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Patients with nonalcoholic fatty liver disease (NAFLD) may show mild cognitive impairment (MCI). The mechanisms involved remain unclear. The plasma concentrations of several cytokines and chemokines were measured in 71 NAFLD patients (20 with and 51 without MCI) and 61 controls. Characterization and activation of leukocyte populations and CD4+ sub-populations were carried out and analyzed by flow cytometry. We analyzed the cytokines released from CD4+ cell cultures and the mRNA expression of transcription factors and receptors in peripheral blood mononuclear cells. The appearance of MCI in NAFLD patients was associated with increased activation of CD4+ T lymphocytes, mainly of the Th17 subtype, increased plasma levels of pro-inflammatory and anti-inflammatory cytokines such as IL-17A, IL-23, IL-21, IL-22, IL-6, INF-γ, and IL-13, and higher expression of the CCR2 receptor. Constitutive expression of IL-17 was found in cultures of CD4+ cells from MCI patients, reflecting Th17 activation. High IL-13 plasma levels were predictive of MCI and could reflect a compensatory anti-inflammatory response to the increased expression of pro-inflammatory cytokines. This study identified some specific alterations of the immune system associated with the appearance of neurological alterations in MCI patients with NAFLD that could be the basis to improve and restore cognitive functions and quality of life in these patients.

Background and aims Underlying mechanisms associated with vascular dysfunction in metabolic syndrome (MetS) remain unclear and can even vary from one vascular bed to another. Methods In this study, MetS was induced by a high-fat, high-sucrose diet, and after 28 weeks, aorta and renal arteries were removed and used for isometric recording of tension in organ baths, protein expression by Western blot, and histological analysis to assess the presence of atherosclerosis. Results MetS induced a mild hypertension, pre-diabetes, central obesity and dyslipidaemia. Our results indicated that MetS did not change the contractile response in either the aorta or renal artery. Conversely, vasodilation was affected in both arteries in a different way. The aorta from MetS showed vascular dysfunction, including lower response to acetylcholine and sodium nitroprusside, while the renal artery from MetS presented a preserved relaxation to acetylcholine and an increased sensitivity to sodium nitroprusside. We did not find vascular oxidative stress in the aorta from MetS, but we found a significant decrease in PPARγ, phospho-Akt (p-Akt) and phospho-eNOS (p-eNOS) protein expression. On the other hand, we found oxidative stress in the renal artery from MetS, and PPARγ, Akt and p-Akt were overexpressed. No evidence of atherosclerosis was found in arteries from MetS. Conclusions MetS affects vascular function differently depending on the vessel. In the aorta, it decreases both the vasodilation and the expression of the PPARγ/Akt/eNOS pathway, while in the renal artery, it increases the expression of PPARγ/Akt signalling pathway without decreasing the vasodilation.

Primary meningeal melanocytomas are rare tumors of the central nervous system. Although they are considered benign neoplasms, some reports describe recurrent rates up to 45%. Little is known about their genetic and epigenetic landscape because of their infrequency. Even less has been described about markers with prognostic value. Here we describe a patient who developed a primary meningeal melanocytoma, suffered 3 recurrences in a period of 6 years and died of the tumor. The genetic and epigenetic changes explored confirmed GNAQ mutation as an initiating event. We found an epigenetic alteration of GSTP1, a feature that has recently been described in meningiomas, from the beginning of the disease. In addition, there was loss of heterozygosity in BRCA1 beginning in the second recurrence that was linked to an increase in the proliferation index; this suggested a progression pathway similar to the one described in uveal melanomas. These findings underscore the necessity of further research focused on these tumors.

Patients with cirrhosis may show minimal hepatic encephalopathy (MHE), for which rifaximin is effective. Metabolic syndrome may be associated with cognitive impairment. Our aims were to evaluate the influence of metabolic syndrome features on response to rifaximin for neurological and inflammatory alterations in MHE. A prospective cohort study was conducted in 63 cirrhotic patients and 30 controls from two tertiary centres recruited between 2015 and 2019. Metabolic syndrome was defined according to the Adult Treatment Panel-III. Patients were classified into 31 without and 32 with MHE according to the Psychometric Hepatic Encephalopathy Score (PHES). All participants performed specific psychometric tests, and inflammatory parameters were studied. Patients with MHE received rifaximin (400 mg/8 h). Response was evaluated by PHES at 3 and 6 months. Response according to metabolic syndrome manifestations was compared. The response rate was 66%. Older age (p = 0.012) and all metabolic syndrome diseases (p p p = 0.011), working memory (p = 0.005), visual coordination (p = 0.013) and lower proportion of activated CD4+ lymphocytes (p = 0.039) at baseline, as well as worse concentration (p = 0.030), bimanual coordination (p = 0.004) and higher levels of intermediate monocytes (p = 0.026), CX3CL1 (p p = 0.022), AHR (p = 0.010) and IgG (p

Patients with nonalcoholic fatty liver disease (NAFLD) may show mild cognitive impairment (MCI). The neurological functions affected remain unclear. The aims were to: (1) Characterize the neuropsychological alterations in NAFLD patients; (2) assess the prevalence of impairment of neurological functions evaluated; (3) develop a new score for sensitive and rapid MCI detection in NAFLD; (4) assess differences in MCI features between patients with nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH); and (5) compare neuropsychological alterations in NAFLD patients with cirrhotic patients with MCI. Fifty-nine NAFLD patients and 53 controls performed psychometric tests assessing different neurological functions: PHES (Psychometric Hepatic Encephalopathy Score) battery, d2, Stroop, Oral SDMT (Symbol Digit Modalities Test), Digit Span, number-letter test, and bimanual and visual-motor coordination tests. NAFLD patients show impairment in attention, mental concentration, psychomotor speed, cognitive flexibility, inhibitory mental control, and working memory. We developed a new, rapid, and sensitive score based on the most affected parameters in NAFLD patients, unveiling that 32% of NAFLD show MCI. Prevalence was similar in NAFL (36%) or NASH (27%) patients, but lower in NAFLD than in cirrhosis (65%). MCI prevalence is significant in NAFLD patients. Psychometric testing is warranted in these patients to unveil MCI and take appropriate measures to reverse and prevent its progression.

