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INTED 2015, 9 th International Technology, Education and Development Conference, March 2 nd-4 th, 2015-Madrid, Spain, A group of lecturers from diverse areas of knowledge of the University of Alcalá have implemented an experience of teaching innovation based on “reflective diaries”. The students hand in to the lecturer every week their “Weekly Reflection Papers” (WRP), in which they schematically express the most important ideas related with the topic presented during the classes of the previous week. They must include their reflections about the aspects they found especially interesting. After having applied this tool for some academic years we introduced a modification called “Guided Weekly Reflection Papers” (GWRP), where the professors suggest a series of questions on which the students must apply the most significant concepts studied each week. This modification enhances student’s motivation, encourages them to achieve more significant and reflective knowledge and generates interest in emergent topics. However, we often detect that the information management needed to solve the proposed questions in the GWRP is not the most suitable one. Therefore our present work is aimed at helping students develop the necessary skills and acquire a searching criterion in the framework of the information literacy. The strategy was focussed on some important items for the acquisition of information competencies. In this communication we analyze the progress of the GWRP tool and we explore the response of students to the information literacy approach.

Entre los supervivientes en España del modelo de prensa de distribución gratuita figura la publi­cación especializada Diario Médico, que lleva 25 años divulgando temas médico-sanitarios entre profesionales del Sistema Nacional de Salud. Se acomete un estudio exploratorio-descriptivo para indagar en sus orígenes y situación actual, prestando atención a su labor en papel, a través del pro­ducto impreso, y en Red, a través de diariomedico.com. Se seleccionan como técnicas la entrevista con su subdirector y el análisis de sus productos. El formato mixto define a Diario Médico: mantiene su compromiso por ofrecer información en papel, a pesar de haber reducido la periodicidad de diaria a semanal; reconduce a sus lectores en papel a Orbyt, quiosco de prensa digital del grupo promotor, Unidad Editorial, donde ofrece diariamente unas siete páginas en pdf con información para suscriptores; y está en la Red, con una edición que se abre a la participación del usuario. El tono divulgativo de sus contenidos y su utilidad para la sociedad, unido al creciente interés del público no especializado por la medicina y salud llevan a este medio, a nuestro parecer, a tener un doble público objetivo: la sociedad en general y los profesionales del Sistema en particular One of the survivors in Spain of the free distribution press is the specialized publication Diario Médi­co, which has been disseminating health issues among professionals of the National Health System for 25 years. We did an exploratory-descriptive study about its origins and current situation, paying attention to its labour in paper, through the printed product, and in Red, through diariomedico.com. The techniques are the interview with its deputy director and the analysis of its products. The mixed format defines Diario Médico: it maintains its commitment to offer information on paper, despite ha­ving reduced the periodicity from daily to weekly; leads its paper readers to Orbyt, the digital press kiosk of the promoter group, Unidad Editorial, where it offers seven pages a day in pdf format with information for subscribers, and on the Web, with an edition that opens to the participation of the user. The informative tone of its contents and its usefulness for society, together with the growing interest of the non-specialized public in medicine and health, lead to Diario Médico, in our opinion, to have a double objective public: society in general and professionals of the System in particular SI

L'ictus constitueix un problema sanitari, social i econòmic de primer ordre, tant en termes d'incidència com de morbimortalitat. Reduir aquesta càrrega és, actualment, una de les tasques prioritàries dels professionals de la salut, especialment de l'Atenció Primària, que és l'escenari principal on s'articulen la promoció de la salut en general, i els diferents nivells de prevenció de l'ictus en particular. Una de les limitacions més importants per a l'assoliment dels objectius de prevenció, però, és la baixa adherència dels pacients a les recomanacions de modificacions d'estil de vida. En les darreres dècades, l'entrevista motivacional s'ha desenvolupat com un mètode eficaç per promoure canvis de conducta en els pacients, ajudant-los a resoldre la seva ambivalència i a assolir les seves motivacions intrínseques Stroke is a major health, social and economic problem, both regarding its incidence and its morbimortality. Thus, reducing this burden is one of the most important tasks physicians have to deal with these days; and Primary Care is the main scenario where promotion of health, in general, and various levels of prevention, in particular, take place. One of the greatest constraints to achieving prevention goals, though, is low compliance with lifestyle recommendations. Over the last few decades, motivational interviewing has developed as an effective method to promote behavior changes in patients, helping them solve their ambivalence and reach their intrinsic motivations.

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina. Fecha de lectura: 9 de Julio de 2007

This study analyzes the dimensional changes of the glands from prostate cancer by applying stereology to estimate the variations in volume, length, surface, and cellular densities of tumor acini. Normal and tumor acini were visualized using immunohistochemistry for cytokeratin18. On immunostained sections, parameters related to the dimensions and cell population of prostate acini were measured. The immunohistochemical expression of proliferative cell nuclear antigen was also measured to correlate the quantitative changes estimated with the proliferative activity of the epithelium. The average cell volume in normal and tumor epithelium was estimated using the method of the nucleator. The relative size of the acini was similar in the carcinoma compared with the normal prostate. Within the acini, the fraction of acinar volume occupied by the epithelium was significantly higher in cancer than in the nontumor prostate. Conversely, the glandular lumen of the cancer acini is lower than in the normal acini. The significant increase of acinar length density in the carcinoma indicates that the glandular tree's growth in the carcinoma is higher and with more branches than in the case of nonneoplastic glands. The basal surface density is higher in the carcinoma than in the controls. The number of epithelial cells per unit length of acini was significantly decreased in the neoplastic glands. This "dilution" of the cell population along the cancer acinus can be explained by the significant increase in the tumor cell's mean cell volume.

