Function of reactive oxygen species during animal development: Passive or active?

AbstractOxidative stress is considered causal of aging and pathological cell death, however, very little is known about its function in the natural processes that support the formation of an organism. It is generally thought that cells must continuously protect themselves from the possible damage caused by reactive oxygen species (ROS) (passive ROS function). However, presently, ROS are recognized as physiologically relevant molecules that mediate cell responses to a variety of stimuli, and the activities of several molecules, some developmentally relevant, are directly or indirectly regulated by oxidative stress (active ROS function). Here we review recent data that are suggestive of specific ROS functions during development of animals, particularly mammals

A Three-Protein Panel to Support the Diagnosis of Sepsis in Children

Sepsis is a syndrome without a standard validated diagnostic test. Early recognition is crucial. Serum proteome analysis in children with sepsis may identify new biomarkers. This study aimed to find suitable blood biomarkers for an early diagnosis of sepsis. An analytical observational case-control study was carried out in a single center. Children admitted to a Pediatric Intensive Care Unit with clinical diagnosed sepsis were eligible for study. A proteomic analysis conducted by mass spectrometry was performed. Forty patients with sepsis and 24 healthy donors were recruited. Proteomics results revealed 44 proteins differentially expressed between patients and healthy controls. Six proteins were selected to be validated: lactoferrin, serum amyloid-A1 (SAA-1), complement factor B, leucine-rich alpha-2 glycoprotein (LRG1), soluble interleukin-2 alpha chain receptor (sCD25) and soluble haptoglobin-hemoglobin receptor. Our results showed that sCD25, SAA-1, and LRG1 had high levels of specificity and sensitivity, as well as an excellent area under the ROC curve (>0.9). Our study provides a serum proteomic analysis that identifies new diagnostic biomarkers in sepsis. SAA-1, sCD25 and LRG1 were able to separate septic from healthy donor, so they could be used together with other clinical and analytical features to improve sepsis diagnosis in children.This work was funded by Research Projects from University of Basque Country (US10/02) and from the Basque Government (SAIO10-PE10BF02, SAIO12-PE12BF002, 2012111052, 2019111056). CICbioGUNE is supported by Basque Department of Industry, Tourism and Trade (Etortek and Elkartek programs), the Innovation Technology Department of the Bizkaia County, the ProteoRed-ISCIII (Grant PRB3 IPT17/0019), CIBERehd Network and Severo Ochoa Grant (SEV-2016-0644)

"Trip": narrativas de la otredad

Este escrito se centrará en el análisis de un cortometraje titulado "TRIP", realizado en el año 2013 por alumnos de la carrera Diseño Multimedial de la Facultad de Bellas Artes, Universidad Nacional de La Plata. El film desafía al espectador a situarse en los márgenes del relato tradicional, lineal, donde la retórica de su lenguaje habilita a reflexionar sobre las perspectivas de la otredad, venciendo la tensión centro-periferia, cuyo centro sancionó la representación de arte periférico reduciéndolo a un mero dato de la realidad. Para ello, se indagarán las teorías de Nelly Richard, Eduardo Grüner y Hans Georg Gadamer desde el contexto latinoamericano.Facultad de Bellas Arte

Producción de factor de crecimiento epidermal humano recombinante biológicamente activo

El factor de crecimiento epidermal humano (hEGF) es un polipéptido de 53 aminoácidos que forma parte del complejo sistema de modulación del crecimiento y desarrollo celular. Cuando el EGF se une a su receptor (EGFR) en la superficie de las células, se produce la dimerización del EGFR seguida de la auto-fosforilación de residuos Tyr en los dominios citoplasmáticas del receptor. Los residuos Tyr fosforilados inician la cascada de eventos que conduce a la síntesis de ADN, ARN y proteínas. A través de la interacción con el EGFR, el EGF cumple una variedad de roles fisiológicos vinculados con el crecimiento celular, proliferación, diferenciación y supervivencia de diferentes tipos celulares.Facultad de Ciencias Médica

Producción de factor de crecimiento epidermal humano recombinante biológicamente activo

El factor de crecimiento epidermal humano (hEGF) es un polipéptido de 53 aminoácidos que forma parte del complejo sistema de modulación del crecimiento y desarrollo celular. Cuando el EGF se une a su receptor (EGFR) en la superficie de las células, se produce la dimerización del EGFR seguida de la auto-fosforilación de residuos Tyr en los dominios citoplasmáticas del receptor. Los residuos Tyr fosforilados inician la cascada de eventos que conduce a la síntesis de ADN, ARN y proteínas. A través de la interacción con el EGFR, el EGF cumple una variedad de roles fisiológicos vinculados con el crecimiento celular, proliferación, diferenciación y supervivencia de diferentes tipos celulares.Facultad de Ciencias Médica