Glioblastoma multiforme (GBM) is the most aggressive human brain tumor, and GBM stem cells (GSC) may be responsible for its recurrence and therapeutic resistance. Toll-like receptors (TLRs), which recognize multiple ligands (endogenous and pathogen-associated) and trigger the immune response of mature immune cells, are also expressed by hematopoietic stem and progenitor cells, where their activation results in the differentiation of these cells into myeloid cells. Since TLR expression has been recently described in neural cells, including neural stem cells, we studied TLR expression by GSCs and the effect of stimulation by TLR ligands on promoting GSC differentiation into mature GBM cells. First, our results showed heterogeneous TLR expression by GBM cells from human tumors and, for the first time, by human GSCs defined by their CD133+ and CD44+ phenotypes. Next, the effect of TLR ligands was studied in in vitro cell cultures of neurospheres and CD44+ cells obtained from two GBM cell lines (U-87 and U-118). The expression of GSC markers diminished in the presence of Pam3CSK4 or LPS (TLR2 and TLR4 ligands, respectively), thus indicating TLR-dependent differentiation. Interestingly, simultaneous treatment with Pam3CSK4 plus temozolomide (TMZ), the reference drug in GBM treatment, significantly increased cell death compared to the effect of the ligand alone, which showed no toxicity, or TMZ alone. These results suggest a synergistic effect between Pam3CSK4 and TMZ based on the induction of TLR-dependent GSC differentiation towards mature GBM cells, which exhibited increased sensitivity to chemotherapy, and provide new perspectives in GBM therapy.

Meningiomas are the most frequent primary brain tumor. Usually, they are curable by surgery, but even after seemingly complete resection, some low-grade lesions recur. Despite recent improvements, signatures having prognostic value in grade I tumors remain poorly characterized. The frequency and delicate location of these tumors suggest that the risk of recurrence might be more accurately predicted. Herein, we show an easy way to evaluate the methylation status of meningiomas and its correlation with the prognosis of the disease. A series of 120 meningiomas, including primary tumors and recurrences, were analyzed histopathologically, and 24 tumor suppressor genes (TSGs) were studied by methylation-specific multiple ligation probe amplification. Long-term follow-up was conducted to classify patients with grade I primary tumors according to their outcomes. We found that hypermethylation in at least one TSG is frequent. The number of hypermethylated TSG per case was significantly higher in recurrences than in primary tumors and in primary benign meningiomas that recurred than in tumors from patients who showed no evidence of disease during follow-up. Finally, hypermethylation in RASSF1A, MLH1, and CDKN2B was an independent prognostic factor associated with the time to recurrence of these benign tumors that were biologically aggressive. To our knowledge, this is one of the widest studies of primary grade I tumors of patients who developed a tumor recurrence. The frequency of epigenetic changes suggests that hypermethylation is an early event in meningiomas, whereas the accumulation of epigenetic changes is related to greater biological aggressiveness and may be a signature of potential clinical relevance.

Meningioma (MN) is an important cause of disability, and predictive tools for estimating the risk of recurrence are still scarce. The need for objective and cost-effective techniques addressed to this purpose is well known. In this study, we present methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as a friendly method for deepening the understanding of the mechanisms underlying meningioma progression. A large follow-up allowed us to obtain 50 samples, which included the primary tumor of 20 patients in which half of them are suffering one recurrence and the other half are suffering more than one. We histologically characterized the samples and performed MS-MLPA assays validated by FISH to assess their copy number alterations (CNA) and epigenetic status. Interestingly, we determined the increase in tumor instability with higher values of CNA during the progression accompanied by an increase in epigenetic damage. We also found a loss of HIC1 and the hypermethylation of CDKN2B and PTEN as independent prognostic markers. Comparison between grade 1 and higher primary MN’s self-evolution pointed to a central role of GSTP1 in the first stages of the disease. Finally, a high rate of alterations in genes that are related to apoptosis and autophagy, such as DAPK1, PARK2, BCL2, FHIT, or VHL, underlines an important influence on cell-death programs through different pathways.

[EN] Multimedia material supports both teachers and students in the teaching-learning process, obtaining satisfactory results. The current educational system uses a mechanical and rigid mechanism in which teaching is fragmented and disconnected by subjects. Our work aims to report a new academic proposal where a new integrative multimedia material is developed about membrane transport between different subjects and degrees in the Health Area. The results were very satisfactory because the students' opinion about the video was very positive and well-rated. This work clarified the need for a change in the educational system., [ES] El material multimedia apoya tanto al profesorado como al alumnado en el proceso enseñanza-aprendizaje obteniendo buenos resultados. El sistema educativo actual utiliza un mecanismo mecánico y rígido en el cual la docencia está fragmentada e inconexa por asignaturas. Nuestro trabajo pretende abordar una nueva propuesta educativa en la que se elabora un material multimedia integrativo sobre el transporte de membrana entre diferentes asignaturas y grados del Área de la Salud. Los resultados fueron muy satisfactorios ya que la opinión del alumnado sobre el vídeo fue muy positiva y bien calificada. Este trabajo elucida la necesidad de un cambio en el sistema educativo.

[EN] The use of smartphones, despite being mainly social, has begun to be implemented in the university environment as a tool for working in class and for communication between students regarding teaching material. However, before creating teaching methodologies that use these devices, it is important to know the opinion that the students have of them. Our objective was to analyze the personal and academic use of Smartphones by Health Sciences students from different Universities. With this objective, a form was created consisting of sociodemographic questions and the Questionnaire on perceptions and attitudes towards learning through mobile devices (CPAAM). Subsequently, a descriptive analysis of the results was carried out. In total, 233 students participated. Our results showed that the personal is the largest use of Smartphones in these students, while the perception of their educational use is relatively low. Obtaining these data is a starting point for future analyzes that associate the use of these devices with the individual situation of the student, as well as for the effectiveness of the implementation of new learning methodologies., [ES] El uso de los dispositivos móviles, a pesar de ser principalmente social, se ha comenzado a implantar en el ámbito universitario como herramienta para trabajar en clase y para la comunicación entre estudiantes de cara al material docente. Sin embargo, antes de la creación de metodologías docentes que utilicen estos dispositivos, es importante conocer la opinión que el estudiantado tiene de los mismos. Nuestro objetivo fue analizar el uso personal y académico de los teléfonos móviles por el estudiantado de Ciencias de la Salud de diferentes Universidades. Para ello, se creó un formulario compuesto por preguntas de carácter sociodemográfico y por el Cuestionario sobre percepciones y actitudes hacia el aprendizaje por dispositivos móviles (CPAAM). Posteriormente, se realizó un análisis descriptivo de los resultados. En total, participaron 233 estudiantes. Nuestros resultados demuestran que el personal es el mayor de los usos de los dispositivos móviles en la población estudiada mientras que la percepción de su uso educativo es relativamente baja. La obtención de estos datos supone un punto de partida para futuros análisis que asocien el uso de estos dispositivos a la situación individual del estudiantado, así como para la efectividad de la implantación de nuevas metodologías docentes.

