The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis

The accurate repair of DNA double-strand breaks (DSBs), highly toxic DNA lesions, is crucial for genome integrity and is tightly regulated during the cell cycle. In mitosis, cells inactivate DSB repair in favor of a tethering mechanism that stabilizes broken chromosomes until they are repaired in the subsequent cell cycle phases. How this is achieved mechanistically is not yet understood, but the adaptor protein TOPBP1 is critically implicated in this process. Here, we identify CIP2A as a TOPBP1-interacting protein that regulates TOPBP1 localization specifically in mitosis. Cells lacking CIP2A display increased radio-sensitivity, micronuclei formation and chromosomal instability. CIP2A is actively exported from the cell nucleus in interphase but, upon nuclear envelope breakdown at the onset of mitosis, gains access to chromatin where it forms a complex with MDC1 and TOPBP1 to promote TOPBP1 recruitment to sites of mitotic DSBs. Collectively, our data uncover CIP2A-TOPBP1 as a mitosis-specific genome maintenance complex

Benefit-risk profile of cytoreductive drugs along with antiplatelet and antithrombotic therapy after transient ischemic attack or ischemic stroke in myeloproliferative neoplasms

We analyzed 597 patients with myeloproliferative neoplasms (MPN) who presented transient ischemic attacks (TIA, n = 270) or ischemic stroke (IS, n = 327). Treatment included aspirin, oral anticoagulants, and cytoreductive drugs. The composite incidence of recurrent TIA and IS, acute myocardial infarction (AMI), and cardiovascular (CV) death was 4.21 and 19.2%, respectively at one and five years after the index event, an estimate unexpectedly lower than reported in the general population. Patients tended to replicate the first clinical manifestation (hazard ratio, HR: 2.41 and 4.41 for recurrent TIA and IS, respectively); additional factors for recurrent TIA were previous TIA (HR: 3.40) and microvascular disturbances (HR: 2.30); for recurrent IS arterial hypertension (HR: 4.24) and IS occurrence after MPN diagnosis (HR: 4.47). CV mortality was predicted by age over 60 years (HR: 3.98), an index IS (HR: 3.61), and the occurrence of index events after MPN diagnosis (HR: 2.62). Cytoreductive therapy was a strong protective factor (HR: 0.24). The rate of major bleeding was similar to the general population (0.90 per 100 patient-years). In conclusion, the long-term clinical outcome after TIA and IS in MPN appears even more favorable than in the general population, suggesting an advantageous benefit-risk profile of antithrombotic and cytoreductive treatment

BNT162B2 mRNA COVID-19 vaccine in heart and lung transplanted young adults: is an alternative SARS-CoV-2 immune response surveillance needed?

[no abstract available

The CIP2A–TOPBP1 axis safeguards chromosome stability and is a synthetic lethal target for BRCA-mutated cancer

BRCA1/2-mutated cancer cells adapt to the genome instability caused by their deficiency in homologous recombination (HR). Identification of these adaptive mechanisms may provide therapeutic strategies to target tumors caused by the loss of these genes. In the present study, we report genome-scale CRISPR-Cas9 synthetic lethality screens in isogenic pairs of BRCA1- and BRCA2-deficient cells and identify CIP2A as an essential gene in BRCA1- and BRCA2-mutated cells. CIP2A is cytoplasmic in interphase but, in mitosis, accumulates at DNA lesions as part of a complex with TOPBP1, a multifunctional genome stability factor. Unlike PARP inhibition, CIP2A deficiency does not cause accumulation of replication-associated DNA lesions that require HR for their repair. In BRCA-deficient cells, the CIP2A-TOPBP1 complex prevents lethal mis-segregation of acentric chromosomes that arises from impaired DNA synthesis. Finally, physical disruption of the CIP2A-TOPBP1 complex is highly deleterious in BRCA-deficient tumors, indicating that CIP2A represents an attractive synthetic lethal therapeutic target for BRCA1- and BRCA2-mutated cancers

Body mass index references: diagnostic accuracy with theupper-arm fat area in Argentine school children

