracellular matrix, and a lower proliferation rate. Additionally, we demonstrated that Grb7Δ was unable to localize in the nuclear fraction and that inhibition of CaM favored the nuclear localization of wild type Grb7. Therefore, we proposed that the CaM‐BD of Grb7 overlapped its nuclear localization sequence (NLS). Besides, we performed in vivo experiments to study the role of the CaM‐BD of Grb7 in tumor growth and tumor‐associated angiogenesis by implanting glioma C6 cells stably expressing EYFP, EYFP‐Grb7 or EYFP‐Grb7Δ in the brain of rats and monitoring the tumor growth and its associated angiogenesis using Magnetic Resonance Imaging (MRI). We found that tumors generated by EYFP‐Grb7Δ‐expressing cells were smaller and less vascularized than those grown from cells expressing its wild type EYFPGrb7 counterpart or EYFP‐expressing control cells, suggesting an anti‐angiogenic effect of the mutant protein. Finally, using co‐immunoprecipitation and Mass Spectrometry‐based proteomics, we described novel Grb7 and/or Grb7Δ binding partners. We validated by Western blot Hsc70 (heat shock cognate 70 protein) and caprin‐1 (cytoplasmic activation/proliferation‐associated protein‐1) as Grb7 and Grb7Δ associated partners, and Nedd4 (neural precursor cell expressed developmentally down‐regulated protein 4) as a Grb7 binding partner.Este trabajo ha sido realizado en el Departamento de Biología del Cáncer del Instituto de Investigaciones Biomédicas “Alberto Sols” (CSICUAM), gracias a una Ayuda a la Formación del Profesorado Universitario (FPU) del Ministerio de Educación.Peer Reviewe

Calmodulin regulates the translocation of Grb7 into the nucleus

We describe in this report the presence of a nuclear localization signal (NLS) overlapping the calmodulin-binding domain (CaM-BD) of the growth factor receptor bound protein 7 (Grb7). We show that deletion of the CaM-BD of Grb7 prevents its nuclear localization, and that its Src homology 2 (SH2) domain might participate as well in the translocation process. Also, treating cells with the CaM antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) enhances the presence of Grb7 in the nucleus. We propose that CaM inhibits the translocation of Grb7 to the nucleus after binding to its CaM-BD and therefore occluding its overlapping NLS.This work was financed by grants (to A.V.) from the Secretaría de Estado de Investigación, Desarrollo e Innovación (SAF2011-23494), the European Commission (contract PITN-GA-2011-289033), and the Consejería de Educación de la Comunidad de Madrid (S2011/BMD-2349). IG-P was supported by a predoctoral fellowship from the Ministerio de Ciencia e Innovación.Peer Reviewe