[ES] Los grupos tutorizados de la asignatura “Biología” de 1º de Medicina (Universitat de València) son un entorno estupendo en el que desarrollas actividades que aúnen el carácter formativo conceptual con el desarrollo competencial transversal. Para ello, en el curso 19-20, hemos implementado la vinculación de la cuenta institucional UV con Microsoft 365, gracias al convenio existente entre ambas entidades para facilitar la utilización de las Tecnologías de la Información y la Comunicación (TICs) en la gestión del tiempo y del intercambio de información. Se propone a los alumnos la elaboración de objetos de aprendizaje propios y originales, en formato animación, que serán utilizados durante los próximos dos años por otros estudiantes y en último término, por asociaciones externas, en un proyecto que trata de aunar el Aprendizaje-Servicio con la utilización de las TIC en un contexto en que el alumno se hace responsable de su aprendizaje y del de sus compañeros., [EN] The tutored groups of the subject “Biology” of 1st year of Medicine (Universitat de València) are a wonderful environment in which you develop activities that combine the character of conceptual training with the transversal development of competences. For this purpose, during the academic year 19-20, we have implemented the link between the UV institutional account with Microsoft 365, thanks to the existing agreement between both entities to facilitate the use of Information and Communication Technologies (ICTs) in the management of the time and information exchange. Students are proposed to create their own original learning objects, in animation format, which will be used over the next two years by other students and ultimately by external associations, in a project that tries to combine Service-Learning with the use of ICT in a context in which students are responsible for their own learning and that of his classmates.

Pleomorphic undifferentiated sarcoma (PUS), also called malignant fibrous histiocytoma, is a soft tissue sarcoma which occurs predominantly in the extremities. Its origin is a poorly defined mesenchymal cell, which derives to histiocytic and fibroblastic cells. The patient, a 58 year-old man, presented a lesion located in the forearm composed by spindle cells and multinucleated giant cells, which expressed vimentin and adopted a histological pattern formed by irregular-swirling fascicles. Cells were cultured in vitro and a new cell line was established. We characterized this new cell line by histological analyses, cytogenetics (using G-bands and spectral karyotype technique) and cytometric analyses. Cells were grown in culture for more than 100 passages. They had elongated or polygonal morphology. The cells presented a saturation rate of 70,980 cells/cm2, a plating efficiency of 21.5% and a mitotic index of 21 mitoses per field. The cell line was tumorigenic in nude mice. The ploidy study using flow cytometry revealed an aneuploid peak with a DNA index of 1.43. A side population was detected, demonstrating the presence of stem and progenitor cells. Cytogenetics showed a hypotriploid range with many clonal unbalanced rearrangements. Loss of p53 gene was evidenced by MLPA. We describe, for the first time, the characterization of a new human PUS TP53-null cell line called mfh-val2. Mfh-val2 presents a wide number of applications as a TP53-null cell line and a great interest in order to characterize genetic alterations influencing the oncogenesis or progression of PUS and to advance in the biological investigation of this tumor.

We report a case of a recurrent clear cell meningioma (CCM) in the frontal lobe of the brain of a 67-year-old man. The patient developed three recurrences: at 3, 10, and 12 years after his initial surgery. Histopathology observations revealed a grade 2 CCM with positivity for vimentin and epithelial membrane antigen. Expression of E-cadherin was positive only in the primary tumour and in the first available recurrence. Fluorescence in situ hybridization analyses demonstrated 1p and 14q deletions within the last recurrence. Multiplex ligation-dependent probe amplification studies revealed a heterozygous partial NF2 gene deletion, which progressed to total loss in the last recurrence. The last recurrence showed homozygous deletions in CDKN2A and CDKN2B. The RASSF1 gene was hypermethylated during tumour evolution. In this report, we show the genetic alterations of a primary ccm and its recurrences to elucidate their relationships with the changes involved in the progression of this rare neoplasm.

A novel cell line derived from a human glioblastoma (GB), named GB-val4, has been established and characterized. GB-val4 cells were hyperdiploid, with many numerical and structural chromosomal rearrangements. The cell line did not show mutations in IDH1/IDH2 genes or EGFR amplification, but it presented two missense mutations in TP53, which imply a very low p53 protein activity within the cell line. Cells also had gain of TP73 copies, hypermethylation of APC, CASP8 and RASSF1, increased expression of ARF1, CDH1 and NF-κB and decreased expression of CDKN2A. Tumorigenity was demonstrated by transplant of GB-val4 cells into athymic nude mice, where solid tumors were grown. Interestingly, a high percentage of GB-val4 cells presented expression of GSC markers CD133 or CD44. These GSC markers were increased in neurosphere cultures, which better mimic solid tumor conditions and maintain the genetic features of the tumor cells. In this study, we aimed to define the characteristics of this novel cell line and its applications in human cancer research. With its genetic features and a poor p53 activity, GB-val4 cells resemble GB tumors. Moreover, the important presence of GSCs in adherent cultures and especially in neurosphere cultures makes GB-val4 an attractive tool to study cancer stem cells, deepen in the knowledge the molecular pathways of GB and develop new therapeutic strategies for patients with these tumors.