BACKGROUND It is unclear whether solid organ transplant (SOT) patients have more severe coronavirus disease 2019 (COVID-19) and worse outcome than the general population. MATERIAL AND METHODS We conducted a case-control study on 32 SOT recipients and 84 non-SOT controls matched for age and sex admitted for confirmed COVID-19. The primary endpoint was in-hospital all-cause mortality rate. Secondary endpoints included severe acute respiratory distress syndrome (ARDS), use of high-flow oxygen therapy, and length of hospital stay. RESULTS The median (IQR) Charlson comorbidity index (CCI) at admission was significantly higher in SOT recipients (6 (3-8) vs 3 (2-4); P

Background: Ecological momentary assessment (EMA) tools appear to be useful interventions for collecting real-time data on patients behavior and functioning. However, concerns have been voiced regarding the acceptability of EMA among patients with schizophrenia and the factors influencing EMA acceptability. Objective: The aim of this study was to investigate the acceptability of a passive smartphone-based EMA app, evidence-based behavior (eB2), among patients with schizophrenia spectrum disorders and the putative variables underlying their acceptance. Methods: The participants in this study were from an ongoing randomized controlled trial (RCT) of metacognitive training, consisting of outpatients with schizophrenia spectrum disorders (F20-29 of 10th revision of the International Statistical Classification of Diseases and Related Health Problems), aged 18-64 years, none of whom received any financial compensation. Those who consented to installation of the eB2 app (users) were compared with those who did not (nonusers) in sociodemographic, clinical, premorbid adjustment, neurocognitive, psychopathological, insight, and metacognitive variables. A multivariable binary logistic regression tested the influence of the above (independent) variables on being user versus nonuser (acceptability), which was the main outcome measure. Results: Out of the 77 RCT participants, 24 (31%) consented to installing eB2, which remained installed till the end of the study (median follow-up 14.50 weeks) in 14 participants (70%). Users were younger and had a higher education level, better premorbid adjustment, better executive function (according to the Trail Making Test), and higher cognitive insight levels (measured with the Beck Cognitive Insight Scale) than nonusers (univariate analyses) although only age (OR 0.93, 95% CI 0.86-0.99; P=048) and early adolescence premorbid adjustment (OR 0.75, 95% CI 0.61-0.93; P=01) survived the multivariable regression model, thus predicting eB2 acceptability. Conclusions: Acceptability of a passive smartphone-based EMA app among participants with schizophrenia spectrum disorders in this RCT where no participant received financial compensation was, as expected, relatively low, and linked with being young and good premorbid adjustment. Further research should examine how to increase EMA acceptability in patients with schizophrenia spectrum disorders, in particular, older participants and those with poor premorbid adjustment. This study was supported by the Universidad Autónoma de Madrid and European Union via the Intertalentum Project Grant-Marie Skodowska Curie Actions (GA 713366) to JDLM who is the principal investigator. This grant, therefore, funds both JDLM's salary and the consumable expenses related to the study. MLB, VGRR, ASEM, PJEA, SSA, LMI, LML, and EBG's salaries come from the Hospital Universitario Fundación Jiménez Díaz, where this study is currently being carried out, which therefore provides the necessary institutional/departmental support for its development. Additional departmental support concerning the use of EMA is provided by the Instituto de Salud Carlos III (Madrid, Spain) (ISCIII PI16/01852), the Madrid Regional Government (Madrid, Spain) (B2017/BMD-3740 AGES-CM 2CM; Y2018/TCS-4705 PRACTICO-CM), and the Spanish Ministerio de Ciencia, Innovación y Universidades (TEC2017-92552-EXP). ASD acknowledges funding support from University College London, which covers his salary. The funders had no role in hypothesis generation, study design, decision to publish, or the manuscript writing. No funder has a conflict of interest in relation to the study's results and findings. The funding bodies supported the peer review for this manuscript.

Background: Tumor necrosis factor-like weak inducer of apoptosis (Tnfsf12; TWEAK) and its receptor Fibroblast growth factor-inducible 14 (Tnfrsf12a; Fn14) participate in the inflammatory response associated with vascular remodeling.However, the functional effect ofTWEAK on vascular smoothmuscle cells (VSMCs) is not completely elucidated. Methods: Next generation sequencing-based methodswere performed to identify genes and pathways regulated by TWEAK in VSMCs. Flow-citometry, wound-healing scratch experiments and transwellmigration assays were used to analyze VSMCs proliferation and migration. Mouse wire injury model was done to evaluate the role of TWEAK/Fn14 during neointimal hyperplasia. Findings: TWEAK up-regulated 1611 and down-regulated 1091 genes in VSMCs. Using a gene-set enrichment method,we found a functionalmodule involved in cell proliferation defined as the minimal network connecting top TWEAK up-regulated genes. In vitro experiments in wild-type or Tnfrsf12a deficient VSMCs demonstrated that TWEAK increased cell proliferation, VSMCs motility and migration. Mechanistically, TWEAK increased cyclins (cyclinD1), cyclin-dependent kinases (CDK4, CDK6) and decreased cyclin-dependent kinase inhibitors (p15lNK4B) mRNA and protein expression. Downregulation of p15INK4B induced by TWEAK was mediated by mitogen-activated protein kinase ERK and Akt activation. Tnfrsf12a or Tnfsf12 genetic depletion and pharmacological intervention with TWEAK blocking antibody reduced neointimal formation, decreasing cell proliferation, cyclin D1 and CDK4/6 expression, and increasing p15INK4B expression compared with wild type or IgG-treated mice in wire-injured femoral arteries. Finally, immunohistochemistry in human coronary arteries with stenosis or in-stent restenosis revealed high levels of Fn14, TWEAK and PCNA in VSMCs enriched areas of the neointima as compared with healthy coronary arteries. Interpretation: Our data define a major role of TWEAK/Fn14 in the control of VSMCs proliferation and migration during neointimal hyperplasia after wire injury in mice, and identify TWEAK/Fn14 as a potential target for treating in-stent restenosis., This work was supported by Instituto de Salud Carlos III (Fondo de Investigaciones Sanitarias ISCiii/FEDER PI13/00395; PI16/01419; PI17/ 01495) and Spanish Biomedical Research Centre in Cardiovascular Disease (CIBERCV) and Metabolic Diseases and Diabetes (CIBERDEM). PM was supported by ISCIII Miguel Servet Program (CP16/00116). CGM was supported by Fundación Conchita Rábago. NMB and VE were supported by the Spanish Ministry of Economy and Competitiveness (Juan de la Cierva IJCI-2016-29630 and Ramón y Ramón Cajal Program RyC-2013-12880, respectively). JMM has been supported a postdoctoral fellowship fromthe American Diabetes Association (Grant 1-15-MI-03) and a postdoctoral fellowship fromthe American Heart Association.