El índice de masa corporal (IMC) es una eficaz herramienta para detectar la sobrecarga ponderal en niños y adolescentes, asociado a la adiposidad corporal. Objetivo. Analizar la concordancia, sensibilidad y especificidad de tres referencias internacionales de IMC/edad (OMS, IOTF y CDC) para diagnosticar el exceso ponderal y conocer su precisión diagnóstica para identificar el exceso de adiposidad con relación al área grasa braquial (AGB) en población infanto juvenil de Argentina. Materiales y métodos. Se realizó un estudio multicéntrico, descriptivo-comparativo y transversal entre 2003 y 2008, en 22.658 niños y adolescentes argentinos de 4 a 13 años de edad. A partir del peso, talla, circunferencia del brazo y pliegue tricipital, se calcularon IMC y AGB. Se analizó la concordancia, sensibilidad y especificidad de referencias de IMC/edad (OMS, CDC, IOTF) y la precisión diagnóstica (curvas ROC) para identificar exceso de adiposidad, a partir del AGB, así como el punto de corte óptimo (PCO). Resultados. Las tres referencias tuvieron buena concordancia. La mayor sensibilidad correspondió a OMS y la mayor especificidad a IOTF. El área bajo la curva (ABC) fue mayor en Z-IMC/IOTF en varones y en Z-IMC/OMS en mujeres. Los PCO mostraron discrepancias, siendo mayores con OMS. Conclusión. Las tres referencias muestran similar precisión diagnóstica para detectar alta reserva calórica, con puntos de corte óptimo para las puntuaciones Z-IMC menores a 2 Z scores. Esto resulta relevante para la identificación de exceso de adiposidad en poblaciones, en relación con la implementación de políticas públicas de prevención de enfermedades crónicas no transmisibles.Introduction: The body mass index (BMI) is an effective tool to detect weight overload in children and adolescents, associated with body adiposity. Objective. To analyze the concordance, sensitivity and specificity of three international BMI/age references (WHO, IOTF and CDC) to diagnose excess weight and to know their diagnostic accuracy to identify excess adiposity in relation to the brachial fat area (BFA) in Argentine child-youth population. Materials and methods. A multicenter, descriptive-comparative and cross-sectional study was carried out between 2003 and 2008 in 22.658 Argentine children and adolescents between aged 4 to 13 years. From the weight, height, arm circumference and tricipital fold, BMI and BFA were calculated. The concordance, sensitivity, and specificity of BMI / age references (WHO, IOTF, CDC,) were analyzed and the diagnostic precision (ROC curves) to identify excess adiposity, from the BFA, as well as the optimal cut-off point (OCP). Results. The three references had good agreement, the highest sensitivity corresponded to WHO and the highest specificity to IOTF. The area under the curve (AUC) was greater in Z-BMI/IOTF in men and in Z-BMI/WHO in women. The OCPs showed discrepancies, being higher with WHO. Conclusion. The three references show similar diagnostic accuracy to detect high caloric reserve, but with cut-off points for Z-BMI scores less than 2 Z scores. This is relevant for the identification of excess adiposity in populations in relation to the implementation of public policies for the prevention of chronic non-communicable diseases.Fil: Lomaglio, Delia Beatriz. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet Noa Sur. Instituto Regional de Estudios Socio-culturales. - Universidad Nacional de Catamarca. Instituto Regional de Estudios Socio-culturales.; ArgentinaFil: Marrodán Serrano, María Dolores. Universidad Complutense de Madrid; EspañaFil: Dipierri, José Edgardo. Universidad Nacional de Jujuy; ArgentinaFil: Alfaro Gómez, Emma Laura. Universidad Nacional de Jujuy. Instituto de Ecorregiones Andinas. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Ecorregiones Andinas; Argentina. Universidad Nacional de Jujuy. Instituto de Biología de la Altura; ArgentinaFil: Bejarano, Ignacio Felipe. Universidad Nacional de Jujuy. Facultad de Humanidades y Ciencias Sociales; ArgentinaFil: Cesani Rossi, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Laboratorio de Investigaciones en Ontogenia y Adaptación; ArgentinaFil: Dahinten, Silvia Lucrecia V.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto de Diversidad y Evolución Austral; ArgentinaFil: Garraza, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Laboratorio de Investigaciones en Ontogenia y Adaptación; ArgentinaFil: Menecier, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Catamarca. Facultad de Ciencias Exactas y Naturales. Centro de Estudios de Antropología Biológica; ArgentinaFil: Navazo, Bárbara. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Laboratorio de Investigaciones en Ontogenia y Adaptación; ArgentinaFil: Quintero, Fabian Anibal. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Laboratorio de Investigaciones en Ontogenia y Adaptación; ArgentinaFil: Román, Estela María. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Católica de Santiago del Estero; ArgentinaFil: Torres, María Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET- La Plata. Instituto de Genética Veterinaria "Ing. Fernando Noel Dulout". Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Instituto de Genética Veterinaria; Argentina. Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto de Ciencias Antropológicas; ArgentinaFil: Zonta, Maria Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Estudios Parasitológicos y de Vectores. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Centro de Estudios Parasitológicos y de Vectores; Argentin