Glioblastoma (GBM) is the most common malignant primary tumor of the central nervous system. With no effective therapy, the prognosis for patients is terrible poor. It is highly heterogeneous and EGFR amplification is its most frequent molecular alteration. In this light, we aimed to examine the genetic heterogeneity of GBM and to correlate it with the clinical characteristics of the patients. For that purpose, we analyzed the status of EGFR and the somatic copy number alterations (CNAs) of a set of tumor suppressor genes and oncogenes. Thus, we found GBMs with high level of EGFR amplification, low level and with no EGFR amplification. Highly amplified tumors showed histological features of aggressiveness. Interestingly, accumulation of CNAs, as a measure of tumor mutational burden, was frequent and significantly associated to shortened survival. EGFR-amplified GBMs displayed both a higher number of concrete CNAs and a higher global tumor mutational burden than their no EGFR-amplified counterparts. In addition to genetic changes previously described in GBM, we found PARK2 and LARGE1 CNAs associated to EGFR amplification. The set of genes analyzed allowed us to explore relevant signaling pathways on GBM. Both PARK2 and LARGE1 are related to receptor tyrosine kinase/PI3K/PTEN/AKT/mTOR-signaling pathway. Finally, we found an association between the molecular pathways altered, EGFR amplification and a poor outcome. Our results underline the potential interest of categorizing GBM according to their EGFR amplification level and the usefulness of assessing the tumor mutational burden. These approaches would open new knowledge possibilities related to GBM biology and therapy.

Glioblastoma multiforme (GBM) is the most aggressive human brain tumor, and GBM stem cells (GSC) may be responsible for its recurrence and therapeutic resistance. Toll-like receptors (TLRs), which recognize multiple ligands (endogenous and pathogen-associated) and trigger the immune response of mature immune cells, are also expressed by hematopoietic stem and progenitor cells, where their activation results in the differentiation of these cells into myeloid cells. Since TLR expression has been recently described in neural cells, including neural stem cells, we studied TLR expression by GSCs and the effect of stimulation by TLR ligands on promoting GSC differentiation into mature GBM cells. First, our results showed heterogeneous TLR expression by GBM cells from human tumors and, for the first time, by human GSCs defined by their CD133

Cirrhotic patients may experience alterations in the peripheral nervous system and in somatosensory perception. Impairment of the somatosensory system could contribute to cognitive and motor alterations characteristic of minimal hepatic encephalopathy (MHE), which affects up to 40% of cirrhotic patients. We assessed the relationship between MHE and alterations in thermal, vibration, and/or heat pain sensitivity in 58 cirrhotic patients (38 without and 20 with MHE according to Psychometric Hepatic Encephalopathy Score) and 39 controls. All participants underwent attention and coordination tests, a nerve conduction study, autonomic function testing, and evaluation of sensory thresholds (vibration, cooling, and heat pain detection) by electromyography and quantitative sensory testing. The detection thresholds for cold and heat pain on the foot were higher in patients with, than those without MHE. This hyposensitivity was correlated with attention deficits. Reaction times in the foot were longer in patients with, than without MHE. Patients with normal sural nerve amplitude showed altered thermal sensitivity and autonomic function, with stronger alterations in patients with, than in those without MHE. MHE patients show a general decrease in cognitive and sensory abilities. Small fibers of the autonomic nervous system and thermal sensitivity are altered early on in MHE, before large sensory fibers. Quantitative sensory testing could be used as a marker of MHE.

Migration of glioblastoma cells into surrounding tissue is one of the main features that makes this tumor incurable. We evaluated whole-genome miRNA expression profiling associated with different EGFR amplification patterns in 30 cases of primary glioblastoma. From the 64 miRNAs that showed differential expression between tumors with a high level of EGFR amplification and tumors without EGFR amplification, 40% were related with cell migration, being miR-200c the most differentially expressed between these two groups. We investigated the effect of miR-200c on ZEB1 expression and cell migration in an in vitro transfection model with a miR-200c mimic, a miR-200c inhibitor and siRNA targeting EGFR in three short-term cultures with different levels of EGFR amplification obtained from resected glioblastomas. The cell culture with the highest EGFR amplification level presented the lowest miR-200c expression and the status of EGFR modulated the effect of miR-200c on ZEB1 expression. Silencing EGFR led to miR-200c upregulation and ZEB1 downregulation in transfected cultures, except in the presence of high levels of EGFR. Likewise, miR-200c upregulation decreased ZEB1 expression and inhibited cell migration, especially when EGFR was not amplified. Our results suggest that modulating miR-200c may serve as a novel therapeutic approach for glioblastoma depending on EGFR status.

Glioblastoma multiforme (GB) is one of the most aggressive tumors. Despite continuous efforts to improve its clinical management, there is still no strategy to avoid a rapid and fatal outcome. EGFR amplification is the most characteristic alteration of these tumors. Although effective therapy against it has not yet been found in GB, it may be central to classifying patients. We investigated somatic-copy number alterations (SCNA) by multiplex ligation-dependent probe amplification in a series of 137 GB, together with the detection of EGFRvIII and FISH analysis for EGFR amplification. Publicly available data from 604 patients were used as a validation cohort. We found statistical associations between EGFR amplification and/or EGFRvIII, and SCNA in CDKN2A, MSH6, MTAP and ADD3. Interestingly, we found that both EGFRvIII and losses on ADD3 were independent markers of bad prognosis (p = 0.028 and 0.014, respectively). Finally, we got an unsupervised hierarchical classification that differentiated three clusters of patients based on their genetic alterations. It offered a landscape of EGFR co-alterations that may improve the comprehension of the mechanisms underlying GB aggressiveness. Our findings can help in defining different genetic profiles, which is necessary to develop new and different approaches in the management of our patients.