Mitosis has been traditionally considered a metabolically inactive phase. We have previously shown, however, that extensive alterations in lipids occur as the cells traverse mitosis, including increased de novo fatty acid (FA) and phosphatidylcholine (PtdCho) synthesis and decreased lysophospholipid content. Given the diverse structural and functional properties of these lipids, we sought to study their metabolic fate and their importance for cell cycle completion. Here we show that FA and PtdCho synthesized at the mitotic exit are destined to the nuclear envelope. Importantly, FA and PtdCho synthesis, but not the decrease in lysophospholipid content, are necessary for cell cycle completion beyond G2/M. Moreover, the presence of alternative pathways for PtdCho synthesis renders the cells less sensitive to its inhibition than to the impairment of FA synthesis. FA synthesis, thus, represents a cell cycle-related metabolic vulnerability that could be exploited for combined chemotherapy. We explored the combination of fatty acid synthase (FASN) inhibition with agents that act at different phases of the cell cycle. Our results show that the effect of FASN inhibition may be enhanced under some drug combinations., Facultad de Ciencias Médicas, Instituto de Investigaciones Bioquímicas de La Plata

Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar y los autores pertenecientes a la UAM, Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that present variable outcomes. To date, no effective therapies or reliable prognostic markers are available for patients who develop metastatic PPGL (mPPGL). Our aim was to discover robust prognostic markers validated through in vitro models, and define specific therapeutic options according to tumor genomic features. Methods: We analyzed three PPGL miRNome datasets (n=443), validated candidate markers and assessed them in serum samples (n=36) to find a metastatic miRNA signature. An integrative study of miRNome, transcriptome and proteome was performed to find miRNA targets, which were further characterized in vitro. Results: A signature of six miRNAs (miR-21-3p, miR-183-5p, miR-182-5p, miR-96-5p, miR-551b-3p, and miR-202-5p) was associated with metastatic risk and time to progression. A higher expression of five of these miRNAs was also detected in PPGL patients’ liquid biopsies compared with controls. The combined expression of miR-21-3p/miR-183-5p showed the best power to predict metastasis (AUC=0.804, P=4.67·10-18), and was found associated in vitro with pro-metastatic features, such as neuroendocrine-mesenchymal transition phenotype, and increased cell migration rate. A pan-cancer multi-omic integrative study correlated miR-21-3p levels with TSC2 expression, mTOR pathway activation, and a predictive signature for mTOR inhibitor-sensitivity in PPGLs and other cancers. Likewise, we demonstrated in vitro a TSC2 repression and an enhanced rapamycin sensitivity upon miR-21-3p expression. Conclusions: Our findings support the assessment of miR-21-3p/miR-183-5p, in tumors and liquid biopsies, as biomarkers for risk stratification to improve the PPGL patients’ management. We propose miR-21-3p to select mPPGL patients who may benefit from mTOR inhibitors, This work was supported by the Instituto de Salud Carlos III (ISCIII), Acción Estratégica en Salud, cofounded by FEDER, [grant number PI14/00240, PI17/01796 to M.R., PI15/00783 to A.C], the Paradifference Foundation [no grant number applicable to M.R.], the ANR [ANR-2011-JCJC-00701 MODEOMAPP to AP.G-R], the European Union [FP7/2007-2013 n° 259735, Horizon 2020 n° 633983 to AP.G-R], Epigénétique et Cancer [EPIG201303 METABEPIC to AP.G-R], the the Ligue Nationale contre le Cancer ["Cartes d'Identité des Tumeurs (CIT) program" to AP.G-R], the Institut National du Cancer, the Direction Générale de l’Offre de Soins [PRT-K 2014, COMETE-TACTIC, INCa-DGOS_8663 to AP.G-R], the Deutsche Forschungsgemeinschaft (DFG) [CRC/Transregio 205/1 “The Adrenal: Central Relay in Health and Disease“ to F.B, M.F and G.E], the Rafael del Pino Foundation [Becas de Excelencia Rafael del Pino 2017 to B.C], the Severo Ochoa Excellence Programme [project SEV-2011-0191 to M.C-F], La Caixa Foundation [B004235 to JM.R-R], the Spanish Ministry of Education, Culture and Sport [grant number FPU16/05527 to M.S.], the Site de Recherche Intégré sur le Cancer-SIRIC [CARPEM Project to N.B.] and the AECC Foundation [grant number AIO15152858 to C.M-C]

The use of peloids as heat-providing therapeutic systems dates back to antiquity. Such systems consist of a liquid phase and an organic or inorganic solid phase. The latter facilitates the handling, preparation and stability of the solid–liquid system, modifying its organoleptic and physicochemical properties, and improves its efficacy and tolerance. Peloids enable the application of heat to very specific zones and the release of heat at a given rate. The aims of this work are to study 16 reference peloids used in medical spa centers as thermo-therapeutic agents as well as to propose nine raw materials as a solid phase for the preparation of peloids. The physical properties studied are the centesimal composition, the instrumental texture and the thermal parameters. In conclusion, the peloids of the medical spas studied are used as thermotherapeutic agents in the treatment of musculoskeletal disorders, especially in knee osteoarthritis and to a lesser extent in back pain and psoriatic arthropathy. The clinical experience in these centers shows that the main effects of the application of their peloids are the reduction of pain, an increase in the joint’s functional capacity and an improvement in the quality of life. As thermotherapeutic agents, all the peloids of the medical spas studied and the pastes (raw materials with distilled water) examined showed a heat flow rate of up to four times lower than that shown by the same amount of water. The raw materials studied can be used as solid phases for the preparation of peloids with mineral waters., This study was financed by the research group UCM-911757 (Universidad Complutense de Madrid, Medical Hydrology

We investigated the clinicopathological features and prognostic factors of patients with peripheral T-cell lymphoma (PTCL) in 13 sites across Spain. Relevant clinical antecedents, CD30 expression and staining pattern, prognostic indices using the International Prognostic Index and the Intergruppo Italiano Linfomi system, treatments, and clinical outcomes were examined. A sizeable proportion of 175 patients had a history of immune-related disorders (autoimmune 16%, viral infections 17%, chemo/radiotherapy-treated carcinomas 19%). The median progression-free survival (PFS) and overall survival (OS) were 7·9 and 15·8 months, respectively. Prognostic indices influenced PFS and OS, with a higher number of adverse factors resulting in shorter survival (P 15% of cells were positive in anaplastic lymphoma kinase-positive and -negative anaplastic large-cell lymphoma and extranodal natural killer PTCL groups. We observed PTCL distribution across subtypes based on haematopathological re-evaluation. Poor prognosis, effect of specific prognostic indices, relevance of histopathological sub-classification, and response level to first-line treatment on outcomes were confirmed. Immune disorders amongst patients require further examination involving genetic studies and identification of associated immunosuppressive factors., This study was sponsored by Takeda.

