A propósito de un caso de neumonía por SARS-CoV-2 tratado con inhibidor de IL-1 / About a case of of SARS-CoV-2 pneumonia treated with IL-1 inhibitor

En la ciudad de Wuhan (provincia de Hubei, China), a finales de diciembre de 2019 se notificaron los primeros casos de una infección respiratoria causada que posteriormente se identificó como un nuevo coronavirus (SARS-CoV-2). Este cuadro se presenta como un síndrome respiratorio leve, en la mayoría de los casos, o una enfermedad más grave, con la aparición de opacidades pulmonares, con dificultad respiratoria y necesidad de ventilación mecánica no invasiva o ingreso en Unidades de Cuidados Intensivos. Estos pacientes con una enfermedad más grave debutan con una tormenta de citoquinas y activación de monocitos/macrófagos. Esta respuesta se observa igualmente en pacientes con linfohistiocitosis hemofagocítica secundaria, infecciones virales o síndrome de activación de macrófagos, enfermedades autoinmunitarias sistémicas y autoinflamatorias. Lo cual constituye una justificación para utilizar medicamentos específicamente dirigidos a reducir la tormenta de citoquinas. En cuanto al tratamiento, la evidencia es muy limitada, no pudiéndose establecer unas recomendaciones consistentes. En este caso clínico vamos a presentar un paciente con evolución satisfactoria tras el uso de inhibidores de la interleucina 1

The first cases of a respiratory infection caused by what was later identified as a new coronavirus (SARS-CoV-2) were reported in Wuhan City, Hubei Province, China in late December 2019. This picture presents as a mild respiratory syndrome, in most cases, or a more serious disease, with the appearance of pulmonary opacities, with respiratory distress and the need for non-invasive mechanical ventilation or admission to intensive care units. These more severely ill patients debut with a cytokine storm and monocyte / macrophage activation. This response is also seen in patients with secondary hemophagocytic lymphohistiocytosis, viral infections, or macrophage activation syndrome, systemic autoimmune, and autoinflammatory diseases. This constitutes a justification for using drugs specifically aimed at reducing the cytokine storm. Regarding treatment, the evidence is very limited, and consistent recommendations cannot be established. In this clinical case, we are going to present a patient with a satisfactory evolution after the use of interleukin inhibitors 1

Cocaine-Associated ST-Elevation Myocardial Infarction: Different Pathophysiological Mechanisms.

There are many underlying mechanisms for cocaine-associated myocardial infarction, and the culprit must be elucidated for appropriate therapeutic management. Optical coherence tomography provides unique insights when angiography alone has limited diagnostic value; it also aids in the decision between conservative management and revascularization strategy and guides coronary interventions.

P53 pathway is a major determinant in the radiosensitizing effect of Palbociclib: Implication in cancer therapy.

Targeting cell cycle has become one of the major challenges in cancer therapy, being Palbociclib, a CDK4/6 inhibitor, an excellent example. Recently, it has been reported that Palbociclib could be a novel radiosensitizer agent. In an attempt to clarify the molecular basis of this effect we have used cell lines from colorectal (HT29, HCT116) lung (A549, H1299) and breast cancer (MCF-7). Our results indicate that the presence of a p53 wild type is strictly required for Palbociclib to exert its radiosensitizing effect, independently of the inhibitory effect exerted on CDK4/6. In fact, abrogation of p53 in cells with functional p53 blocks the radiosensitizing effect of Palbociclib. Moreover, no radiosensitizing effect is observed in cells with non-functional p53, but restoration of p53 function promotes radiosensitivity associated to Palbociclib. Furthermore, the presence of Palbociclib blocks the transcriptional activity of p53 in an ATM-dependent-fashion after ionizing radiation exposure, as the blockage of p21/WAF1 expression demonstrates. These observations are a proof of concept for a more selective therapy, based on the combination of CDK4/6 inhibition and radiotherapy, which would only benefit to those patients with a functional p53 pathway.

