EphrinA4 plays a critical role in α4 and αL mediated survival ofhuman CLL cells during extravasation

A role of endothelial cells in the survival of CLL cells during extravasation is presently unknown. Herein we show that CLL cells but not normal B cells can receive apoptotic signals through physical contact with TNF-α activated endothelium impairing survival in transendothelial migration (TEM) assays. In addition, the CLL cells of patients having lymphadenopathy (LApos) show a survival advantage during TEM that can be linked to increased expression of α4 and αL integrin chains. Within this context, ephrinA4 expressed on the surface of CLL cells sequestrates integrins and inactivates them resulting in reduced adhesion and inhibition of apoptotic/survival signals through them. In agreement, ephrinA4 silencing resulted in increased survival of CLL cells of LApos patients but not LA neg patients. Similarly was observed when a soluble ephrinA4 isoform was added to TEM assays strongly suggesting that accumulation of this isoform in the serum of LApos patients could contribute to CLL cells dissemination and survival in vivo. In supporting, CLL lymphadenopathies showed a preferential accumulation of apoptotic CLL cells around high endothelial venules lacking ephrinA4. Moreover, soluble ephrinA4 isolated from sera of patients increased the number and viability of CLL cells recovered from the lymph nodes of adoptively transferred mice. Finally, we present evidence suggesting that soluble ephrinA4 mediated survival during TEM could enhance a transcellular TEM route of the CLL cells. Together these findings point to an important role of ephrinA4 in the nodal dissemination of CLL cells governing extravasation and survival

Estudio mineralógico de los sedimentos de la Laguna de El Hito (Cuenca)

Trabajo presentado en la XXXVII Reunión de la Sociedad Española de Mineralogía (SEM)celebrada en Madrid (España) el día 12 de Julio de 2018, en la Facultad de Ciencias Geológicas de la Universidad Complutense de MadridPeer reviewe

Waiting time dictates impact of frailty: A Spanish multicenter prospective study

Background & aims: Frailty is prevalent in liver transplant (LT) candidates. It is considered an independent predictor of adverse outcomes pre- and post-transplant according to data obtained in the United States. We aimed to externally validate the liver frailty index (LFI) in a multicenter cohort of LT candidates. Methods: Outpatients with cirrhosis were prospectively recruited from five Spanish centers (2018-2020). Patients were defined as "frail" by an optimal cut-off of LFI ≥4.5. Patients were followed for at least 6 months to study associations of pre-LT frailty with pre- and post-transplant mortality, length of hospital and intensive care unit (ICU) stays, risk of early (<30 days) and late (30-90 days) post-transplant complications, retransplantation and cardiovascular events. Results: Of 212 patients included, 45 patients (21%) were frail pre-LT, and the median LFI was 3.9 (IQR 3.5-4.4). After a median waiting time of 78 days, 2% died or were delisted for clinical worsening. The LFI at baseline was not predictive of mortality/delisting in LT candidates in univariable or multivariable analyses after adjusting for age and MELD-Na score (hazard ratio 1.48; p = 0.586). In contrast, compared to non-frail patients, frail LT candidates had a significantly higher length of hospital stay (9 vs. 13 days; p = 0.001) and rate of early (<30 days) post-transplant complications (55% vs. 100%; p = 0.021). Conclusions: In the context of a short LT waiting time, frailty does not impact pretransplant mortality and/or delisting. In contrast, LT frailty is predictive of higher post-transplant complication rates and length of hospital stay. Whether strategies aimed at pre- and/or re-habilitation are beneficial in settings with short waiting times needs to be confirmed in prospective studies. Impact and implications: Literature is scarce on the actual impact of physical frailty on adverse outcomes in the liver transplant scenario outside North America. Evidence-based justification to extend the use of objective frailty tools in the decision-making processes in other liver transplant settings is needed. This study is the first to evaluate the predictive value of the liver frailty index in outpatients in the European liver transplant setting, showing that in a low MELD, high access system, frailty does not impact pretransplant mortality and/or delisting but is predictive of higher complication rates and longer post-transplant length of stay. In practical ways, physicians should consider physical frailty as a vital sign to be measured systematically and routinely during clinic visits; researchers are encouraged to initiate prospective studies to evaluate the benefit of applying strategies aimed at pre- and or re-habilitation in liver transplant settings with short waiting times