Identification and Functional Analysis of a Novel CTNNB1 Mutation in Pediatric Medulloblastoma

Medulloblastoma is the primary malignant tumor of the Central Nervous System (CNS) most common in pediatrics. We present here, the histological, molecular, and functional analysis of a cohort of 88 pediatric medulloblastoma tumor samples. The WNT-activated subgroup comprised 10% of our cohort, and all WNT-activated patients had exon 3 CTNNB1 mutations and were immunostained for nuclear β-catenin. One novel heterozygous CTNNB1 mutation was found, which resulted in the deletion of β-catenin Ser37 residue (ΔS37). The ΔS37 β-catenin variant ectopically expressed in U2OS human osteosarcoma cells displayed higher protein expression levels than wild-type β-catenin, and functional analysis disclosed gain-of-function properties in terms of elevated TCF/LEF transcriptional activity in cells. Our results suggest that the stabilization and nuclear accumulation of ΔS37 β-catenin contributed to early medulloblastoma tumorigenesis.This work was funded by Asociación Pablo Ugarte APU (BC/A/14/015), Pequerropa (BC/A/15/010), and the childhood cancer support Platform from EITB Media, SAU (BIO13/CI/016/BC). R.P. was funded by Ministerio de Economía y Competitividad (Spain and Fondo Europeo de Desarrollo Regional, grant number SAF2016-79847-R). C.E.N.-X. was funded by Instituto de Salud Carlos III (Spain and the European Social Fund+, grant number: CP20/00008). P.A.-P. was supported by a Basque Government fellowship (PRE_2020_2_0116)

Identification of germline cancer predisposition variants in pediatric sarcoma patients from somatic tumor testing

Genetic predisposition is an important risk factor for cancer in children and adolescents but detailed associations of individual genetic mutations to childhood cancer are still under intense investigation. Among pediatric cancers, sarcomas can arise in the setting of cancer predisposition syndromes. The association of sarcomas with these syndromes is often missed, due to the rarity and heterogeneity of sarcomas and the limited search of cancer genetic syndromes. This study included 43 pediatric and young adult patients with different sarcoma subtypes. Tumor profiling was undertaken using the Oncomine Childhood Cancer Research Assay (Thermo Fisher Scientific). Sequencing results were reviewed for potential germline alterations in clinically relevant genes associated with cancer predisposition syndromes. Jongmans´ criteria were taken into consideration for the patient selection. Fifteen patients were selected as having potential pathogenic germline variants due to tumor sequencing that identified variants in the following genes: CDKN2A, NF1, NF2, RB1, SMARCA4, SMARCB1 and TP53. The variants found in NF1 and CDKN2A in two different patients were detected in the germline, confirming the diagnosis of a cancer predisposition syndrome. We have shown that the results of somatic testing can be used to identify those at risk of an underlying cancer predisposition syndrome.This work was funded by Research Projects from Navarra Government (Ref. 54/2018), the Jesús de Gangoiti Barrera Foundation (FJGB18/004 and FJGB19/001), Asociación Pablo Ugarte APU (APU-osteosarcoma), La Cuadri del Hospi (BC/A/17/008), EITB Media AND BIOEF, SAU (BIO20/CI/015/BCB and BIO20/CI/011/BCB), Basque Government (2021111030) and Fundación La Caixa with Niños Contra el Cáncer. P.A.-P. is supported by a Basque Government fellowship (PRE_2021_2_0048)