Unidad médico-quirúrgica de Cardiología Pediátrica y Cardiopatías Congénitas del Hospital Universitario Ramón y Cajal de Madrid / Medical-surgical unit of Pediatric Cardiology and Congenital Heart Diseases of the Hospital Ramón y Cajal of Madrid

Desde su creación, en el año 1977 por el Dr. Manolo Quero, coincidiendo con la apertura del Hospital, el Servicio de Cardiología Pediátrica y Cardiopatías Congénitas del Hospital Ramón y Cajal, ha sido y es centro de referencia donde se siguen enfermos de toda la geografia española. Se creó para dar atención especializada a la gran demanda existente en aquellos años. Y, después de casi 40 años, tenemos la gran satisfacción de poder seguir viendo a esos niños, ya convertidos en adultos, y seguimos ofreciéndoles la asistencia necesaria para tratar las cardiopatías complejas de la mayoria de ellos. Este Servicio se ha caracterizado, tanto por su actividad asistencial como por su actividad docente e investigadora, que ha propiciado que sea distinguido como Centro de Referencia Nacional (CSUR). Hoy en día, contarnos con un Servicio mixto de 7 facultativos, provenientes de la Pediatria y de la Cardiología y especializados en la Cardiología Pediátrica y las Cardiopatías Congénitas. El Servicio cuenta con varias Unidades especializadas como la de Hemodinámica Intervencionista Infantil y en Cardiopatías Congénitas, Hipertensión Pulmonar Pediátrica y Unidad de Arritmias Pediátricas y en Cardiopatias Congenitas, entre otros. Nuestro Servicio se integra en un equipo multidisciplinar, compuesto por cirujanos cardiacos, intensivistas pediátricos, anestesistas, obstetras, radiólogos, rehabilitadores y enfermería especializada, entre otros, que permiten la atención integral al enfermo. La gran mayoría de las consultas externas se organizan con la filosofía de la consulta de alta resolución. Realizándose la mayoría de las exploraciones y técnicas complementarias (electrocardiograma, ecocardicigrafía, Holter, ergometría) en el mismo día de la consulta (AU)

Since its creation in 1977 by Dr. Manolo Quero, coinciding with the opening of the Hospital, the Ramon y Cajal Hospital Pediatric Cardiology and Congenital Heart Disease Unit has been and is a referral center where patients coming from any Spanish region can get specialized and personalized integral care for children with congenital heart disease. After almost 40 years, the Service has integrated also the care of our grown up patients with congenital heart defects, into a transversal care unit. This service is characterized by its healthcare activity and its teaching and research that have led it to be distinguished as a National Reference Center (CSUR) activity. Today we are 7 physicians who perform our functions in different sections and allowed to specialize and create units as Hemodynamics, pulmonary hypertension and arrhythmias among others. Our cardiology department is integrated into a also has a rnultidisciplinary team including cardiac surgeons, pediatric intensivists, anesthesiologists, radiologist, physiotherapist, among others that allow for comprehensive patient care nursing. Our outpatient visits are Organized with the philosophy of "high resolution" visits and all the complementary examinations and functional tests) EKG, echocardiography, Holter cardiopulmonary exercise testing, and sometimes in the MRI) are done in the same day of the external visit (AU)

La retina, una ventana al bagaje cardiovascular / The retina, a window to the cardiovascular baggage

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CHK1 expression in Gastric Cancer is modulated by p53 and RB1/E2F1: implications in chemo/radiotherapy response.

Radiation has a limited but relevant role in the adjuvant therapy of gastric cancer (GC) patients. Since Chk1 plays a critical function in cellular response to genotoxic agents, we aimed to analyze the role of Chk1 in GC as a biomarker for radiotherapy resistance. We analyzed Chk1 expression in AGS and MKN45 human GC cell lines by RT-QPCR and WB and in a small cohort of human patient's samples. We demonstrated that Chk1 overexpression specifically increases resistance to radiation in GC cells. Accordingly, abrogation of Chk1 activity with UCN-01 and its expression with shChk1 increased sensitivity to bleomycin and radiation. Furthermore, when we assessed Chk1 expression in human samples, we found a correlation between nuclear Chk1 accumulation and a decrease in progression free survival. Moreover, using a luciferase assay we found that Chk1's expression is controlled by p53 and RB/E2F1 at the transcriptional level. Additionally, we present preliminary data suggesting a posttranscriptional regulation mechanism, involving miR-195 and miR-503, which are inversely correlated with expression of Chk1 in radioresistant cells. In conclusion, Chk1/microRNA axis is involved in resistance to radiation in GC, and suggests Chk1 as a potential tool for optimal stratification of patients susceptible to receive adjuvant radiotherapy after surgery.

