Hypoxic Cell Waves around Necrotic Cores in Glioblastoma: A Biomathematical Model and its Therapeutic Implications

Glioblastoma is a rapidly evolving high-grade astrocytoma that is distinguished pathologically from lower grade gliomas by the presence of necrosis and microvascular hiperplasia. Necrotic areas are typically surrounded by hypercellular regions known as "pseudopalisades" originated by local tumor vessel occlusions that induce collective cellular migration events. This leads to the formation of waves of tumor cells actively migrating away from central hypoxia. We present a mathematical model that incorporates the interplay among two tumor cell phenotypes, a necrotic core and the oxygen distribution. Our simulations reveal the formation of a traveling wave of tumor cells that reproduces the observed histologic patterns of pseudopalisades. Additional simulations of the model equations show that preventing the collapse of tumor microvessels leads to slower glioma invasion, a fact that might be exploited for therapeutic purposes.Comment: 29 pages, 9 figure

Autophagy is activated and involved in cell death with participation of cathepsins during stress-induced microspore embryogenesis in barley

Microspores are reprogrammed towards embryogenesis by stress. Many microspores die after this stress, limiting the efficiency of microspore embryogenesis. Autophagy is a degradation pathway that plays critical roles in stress response and cell death. In animals, cathepsins have an integral role in autophagy by degrading autophagic material; less is known in plants. Plant cathepsins are papain-like C1A cysteine proteases involved in many physiological processes, including programmed cell death. We have analysed the involvement of autophagy in cell death, in relation to cathepsin activation, during stress-induced microspore embryogenesis in Hordeum vulgare. After stress, reactive oxygen species (ROS) and cell death increased and autophagy was activated, including HvATG5 and HvATG6 up-regulation and increase of ATG5, ATG8, and autophagosomes. Concomitantly, cathepsin L/F-, B-, and H-like activities were induced, cathepsin-like genes HvPap-1 and HvPap-6 were up-regulated, and HvPap-1, HvPap-6, and HvPap-19 proteins increased and localized in the cytoplasm, resembling autophagy structures. Inhibitors of autophagy and cysteine proteases reduced cell death and promoted embryogenesis. The findings reveal a role for autophagy in stress-induced cell death during microspore embryogenesis, and the participation of cathepsins. Similar patterns of activation, expression, and localization suggest a possible connection between cathepsins and autophagy. The results open up new possibilities to enhance microspore embryogenesis efficiency with autophagy and/or cysteine protease modulators.España, MINECO AGL2014-52028-R and AGL2017-82447-

Combined therapies of antithrombotics and antioxidants delay in silico brain tumor progression

Glioblastoma multiforme, the most frequent type of primary brain tumor, is a rapidly evolving and spatially heterogeneous high-grade astrocytoma that presents areas of necrosis, hypercellularity and microvascular hyperplasia. The aberrant vasculature leads to hypoxic areas and results in an increase of the oxidative stress selecting for more invasive tumor cell phenotypes. In our study we assay in silico different therapeutic approaches which combine antithrombotics, antioxidants and standard radiotherapy. To do so, we have developed a biocomputational model of glioblastoma multiforme that incorporates the spatio-temporal interplay among two glioma cell phenotypes corresponding to oxygenated and hypoxic cells, a necrotic core and the local vasculature whose response evolves with tumor progression. Our numerical simulations predict that suitable combinations of antithrombotics and antioxidants may diminish, in a synergetic way, oxidative stress and the subsequent hypoxic response. This novel therapeutical strategy, with potentially low or no toxicity, might reduce tumor invasion and further sensitize glioblastoma multiforme to conventional radiotherapy or other cytotoxic agents, hopefully increasing median patient overall survival time.Comment: 8 figure