Extended composite index of anthropometric failure in Argentinean preschool and school children

Objective: The Composite Index of Anthropometric Failure (CIAF) can only be applied to children under 5 years of age and does not contemplate obesity. The aim of this study was to propose an Extended CIAF (ECIAF) that combines the characterization of malnutrition due to undernutrition and excess weight, and apply it in six Argentine provinces. Design: ECIAF excludes children not in anthropometric failure (group A) and was calculated from a percentage of children included in malnutrition categories B: wasting only; C: wasting and underweight; D: wasting, stunting and underweight; E: stunting and underweight; F: stunting only; Y: underweight only; G: only weight excess; and H: stunting and weight excess. Setting: Cross-sectional study conducted in Buenos Aires, Catamarca, Chubut, Jujuy, Mendoza and Misiones (Argentina). Participants: 10 879 children of both sexes aged between 3 and 13·99. Results: ECIAF in preschool children (3 to 4·99 years) was 15·1 %. The highest prevalence was registered in Mendoza (16·7 %) and the lowest in Misiones (12·0 %). In school children (5 to 13·99 years) ECIAF was 28·6 %. Mendoza also recorded the highest rate (30·7 %), while Catamarca and Chubut had the lowest values (27·0 %). In the whole sample, about 25 % of the malnutrition was caused by undernutrition and 75 % by excess weight. Conclusions: The ECIAF summarizes anthropometric failure by both deficiency and excess weight and it highlights that a quarter of the malnutrition in the Argentine population was caused by undernutrition, although there are differences between Provinces (P < 0·05). ECIAF estimates are higher than those of CIAF or under-nutrition.Instituto de Genética VeterinariaCentro de Estudios Parasitológicos y de Vectore

Estudio comparativo de los percentiles de circunferencia, área muscular y área grasa del brazo en niños argentinos y estadounidenses de 4-14 años