Mad2 and BubR1 modulates tumourigenesis and paclitaxel response in MKN45 gastric cancer cells.

Aneuploidy and chromosomal instability (CIN) are common features of gastric cancer (GC), but their contribution to carcinogenesis and antitumour therapy response is still poorly understood. Failures in the mitotic checkpoint induced by changes in expression levels of the spindle assembly checkpoint (SAC) proteins cause the missegregation of chromosomes in mitosis as well as aneuploidy. To evaluate the possible contribution of SAC to GC, we analyzed the expression levels of proteins of the mitotic checkpoint complex in a cohort of GC cell lines. We found that the central SAC proteins, Mad2 and BubR1, were the more prominently expressed members in disseminated GC cell lines. Silencing of Mad2 and BubR1 in MKN45 and ST2957 cells decreased their cell proliferation, migration and invasion abilities, indicating that Mad2 and BubR1 could contribute to cellular transformation and tumor progression in GC. We next evaluated whether silencing of SAC proteins could affect the response to microtubule poisons. We discovered that paclitaxel treatment increased cell survival in MKN45 cells interfered for Mad2 or BubR1 expression. However, apoptosis (assessed by caspase-3 activation, PARP proteolysis and levels of antiapoptotic Bcl 2-family members), the DNA damage response (assessed by H2Ax phosphorylation) and exit from mitosis (assessed by Cyclin B degradation and Cdk1 regulation) were activated equally between cells, independently of Mad2 or BubR1-protein levels. In contrast, we observed that the silencing of Mad2 or BubR1 in MKN45 cells showed the induction of a senescence-like phenotype accompanied by cell enlargement, increased senescence-associated ß-galactosidase activity and increased IL-6 and IL-8 expression. In addition, the senescent phenotype is highly increased after treatment with PTX, indicating that senescence could prevent tumorigenesis in GC. In conclusion, the results presented here suggest that Mad2 and BubR1 could be used as prognostic markers of tumor progression and new pharmacological targets in the treatment for GC.

Targeting Chk2 improves gastric cancer chemotherapy by impairing DNA damage repair.

Our results demonstrate that the addition of cisplatin after paclitaxel-induced mitotic arrest was more effective than individual treatment on gastric adenocarcinoma cells (MKN45). However, the treatment did not induce benefits in cells derived from lymph node metastasis (ST2957). Time-lapse microscopy revealed that cell death was caused by mitotic catastrophe and apoptosis induction, as the use of the caspase inhibitor z-VAD-fmk decreased cell death. We propose that the molecular mechanism mediating this cell fate is a slippage suffered by these cells, given that our Western blot (WB) analysis revealed premature cyclin B degradation. This resulted in the cell exiting from mitosis without undergoing DNA damage repair, as demonstrated by the strong phosphorylation of H2AX. A comet assay indicated that DNA repair was impaired, and Western blotting showed that the Chk2 protein was degraded after sequential treatment (paclitaxel-cisplatin). Based on these results, the modulation of cell death during mitosis may be an effective strategy for gastric cancer therapy.