Although the stress response in eukaryotes depends on early events triggered in cells by environmental insults, long-term processes such as aging are also affected. The loss of cellular proteostasis greatly impacts aging, which is regulated by the balancing of protein synthesis and degradation systems. As translation is the input event in proteostasis, we decided to study the role of translational activity on cell lifespan. Our hypothesis was that a reduction on translational activity or specific changes in translation may increase cellular longevity. Using mutant strains of Schizosaccharomyces pombe and various stress conditions, we showed that translational reduction caused by phosphorylation of eukaryotic translation initiation factor 2 (eIF2) during the exponential growth phase enhances chronological lifespan (CLS). Furthermore, through next-generation sequence analysis, we found eIF2α phosphorylation-dependent translational activation of some specific genes, especially those involved in autophagy. This fact, together with the observed regulation of autophagy, points to a conserved mechanism involving general and specific control of translation and autophagy as mediators of the role of eIF2α phosphorylation in aging., Ministerio de Ciencia, Innovación y Universidades (BFU2013-45003-R and BFU2017-84955-R) and Fundación Ramón Areces (“XVII Concurso Nacional”) and by Universidad Autónoma de Madrid

Background: High-density lipoproteins (HDL) are a complex mixture of lipids and proteins with vasculoprotective properties. However, HDL components could suffer post-translational modifications (PTMs) under pathological conditions, leading to dysfunctional HDL. We studied whether HDL are modified in abdominal aortic aneurysm (AAA) and the effect on HDL functionality. Methods: HDL were isolated by ultracentrifugation from AAA tissue (HDL-T) and from plasma of healthy volunteers and then incubated with AAA tissue-conditioned medium (HDL-AAA CM). PTMs from these particles were characterized using Comet-PTM. The ability of HDL-AAA CM for promoting cholesterol efflux was determined ex vivo and in vivo by using J774A.1 [ 3 H]cholesterol-labeled mouse macrophages and after injecting [ 3 H]cholesterol-labeled mouse macrophages and HDL into the peritoneal cavity of wild-type C57BL/6 mice, respectively. Trp50 and Trp108 oxidized forms of APOA1 in HDL incubated with conditioned-medium of activated neutrophils and in plasma of AAA patients and controls were measured by targeted parallel reaction monitoring. Findings: Oxidation was the most prevalent PTM in apolipoproteins, particularly in APOA1. Trp50 and Trp108 in APOA1 were the residues most clearly affected by oxidation in HDL-T and in HDL-AAA CM, when compared to their controls. In addition, cholesterol efflux was decreased in macrophages incubated with HDL-AAA CM in vitro and a decreased macrophage-to-serum reverse cholesterol transport was also observed in mice injected with HDL-AAA CM. Finally, both oxidized Trp50 and Trp108 forms of APOA1 were increased in HDL incubated with conditioned-medium of activated neutrophils and in plasma of AAA patients in relation to controls. Interpretation: Oxidative modifications of HDL present in AAA tissue and plasma were closely associated with the loss of vasculoprotective properties of HDL in AAA. Fund: MINECO, ISCiii-FEDER, CIBERDEM, CIBERCV and LA CAIXA., This work was partly funded by the Spanish MINECO (SAF2016- 80843-R and BIO2015-67580-P), Fondo de Investigaciones Sanitarias ISCiii-FEDER (Biobancos RD09/0076/00101, and ProteoRed PRB2 IPT13/0001 and PRB3 PT17/0019), Instituto de Salud Carlos III (PI1600139), and FEDER “Una manera de hacer Europa”, CIBERDEM and CIBERCV are Instituto de Salud Carlos III projects. The project leading to these results has also received funding from “la Caixa” Banking Foundation under the project code HR17-00247. The CNIC is supported by the MINECO and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505)

Introduction and objectives: Recurrence rates for patients presenting with non-muscle invasive bladder carcinoma (NMIBC) can be as high as 60% during the first year after a transurethral resection of bladder tumor (TURBT). Currently, an immediate postoperative instillation of chemotherapy (IPOIC) is recommended for the prevention of recurrences in patients with low to intermediate risk disease. Although in real clinical practice this specific instillation of chemotherapy has many difficulties to be standardized, including its contraindications (suspected or confirmed bladder perforation, wide or extensive resection and, continuous bladder irrigation requirement), which will only make it feasible for around 30% of patients. We propose in this controlled study, to administer an immediate neoadjuvant instillation of chemotherapy (INAIC), which can be applied technically to all patients, no matter the surgical outcomes and compare it with a control group. We expect to find a reduction in the recurrence rate in the experimental group of at least 15%. Methods: We designed a phase IV, randomized, controlled, open label clinical trial. Main inclusion criteria are: patients with a clinical diagnosis of localized, papillary-type bladder cancer (suspected low to intermediate risk) with a disease-free interval of at least 6 months. Eligible patients will be allocated into group A (INAIC plus TURBT) or group B (TURBT) using a computer-generated block randomization sequence/ratio 1:1. Time to recurrence of both groups will be analyzed and compared using Kaplan- Meier estimates, log-rank tests and, Cox-regression. Univariate and multivariate analyzes will be performed to determine factors which influence recurrence. The study has received the approval of the Ethics Committee for Drug Research (CEIm) of La Paz University Hospital and the Spanish Agency for Medicines and Health Products, This study received funding from grants ‘‘Rafael Molla y Rodrigo” from the Foundation for Research in Urology (Spanish Urological Association) and Immunothercan-CM(B2017/BM D3733) from the Local Government of the Community of Madrid, Madrid, Spain.