Background: mid-upper arm circumference (MUAC), subcutaneous fat and muscle measurements are an alternative method to diagnose overweight and evaluate growth as well as protein and energy reserves. Aim: to compare MUAC, arm muscle area (AMA) and arm fat area (AFA) measurements of Argentinean boys and girls (Sa) with reference curves for US boys and girls (R). Subjects and methods: data from 22,736 school-children aged 4-14 years from six Argentinean provinces were collected. MUAC and triceps skinfold thickness were measured and the derived AMA and AFA measures were calculated. Analyses were performed with GAMLSS using the R software. Differences in mean values of Sa and R were compared in percentiles 3, 50 and 97. Results: mean values of MUAC and AMA in boys and girls were higher in R than in Sa at all ages; conversely, AFA values were lower. Conclusions: our results confirm differences in upper arm anthropometry of Argentinean school-children with respect to the US reference. The higher adipose tissue and lower skeletal muscle mass observed in Argentinean children could be partly associated with the different ethnic origin of both populations. However, differences should be interpreted in the context of an obesogenic environment, which has favored a calorie-protein imbalanceAntecedentes: la medición de la circunferencia del brazo (MUAC), así como la estimación de la grasa subcutánea y muscular constituyen un método alternativo para diagnosticar el sobrepeso y evaluar el crecimiento y las reservas proteicas y energéticas. Objetivo: comparar las mediciones de MUAC, área muscular (AMA) y área grasa (AFA) del brazo de niños y niñas argentinos (Sa) con curvas de referencia para niños y niñas de Estados Unidos (R). Sujetos y métodos: se recopilaron datos de 22,736 escolares de 4 a 14 años de edad de seis provincias argentinas. Se obtuvieron medidas de MUAC y pliegue subcutáneo tricipital y se calcularon AMA y AFA. Los análisis se realizaron con GAMLSS utilizando el software R. Las diferencias en los valores medios de Sa y R se compararon para los percentiles 3, 50 y 97. Resultados: a todas las edades los valores medios de MUAC y AMA en niños y niñas fueron más altos en R que en Sa; por el contrario, los valores de AFA fueron más bajos. Conclusiones: nuestros resultados confirman la existencia de diferencias en la antropometría mesobraquial de los niños argentinos con respecto a los de la referencia. La mayor cantidad de tejido adiposo y menor de tejido muscular observada en los niños argentinos de ambos sexos puede ser parcialmente asociada con el diferente origen étnico de ambas poblaciones. Sin embargo, las diferencias podrían interpretarse en el contexto de un ambiente obesogénico, el cual habría favorecido el desbalance proteico-calórico.Facultad de Ciencias Naturales y MuseoInstituto de Genética VeterinariaCentro de Estudios Parasitológicos y de Vectore

Reference percentiles for mid-upper arm circumference, upper arm muscle and fat areas in the Argentine child and adolescent population (4-14 years old)

Introducción: La circunferencia del brazo (CB) se reconoce como buen indicador del estado nutricional. Objetivo: Estimar los percentilos de referencia para la CB y las áreas muscular (AM) y grasa (AG) del brazo en la población infantojuvenil argentina mediante el empleo del método LMS (lambda, mu, sigma, en inglés). Materiales y métodos: La muestra estuvo constituida por escolares de 4,0 a 13,9 años residentes en Jujuy, Catamarca, Misiones, Buenos Aires, Mendoza y Chubut. Las mediciones antropométricas de la CB y del pliegue tricipital se realizaron entre 2003 y 2008 siguiendo protocolos estandarizados. Se estimaron las AM, AG, se calcularon los percentilos por edad y sexo, y se compararon mediante el análisis de la varianza. Resultados: Se incluyeron 22 736 escolares (11397 varones y 11339 mujeres). Los valores correspondientes al percentilo 50 fueron superiores, en las mujeres, para CB y AG, y, en los varones, para AM. Las curvas de CB presentaron incrementos más marcados a partir de los 7 años en todos los percentilos, para ambos sexos. Un patrón similar se observó para AM, con valores superiores en los varones. Por último, el AG mostró aumento constante en las mujeres y estabilización en los varones a partir de los 11 años. Se observaron diferencias para la edad. Conclusiones: Los valores de percentilos, tabulados y graficados, de la CB y de las AM y AG del brazo pueden constituir una referencia local para estudios epidemiológicos y antropológicos.Introduction: Mid-upper arm circumference (MUAC) is widely recognized as an adequate indicator of nutritional status. Objective: To estimate the reference percentiles for MUAC, upper arm muscle area (UAMA), and upper arm fat area (UAFA) in the Argentine child and adolescent population using the LMS method (lambda, mu, sigma) Materials and methods: The sample was made up of schoolchildren aged 4.0-13.9 years living in Jujuy, Catamarca, Misiones, Buenos Aires, Mendoza, and Chubut. MUAC and tricipital skinfold anthropometric measurements were obtained between 2003 and 2008 as per standardized protocols. UAMA and UAFA were calculated, and percentiles by age and sex were estimated and compared using an analysis of variance. Results: A total of 22 736 schoolchildren (11 397 boys and 11 339 girls) were included. The 50th percentile was higher for the MUAC and UAFA among girls and for the UAMA among boys. The MUAC curves showed sharper increases as of 7 years old in all percentiles among both boys and girls. A similar pattern was observed for the UAMA, with higher values among boys. Lastly, the UAFA showed a constant increase among girls and a stabilization among boys as of 11 years old. Differences for age were observed. Conclusions: The tabulated and plotted percentiles and the MUAC, UAMA, and UAFA may be used as local references for epidemiological and anthropological studies.Facultad de Ciencias Veterinarias (FCV)Instituto de Genética Veterinaria (IGEVET)Centro de Estudios Parasitológicos y de Vectores (CEPAVE)Facultad de Ciencias Naturales y Museo (FCNM