[EN] Cell cultures allow the maintenance of living cells outside the body. This technique is fundamental to study the biological, biochemical and physiological properties of cells and can be used as an experimental model in vitro in the field of biomedical research. The teaching in the laboratory of this technique presents numerous difficulties at a practical, logistical and economic level. On the other hand, the learning of cell culture protocols is an important part of the student's training in Cell Biology. Based on the routine practices carried out within a cell culture laboratory, we have developed the virtual 3D simulator of a cell culture laboratory "Cellusim". In "Cellusim" you can perform basic tasks of the cell culture of an established cell line of your own (Mel-RC08, Gil-Benso et al., 2012). To make Cellusim more attractive and intuitive to students, it has been developed in the Unity graphic environment, commonly used for the development of video games. The system includes the simulator in Unity, a mysql server with users, passwords and logs and a web of help and explanatory videos. In the simulator the student can virtually execute the essential tasks that are performed in a cell culture laboratory, such as thawing cells, seeding the cells, preparing and changing culture media and making cell subcultures. Cellusim is a training tool that allows users to discover the basics of cell culture techniques in a simple and fast way and without the economic costs or time consumption derived from doing the same work in a real laboratory. In order to evaluate the students' learning, Cellusim can be executed in training mode and in evaluation mode, allowing the student to perform all the processes as many times as necessary to become familiar with the protocols and when be able to execute them in evaluation mode. In evaluation mode, Cellusim records student errors in order to score the acquired training. In this communication we present the Cellusim project and the results of the first experiences with volunteer students of Master's Degrees in the School of Medicine., [ES] Los cultivos celulares permiten el mantenimiento de células vivas fuera del organismo. Esta técnica es fundamental para estudiar las propiedades biológicas, bioquímicas y fisiológicas de las células y puede ser utilizada como modelo experimental in vitro en el ámbito de la investigación biomédica. La enseñanza en el laboratorio de esta técnica presenta numerosas dificultades a nivel práctico, logístico y económico. Por otra parte, el aprendizaje de los protocolos del cultivo celular resultan una parte importante de la formación del alumno de Biología Celular. Basándonos en las prácticas rutinarias llevadas a cabo dentro de un laboratorio de cultivos celulares, hemos desarrollado el simulador virtual 3D de un laboratorio de cultivos celulares “Cellusim”. En “Cellusim” se pueden realizar tareas básicas del cultivo celular de una línea celular establecida propia (Mel‐RC08, Gil‐Benso y cols., 2012). Para hacer Cellusim más atractivo e intuitivo a los alumnos, ha sido desarrollado en el entorno gráfico Unity, utilizado habitualmente para el desarrollo de videojuegos. El sistema incluye el simulador en Unity, un servidor mysql con usuarios, contraseñas y registros y una web de ayuda y videos explicativos. En el simulador el alumno puede ejecutar de modo virtual las tareas esenciales que se realizan en un laboratorio de cultivos celulares, tales como la descongelación de células, el sembrado de las células, la preparación y el cambio de medios de cultivo y el subcultivo celular o técnica de doblaje. Cellusim es una herramienta formativa que permite a los usuarios descubrir los fundamentos de las técnicas básicas de cultivo celular de una manera sencilla, rápida y sin los costes económicos ni el consumo de tiempo derivados de realizar el mismo trabajo en un laboratorio real. Para poder evaluar el aprendizaje de los alumnos, Cellusim puede ser ejecutado en modo entrenamiento y en modo evaluación, permitiendo que el alumno realice todos los procesos las veces que sea necesario para familiarizarse con los protocolos y que cuando esté en condiciones pueda ejecutarlas en modo evaluación. En modo evaluación, Cellusim registra los errores del alumno para poder puntuar la formación adquirida. En esta comunicación presentamos el proyecto Cellusim y los resultados de las primeras experiencias con alumnos voluntarios de Master de la Facultad de Medicina.

[EN] Dramatization as a teaching methodology remains relatively unknown in higher education. It can be especially useful to work cross-disciplinary skills because of the cooperative nature that is intrinsic to the theater itself. The subjects and disciplines that can benefit from it must be adequately valued by teachers. Here we present an activity in small groups, focused on rare diseases with a known genetic cause, in which the theater is used as a motivating axis to gather information and organize it by creating a storyline., [ES] La teatralización como metodología de enseñanza es una gran desconocida en la educación superior. Su utilización para trabajar competencias transversales puede resultar especialmente útil por el carácter cooperativo intrínseco al propio teatro y las temáticas y disciplinas que pueden beneficiarse de ella deben ser adecuadamente valoradas por los docentes. Presentamos una actividad en grupos tutorizados, centrada en enfermedades raras con causa genética conocida, en la que el teatro sirve como eje motivador para recabar la información y organizarla creando un hilo argumental.

[EN] The multimedia material used as a teaching medium in the classroom can help the teaching-learning process of the students. It also helps the teacher in his work of transmitting information from another point of view more striking and entertaining. This would cause an enlargement and enrichment in the recipient's experience to assimilate more quickly, dynamically and fluidly. In this study we analyze the grades obtained with and without the help of a multimedia material prepared by teachers. Subsequently, the opinion of the students is collected through an anonymous and voluntary survey allowing the teachers to collect the information necessary for the search to improve the quality of teaching., [ES] El material multimedia usado como medio didáctico en el aula puede ayudar al proceso enseñanza-aprendizaje del alumnado. Además le sirve de apoyo al profesor en su labor de trasmitir la información desde otro punto de vista más llamativo y entretenido. Esto provocaría una ampliación y enriquecimiento en la experiencia del receptor para asimilar el contenido didáctico de manera más rápida, dinámica y fluida. En este estudio se analizan las calificaciones obtenidas con y sin ayuda de un material multimedia elaborado por profesores. Posteriormente, se recoge la opinión del alumnado mediante una encuesta anónima y voluntaria permitiendo al profesorado recoger la información necesaria para a partir de ésta, elaborar unos objetivos de mejora de la calidad de la enseñanza.