Background: In an electronic health context, combining traditional structured clinical assessment methods and routine electronic health-based data capture may be a reliable method to build a dynamic clinical decision-support system (CDSS) for suicide prevention. Objective: The aim of this study was to describe the data mining module of a Web-based CDSS and to identify suicide repetition risk in a sample of suicide attempters. Methods: We analyzed a database of 2802 suicide attempters. Clustering methods were used to identify groups of similar patients, and regression trees were applied to estimate the number of suicide attempts among these patients. Results: We identified 3 groups of patients using clustering methods. In addition, relevant risk factors explaining the number of suicide attempts were highlighted by regression trees. Conclusions: Data mining techniques can help to identify different groups of patients at risk of suicide reattempt. The findings of this study can be combined with Web-based and smartphone-based data to improve dynamic decision making for clinicians., This study received a Hospital Clinical Research Grant (PHRC 2009) from the French Health Ministry. None of the funding sources had any involvement in the study design; collection, analysis, or interpretation of data; writing of the report; or the decision to submit the paper for publication. This study was funded partially by Instituto de Salud Carlos III (ISCIII PI13/02200; PI16/01852), Delegación del Gobierno para el Plan Nacional de Drogas (20151073), and the American Foundation for Suicide Prevention (LSRG-1-005-16).

Background: In hypoxic tumors, positive feedback between oncogenic KRAS and HIF-1α involves impressive metabolic changes correlating with drug resistance and poor prognosis in colorectal cancer. Up to date, designed KRAS-targeting molecules do not show clear benefits in patient overall survival (POS) so pharmacological modulation of aberrant tricarboxylic acid (TCA) cycle in hypoxic cancer has been proposed as a metabolic vulnerability of KRAS-driven tumors. Methods: Annexin V-FITC and cell viability assays were carried out in order to verify vitamin C citotoxicity in KRAS mutant SW480 and DLD1 as well as in Immortalized Human Colonic Epithelial Cells (HCEC). HIF1a expression and activity were determined by western blot and functional analysis assays. HIF1a direct targets GLUT1 and PDK1 expression was checked using western blot and qRT-PCR. Inmunohistochemical assays were perfomed in tumors derived from murine xenografts in order to validate previous observations in vivo. Vitamin C dependent PDH expression and activity modulation were detected by western blot and colorimetric activity assays. Acetyl-Coa levels and citrate synthase activity were assessed using colorimetric/fluorometric activity assays. Mitochondrial membrane potential (Δψ) and cell ATP levels were assayed using fluorometric and luminescent test. Results: PDK-1 in KRAS mutant CRC cells and murine xenografts was downregulated using pharmacological doses of vitamin C through the proline hydroxylation (Pro402) of the Hypoxia inducible factor-1(HIF-1)α, correlating with decreased expression of the glucose transporter 1 (GLUT-1) in both models. Vitamin C induced remarkable ATP depletion, rapid mitochondrial Δψ dissipation and diminished pyruvate dehydrogenase E1-α phosphorylation at Serine 293, then boosting PDH and citrate synthase activity. Conclusion: We report a striking and previously non reported role of vitamin C in the regulation of the pyruvate dehydrogenase (PDH) activity, then modulating the TCA cycle and mitochondrial metabolism in KRAS mutant colon cancer. Potential impact of vitamin C in the clinical management of anti-EGFR chemoresistant colorectal neoplasias should be further considered., This research is supported by Ministerio de Ciencia e Innovación, Centro para el Desarrollo Tecnológico Industrial (CDTI) and Universidad Católica San Antonio (Murcia)

Omeprazole, a proton pump inhibitor used to treat peptic ulcer and gastroesophageal reflux disease, has been associated to chronic kidney disease and acute interstitial nephritis. However, whether omeprazole is toxic to renal cells is unknown. Omeprazole has a lethal effect over some cancer cells, and cell death is a key process in kidney disease. Thus, we evaluated the potential lethal effect of omeprazole over tubular cells. Omeprazole induced dose-dependent cell death in human and murine proximal tubular cell lines and in human primary proximal tubular cell cultures. Increased cell death was observed at the high concentrations used in cancer cell studies and also at lower concentrations similar to those in peptic ulcer patient serum. Cell death induced by omeprazole had features of necrosis such as annexin V/7-AAD staining, LDH release, vacuolization and irregular chromatin condensation. Weak activation of caspase-3 was observed but inhibitors of caspases (zVAD), necroptosis (Necrostatin-1) or ferroptosis (Ferrostatin-1) did not prevent omeprazole-induced death. However, omeprazole promoted a strong oxidative stress response affecting mitochondria and lysosomes and the antioxidant N-acetyl-cysteine reduced oxidative stress and cell death. By contrast, iron overload increased cell death. An adaptive increase in the antiapoptotic protein BclxL failed to protect cells. In mice, parenteral omeprazole increased tubular cell death and the expression of NGAL and HO-1, markers of renal injury and oxidative stress, respectively. In conclusion, omeprazole nephrotoxicity may be related to induction of oxidative stress and renal tubular cell death, Supported by FIS CP12/03262, CP14/00133, PI16/02057, PI16/ 01900, PI18/01366, PI19/00588, PI19/00815, DTS18/00032, ERAPerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, ISCIII-RETIC REDinREN RD016/0009 FEDER funds, Sociedad Española de Nefrología, Fundacion Renal Iñigo Álvarez de Toledo (FRIAT), ISCIII Miguel Servet (ABS, MDS-N), ISCIII Sara Borrell (JMM-M), Comunidad de Madrid CIFRA2 B2017/BMD-3686 (MF-B and DM-S)

[Rationale]: Gastric cancer (GC) is a solid tumor that contains subpopulations of cancer stem cells (CSCs), which are considered drivers of tumor initiation and metastasis; responsible for therapeutic resistance; and promoters of tumor relapse. The balance between symmetric and asymmetric division is crucial for stem cell maintenance. The objective of this study is to evaluate the role of MAD2, a key protein for proper mitotic checkpoint activity, in the tumorigenesis of GC., [Methods]: Gastric cancer stem cells (GCSCs) were obtained from MKN45, SNU638 and ST2957 cell lines. Pluripotency and stemness markers were evaluated by RT-qPCR and autofluorescence and membrane markers by flow cytometry. Relevant signal transduction pathways were studied by WB. We analysed cell cycle progression, migration and invasion after modulation of MAD2 activity or protein expression levels in these in vitro models. In vivo assays were performed in a nude mouse subcutaneous xenograft model., [Results]: We found that NANOG, CXCR4 and autofluorescence are common and consistent markers for the GCSCs analysed, with other markers showing more variability. The three main signalling pathways (Wnt/β-catenin; Hedgehog and Notch) were activated in GCSCs. Downregulation of MAD2 in MKN45CSCs decreased the expression of markers CXCR4, CD133, CD90, LGR5 and VIM, without affecting cell cycle profile or therapy resistance. Moreover, migration, invasion and tumor growth were clearly reduced, and accordingly, we found that metalloprotease expression decreased. These results were accompanied by a reduction in the levels of transcription factors related with epithelial-to-mesenchymal transition., [Conclusions]: We can conclude that MAD2 is important for GCSCs stemness and its downregulation in MKN45CSCs plays a central role in GC tumorigenesis, likely through CXCR4-SNAI2-MMP1. Thus, its potential use in the clinical setting should be studied as its functions appear to extend beyond mitosis., This work was supported by Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III, Spain, grants PI17-01401 (PR) and PI18/00757 (BS,Jr), (all co-financed through Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa”). NPL was supported by a grant FPU15/04669, funded by Ministerio de Educación, Cultura y Deporte, Spain. NPL is a fellow of the Doctoral Program in Molecular Biosciences, UAM, Madrid, Spain. BS,Jr was supported by a Ramón y Cajal Merit Award (RYC-2012-12104) from the Ministerio de Economía y Competitividad, Spain.