Reference percentiles for mid-upper arm circumference, upper arm muscle and fat areas in the Argentine child and adolescent population (4-14 years old)

Introducción: La circunferencia del brazo (CB) se reconoce como buen indicador del estado nutricional. Objetivo: Estimar los percentilos de referencia para la CB y las áreas muscular (AM) y grasa (AG) del brazo en la población infantojuvenil argentina mediante el empleo del método LMS (lambda, mu, sigma, en inglés). Materiales y métodos: La muestra estuvo constituida por escolares de 4,0 a 13,9 años residentes en Jujuy, Catamarca, Misiones, Buenos Aires, Mendoza y Chubut. Las mediciones antropométricas de la CB y del pliegue tricipital se realizaron entre 2003 y 2008 siguiendo protocolos estandarizados. Se estimaron las AM, AG, se calcularon los percentilos por edad y sexo, y se compararon mediante el análisis de la varianza. Resultados: Se incluyeron 22 736 escolares (11397 varones y 11339 mujeres). Los valores correspondientes al percentilo 50 fueron superiores, en las mujeres, para CB y AG, y, en los varones, para AM. Las curvas de CB presentaron incrementos más marcados a partir de los 7 años en todos los percentilos, para ambos sexos. Un patrón similar se observó para AM, con valores superiores en los varones. Por último, el AG mostró aumento constante en las mujeres y estabilización en los varones a partir de los 11 años. Se observaron diferencias para la edad. Conclusiones: Los valores de percentilos, tabulados y graficados, de la CB y de las AM y AG del brazo pueden constituir una referencia local para estudios epidemiológicos y antropológicos.Introduction: Mid-upper arm circumference (MUAC) is widely recognized as an adequate indicator of nutritional status. Objective: To estimate the reference percentiles for MUAC, upper arm muscle area (UAMA), and upper arm fat area (UAFA) in the Argentine child and adolescent population using the LMS method (lambda, mu, sigma) Materials and methods: The sample was made up of schoolchildren aged 4.0-13.9 years living in Jujuy, Catamarca, Misiones, Buenos Aires, Mendoza, and Chubut. MUAC and tricipital skinfold anthropometric measurements were obtained between 2003 and 2008 as per standardized protocols. UAMA and UAFA were calculated, and percentiles by age and sex were estimated and compared using an analysis of variance. Results: A total of 22 736 schoolchildren (11 397 boys and 11 339 girls) were included. The 50th percentile was higher for the MUAC and UAFA among girls and for the UAMA among boys. The MUAC curves showed sharper increases as of 7 years old in all percentiles among both boys and girls. A similar pattern was observed for the UAMA, with higher values among boys. Lastly, the UAFA showed a constant increase among girls and a stabilization among boys as of 11 years old. Differences for age were observed. Conclusions: The tabulated and plotted percentiles and the MUAC, UAMA, and UAFA may be used as local references for epidemiological and anthropological studies.Facultad de Ciencias Veterinarias (FCV)Instituto de Genética Veterinaria (IGEVET)Centro de Estudios Parasitológicos y de Vectores (CEPAVE)Facultad de Ciencias Naturales y Museo (FCNM