Arritmias en la edad pediátrica / Arrhythmias in the pediatric age

Las arritmias pueden ser debidas a anomalías en la formación de impulsos (automatismos), anomalías en la propagación de impulsos, por defecto (como los bloqueos o retrasos en la conducción), o bien por anomalías en la influencia del sistema autónoma. Estas alteraciones pueden desarrollarse de forma aislada o combinada, e igualmente pueden afectar a cualquier región del miocardio, dentro o fuera del sistema de conducción. Será fundamental una buena historia clínica encaminada a descartar la causa subyacente de la arritmia: enfermedad cardíaca congénita o adquirida como Kawasaki, miocarditis o fiebre reumática, así como la presencia de antecedentes familiares de arritmia o muerte súbita. Los síntomas producidos por las arritmias son determinados por sus efectos en el gasto cardíaco, la presencia o ausencia de cardiopatía y por la edad del paciente. En la exploración física podremos distinguir arritmias benignas con datos como variaciones de la frecuencia cardíaca con el ciclo respiratorio o latidos ectópicos aislados, detectar taquicardias o bradicardias cuando a la auscultación la frecuencia cardíaca se encuentre por encima o por debajo de lo normal para su edad, o anomalías asociadas como soplo cardíaco, roce pericárdico.. Dentro del ámbito de la atención primaria se debe también realizar un electrocardiograma con 12 derivaciones con tira de ritmo de 30 segundos donde podremos encontrar preexcitación, bloqueos, etc. Si a pesar de toda información no llegamos a un diagnóstico de la arritmia, se requerirá la derivación a un cardiólogo pediatra, quien deberá efectuar una monitorización ambulatoria de 24 h (holter) o dispositivos externos (60 días) o implantables (2 años) cuando la arritmia no queda registrada en un holter convencional por su frecuencia de aparición; y test de esfuerzo capaz de detectar arritmias o cambios electrocardiográficos relacionados con el ejercicio como cambios de grado de bloqueo, preexcitación emergente con el ejercicio o ectopia ventricular. Asimismo se realizará ecocardiograma para descartar cardiopatía estructural o afectación en la función cardíaca por arritmia mantenida. Se indicará estudio electrofisiológico ante determinadas circunstancias: -Para el diagnóstico y tratamiento de bradiarritmias, para correlacionar la clínica en bradiarritmias adquiridas, y para determinar el nivel de bloqueo auriculoventricular. En taquiarritmias, para definir el mecanismo de producción tanto en QRS estrecho como ancho, determinar el riesgo de muerte súbita y decidir la actitud terapéutica (ablación, desfibrilador implantable, tratamiento farmacológico o actitud expectante). Síncopes de causa desconocida (AU)

Arrhythmias may be due to abnormalities in the formation of impulses (automatisms), abnormalities in the impulse propagation, by defect (such as conduction blocks or delays) or by Access (as fixed or functional “reentry” circuits), or because of abnormalities in the influence of the autonomous system. These alterations may develop in an isolated or combined way and also may affect any region of the myocardium, within or outside of the conduction system. A good clinical history aimed at ruling out the underlying cause of the arrhythmia, that is congenital heart disease or acquired heart disease such as Kawasaki, myocarditis or rheumatic fever, as well as the presence of family back grounds of arrhythmia or sudden death, is fundamental. These symptoms produced by arrhythmias are determined by their effects on the cardiac output, the presence or absence of her at disease and the patient´s age. In the physical examination, we can distinguish benign arrhythmias with data such as variations of the heart rate with the respiratory cycle or isolated ectopic beats, detect tachycardia’s or bradycardias when the auscultation of the heart rate is above or below normal for the subject´s age, or abnormalities associated with heart murmur, pericardial rub, etc. Within the primary care setting, a 12-lead electrocardiogram with the 30-second rhythm strip that can show pre-excitation, blocks, etc, should also be performed. If, in spite of all the information, we do not reach a diagnoses of arrhythmia, the patient should be referred to a pediatric cardiologist who should perform 24-hour ambulatory monitoring (Holter) or monitoring with external devices (60 days) or implantable devices (2 years) when the arrhythmia is not registered on the conventional Holter by its frequency of appearance. A stress test capable of detecting arrhythmias or electrocardiogram changes related with exercise such as changes in the degree of block, emerging pre-excitation with exercise or ventricular ectopic should also be carried out. Furthermore, an echocardiogram should be performed to rule out structural heart disease or abnormality in the heart function due to maintained arrhythmia. An electrophysiological study is indicated when certain circumstances exist: for the diagnosis and treatment of bradyarrhythmias, to correlate the symptoms in acquired bradyarrhythmias, and to determine the level of atrioventricular block. – In tachyarrhythmias, to define the production mechanism both in narrow and wide QRS, to determine the risk of sudden death and to decide the therapeutic approach (ablation, implantable defibrillator, pharmacological treatment or waiting attitude). – Syncopes of unknown cause (AU)