[EN] The main objective of this paper is to analyze the opinion and perspective that the students have in view of the methodology of working in tutored groups. This methodology adopted in the teaching-learning process is important for the development of competences. The ability to work in a team and the ability to communicate are very significant transversal competences that have a great impact or potential in student learning. This paper presents an analysis of student assessments collected through anonymous opinions after the elaboration of a tutorial work carried out in a group in the Medicine Degree of the University of Valencia during the years 2015-2016 and 2016- 2017. It is essential to take into account the opinion of the students to adopt measures of teacher improvement, correct or modify the methodology and solve situations arising in the real learning environment. Our conclusion is the students' perspective is very positive and they like the methodology of working in tutored groups., [ES] El objetivo de este trabajo es analizar la opinión y perspectiva que tiene el alumnado ante la metodología de trabajar en grupos tutorizados. Esta metodología adoptada en el proceso de enseñanza-aprendizaje es importante para el desarrollo de competencias. La capacidad de trabajo en equipo y la capacidad para comunicarse son competencias transversales muy significativas y que tienen un gran impacto o potencial en el aprendizaje del alumno. Se presenta en este trabajo un análisis de las valoraciones del alumnado recogidas mediante opiniones anónimas después de la elaboración de un trabajo tutorizado realizado en grupo en el Grado de Medicina de la Universitat de València durante los cursos 2015-2016 y 2016-2017. Es fundamental tener en cuenta la opinión del alumnado para adoptar medidas de mejora docente, corregir o modificar la metodología y resolver situaciones surgidas en el entorno real de aprendizaje. Nuestra conclusión es que la perspectiva del alumnado es muy positiva que les gusta la metodología de trabajar en grupos tutorizados.

[EN] After the success last year using gamification as a motivating method in the degree of Biomedical Engineering (UV-UPV), we introduce it this year in degree in Podiatry (UV). On the basis of the results of our first study, we focus on the use of Kahoot application in order to improve our students’ motivation and subsequently, their califications. Despite the short timeexperience, the improvement in academic results has been evident. Although it could be due to many causes, it has been influenciated by this action. In addition, during the development of this type of activity the involvement and fun of our students does not cease to amaze us. They enjoy their successes and also their failures. We enjoyed with an spectacular feedback, which was almost non-existent during the classic class format., [ES] Tras el éxito el curso pasado de la gamificación como método motivador en el grado de Ingeniería Biomédica (UV-UPV), utilizamos el método este año en el grado en Podología (UV). A la luz de los resultados del primer estudio nos centramos en el uso de la aplicación Kahoot, para tratar de mejorar la motivación de los estudiantes hacia nuestra asignatura, y en consecuencia, sus calificaciones. A pesar de lo corta que es la experiencia, hemos obtenido una importante mejora en el rendimiento, que si bien puede atribuirse a diveresas causas, en parte ha sido influenciada por esta iniciativa. Durante el desarrollo de este tipo de actividad no deja de sorprendernos la implicación y diversión de nuestros estudiantes. Ellos disfrutan de sus aciertos y también de sus fallos. Nosotros disfrutamos de un feedback espectacular, que era casi inexistente con el formato clásico de clase.

Resumen La astenia en el paciente con cancer es definida como una sensacion abrumadora y persistente de cansancio o agotamiento relacionado con el cancer o el tratamiento de este, que disminuye o impide la capacidad para el trabajo mental o fisico en el contexto de su actividad diaria y a pesar de un buen descanso. Es uno de los primeros sintomas que puede presentarse en el paciente con cancer, afectando de manera importante a la calidad de vida. El objetivo de esta revision es detallar las diferentes causas que influyen en la astenia y describir las escalas de medida que mas frecuentemente se utilizan para estudiarla. La metodologia empleada en esta revision es narrativa. En esta revision describimos como la astenia es un concepto multidimensional, ya que casi siempre esta provocada o influenciada por multiples causas. Esta multidimensionalidad interviene tambien en la comprension de la fisiopatologia. Por esta razon en esta revision diferenciaremos entre astenia primaria y secundaria definiendo y detallando cada una de ellas. Por otro lado, tambien analizamos el tipo de escalas empleadas para medir la astenia diferenciando entren las que miden la astenia de forma primaria o las que la miden desde un punto de vista multidimensional.

[EN] Technological development offers several new opportunities to improve the quality of teaching. Under the ongoing task as a teachers of motivating and teaching how to learn to our students, we present the results of a session that consisted of two gamificated and groupal activities (quiz format) and a single self-assessment, based all of them on the use of their own electronic enabled devices (bring your own device). This implies an enriching, fun and practical experience to approach the course, and it provided interesting feedback to continue implementing new technologies at the university., [ES] El desarrollo tecnológico ofrece infinidad de nuevas posibilidades para mejorar la calidad de la docencia. Bajo la continua tarea como docentes de motivar y enseñar a aprender a los alumnos, presentamos los resultados de una sesión que constó de dos actividades grupales gamificadas (formato concurso) y una individual de autoevaluación, fundamentadas en el uso de sus propios dipositivos electrónicos (bring your own device). Supuso una experiencia enriquecedora, divertida y práctica para el abordaje de la asignatura, y nos proporcionó un interesante “feedback” para continuar implementando las nuevas tecnologías en la universidad.

[EN] The main objective of this paper is to describe the experience developed in university teaching using gamification as a teaching tool. Gamification is the term used to refer to the application of game mechanics in areas in which gaming is not typically used. Our working hypothesis is based on the idea that gaming can be a new methodology that favors the settlement and internalizing the concepts taught by making the learning process and integrate asset and related contents of an attractive and motivating way for students.In order to assess the experience of students we have spent an anonymous survey and we have analyzed their answers. Our conclusion is that gamification has a good welcome and it is able to increase the level of attention and knowledge consolidation, [ES] El objetivo fundamental del presente trabajo es describir la experiencia desarrollada en docencia universitaria usando la gamificación como herramienta docente. El término de gamificación se utiliza para referirnos a la aplicación de mecánicas de juego en ámbitos que normalmente no son lúdicos. Nuestra hipótesis de trabajo se basa en que el juego puede ser una nueva metodología que favorezca el asentamiento e interiorización de los conceptos impartidos haciendo que el proceso de aprendizaje sea activo y que integren y relacionen contenidos de un modo atractivo y motivante para el alumnado. Con el fin de valorar la experiencia del alumnado distribuimos una encuesta anónima y analizamos sus respuestas. Nuestra conclusión es que la gamificación tiene una buena acogida y consigue aumentar el grado de atención y de consolidación de conocimientos.