Phosphorus Availability Regulates TORC1 Signaling via LST8 in Chlamydomonas

Target of rapamycin complex 1 (TORC1) is a central regulator of cell growth. It balances anabolic and catabolic processes in response to nutrients, growth factors, and energy availability. Nitrogen- and carbon-containing metabolites have been shown to activate TORC1 in yeast, animals, and plants. Here, we show that phosphorus (P) regulates TORC1 signaling in the model green alga Chlamydomonas (Chlamydomonas reinhardtii) via LST8, a conserved TORC1 subunit that interacts with the kinase domain of TOR. P starvation results in a sharp decrease in LST8 abundance and downregulation of TORC1 activity. A hypomorphic lst8 mutation resulted in decreased LST8 abundance, and it both reduced TORC1 signaling and altered the cellular response to P starvation. Additionally, we found that LST8 levels and TORC1 activity were not properly regulated in a mutant defective in the transcription factor PSR1, which is the major mediator of P deprivation responses in Chlamydomonas. Unlike wild-type cells, the psr1 mutant failed to downregulate LST8 abundance and TORC1 activity when under P limitation. These results identify PSR1 as an upstream regulator of TORC1 and demonstrate that TORC1 is a key component in P signaling in Chlamydomonas.España Ministerio de Economía y Competitividad (grants BFU2015-68216-P and PGC2018-099048- B-100 to J.L.C. and grant BIO2015-74432-JIN to M.E.P.-P.)National Science Foundation (CAREER award MCB-1552522 to L.M.H. and grant MCB-1616820 to J.G.U.)European Commission (grant number 750996

Fatores de estresse percebidos entre carreiras de enfermagem recém entradas

Objective: To determine the prevalent stress factors among new students to the Faculties of Nursing at the Faculties of Nursing at the Universities of Cadiz, Cordoba, Huelva and Seville, and the influence of socio-demographic, academic, socio-economic, orientation and health factors. Design: A descriptive, observational and cross-sectional study. Methodology: 617 first year nursing students were surveyed (with a 95.66 % response rate) by means of two questionnaires, one for socio-demographics and health, the other for the stress perceived by new students. A descriptive analysis of the stress factors was then carried out for the frequency, mean and standard deviation. The relation between factors was examined through differential analysis by means of the Mann-Whitney U and Kruskal-Wallis non-parametric tests. Results: The situations of greatest anxiety among new undergraduates are “taking examinations” and “the amount of work I have to do”. Consequently, the most stressful factor is “academic stress” whilst the least stressful is “feelings of loneliness”. The students who feel most stress across various factors can be identified as: over 25, women, studying outside their home province, and living in rented accommodation during the academic year. Conclusions: Starting a degree in nursing is a stressful time, and students can find their health, quality of life and academic performance negatively affected. The main determinants of stress among new undergraduates are the joint demands of examinations and workload. It would undoubtedly be enlightening to examine this issue further in order to find the possible causes of the problem and to develop strategies that can help in its prevention and so improve the students’ experience of university.Objetivo: Conocer los factores de estrés más prevalentes en el alumnado novel de las Facultades de Enfermería de las Universidades de Cádiz, Córdoba, Huelva y Sevilla, así como su relación con sus características sociodemográficas, académicas, socioeconómicas, de orientación y de salud. Diseño: Estudio observacional, descriptivo, transversal. Metodología: Se encuestó a un total de 617 estudiantes (tasa de respuesta del 95,66 %) del primer curso del grado en Enfermería. Los participantes completaron dos cuestionarios: uno sociodemográfico y de salud; y un  cuestionario de estrés percibido por alumnos noveles. Se realizó un análisis descriptivo de los factores de estrés con frecuencia, media y desviación típica. Las relaciones se examinaron con análisis diferencial a través de estudios no paramétricos U Mann-Whitney y Kruskal-Wallis. Resultados: Las situaciones que más estrés causan a los nuevos universitarios son: “hacer frente a los exámenes” y “la cantidad de trabajo que tengo que afrontar”. En consecuencia, el factor más estresante es el “estrés académico” y el menos estresante el “sentimiento de soledad”. Los estudiantes que perciben mayor estrés en varios factores son: mayores de 25 años, mujeres, el alumnado que procede de otras provincias y los que viven de alquiler durante el curso académico. Conclusiones: La entrada a la universidad produce factores de estrés en el alumnado de enfermería, que pueden afectar a su salud, su calidad de vida y su rendimiento académico. Hacer frentes a los exámenes y la alta carga académica son las principales determinantes de estrés. Sin embargo, sería conveniente indagar más en esta línea con el fin de conocer las posibles causas de este problema y poder desarrollar estrategias de prevención que mejoren la calidad de vida de estos estudiantes.Objetivo: Conhecer os fatores de estresse mais prevalentes em novos alunos das Faculdades de Enfermagem das Universidades de Cádis, Córdoba, Huelva e Sevilha, bem como sua relação com suas características sociodemográficas, acadêmicas, socioeconômicas, de orientação, educacionais e saúde. Delineamento: Estudo observacional, descritivo, transversal. Metodologia: Foram pesquisados ​​617 alunos (taxa de resposta de 95,66 %) do primeiro ano do curso de Enfermagem. Os participantes responderam a dois questionários: sociodemográfico e de saúde; e questionário de estresse percebido por alunos iniciantes. Foi realizada análise descritiva dos fatores de estresse com frequência, média e desvio padrão. Os relacionamentos foram examinados com análise diferencial por meio de estudos não paramétricos de U Mann-Whitney e Kruskal-Wallis. Resultados: As situações que mais estressam os novos estudantes universitários são “fazer exames” e “a quantidade de trabalho que tenho que enfrentar”. Conseqüentemente, o fator mais estressante é o “estresse acadêmico” e o menos estressante são os “sentimentos de solidão”. Os alunos que percebem o maior estresse em vários fatores são: maiores de 25 anos, mulheres, alunos que vêm de outras províncias e aqueles que vivem de aluguel durante o ano letivo. Conclusões: O ingresso na universidade produz fatores estressantes nos estudantes de enfermagem, que podem afetar sua saúde, sua qualidade de vida e seu desempenho acadêmico. A realização de exames e a alta carga acadêmica são apontados como os principais determinantes do estresse. No entanto, seria conveniente aprofundar as investigações nesse sentido para conhecer as possíveis causas desse problema e poder desenvolver estratégias de prevenção que melhorem a qualidade de vida desses alunos

