El control de la secreción ácida gástrica en el ratón: cambios asociados a la gastritis o a la falta del receptor de tipo 2 de la somatostatina.

RESUMEN Este estudio caracteriza los mecanismos de control de la secreción ácida gástrica en el ratón, in vivo, en diferentes condiciones experimentales, incluyendo el empleo tanto de animales normales como de animales con potenciales alteraciones en la función gástrica y sus mecanismos de control, como es el caso de la irritación química con yodoacetamida o la manipulación genética dirigida a interferir factores directamente implicados en la regulación de la función gástrica, en este caso el receptor de tipo 2 de la somatostatina (SSTR2). El primer modelo empleado se basa en la inducción de una gastritis mediante la administración oral del irritante químico yodoacetamida durante 6 días. Los estudios morfológicos realizados muestran que el tratamiento con yodoacetamida induce una gastritis leve caracterizada por la presencia de un infiltrado inflamatorio difuso, con un incremento en el número de mastocitos en la submucosa, y la ausencia de lesiones aparentes, macro o microscópicas, en la mucosa. Durante la gastritis, se alteran los mecanismos de control de la secreción ácida gástrica, lo que resulta en una elevada tasa de secreción basal y una respuesta hipersecretora a los secretagogos gastrina e histamina, sin afectarse significativamente la tasa de vaciamiento gástrico. Mediadores de origen mastocitario incrementan la respuesta secretora, tal y como sugieren los experimentos con cromoglicato sódico; mientras que las prostaglandinas tienden a compensar estados de hipersecreción minimizando la exposición de la mucosa al ácido, contribuyendo a mantener su integridad. El segundo modelo empleado se basa en el uso de animales modificados geneticamente, carentes del receptor SSTR2 (SSTR2 -/-). Los resultados obtenidos muestran que estos animales son aparentemente normales en cuanto a su morfología gástrica, abundancia relativa de células con inmunoreactividad de tipo gastrina y somatostatina en la mucosa, respuesta secretora al alimento y vaciamiento gástrico. Sin embargo, durante la anestesia con uretano se pone de manifiesto la falta del receptor SSTR2, resultando en una secreción ácida gástrica basal entre 10 y 15 veces superior en los animales SSTR2 -/- con respecto a los animales no manipulados genéticamente. Esta elevada secreción basal es totalmente dependiente de las vías gastrina-histamina. El uso combinado de ratones SSTR2 -/-, la inmunoneutralización in vivo de la gastrina y la somatostatina endógenas y la manipulación farmacológica de los receptores de somatostatina (SSTR1-5) con agonistas selectivos y con el antagonista SSTR2, PRL-2903, ha permitido demostrar que en el ratón, al igual que en otras especies, los efectos periféricos de la somatostatina sobre la secreción ácida gástrica están mediados en su totalidad por receptores SSTR2. La actividad antisecretora de la somatostatina frente a los secretagogos pentagastrina e histamina y la presencia de receptores SSTR2 en células parietales y de tipo enterocromafin (ECL) hace plausible la hipótesis de que la somatostatina regule la secreción ácida gástrica a través de un mecanismo paracrino que implica la inhibición de la liberación de histamina de ECL y, en menor medida, un efecto inhibitorio directo sobre las células parietales. Finalmente, se han caracterizado los efectos sobre la secreción ácida gástrica de los neuropéptidos bombesina y PACAP. Los resultados obtenidos muestran que ambos actúan periféricamente inhibiendo la secreción ácida gástrica, sin que haya evidencias de que medien respuestas estimulantes. El uso combinado de animales carentes del receptor SSTR2, la inmunoneutralización in vivo de la somatostatina endógena y el bloqueo farmacológico de los receptores SSTR2 demuestra que los efectos antisecretores de la bombesina y del PACAP están mediados a través de la liberación de somatostatina y la consiguiente activación de receptores SSTR2. Estos resultados, junto a observacionesp revias con otros neuropéptidos inhibitorios, sugieren que la vía somatostatina-receptores SSTR2 puede ser un mecanismo común para generar respuestas secretoras inhibitorias en el estómago. __________________________________________________________________________________________________This study characterizes the regulatory mechanisms of gastric acid secretion in mice, in vivo, in different experimental conditions. First, we characterized pathophysiological alterations linked to gastritis of non infectious origin, induced by exposure of the gastric mucosa to the chemical irritant iodoacetamide. Secondly, we studied the role of somatostatin receptors (SSTR1-5), with special emphasis on SSTR2 receptors, on the regulation of gastric acid secretion and the secretory effects of the neuropeptides bombesin and PACAP. In mice, orally administered iodoacetamide induces a mild gastritis characterised by a moderate inflammatory infiltrate, with an increase in the number of mast cells in the submucosa, without any evidence of macro or microscopic damage. However, basal gastric acid secretion and secretory responses to secretagogues were increased during gastritis. Changes in basal secretion might be related to alterations in the feedback control mechanisms between gastrin and somatostatin, as suggested for other inflammatory models. Enhanced secretory responses to secretagogues (pentagastrin and histamine) were blocked by the mast cells stabilizer, sodium cromoglycate, suggesting a mast cells contribution in these hipersecretory responses. On the other hand, pretreatment with indomethacin further enhanced the secretory responses to pentagastrin and histamine suggesting a prostaglandin-dependent counteracting mechanism that might act reducing hypersecretory responses to minimize acid production and exposure of the gastric mucosa. The use of genetically modified mice (knockout for the gene encoding for SSTR2 receptors) together with the immunoneutralization of endogenous somatostatin and the pharmacological manipulation of somatostatin receptors, using selective agonists and antagonists, clearly demonstrates that the antisecretory effects of somatostatin are mediated through SSTR2 receptors. Moreover, similar experimental approach served to demonstrate that the antisecretory effects of the neuropeptides bombesin and PACAP depend upon the release of somatostatin and the activation of SSTR2 receptors. These observations, together with previous studies characterizing the mechanism of action of several inhibitory mediators, suggests that gastric D cells may function as a common target for a variety of inhibitory peptides, which input will be translated into the release of somatostatin and the activation of SSTR2 receptors, leading to an inhibition of acid output

