Analysis of senescence-like growth arrest induced by RUNX1 and its fusion derived oncoproteins

Cellular senescence is an end point of a signal transduction programme leading to irreversible cell cycle arresst accompanied by characteristic alterations to cell morphology, biochemical properties and gene expression profile. This phenotype can be triggered by a variety of stimuli including telomere shortening, DNA damage or activated oncogenes. Senescence is now recognised as a tumour suppressor mechanism mediated by p53 and pRB pathways which act to prevent the proliferatio of cells that are at risk of tumourigenic transformation. RUNX1 is a transcription factor essential for definitive hematopoiesis and is frequently targeted in human leukaemias by chromosomal rearrangements. RUNX1 has been also demonstrated to act as a dominant oncogene in mice and the ectopic expression of RUNX1 in murine embryonic fibroblasts has been shown to cause senescence. The central aim of this study was to investigate the mechanism of senescence induction by RUNX1 and its fusion derived leukaemogenic oncoproteins in primary fibroblasts. My work showed that RUNX1 induces a strong senescence-like response in murine and human primary fibroblasts that requires intact DNA binding, CBFB interaction and C-terminal transcriptional activation/repression domains. However, surprising differences were found between the major RUNX1 fusion oncoprotein derivatives. The N-terminal fusion protein TEL-RUNX1 fails to induce senescence despite retention of a virtually full-lenght RUNX1 moiety, while the senescence-inducing potential is exaggerated in the truncated C-terminal fusion protein RUNX1-ETO (AML1-ETO). The potential to drive senescence is retained by the deletion mutant RUNX1-ETO[]469 which lacks critical corepressor binding sites suggesting that the repression of target genes may be a primary mechanism implicated in RUNX1-ETO induced senescence. Interestingly, CBFB-MYH11 fusion oncoprotein that affects RUNX1 indirectly by targeting CBFB cn also induce senescence when ectopically expressed in human primary cells. The RUNX1 and RUNX1-ETO induced senescent phenotypes differ from archetypal H-Ras [superscript v12] as arrest occurs without a preliminary phase of proliferation and the arrested cells lack prominent foci of DNA strand breaks and chromatin condensation. Notably however, RUNX1 and RUNX1-ETO display differences in their potency and the extent of engagement of p53 and Rb effector pathways. RUNX1-ETO is highly dependent on p53 function and unlike RUNX1 drives senescence in cells lacking intact p16Ink4a. RUNX1-ETO appears to exert its unique effects through potent induction of reactive oxygen species and p38MAPK phosphorylation. These findings illustrate the heterogeneous manifestations of senescence-like growth arrest and elucidate the distinctive biology and oncogenic properies of RUNX1 and its fusion derivatives

Letter from the Editors

Introduction to Volume 1 (2019), Issue 1 of Climate and Societ

A case report of Gitelman syndrome resulting from two novel mutations in SLC12A3 gene

AbstractIntroductionHypokalaemia is a common clinical problem. A potential but commonly overlooked cause of hypokalaemia is Gitelman syndrome.Material and methodsA 26-year-old man was admitted to the hospital due to syncope with general and muscular weakness and muscle cramps. The patient's history revealed previous recurrent syncope events associated to hypokalaemia with the lowest serum potassium value being 2.6mmol/l. At admission, blood pressure was normal and no changes were found at physical examination. Laboratory tests showed mild hypokalaemia (3.0mmol/l), hypomagnesaemia (1.36mg/dl), hypocalciuria (< 40mg/24h), and metabolic alkalosis (HCO3− 29.7mmol/l, BE 5.3mmol/l).ResultsFurther laboratory tests (FeK, TTKG) confirmed inappropriate kaliuresis. Conn's disease was excluded by hormonal and imaging assessments. Genetic testing was performed and two novel heterozygous mutations: c.35_36insA and c.1095+5G>A were found in transcript NM_000339.2 in SLC12A3 gene.ConclusionThe patient was diagnosed with Gitelman syndrome and was treated with supplements of potassium and magnesium

Detección de lesiones cutáneas en imágenes basado en redes generativas adversarias