Milk Density in Two Dairy Collection Routes for Pasteurizing Plant in Camagüey.

Milk density values were assessed in two  dairy collection routes (Route 6 and Purialito)  for Pasteurizing Plant in Camagüey, Cuba. The study was carried out in the months of March-April-May, 2013, where 179 samples were as-sessed, and a density values database was created. A descriptive statistical analysis for density was performed with SPSS 15.0. Using simple variance analysis through a general linear model, the effects of route, month, and their int e-ractions on milk  weight, were measured. The multiple comparison test (Tuckey) was performed to contrast density differences between months. Route and month significantly influenced on milk density (P ≤ 0.05); the same behavior was observed for  route-month interaction (P ≤ 0.05). The mean values and ranges of dairy density were within the normal limits, though in May they decreased to  1.027 g/cm3 . The multiple comparison test  (Tuckey) showed significant levels (P ≤ 0.001) between March and April; and March and May (P ≤ 0.05); no statistical significant dif-ferences were observed between April and May. The better route was Purialito in terms of dairy density

ATIPICIDADES EN UN CASO CON DISPLASIA ARRITMOGÉNICA DEL VENTRÍCULO DERECHO O ENFERMEDAD DE UHL / Report of an atypical case with arrhythmogenic right ventricular dysplasia or Uhl´s anomaly

ResumenLa displasia arritmogénica del ventrículo derecho es una miocardiopatía caracterizada por arritmias ventriculares malignas y anomalías estructurales progresivas, que afectan primariamente al ventrículo derecho. Se presenta por una sustitución progresiva parcial o masiva del miocardio por tejido adiposo o fibroadiposo. La enfermedad de Uhl puede ser una manifestación extrema y generalizada de la displasia arritmogénica del ventrículo derecho, trastorno congénito muy poco frecuente con ausencia de miocardio ventricular derecho, por lo que sus paredes son delgadas como el papel. Se comenta el caso de un paciente masculino de 56 años que presentó pérdida de conocimiento y se le realizó el diagnóstico clínico y ecocardiográfico. Se discuten las características clínicas, el diagnóstico y la conducta a seguir ante esta cardiopatía potencialmente letal en pacientes que sufren síncope, taquicardia ventricular o parada cardíaca. / AbstractArrhythmogenic right ventricular dysplasia is a cardiomyopathy characterized by malignant ventricular arrhythmias and progressive structural abnormalities, affecting primarily the right ventricle. It appears due to a partial or massive progressive replacement of the myocardium by fibroadipose or adipose tissue. Uhl's disease may be an extreme and widespread manifestation of arrhythmogenic right ventricular dysplasia, a rare congenital disorder with absence of right ventricular myocardium, so that its walls are paper thin. The case of a 56 year old male patient who had loss of consciousness and underwent clinical and echocardiographic diagnosis is presented. The clinical features, diagnosis and action to take against this potentially fatal heart disease in patients with syncope, ventricular tachycardia or cardiac arrest are discussed