Langerhans cell histiocytosis. Advances in pathogenesis and clinical practice

La histiocitosis de células de Langerhans (HCL) es un tipo de neoplasia hematológica de origen mieloide, que puede afectar a diferentes órganos o tejidos, con gran variabilidad en la presentación clínica y comportamiento biológico, por lo que puede simular diferentes enfermedades. Se recomienda realizar diversas pruebas clínicas, analíticas y de imagen, para determinar la extensión de la afectación, que puede ser única o multisistémica, y la presen- cia o no de disfunción en órganos de riesgo como sistema hematopoyético, hígado y bazo. El diagnóstico se debe confirmar mediante biopsia y estudio histológico. Los estudios molecula- res han permitido identificar mutaciones en la vía MAPK, lo que han ampliado las opciones terapéuticas. El diagnóstico es complejo y existe controversia en el manejo de ciertos casos. Las recomendaciones terapéuticas dependen de la localización de las lesiones y de la extensión de la afectación. Los estudios colaborativos internacionales han demostrado la efectividad de terapias prolongadas combinadas como vinblastina y prednisona en formas graves o multisis- témicas y destaca el papel beneficioso de fármacos antiinflamatorios como indometacina y de otras combinaciones de citostáticos. La HCL representa un buen ejemplo de la importancia de la medicina de precisión y del beneficio de la identificación de dianas moleculares, comunes a diferentes neoplasias, para desarrollar nuevas terapias dirigidas. Los inhibidores de la vía MAPK representan una alternativa terapéutica en casos refractarios y en las formas neurodegenera- tivas de la HCL. Los estudios moleculares pueden contribuir en el pronóstico, el tratamiento y el seguimiento, especialmente en las formas gravesLangerhans cell histiocytosis (LCH) is a type of myeloid neoplasia that can affect different organs or tissues and exhibits substantial variability in its clinical presentation and biological behaviour, so it may mimic different diseases. Performance of different clinical assessments and laboratory and imaging tests is recommended to determine the extent of involvement, which may be of a single location or multisystemic, and the presence or absence of dysfunction in risk organs, such as the haematopoietic system, liver and spleen. The diagnosis must be confirmed by histological examination of a biopsy sample. Molecular tests have identified mutations in the mitogen-activated protein kinase (MAPK) pathway, which has expanded treatment options. The diagnosis is complex and there is controversy regarding the management of certain cases. Treatment recommendations depend on the location of the lesions and the extent of involvement. International collaborative studies have demonstrated the effectiveness of prolonged combination therapies such as vinblastine and prednisone in severe or multisystemic forms, and anti-inflammatory drugs such as indomethacin and other cytostatic combinations have proven beneficial. LCH is a good example of the importance of precision medicine and the benefit of identifying molecular targets, common to different neoplasms, to develop new therapies. MAPK pathway inhibitors offer an alternative treatment option in refractory cases and neurodegenerative forms of LCH. Molecular testing can contribute to the prognosis, treatment and follow-up of LCH, especially in severe forms of diseaseEste trabajo ha sido financiado parcialmente por los fondos del Proyecto de Investigación sobre Histiocitosis de la Fundación Vasca de Innovación e Investigación Sanitaria BIOEF (BIO16/ER/020/BC) y de la Asociación Española contra la Histiocitosis-ACHE (BC/A/15/012, BIOEF11/017, BIOEF09/047

Altered Expression of CD300a Inhibitory Receptor on CD4+ T Cells From Human Immunodeficiency Virus-1-Infected Patients: Association With Disease Progression Markers

The ability of the CD300a inhibitory receptor to modulate immune cell functions and its involvement in the pathogenesis of many diseases has aroused a great interest in this molecule. Within human CD4+ T lymphocytes from healthy donors, the inhibitory receptor CD300a is differentially expressed among different T helper subsets. However, there are no data about the expression and regulation of CD300a receptor on CD4+ T cells from human immunodeficiency virus (HIV)-1-infected patients. The objective of this study was to investigate the expression of CD300a on CD4+ T cells from HIV-infected patients on suppressive combined antiretroviral therapy (cART) and cART naïve patients. Our results have demonstrated that the expression levels of this inhibitory receptor were higher on CD4+ T cells from HIV-1 infected subjects compared with healthy donors, and that cART did not reverse the altered expression of CD300a receptor in these patients. We have observed an increase of CD300a expression on both PD1+CD4+ and CD38+CD4+ T cells from HIV-1 infected people. Interestingly, a triple positive (CD300a+PD1+CD38+) subset was expanded in naïve HIV-1 infected patients, while it was very rare in healthy donors and patients on cART. Finally, we found a negative correlation of CD300a expression on CD4+ T lymphocytes and some markers associated with HIV-1 disease progression. Thus, our results show that HIV-1 infection has an impact in the regulation of CD300a inhibitory receptor expression levels, and further studies will shed light into the role of this cell surface receptor in the pathogenesis of HIV infection

Identification of germline cancer predisposition variants in pediatric sarcoma patients from somatic tumor testing

Genetic predisposition is an important risk factor for cancer in children and adolescents but detailed associations of individual genetic mutations to childhood cancer are still under intense investigation. Among pediatric cancers, sarcomas can arise in the setting of cancer predisposition syndromes. The association of sarcomas with these syndromes is often missed, due to the rarity and heterogeneity of sarcomas and the limited search of cancer genetic syndromes. This study included 43 pediatric and young adult patients with different sarcoma subtypes. Tumor profiling was undertaken using the Oncomine Childhood Cancer Research Assay (Thermo Fisher Scientific). Sequencing results were reviewed for potential germline alterations in clinically relevant genes associated with cancer predisposition syndromes. Jongmans¿ criteria were taken into consideration for the patient selection. Fifteen patients were selected as having potential pathogenic germline variants due to tumor sequencing that identified variants in the following genes: CDKN2A, NF1, NF2, RB1, SMARCA4, SMARCB1 and TP53. The variants found in NF1 and CDKN2A in two different patients were detected in the germline, confirming the diagnosis of a cancer predisposition syndrome. We have shown that the results of somatic testing can be used to identify those at risk of an underlying cancer predisposition syndrome