Chondrosarcomas are malignant cartilage-forming tumors that represent the third most common malignant solid tumor of bone. In patients with grades II and III, local recurrence, increasing tumor size and dedifferentiation have been associated with lower survival rates. These biologically poorly-understood neoplasms vary considerably in clinical presentation and biological behavior. Cytogenetic studies have shown that heterogeneity is related to karyotypic complexity; moreover, alterations in the 9p21 locus and TP53 gene are related to disease progression. Despite the relatively high frequency of chondrosarcoma only a limited number of cell lines exist in the scientific community, limiting the possibility to study hypothesis-derived research or primary drug interaction necessary for pre-clinical studies. We report a chondrosarcoma cell line, CH-3573, derived from a primary tumor that may serve as a useful tool for both in vitro and in vivo models to study the molecular pathogenesis. In addition, xenograft passages in nude mice were studied to characterize the genetic stability over the course of tumor progression. In contrary to other reported cell lines, an important feature of our established cell line was the retained matrix production, a characteristic feature of a conventional grade II chondrosarcoma. The cell line (CH-3573) was characterized by pathological, immunohistochemical and molecular genetic methods.

Resumen Objetivo Evaluar la mejora del nivel de calidad en el proceso de prescripcion-transcripcion de ordenes medicas, tras la implantacion de la hoja de prescripcion preimpresa. Metodo Se definieron nueve criterios de calidad: cuatro relativos a la prescripcion del medicamento (nombre, dosis, via, pauta) y cinco a su transcripcion (nombre, presentacion, dosis, via, periodicidad). Se evaluo el cumplimiento sobre las prescripciones de 7 dias consecutivos, en una unidad de hospitalizacion de medicina interna. Se efectuaron dos medidas: la primera con una orden medica manual y la segunda con una orden medica preimpresa, en la que figura el tratamiento del dia anterior y sobre el se introducen manualmente las modificaciones. Resultados En la primera evaluacion, sobre 620 medicamentos prescritos, el numero de incumplimientos fue de 767. De ellos, el 92,5% correspondio a criterios de prescripcion y el 7,5% a criterios de transcripcion. Los criterios de prescripcion con mas incumplimientos fueron: la via de administracion (42%), la dosis (29%) y la pauta (15,5%). El criterio de transcripcion mas incumplido fue el de periodicidad (3%). En el estudio de revaluacion, el total de incumplimientos se redujo a 183. Las diferencias fueron estadisticamente significativas para todos los criterios de prescripcion y para dos de transcripcion. Conclusiones En primer lugar, la implantacion de la hoja preimpresa ha supuesto una mejora importante en el nivel de calidad del proceso de prescripcion-transcripcion de ordenes medicas, en los aspectos formales evaluados; en segundo lugar, los criterios de prescripcion supusieron mas del 90% de los incumplimientos, lo que plantea nuevas intervenciones destinadas a informar al medico prescriptor; y por ultimo, el alto nivel de cumplimiento de los criterios de transcripcion lo convierte en objetivo de medidas de monitorizacion.

Glioblastoma (GBM) is the most frequent and malignant primary brain tumor. Conventional therapy of surgical removal, radiation and chemotherapy is largely palliative. Major vault protein (MVP), the main component of the vault organelle has been associated with multidrug resistance by reducing cellular accumulation of chemotherapeutic agents. With regard to cancer, MVP has been shown to be overexpressed in drug resistance development and malignant progression. The aim of the present study was to evaluate the MVP gene dosage levels in 113 archival samples from GBM and its correlation with patients' survival and epidermal growth factor receptor (EGFR) and phosphatase and tensin homolog (PTEN) gene dosages. Fluorescent in situ hybridization revealed polysomy of chromosome 7 in 76.1% of the GBMs and EGFR amplification in a 64.6% of the tumors. Genetic status of EGFR, PTEN and MVP copies was determined by multiplex ligation-dependent probe amplification (MLPA) technique. 31% of the tumors showed the EGFR is variant III mutation (EGFRvIII) mutation and 74.3% of them presented amplification of MVP gene. Amplification of EGFR and MVP was found in a 63.7% and 56.6% of the GBM, respectively. An inverse correlation between MVP and PTEN dosage values was observed. Besides, an inverse relationship between the survival of the patients treated with chemotherapy and the levels of MVP copies was determined. In conclusion, our study reveals an important role of MVP, together with EGFRvIII and PTEN, in the progression of GBM and proposes it as a novel and interesting target for new treatment approaches.

Objective:Knowledge of symptom prevalence and adequate assessment of such symptoms at the end of life is important in clinical practice. We determined the frequency and severity of symptom distress and delirium using the Edmonton Assessment Scale (ESAS) and the Memorial Delirium Assessment Scale (MDAS) and evaluated the clinical utility of the Nursing Delirium Screening Scale (Nu-DESC) as scored by a caregiver as a screening tool for delirium.Method:We conducted a secondary analysis of the data from a previous randomized controlled trial on parenteral hydration at the end of life of patients admitted to home hospice. Only patients that had assessments within the last week of life were included. We collected the ESAS, MDAS, Nu-DESC, and Richmond Agitation Sedation Scale (RASS) results. The sensitivity and specificity of the Nu-DESC were then calculated.Results:Some 78 of 261 patients were included in our study, 62 (80%) of which had moderate-to-severe symptoms corresponding to an ESAS score >4. These symptoms include: 73 (94%) anorexia, 63 (81%) fatigue, 56 (73%) drowsiness, 58 (75%) decreased well-being, and 39 (51%) pain. Delirium was diagnosed in 34 (44%) of patients using the MDAS. The Nu-DESC was found to have a sensitivity of 35%, a specificity of 80%, a positive predictive value (PPV) of 58%, and an negative predictive value (NPV) of 61% when used by caregivers.Significance of Results:Hospice patients at the end of life have a high rate of symptom distress and delirium. The Nu-DESC is not a reliable tool for screening delirium when scoring is conducted by a caregiver. Our study illustrates the need for routine use of assessment tools to improve care.

A flow-injection configuration for the chemiluminescent (CL) determination of chlorpromazine, trimeprazine and trifluoperazine is proposed. The procedure is based on the oxidation of the drugs by Fe(III) perchlorate. The Fe(II) formed is measured by its catalytic effect on the CL luminol reaction in the absence of added oxidant. Linear calibration graphs were obtained between 2.0×10 −6 and 1.0×10 −4 M for all three drugs. The applicability of the method to the determination of these phenothiazines was demonstrated by investigating the effect of potential interferences and by analysing commercial pharmaceutical preparations.