Delay effects in the response of low-grade gliomas to radiotherapy: a mathematical model and its therapeutical implications

Low-grade gliomas (LGGs) are a group of primary brain tumours usually encountered in young patient populations. These tumours represent a difficult challenge because many patients survive a decade or more and may be at a higher risk for treatment-related complications. Specifically, radiation therapy is known to have a relevant effect on survival but in many cases it can be deferred to avoid side effects while maintaining its beneficial effect. However, a subset of LGGs manifests more aggressive clinical behaviour and requires earlier intervention. Moreover, the effectiveness of radiotherapy depends on the tumour characteristics. Recently Pallud et al. (2012. Neuro-Oncology, 14, 1-10) studied patients with LGGs treated with radiation therapy as a first-line therapy and obtained the counterintuitive result that tumours with a fast response to the therapy had a worse prognosis than those responding late. In this paper, we construct a mathematical model describing the basic facts of glioma progression and response to radiotherapy. The model provides also an explanation to the observations of Pallud et al. Using the model, we propose radiation fractionation schemes that might be therapeutically useful by helping to evaluate tumour malignancy while at the same time reducing the toxicity associated to the treatmen

Cell death during the postnatal morphogenesis of the normal rabbit kidney and in experimental renal polycystosis

We have studied, by means of optic and electron microscopy, the normal and abnormal cell death that takes place during the postnatal morphogenesis of rabbit kidney, and in the experimental renal polycystosis produced by methylprednisolone acetate. In the normal kidney intertubular cell death can be observed during the first 20 days of the postnatal development. However, cell death in the normal metanephric blastema is a very rare event. In the polycystic kidney numerous dead cells can be seen between the third and forty eighth days after injection. The topography and morphology of the dead cells depend on the stage in the evolution of the disease. In the 'stage of renal immaturity', dying and dead cells are present in the nephrogenic tissue, in the dilating collecting tubules and in the intertubular spaces. In this stage the cellular pathology is essentially nuclear. In the stage of tubular cysts, the dead cells are mostly located in the walls of cysts, with some dead cells, but mostly cellular debris in their lumina. At this stage the cellular pathology is basically cytoplasmic. The dead cells are eventually digested by what appear to be phagocytes of tubular epithelial origin. It is suggested that cell death is an important factor in the evolution of the lesions of renal polycystosis induced by corticosteroids, and probably in the initiation of the pathological process as wel

Calcificaciones discales idiopáticas en la infancia: A propósito de un caso

Las calcificaciones discales en la infancia constituyen una rara entidad; frecuentemente son asintomáticas, pero en ocasiones producen síntomas como cervicalgia o dorsalgia. El pronóstico suele ser bueno en casi todos los pacientes. Presentamos el caso de un niño de 11 años de edad, que consultó por dolor en región dorsal, fiebre y una velocidad de sedimentación globular elevada. La radiología nos mostró la presencia de 2 calcificaciones discales en el segmento torácico. Tras una semana de tratamiento conservador, se produce una completa resolución del cuadro clínico, persistiendo las calcificaciones discales.Invertebral disc calcification in childhood is rare. Most frequently are not symptomatic, but occasionally evoke symptoms like neck pain or back pain. The prognosis of nearly all patients is good. We report on a 11-year-old child, who suffered from acute back pain, fever and elevated erythrocyte sedimentation rates. The X-Ray revealed two calcified discs in the thoracic region. After one week of conservative treatment, a complete resolution of the symptoms is observed, however the radiologic findings showed the persistence of invertebral disc calcifications