El CAV-AEP publica anualmente el calendario de vacunaciones que estima idóneo para los niños residentes en España, teniendo en cuenta la evidencia científica disponible. Se mantiene el esquema 2 + 1 (2, 4 y 11 meses) con vacunas hexavalentes (DTPa-VPI-Hib-HB) y con antineumocócica conjugada 13-valente. Se aconseja un refuerzo a los 6 años, preferentemente con DTPa (si está disponible), junto a una dosis de polio para aquellos que recibieron esquemas 2 + 1, así como vacunación con Tdpa en adolescentes y en cada embarazo, preferentemente entre las 27 y las 32 semanas. La vacuna del rotavirus debería ser sistemática para todos los lactantes. Se sigue proponiendo la incorporación en el calendario de la vacuna antimeningocócica B, con esquema 2 + 1 en lactantes. Además de la inclusión de la vacuna antimeningocócica conjugada tetravalente (MenACWY) a los 12 años con rescate hasta los 18 años, inclusive, el CAV recomienda que esta vacuna sea introducida también a los 12 meses de edad, sustituyendo a MenC. Igualmente, se recomienda en los mayores de 6 semanas de edad con factores de riesgo o que viajen a países de elevada incidencia de estos serogrupos. Se emplearán esquemas de 2 dosis para triple vírica (12 meses y 3-4 años) y varicela (15 meses y 3-4 años). La segunda dosis se podría aplicar como vacuna tetravírica. Se recomienda la vacunación sistemática universal frente al VPH, tanto a chicas como a chicos, preferentemente a los 12 años, debiendo realizar un mayor esfuerzo para mejorar las coberturas. La de 9 genotipos amplía la cobertura para ambos sexos, The CAV-AEP annually publishes the immunisation schedule considered optimal for all children resident in Spain, taking into account the available evidence. The 2 + 1 schedule is recommended (2, 4, and 11 months) with hexavalent vaccines (DTPa- VPI-Hib-HB) and with 13-valent pneumococcal conjugate. A 6-year booster is recommended, preferably with DTPa (if available), with a dose of polio for those who received 2 + 1 schemes, as well as vaccination with Tdpa in adolescents and in each pregnancy, preferably between 27 and 32 weeks. Rotavirus vaccine should be systematic for all infants. Meningococcal B vaccine, with a 2+1 schedule, should be included in routine calendar. In addition to the inclusion of the conjugated tetravalent meningococcal vaccine (MenACWY) at 12 years of age with catch up to 18 years, inclusive, the CAV recommends this vaccine to be also included at 12 months of age, replacing MenC. Likewise, it is recommended in those over 6 weeks of age with risk factors or who travel to countries with a high incidence of these serogroups. Two-dose schedules for MMR (12 months and 3-4 years) and varicella (15 months and 3-4 years) will be used. The second dose could be applied as a tetraviral vaccine. Universal systematic vaccination against HPV is recommended, both for girls and boys, preferably at 12 years, and greater effort should be made to improve coverage. The 9 genotype extends coverage for both genders

Introduction Patients affected by von Hippel-Lindau (VHL) disease experience an increased risk for bi-lateral, synchronous, and metachronous renal cell carcinoma (RCC). Oncologic and functional outcomes are the main goals in the management of renal masses. We present our protocol for patients with VHL disease-associated RCC alongside functional and oncologic results observed in our series. Material and methods We performed a retrospective analysis of our clinical database of patients with VHL disease-associated RCC referred to our department between June 2005 and December 2017. We offer surveillance for lesions 3 cm or growth rate >1 cm/year. Results Our series comprises 14 patients, of whom 13 had undergone at least one invasive procedure for RCC, mean age at first intervention was 27 years (range 18–60). Overall, 30 interventions were performed in 21 kidneys: four radical nephrectomies, 13 RFAs, 12 NSSs, and one embolization. During follow-up (median time: 41 months, range: 6–149), eight patients (57%) presented with new lesions that required treatment, with a mean time between treatments of 32 ±18.5 months. No metastatic progression or need for dialysis was recorded; the success rate for RFA was 85%. Conclusions Management of VHL kidney disease by NSS is the standard of care with a cut-off at 3 cm, ablative procedures should be offered to lesions ranging 2–3 cm in size. Follow-up should be done strictly in referral centers that can provide all treatment options to renal function and control oncologic progression., This research was funded by Madrid Regional Government Research Grant [S2010/BMD-2326 IMMUNOTHERCAN-CM (B2017/BMD-3733)/FEDER