Around 20% of meningiomas histologically benign may be clinically aggressive and recur. This strongly affects management of meningioma patients. There is a need to evaluate the potential aggressiveness of an individual meningioma. Additional criteria for better classification of meningiomas will improve clinical decisions as well as patient follow up strategy after surgery. The aim of this study was to determine the relationship between gene expression profiles and new metabolic subgroups of benign meningioma with potential clinical relevance. Forty benign and fourteen atypical meningioma tissue samples were included in the study. We obtained metabolic profiles by NMR and recurrence after surgery information for all of them. We measured gene expression by oligonucleotide microarray measurements on 19 of them. To our knowledge, this is the first time that distinct gene expression profiles are reported for benign meningioma molecular subgroups with clinical correlation. Our results show that metabolic aggressiveness in otherwise histological benign meningioma proceeds mostly through alterations in the expression of genes involved in the regulation of transcription, mainly the LMO3 gene. Genes involved in tumor metabolism, like IGF1R, are also differentially expressed in those meningioma subgroups with higher rates of membrane turnover, higher energy demand and increased resistance to apoptosis. These new subgroups of benign meningiomas exhibit different rates of recurrence. This work shows that benign meningioma with metabolic aggressiveness constitute a subgroup of potentially recurrent tumors in which alterations in genes regulating critical features of aggressiveness, like increased angiogenesis or cell invasion, are still no predominant. The determination of these gene expression biosignatures may allow the early detection of clinically aggressive tumors.

The spectrophotometric determination of trace amounts of ambroxol was carried out by liquid-liquid extraction using Bromothymol Blue with a flow-injection system. The determination of ambroxol in the range 8 × 10−6–4 × 10−4 M was possible with a sampling frequency of 40 samples h−1. The method was satisfactorily applied to the determination of ambroxol in pharmaceutical preparations.

A novel human malignant melanoma cell line, designated MEL-RC08, was established from a pericranial metastasis of a malignant melanoma of the skin. The cell line has been subcultured for more than 150 passages and is tumorigenic in nude mice. Growth kinetics, cytogenetics, flow cytometry, and molecular techniques for analysis of the genes implicated in cell cycle control; mutations in BRAF, NRAS, C-KiT, RB, and TP53 genes; and amplification of MDM2, CDK4, and cyclin D1 have been studied. Cytogenetically, the tumor and the cell line showed a hypertriploid karyotype with many clonal numeric and structural abnormalities. DNA flow cytometry showed an aneuploid peak with a DNA index value of 1.5. Mutations in TP53 and BRAF genes were demonstrated in both tumor and cell line. Furthermore, stem cell marker CD133 expression was detected in most cells, together with other stem cell markers, suggesting the presence of cells with tumor-initiating potential in this cell line.

Food-drug interactions can produce negative effects in the safety and efficacy of drug therapy, as well as in the nutritional status of the patient. However, the data commonly provided to the prescriber about possible nutrient-pharmacological compound interactions and the recommendations for their prevention are often scarce. The summary of product characteristics (SmPC) of a proprietary medicinal product, as authorised by the health authorities in Europe, is usually the main source of information for the health professional. Therefore, the SmPC can be a useful tool to prevent or reduce food-drug interactions and, as a consequence, improve the therapeutical approach.The aim of this study was to assess the information about food-drug interactions with potential clinical relevance as it is described in the SmPCs of the authorised medicinal products in a European Union country (Spain).A bibliographical search of food-drug interactions, including nutrients and alcohol, was carried out. The adequate information to be included in the SmPC was defined in accordance with the European Recommendations in this field. The SmPCs of the medicinal products containing selected active substances were examined with emphasis on food-drug interactions.It was found that, frequently, the information concerning food-drug interactions as is mentioned in the SmPC of the authorised medicinal products in Spain does not fulfil the current recommendations, both in quantity and quality. Indeed, the available data reveal that the food-drug information is only mentioned in 72.7% of all SmPC where it should be and it was only found in the specific section for interactions in 36.0% of all cases. The description and agreement with recommendations for each SmPC item ranged between 4.2% and 36.0% and between 31.8% and 49.0%, respectively. Some related factors, such as the clinical relevance of the interaction, the existence of an authorised SmPC and the registration procedure followed, influence the information characteristics concerning food-drug interactions.The SmPC is a suboptimal source of information for food-drug interactions.

Dear Editor: The final question that a researcher asks once his or her work is completed is ‘‘which journal should I send this article to?’’ It is recommended that researchers publish their articles in one of the 3,700 leading world scientific journals that are included in the Science Citation Index (SCI); the highest impact factor (IF) is specified according to the Journal of Citation Report, with the higher position specified within its subcategory, Journal. There are criticisms relating to the equity, opportunity, and interest of measure research within these criteria, but evaluation agencies constantly seek to obtain this quality indicator in order to compare curricula for professional promotion or in the competition for grants. Ultimately, researchers, like any other human beings, must make an income from their work, and the prestige emanating from these classifications may be important in enabling them to achieve that. Our research question could therefore be of relevance to many professional groups. The objective of this work is to identify in the journals in which the most active palliative care researchers have published their works in the last three years. In order to find out who these active researchers are, we selected the authors that contributed in excess of six abstracts to one or both of the European Association of Palliative Care Research Congresses, which took place in Venetia and Trondheim (2006 and 2008, respectively). Then, we searched the SCI in order to obtain references from the work of these researchers between 2007 and 2009. From the SCI references, we ranked the journals by frequency, noting both the 2008 IF and the best quartile position within the category of each journal. We found the 28 most active researchers in the last two European Research Congresses. These authors contributed 516 references in 119 different SCI journals during the last three years (Table 1). In Table 2 we demonstrate the distribution by journal: 232 of the articles (45%) belong to five main journals of the Health Care Science and Service category: Palliative Medicine (18%), Journal of Palliative Care (13%), Journal of Pain and Symptom Management (12%), Journal of Palliative Medicine (7%), and Supportive Care in Cancer (5%). It is also important to emphasize the contribution of palliative care researchers to journals classified within the category of Oncology: 72 articles (14%) were published in journals included in this category. Other categories where in excess of three articles were published include anesthesia, health care science, general medicine, neurology, nursing, pharmacology, psychology and public environmental and occupational