Programa de educación para la salud dirigido a padres de recién nacidos prematuros durante la estancia hospitalaria

Introducción: La prematuridad es el mayor desafío clínico en medicina perinatal. En los últimos años los cuidados al prematuro y su familia han sufrido una gran evolución. Actualmente se están implementando programas de apoyo a las familias durante la estancia hospitalaria. Estos programas parentales aumentan los conocimientos sobre los cuidados de los prematuros. Además, son una herramienta eficaz para disminuir la ansiedad o estrés parental. Objetivos: Diseñar un Programa de Educación para la Salud para padres de recién nacidos prematuros, con el objetivo de aumentar sus conocimientos sobre cuidados neonatales, así como habilidades para la detección de situaciones de alarma. Metodología: Se realizó una revisión bibliográfica con bases de datos y páginas web para conocer la evidencia científica respecto a los recién nacidos prematuros y sus familias, con el fin de elaborar un programa de educación sobre cuidado neonatal y apoyo parental. Conclusiones: La educación sanitaria temprana sobre los cuidados de un prematuro resulta muy eficaz para el neonato y su familia. El personal de enfermería se convierte en el lazo de unión entre el recién nacido y sus padres, así como una red de apoyo para los mismos.<br /

Angiotensin II Induces Leukocyte–Endothelial Cell Interactions In Vivo Via AT1 and AT2 Receptor–Mediated P-Selectin Upregulation

Background—Angiotensin II (Ang II) plays a critical role in the development of vascular lesions in hypertension, atherosclerosis, and several renal diseases. Because Ang II may contribute to the leukocyte recruitment associated with these pathological states, the aim of the present study was to assess the role of Ang II in leukocyte–endothelial cell interactions in vivo. Methods and Results—Intravital microscopy of the rat mesenteric postcapillary venules was used. Sixty minutes of superfusion with 1 nmol/L Ang II induced a significant increase in leukocyte rolling flux (83.8±20.7 versus 16.4±3.1 cells/min), adhesion (11.4±1.0 versus 0.8±0.5 cells/100 µm), and emigration (4.0±0.7 versus 0.2±0.2 cells/field) without any vasoconstrictor activity. These effects were not mediated by mast cell activation. Intravenous pretreatment with AT1 (losartan) or AT2 (PD123,319) receptor antagonists significantly reduced Ang II–induced responses. A combination of both receptor antagonists inhibited the leukocyte rolling flux, adhesion, and extravasation elicited by Ang II at 60 minutes. Pretreatment of animals with fucoidin or an adhesion-blocking anti–rat P-selectin monoclonal antibody abolished Ang II–induced leukocyte responses. Furthermore, rat platelet P-selectin expression was not affected by Ang II stimulation. Conclusions—Ang II induces significant leukocyte rolling, adhesion, and emigration, which may contribute not only to hypertension but also to the onset and progression of the vascular damage associated with disease states in which plasma levels of this peptide are elevated.Piqueras Ruiz, Laura, [email protected] ; Alvarez Ribelles, Angeles, [email protected] ; Esplugues Mota, Juan Vicente, [email protected] ; Sanz Ferrando, Maria Jesus, [email protected]