Transcription factor NRF2 orchestrates a cellular defense against oxidative stress and, so far, has been involved in tumor progression by providing a metabolic adaptation to tumorigenic demands and resistance to chemotherapeutics. In this study, we discover that NRF2 also propels tumorigenesis in gliomas and glioblastomas by inducing the expression of the transcriptional co-activator TAZ, a protein of the Hippo signaling pathway that promotes tumor growth. The expression of the genes encoding NRF2 (NFE2L2) and TAZ (WWTR1) showed a positive correlation in 721 gliomas from The Cancer Genome Atlas database. Moreover, NRF2 and TAZ protein levels also correlated in immunohistochemical tissue arrays of glioblastomas. Genetic knock-down of NRF2 decreased, while NRF2 overexpression or chemical activation with sulforaphane, increased TAZ transcript and protein levels. Mechanistically, we identified several NRF2-regulated functional enhancers in the regulatory region of WWTR1. The relevance of the new NRF2/TAZ axis in tumorigenesis was demonstrated in subcutaneous and intracranial grafts. Thus, intracranial inoculation of NRF2-depleted glioma stem cells did not develop tumors as determined by magnetic resonance imaging. Forced TAZ overexpression partly rescued both stem cell growth in neurospheres and tumorigenicity. Hence, NRF2 not only enables tumor cells to be competent to proliferate but it also propels tumorigenesis by activating the TAZ-mediated Hippo transcriptional program., Graphical abstract Scheme showing the main findings of this study: NRF2 induces target genes such as GCLC, NQO1, HMOX1, etc. that in cancer cells may provide a cytoprotective response to stressful signals including radiotherapy and chemotherapy. In addition, we show here that NRF2 also induces the expression of WWTR1, encoding the transcription factor TAZ, that provides direct input into cancer progression by activating a battery of genes that participate in proliferative responses and cancer stem cell renewal. The combined expression of NRF2 and its target TAZ are characteristic of poor prognosis in glioblastomas.Image 1, Highlights • Expression of NRF2 and TAZ positively correlate in gliomas and glioblastomas. • NRF2 regulates the expression of WWTR1 encoding the transcription co-activator TAZ in glioma stem cells. • TAZ provides a redox-independent mechanism of NRF2 induction of glioblastomas. • Downregulation of the new NRF2/TAZ axis may provide a novel therapy for glioblastomas.

Background: The recently published COMPLETE trial has demonstrated that patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease (MVD), who underwent successful percutaneous coronary intervention (PCI) of both culprit and non-culprit (vs. culprit-only) lesions had a reduced risk of major adverse cardiac events (MACE), but not of cardiovascular or total mortality. The aim of this meta-analysis was to assess the efficacy of complete revascularization on cardiovascular or total mortality reduction using available randomized controlled trials (RCTs) including the COMPLETE trial, in hemodynamically stable STEMI patients with MVD. Methods: PubMed, MEDLINE, Embase, Scopus, Google Scholar, CENTRAL and ClinicalTrials.gov databases search identified 10 RCTs of 7033 patients with STEMI and MVD which compared complete (n = 3420) vs. only culprit lesion (n = 3613) PCI for a median 27.7 months follow-up. Random effect risk ratios were used to estimate for efficacy and safety outcomes. Results: Complete revascularization reduced the risk of MACE (10.4% vs.16.6%; RR = 0.59, 95% CI: 0.47 to 0.74, p < 0.0001), CV mortality (2.87% vs. 3.72%; RR = 0.73, 95% CI: 0.56 to 0.95, p = 0.02), reinfarction (5.1% vs. 7.1%; RR = 0.67, 95% CI: 0.52 to 0.86, p = 0.002), urgent revascularization (7.92% vs.17.4%; RR = 0.47, 95% CI: 0.30 to 0.73, p < 0.001), and CV hospitalization (8.68% vs.11.4%; RR = 0.65, 95% CI: 0.44to 0.96, p = 0.03) compared with culprit only revascularization. All-cause mortality, stroke, major bleeding events, or contrast induced nephropathy were not affected by the revascularization strategy. Conclusion: The findings of this meta-analysis suggest that in patients with STEMI and MVD, complete revascularization is superior to culprit-only PCI in reducing the risk of MACE outcomes, including cardiovascular mortality, without increasing the risk of adverse safety outcomes.

Luminescent nano-thermometry is a fast-developing technique with great potential for in vivo sensing, diagnosis, and therapy. Unfortunately, it presents serious limitations. The luminescence generated by nanothermometers, from which thermal readout is obtained, is strongly distorted by the attenuation induced by tissues. Such distortions lead to low signal levels and entangle absolute and reliable thermal monitoring of internal organs. Overcoming both limitations requires the use of high-brightness luminescent nanothermometers and adopting more complex approaches for temperature estimation. In this work, it is demonstrated how superbright Ag2S nanothermometers can provide in vivo, reliable, and absolute thermal reading of the liver during laser-induced hyperthermia. For that, a new procedure is designed in which thermal readout is obtained from the combination of in vivo transient thermometry measurements and in silico simulations. The synergy between in vivo and in silico measurements has made it possible to assess relevant numbers such as the efficiency of hyperthermia processes, the total heat energy deposited in the liver, and the relative contribution of Ag2S nanoparticles to liver heating. This work provides a new way for absolute thermal sensing of internal organs with potential application not only to hyperthermia processes but also to advanced diagnosis and therapy., This work was supported by the Spanish Ministry of Economy and Competitiveness under projects MAT2016‐75362‐C3‐1‐R, MAT2017‐83111R, and MAT2017‐85617‐R, by the Instituto de Salud Carlos III (PI16/00812), by the Comunidad Autónoma de Madrid (B2017/BMD‐3867 RENIM‐CM), and cofinanced by the European Structural and investment fund. Additional funding was provided by the European Union's Horizon 2020 FET Open programme (Grant Agreement No. 801305, NanoTBTech), the Fundación para la Investigación Biomédica del Hospital Universitario Ramón y Cajal project IMP18_38 (2018/0265), and also by COST action CA17140. Y.S. acknowledges a scholarship from the China Scholarship Council (No. 201806870023). I.Z.G. thanks UCM‐Santander for a predoctoral contract (CT63/19‐CT64/19). D.O. and I.R. acknowledge financial support from the Community of Madrid under Contract No. PEJD‐2017‐PRE/IND‐3663, and from the Spanish Ministry of Science and Innovation through the Ramón y Cajal grant RYC2018‐025253‐I, Research Networks grant RED2018‐102626‐T and the PID2019‐106211RB‐I00 grant as well as the Ministry of Economy and Competitiveness through the grants MAT2017‐85617‐R, MAT2017‐88148R and the “Severo Ochoa” Program for Centers of Excellence in R&D (SEV‐2016‐0686). D.O. and I.R. also acknowledge support from the “NoCanTher” project, which has received funding from the European Union's Horizon 2020 research and innovation programme under Grant Agreement No. 685795. E.X. is grateful for a Juan de la Cierva Formación scholarship (FJC2018‐036734‐I).