Shift work and colorectal cancer risk in the MCC-Spain case-control study

Objectives Shift work that involves circadian disruption has been associated with a higher cancer risk. Most epidemiological studies to date have focused on breast cancer risk and evidence for other common tumors is limited. We evaluated the risk for colorectal cancer (CRC) in relation to shift work history in a population-based case-control study in Spain. Methods This analysis included 1626 incident CRC cases and 3378 randomly selected population controls of both sexes, enrolled in 11 regions of Spain. Sociodemographic and lifestyle information was assessed in face-to-face interviews. Shift work was assessed in detail throughout lifetime occupational history. We estimated the risk of colon and rectal cancer associated with rotating and permanent shift work (ever, cumulative duration, age of first exposure) using unconditional logistic regression analysis adjusting for potential confounders. Results Having ever performed rotating shift work (morning, evening and/or night) was associated with an increased risk for CRC [odds ratio (OR) 1.22, 95% confidence interval (95% CI) 1.04-1.43], as compared to day workers. Having ever worked permanent night shifts (?3 nights/month) was not associated with CRC risk (OR 0.79, 95% CI 0.62-1.00). OR increased with increasing lifetime cumulative duration of rotating shift work (P-value for trend 0.005) and were highest among subjects in the top quartiles of exposure (3 rdquartile, 20-34 years, OR 1.38, 95%CI 1.06-1.81; 4 thquartile, ?35 years, OR 1.36, 95% CI 1.02-1.79). Conclusions These data suggest that rotating shift work may increase the risk of CRC especially after long-term exposures

Impact of hospitalization on nutritional status in persons aged 65 years and over (NUTRIFRAG Study): Protocol for a prospective observational study

Background: Malnutrition is a recurring problem that has become more relevant in recent years. The aim of this study is to assess the risk of malnutrition and nutritional status on admission and its evolution until discharge in patients aged 65 and over admitted to medical and surgical hospitalization units in hospitals of the Spanish National Health System. Methods: Prospective observational study to be carried out in the medical-surgical hospitalization units of 9 public hospitals between 01/09/2022 and 31/12/2024. Using consecutive sampling, a total of 4077 patients will be included (453 in each hospital). Variables included are related to the care process, functionality, cognition and comorbidity, risk profile, nutritional status and dysphagia; as well as frailty, dietary quality and contextual variables. The incidence of risk of malnutrition, undernutrition and dysphagia during the care process and at discharge will be calculated. The association with risk factors will be studied with logistic regression models and multivariate Cox regression models. In addition, an analysis of participants' satisfaction with food services will be carried out. The study was approved by the Ethics and Research Committee on 30/09/2020, approved for funding on 02/12/2021 and with registration number RBR-5jnbyhk in the Brazilian clinical trials database (ReBEC) for observational studies. Discussion: Some studies address nutritional status or dysphagia in older people in various care settings. However, there is a lack of large sample studies including both processes of the impact of hospitalization. The results of the project will provide information on the incidence and prevalence of both pathologies in the study subjects, their associated factors and their relationship with the average length of stay, mortality and early readmission. In addition, early detection of a problem such as malnutrition related to the disease and/or dysphagia during a hospital stay will favor the action of professionals to resolve both pathologies and improve the health status of patients.This study has been funded by Instituto de Salud Carlos III (ISCIII) through the project "PI21/00738" and co-funded by the European Union. The funders did not and will not have a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S

Vasa picta ibérica. Talleres de cerámica del Sureste hispano (s.II a.C-I d.C.)

Coordinadores: Trinidad Tortosa Rocamora y Antonio M. Poveda Navarro.Este libro recoge los resultados de la propuesta del Seminario organizado en Elda (Alicante) que, como su título indica, recoge análisis sobre el interesante conjunto de materiales vasculares que se enmarcan en un tiempo y una geografía precisa del sureste peninsular, área valenciana y albacetense. Esta iniciativa nos pareció que, en este momento, adquiría un valor añadido ya que nuevas revisiones obtenidas a la luz de antiguas informaciones, hoy revisadas o la información aportada por nuevos contextos, con estudios, como los aquí presentados, configuran el momento oportuno para dedicar una obra a estos objetos arqueológicos tan significativos en la bibliografía, sobre todo, del siglo XX. El Monastil, el Tossal de Manises, el Tolmo de Minateda, el Cabecico del Tesoro… son algunos de los nombres iconos de esta cerámica que vuelven a lucir en esta obra. Por otra parte, el libro guarda una estructura un tanto peculiar debido al ámbito global al que pretende atender y que se convierte, en nuestra opinión, en su valor añadido. Se trata del propio hecho de que lo presentemos como homenaje a Ricardo Olmos, quien ha dedicado parte de su obra a tratar algunos de los temas específicos que se afrontan en estas páginas, como por ejemplo, en el caso de los estudios sobre la Alcudia (Elche, Alicante). Los avances que este investigador ha venido proporcionando a lo largo del tiempo han supuesto para la disciplina de la iconografía arqueológica, un avance en la metodología y en el conocimiento del ámbito ibérico. Finalizamos estas páginas con un entrañable recuerdo hacia una de las primeras arqueólogas que observó y sistematizó la cerámica ibérica en la provincia alicantina, Solveig Nordström (1923-2021), desaparecida en el tiempo en el que se imprimía este libro.Esta publicación se integra en el proyecto nacional de I+D+i: HAR2017-87897-P, Reubicando los objetos ibéricos del MAN: de rituales, biografías y observaciones a través de los modelos 3D.Peer reviewe

A2ML1 and otitis media : novel variants, differential expression, and relevant pathways

A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061 + 1 G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular, RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media.Peer reviewe