Actualización en intervencionismo / Update in interventionism

El gran desarrollo de las técnicas de imagen en el estudio de las cardiopatías congénitas permite aumentar la calidad y resultado del intervencionismo en cardiología pediátrica, tanto en la indicación y contraindicación de los procedimientos como en su planificación y elección de los diferentes implantes. La ecocardiografía en •D muestra íntegramente la anatomía del septum interauricular (SIA) facilitando el procedimiento de cierre de los diferentes orificios. La angiografía rotacional en la misma sala de cateterismo muestra, en una sola inyección de contraste, toda la anatomía cardíaca y vascular en múltiples angulaciones, permitiendo diseñar la estrategia de intervencionismo a realizar y la curva ideal de los catéteres a emplear. Las medidas del defecto interatrial, espesor relativo de los bores existente, tamaños de la comunicación interventricular o diámetro del anillo aórtico, cada vez pertenecen más a la ecocardiografía que a la angiografía. La morfología del arco e istmo aórticos y el tamaño y función del ventrículo derecho (VD) son patrimonio de la resonancia magnética nuclear (RMN). No obstante, la evaluación hemodinámica del corazón malformado, la fluorografía de alta resolución para fracturas de stents o patillas de dispositivos y la integración de la angiografía rotacional en el plano principal de estudio convierten la sala de hemodinámica en un lugar de estudio fisiopatológico y tratamiento endovascular. Existen patologías que pueden ser ya consideradas como rescatadas dela cirugía convencional, como los ductus de cualquier tamaño, estenosis pulmonar, recoartaciones de aorta, fístulas coronarias, entre otras (AU)

The important developments in imaging techniques for the study of congenital heart diseases allows the interventionalist to an increase in quality, safety and outcome of the procedures, also helping to improve the accuracy in the indications, catheterization procedures. Rotational angiography shows the entire cardiac and vascular anatomy in multiple angles adding important anatomical information, in a single contrast injection and making it possible to design the interventional strategy to be performed and the ideal curve of the catheters to be used. Assessment of the size of the atrial or ventricular septal defects, relative thickness of the existing borders on the diameter of the aortic annulus, can be safely estimated now with ECHO techniques, during the procedure, instead of angiographic measures. The morphology of the aortic arch and the size and function of the right ventricle (RV) are now accurately assessed with the nuclear magnetic resonance (MRI). However, the hemodynamic evaluation of the malformed heart and a high resolution fluorography for stent or device strut fractures and the integration of the rotational angiography in the principal study plane, converts the catheterization laboratory in a sophisticated tool for the study of pathophysiology and treatment of simple and complex congenital heart disease. Several lesions can be considered at the present time as non surgical candidates, due to the result improvement of catheter based techniques. Among them, patent ductus arteriosus of any size, pulmonary valvar stenosis, a variety of native and post operative aortic coarctations, coronary fistulas, branch pulmonary arterial stenosis and multiple dehiscence’s and heart holes, can be sorted out in the catheter laboratory with very low morbidity and mortality (AU)

DUSP1/MKP1 promotes angiogenesis, invasion and metastasis in non-small-cell lung cancer.

DUSP1/MKP1 is a dual-specific phosphatase that regulates MAPKs activity, with an increasingly recognized role in tumor biology. To understand more about the involvement of DUSP1 in lung cancer, we performed gene expression analyses of parental and DUSP1-interfered H460 non-small-cell lung cancer (NSCLC) cells. Downregulation of DUSP1 induced changes in the expression levels of genes involved in specific biological pathways, including angiogenesis, MAP kinase phosphatase activity, cell-cell signaling, growth factor and tyrosine-kinase receptor activity. Changes in the expression of some of these genes were due to modulation of c-Jun-N-terminal kinase and/or p38 activity by DUSP1. Complementary functional assays were performed to focus on the implication of DUSP1 in angiogenesis and metastasis. In H460 cells, interference of DUSP1 resulted in a diminished capacity to invade through Matrigel, to grow tumors in nude mice and also to induce metastasis through tail-vein injection. Furthermore, the angiogenic potential of H460 cells was also impaired, correlating with a decrease in VEGFC production and indicating that DUSP1 could be required to induce angiogenesis. Finally, we studied whether a similar relationship occurred in patients. In human NSCLC specimens, DUSP1 was mainly expressed in those tumor cells close to CD31 vascular structures and a statistically significant correlation was found between VEGFC and DUSP1 expression. Overall, these results provide evidence for a role of DUSP1 in angiogenesis, invasion and metastasis in NSCLC.