[Background and Purpose]: The humoral immune response in cancer patients can be used for early detection of the disease. Autoantibodies raised against tumor-associated antigens (TAAs) are promising clinical biomarkers for reliable cancer diagnosis, prognosis, and therapy monitoring. In this study, an electrochemical disposable multiplexed immunosensing platform able to integrate difficult- and easy-to-express colorectal cancer (CRC) TAAs is reported for the sensitive determination of eight CRC-specific autoantibodies., [Methods]: The electrochemical immunosensing approach involves the use of magnetic microcarriers (MBs) as solid supports modified with covalently immobilized HaloTag fusion proteins for the selective capture of specific autoantibodies. After magnetic capture of the modified MBs onto screen-printed carbon working electrodes, the amperometric responses measured using the hydroquinone (HQ)/H2O2 system were related to the levels of autoantibodies in plasma., [Results]: The biosensing platform was applied to the analysis of autoantibodies against 8 TAAs described for the first time in this work in plasma samples from healthy asymptomatic individuals (n=3), and patients with high-risk of developing CRC (n=3), and from patients already diagnosed with colorectal (n=3), lung (n=2) or breast (n=2) cancer. The developed bioplatform demonstrated an improved discrimination between CRC patients and controls (asymptomatic healthy individuals and breast and lung cancer patients) compared to an ELISA-like luminescence test., [Conclusions]: The proposed methodology uses a just-in-time produced protein in a simpler protocol, with low sample volume, and involves cost-effective instrumentation, which could be used in a high-throughput manner for reliable population screening to facilitate the detection of early CRC patients at affordable cost., This work was supported by the financial support of the PI17CIII/00045 grant from the AES-ISCIII program to R.B., cofounded by FEDER funds. The financial support of the CTQ2015-64402-C2-1-R (Spanish Ministerio de Economía y Competitividad) and RTI2018-096135-B-I00 (Ministerio de Ciencia, Innovación y Universidades) Research Projects and the TRANSNANOAVANSENS-CM Program from the Comunidad de Madrid (Grant S2018/NMT-4349) to P.Y-S., S.C. and JM.P are gratefully acknowledged. G.D. acknowledges the financial support of PI15/00246 grant of the FIS and Cátedra UAM-Roche en Medicina de Innovación. M.G-A. was supported by a contract of the Programa Operativo de Empleo Juvenil y la Iniciativa de Empleo Juvenil (YEI) with the participation of the Consejería de Educación, Juventud y Deporte de la Comunidad de Madrid y del Fondo Social Europeo. A.M-C. is a recipient of a FPU fellowship from the Ministerio de Educación, Cultura y Deporte. G.S-F. is recipient of a predoctoral contract (grant number 1193818N) supported by The Flanders Research Foundation (FWO). Predoctoral contracts from the Spanish Ministerio de Economía y Competitividad (E.P.) and Universidad Complutense de Madrid (V.R.V-M.) are also gratefully acknowledged.

Chronic neuroinflammation is a hallmark of the onset and progression of brain proteinopathies such as Alzheimer disease (AD) and it is suspected to participate in the neurodegenerative process. Transcription factor NRF2, a master regulator of redox homeostasis, controls acute inflammation but its relevance in low-grade chronic inflammation of AD is inconclusive due to lack of good mouse models. We have addressed this question in a transgenic mouse that combines amyloidopathy and tauopathy with either wild type (AT-NRF2-WT) or NRF2-deficiency (AT-NRF2-KO). AT-NRF2-WT mice died prematurely, at around 14 months of age, due to motor deficits and a terminal spinal deformity but AT-NRF2-KO mice died roughly 2 months earlier. NRF2-deficiency correlated with exacerbated astrogliosis and microgliosis, as determined by an increase in GFAP, IBA1 and CD11b levels. The immunomodulatory molecule dimethyl fumarate (DMF), a drug already used for the treatment of multiple sclerosis whose main target is accepted to be NRF2, was tested in this preclinical model. Daily oral gavage of DMF during six weeks reduced glial and inflammatory markers and improved cognition and motor complications in the AT-NRF2-WT mice compared with the vehicle-treated animals. This study demonstrates the relevance of the inflammatory response in experimental AD, tightly regulated by NRF2 activity, and provides a new strategy to fight AD., This work was funded by SAF2016-76520-R of the Spanish Ministry of Economy and Competitiveness, a Pathfinder grant of the Centres of Excellence in Neurodegeneration (COEN) of the EU-Joint Program for Neurodegenerative diseases, and European Regional Development Fund, Competitiveness Operational Program 2014–2020, through the grant P_37_732/2016 REDBRAIN and a collaborative CIBERNED project PI2017/04-3. M.P. is recipient of a FPU fellowship of Autonomous University of Madrid.

Background: Recent reports have identified distinct genomic patterns in ovarian carcinoma, including proliferative and mesenchymal-like groups, with worse outcome. The exact mechanisms driving the onset and progression of these tumors are still poorly understood. Additionally, researchers are concerned about the correct subtype stratification of the available cell line models, and the exploration of alternatives to monolayer culture. Identification of biomarkers to stratify cell lines, characterization of important processes as epithelial-mesenchymal transition (EMT), and the use of three-dimensional (3D) cultures as alternative models could be useful for cell line classification. Methods and Results: In this work, we present a descriptive analysis of 16 commonly used ovarian cancer cell lines. We have studied their morphology in 2- and 3D culture, and their response to cisplatin, observing in the majority of them an increased resistance in 3D. We have also performed an immunohistochemical analysis for proliferation marker Ki-67, and EMT related markers to establish phenotypes. Epithelial cells tend to show higher proliferative rates, and mesenchymal cells show an increase in EMT related markers, especially when cultured in 3D conditions. Conclusions: We have stated the complex heterogeneity of ovarian cancer models, resembling primary tumors, agreeing with the argument that the cell line model for in vitro experiments must be carefully chosen. Our results also support that tridimensional culture could be a very helpful alternative in ovarian cancer research. Regarding EMT, a very important process for the development of this disease, some related biomarkers might be further characterized for their role in this disease development, This work was funded by Instituto de Salud Carlos III (ISCIII) and Fondo Europeo de Desarrollo Regional (FEDER), as part of PN I+D+I 2008–2011 Program (#PI10/630) and Fundación Mutua Madrileña Funding Program. VHS was supported by a phD fellowship program (#FI11/00538, ISCIII) and CIBERONC CB16/12/00398