El propósito de este Trabajo Fin de Grado es conocer y poner en práctica las redes generativas adversarias en un problema real. Para ello, primero se estudia el panorama actual en el que esta arquitectura está siendo utilizada. Posteriormente, se crea una red GAN (generative adversarial network) y se evalúan los resultados. Tras profundizar en la parte teórica se pasa a la práctica utilizando Keras y Kaggle (plataforma online de data science) para crear la red generativa. El objetivo de esta red es generar nuevas imágenes y utilizarlas como data augmentation en un problema de clasificación. Este problema de clasificación es la ISIC-2019, una competición a nivel mundial en la que se buscan modelos capaces de clasificar entre ocho tipos de cáncer de piel. El flujo de trabajo es el siguiente: 1) La red creada genera im´agenes de un tipo de c´ancer de piel en particular (Actinic Keratosis). 2) Estas im´agenes se a˜naden al conjunto ´ de datos original y 3) se realiza una comparación para ver si el modelo clasificatorio mejora o no introduciendo nuevas imágenes creadas. Los resultados obtenidos muestran que no se ha sido capaz de mejorar el rendimiento del modelo clasificatorio con las nuevas imágenes generadas por la red GAN. Esto se debe por un lado a que la red GAN no es capaz de aprender lo suficiente, debido a la escasez de datos, y por otro a la carencia de poder computacional. Aún a pesar de no obtener los resultados esperados, se ha cumplido el objetivo: ahondar en el conocimiento de las redes generativas adversarias y utilizarlas en un problema de la vida real. También, tras realizar este Trabajo Fin de Grado brotan una serie de preguntas para un estudio a posteriori: ¿Se puede aplicar el data augmentation con la arquitectura GAN en la mayoría de los problemas? ¿Cómo se puede afrontar un conjunto de datos muy desbalanceado, es decir, donde algunas categorías tienen mucho peso mientras que otras muy poco? ¿Puede una red GAN ser pieza diferenciante para este tipo de problemas

High-resolution imaging of the Pyrenees and Massif Central from the data of the PYROPE and IBERARRAY portable array deployments

International audienceThe lithospheric structures beneath the Pyrenees, which holds the key to settle long-standing controversies regarding the opening of the Bay of Biscay and the formation of the Pyrenees, are still poorly known. The temporary PYROPE and IBERARRAY experiments have recently filled a strong deficit of seismological stations in this part of western Europe, offering a new and unique opportunity to image crustal and mantle structures with unprecedented resolution. Here we report the results of the first tomographic study of the Pyrenees relying on this rich data set. The important aspects of our tomographic study are the precision of both absolute and relative traveltime measurements obtained by a nonlinear simulated annealing waveform fit and the detailed crustal model that has been constructed to compute accurate crustal corrections. Beneath the Massif Central, the most prominent feature is a widespread slow anomaly that reflects a strong thermal anomaly resulting from the thinning of the lithosphere and upwelling of the asthenosphere. Our tomographic images clearly exclude scenarios involving subduction of oceanic lithosphere beneath the Pyrenees. In contrast, they reveal the segmentation of lithospheric structures, mainly by two major lithospheric faults, the Toulouse fault in the central Pyrenees and the Pamplona fault in the western Pyrenees. These inherited Hercynian faults were reactivated during the Cretaceous rifting of the Aquitaine and Iberian margins and during the Cenozoic Alpine convergence. Therefore, the Pyrenees can be seen as resulting from the tectonic inversion of a segmented continental rift that was buried by subduction beneath the European plate

Leukocyte trafficking in alveoli and airway passages

Many pulmonary diseases preferentially affect the large airways or the alveoli. Although the mechanisms are often particular to each disease process, site-specific differences in leukocyte trafficking and the regulation of inflammation also occur. Differences in the process of margination, sequestration, adhesion, and migration occur that can be attributed to differences in anatomy, hemodynamics, and the expression of proteins. The large airways are nourished by the bronchial circulation, whereas the pulmonary circulation feeds the distal lung parenchyma. The presence of different cell types in large airways from those in alveoli might contribute to site-specific differences in the molecular regulation of the inflammatory process