Differential molecular response in mice and human thymocytes exposed to a combined-dose radiation regime

In the quest for more effective radiation treatment options that can improve both cell killing and healthy tissue recovery, combined radiation therapies are lately in the spotlight. The molecular response to a combined radiation regime where exposure to an initial low dose (priming dose) of ionizing radiation is administered prior to a subsequent higher radiation dose (challenging dose) after a given latency period have not been thoroughly explored. In this study we report on the differential response to either a combined radiation regime or a single challenging dose both in mouse in vivo and in human ex vivo thymocytes. A differential cell cycle response including an increase in the subG1 fraction on cells exposed to the combined regime was found. Together with this, a differential protein expression profiling in several pathways including cell cycle control (ATM, TP53, p21CDKN1A), damage response (γH2AX) and cell death pathways such as apoptosis (Cleaved Caspase-3, PARP1, PKCδ and H3T45ph) and ferroptosis (xCT/GPX4) was demonstrated. This study also shows the epigenetic regulation following a combined regime that alters the expression of chromatin modifiers such as DNMTs (DNMT1, DNMT2, DNMT3A, DNMT3B, DNMT3L) and glycosylases (MBD4 and TDG). Furthermore, a study of the underlying cellular status six hours after the priming dose alone showed evidence of retained modifications on the molecular and epigenetic pathways suggesting that the priming dose infers a “radiation awareness phenotype” to the thymocytes, a sensitization key to the differential response seen after the second hit with the challenging dose. These data suggest that combined-dose radiation regimes could be more efficient at making cells respond to radiation and it would be interesting to further investigate how can these schemes be of use to potential new radiation therapie

Novel Immune Features of the Systemic Inflammation Associated with Primary Hypercholesterolemia: Changes in Cytokine/Chemokine Profile, Increased Platelet and Leukocyte Activation

Primary hypercholesterolemia (PH) is associated with a low grade systemic inflammation that is likely the main driver of premature atherosclerosis. Accordingly, we characterized the immune cell behaviour in PH and its potential consequences. Whole blood from 22 PH patients and 21 age-matched controls was analysed by flow cytometry to determine the percentage of leukocyte immunophenotypes, activation, and platelet-leukocyte aggregates. Plasma markers were determined by Enzyme-Linked ImmunoSorbent Assay (ELISA). The adhesion of platelet-leukocyte aggregates to tumor necrosis factor-α (TNFα)-stimulated arterial endothelium was investigated using the dynamic model of the parallel-plate flow chamber. PH patients presented greater percentage of Mon 3 monocytes, Th2 and Th17 lymphocytes, activated platelets, and leukocytes than controls. The higher percentages of circulating platelet-neutrophil, monocyte and lymphocyte aggregates in patients caused increased platelet-leukocyte adhesion to dysfunctional arterial endothelium. Circulating CXCL8, CCL2, CX3CL1, and IL-6 levels positively correlated with key lipid features of PH, whereas negative correlations were found for IL-4 and IL-10. We provide the first evidence that increased platelet and leukocyte activation leads to elevated platelet-leukocyte aggregates in PH and augmented arterial leukocyte adhesiveness, a key event in atherogenesis. Accordingly, modulation of immune system behavior might be a powerful target in the control of further cardiovascular disease in PH

Comprehensive characterization of a novel, oncogenic and targetable SEPTIN6::ABL2 fusion in T-ALL

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SOCS3 deregulation contributes to aberrant activation of the JAK/STAT pathway in precursor T-cell neoplasms

Despite the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway being frequently altered in T-ALL/LBL, no specific therapy has been approved for T-ALL/LBL patients with constitutive signalling by JAK/STAT, so there is an urgent need to identify pathway members that may be potential therapeutic targets. In the present study, we searched for JAK/STAT pathway members potentially modulated through aberrant methylation and identified SOCS3 hypermethylation as a recurrent event in T-ALL/LBL. Additionally, we explored the implications of SOCS3 deregulation in T-ALL/LBL and demonstrated that SOCS3 counteracts the constitutive activation of the JAK/STAT pathway through different molecular mechanisms. Therefore, SOCS3 emerges as a potential therapeutic target in T-ALL/LBLComunidad de Madrid, Grant/Award Number: B2017/BMD-3778; LINFOMAS-CM; Fundación Científica Asociación Española Contra el Cáncer, Grant/Award Number: PROYE18054PIRI; Fundación Ramón Areces, Grant/Award Number: CIVP19S7917; Instituto de Investigación Sanitaria Fundación Jiménez Díaz; Ministerio de Ciencia, Innovación y Universidades, Grant/ Award Number: RTI2018- 093330-B-I00 and MCIU/FEDER; Ministerio de Economía y Competitividad, Grant/Award Number: SAF2015-70561-R and MINECO/FEDE