Checkpoint kinase 1 modulates sensitivity to cisplatin after spindle checkpoint activation in SW620 cells.

Aneuploidy is a common feature of tumours that arise by errors in chromosome segregation during mitosis. The aim of this study was to evaluate possible signaling pathways involved in sensitization to chemotherapy in cells with chromosomal instability. We designed a screen using the fission yeast Squizossaccharomyces pombe, to isolate strains showing a phenotype of chromosome mis-segregation and higher sensitivity to the antitumoral drug Bleomycin. We examined differences in gene expression using a comparative analysis of genome-wide expression of the wild type strain and one of the mutants. The results revealed a set of genes involved in cell cycle control, including Mad3/BubR1 and Chk1. We then studied the levels of these two proteins in colorectal cancer human cell lines with different genomic content. Among these, SW620 cells showed higher BubR1 and Chk1 mRNA levels than control cells under normal conditions. Since Chk1 is required for both S and G2/M checkpoints, and the microtubule-destabilizing agent, nocodazole induces mitotic arrest, we attempted to investigate the potential anticancer effects of nocodazole in combination with cisplatin. These studies showed that SW620 cells undergo synergistic cell death after spindle checkpoint activation followed by cisplatin treatment, suggesting a role of Chk1 in this checkpoint, very likely dependent on BubR1 protein. Importantly, Chk1-depleted SW620 cells lost this synergistic effect. In summary, we propose that Chk1 could be a biomarker predictive of the efficacy of chemotherapy across different types of tumors with aneuploidy. These findings may be potentially very useful for the stratification of patients for treatment.

Acantosis nigricans en mujer de 43 años / No disponible

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Clinical impact of aneuploidy on gastric cancer patients

Gastric cancer is a leading cause of death worldwide. Nowadays, complete surgical resection and TNM at diagnosis are the main prognostic factors. In spite of this, many patients will have a recurrence after surgery and die within a few months or years. That means that we need more accurate prognostic factors to design specific approaches for individual patients. Chromosome instability is a feature of gastric cancer commonly associated to chromosomal aberrations that leads to major modifications of DNA content globally termed as aneuploidy. In this regard, many authors' opinions diverge regarding the clinical impact of aneuploidy. This review will summarise data on the clinical impact of aneuploidy on clinical practice, the biological mechanisms that underlie chromosomal instability that induces aneuploidy and the relevance of specific chromosomal aneuploidy to cancer biology (AU)

hCCR4/cNOT6 targets DNA-damage response proteins.

Radio and chemotherapy are the election options besides surgical resection, in cancer treatment. However, resistance to chemotherapy limits the effectiveness of therapy in the clinic. An improved knowledge of the mechanisms underlying the resistance to treatment would generate new therapeutic strategies. Genetic suppressor elements (GSEs) are short, biologically active, cDNA fragments that interfere with the function of their cognate gene. By selection of genetic suppressor elements (GSEs) conferring resistance to cisplatin, we identified the GSE11, that corresponds to the hCCR4/CNOT6 gene that mediates cellular sensitivity to the drug. Expression of GSE11-hCCR4 reduces hCCR4 protein levels in cells. Targeting hCCR4 with GSE11 or with siRNA, decreases sensitivity of mammalian cells to DNA-damaging agents. Overexpression of hCCR4 targets Chk2 following exposure to cisplatin, without interfering with the upstream ATM/ATR pathway, however histone gammaH2AX is strongly phosphorylated in these cells compared to control cells. Our results uncover a new function for a human protein involved in chemotherapy response. This finding introduces a new pharmacological target in the treatment of solid tumours.