Experience sampling methods for the personalised prediction of mental health problems in Spanish university students: protocol for a survey-based observational study within the PROMES-U project

IntroductionThere is a high prevalence of mental health problems among university students. Better prediction and treatment access for this population is needed. In recent years, short-term dynamic factors, which can be assessed using experience sampling methods (ESM), have presented promising results for predicting mental health problems.Methods and analysisUndergraduate students from five public universities in Spain are recruited to participate in two web-based surveys (at baseline and at 12-month follow-up). A subgroup of baseline participants is recruited through quota sampling to participate in a 15-day ESM study. The baseline survey collects information regarding distal risk factors, while the ESM study collects short-term dynamic factors such as affect, company or environment. Risk factors will be identified at an individual and population level using logistic regressions and population attributable risk proportions, respectively. Machine learning techniques will be used to develop predictive models for mental health problems. Dynamic structural equation modelling and multilevel mixed-effects models will be considered to develop a series of explanatory models for the occurrence of mental health problems.Ethics and disseminationThe project complies with national and international regulations, including the Declaration of Helsinki and the Code of Ethics, and has been approved by the IRB Parc de Salut Mar (2020/9198/I) and corresponding IRBs of all participating universities. All respondents are given information regarding access mental health services within their university and region. Individuals with positive responses on suicide items receive a specific alert with indications for consulting with a health professional. Participants are asked to provide informed consent separately for the web-based surveys and for the ESM study. Dissemination of results will include peer-reviewed scientific articles and participation in scientific congresses, reports with recommendations for universities’ mental health policy makers, as well as a well-balanced communication strategy to the general public

Search for vector-boson resonances decaying to a top quark and bottom quark in the lepton plus jets final state in pp collisions at s=13 TeV with the ATLAS detector

A search for new charged massive gauge bosons, W, is performed with the ATLAS detector at the LHC. Data were collected in proton–proton collisions at a center-of-mass energy of s=13 TeV and correspond to an integrated luminosity of 36.1 fb. This analysis searches for W bosons in the W→tb¯ decay channel in final states with an electron or muon plus jets. The search covers resonance masses between 0.5 and 5.0 TeV and considers right-handed W bosons. No significant deviation from the Standard Model (SM) expectation is observed and upper limits are set on the W→tb¯ cross section times branching ratio and the W boson effective couplings as a function of the W boson mass. For right-handed W bosons with coupling to the SM particles equal to the SM weak coupling constant, masses below 3.15 TeV are excluded at the 95% confidence level. This search is also combined with a previously published ATLAS result for W→tb¯ in the fully hadronic final state. Using the combined searches, right-handed W bosons with masses below 3.25 TeV are excluded at the 95% confidence level.Peer Reviewe

Search for heavy particles decaying into a top-quark pair in the fully hadronic final state in pp collisions at s =13 TeV with the ATLAS detector

A search for new particles decaying into a pair of top quarks is performed using proton-proton collision data recorded with the ATLAS detector at the Large Hadron Collider at a center-of-mass energy of s=13 TeV corresponding to an integrated luminosity of 36.1 fb-1. Events consistent with top-quark pair production and the fully hadronic decay mode of the top quarks are selected by requiring multiple high transverse momentum jets including those containing b-hadrons. Two analysis techniques, exploiting dedicated top-quark pair reconstruction in different kinematic regimes, are used to optimize the search sensitivity to new hypothetical particles over a wide mass range. The invariant mass distribution of the two reconstructed top-quark candidates is examined for resonant production of new particles with various spins and decay widths. No significant deviation from the Standard Model prediction is observed and limits are set on the production cross-section times branching fraction for new hypothetical Z′ bosons, dark-matter mediators, Kaluza-Klein gravitons and Kaluza-Klein gluons. By comparing with the predicted production cross sections, the Z′ boson in the topcolor-assisted-technicolor model is excluded for masses up to 3.1-3.6 TeV, the dark-matter mediators in a simplified framework are excluded in the mass ranges from 0.8 to 0.9 TeV and from 2.0 to 2.2 TeV, and the Kaluza-Klein gluon is excluded for masses up to 3.4 TeV, depending on the decay widths of the particles.Peer Reviewe