Development of a preclinical therapeutic model of human brain metastasis with chemoradiotherapy.

Currently, survival of breast cancer patients with brain metastasis ranges from 2 to 16 months. In experimental brain metastasis studies, only 10% of lesions with the highest permeability exhibited cytotoxic responses to paclitaxel or doxorubicin. Therefore, radiation is the most frequently used treatment, and sensitizing agents, which synergize with radiation, can improve the efficacy of the therapy. In this study we used 435-Br1 cells containing the fluorescent protein (eGFP) gene and the photinus luciferase (PLuc) gene to develop a new brain metastatic cell model in mice through five in vivo/in vitro rounds. BR-eGFP-CMV/Luc-V5 brain metastatic cells induce parenchymal brain metastasis within 60.8 ± 13.8 days of intracarotid injection in all mice. We used this model to standardize a preclinical chemoradiotherapy protocol comprising three 5.5 Gy fractions delivered on consecutive days (overall dose of 16.5 Gy) which improved survival with regard to controls (60.29 ± 8.65 vs. 47.20 ± 11.14). Moreover, the combination of radiotherapy with temozolomide, 60 mg/Kg/day orally for five consecutive days doubled survival time of the mice 121.56 ± 52.53 days (Kaplan-Meier Curve, p < 0.001). This new preclinical chemoradiotherapy protocol proved useful for the study of radiation response/resistance in brain metastasis, either alone or in combination with new sensitizing agents.

RANK is a poor prognosis marker and a therapeutic target in ER-negative postmenopausal breast cancer.

Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor, denosumab, in breast cancer patients, beyond the bone, is unclear. Aiming to select patients who may benefit from denosumab, we hereby analyzed RANK and RANKL protein expression in more than 2,000 breast tumors (777 estrogen receptor-negative, ER- ) from four independent cohorts. RANK protein expression was more frequent in ER- tumors, where it associated with poor outcome and poor response to chemotherapy. In ER- breast cancer patient-derived orthoxenografts (PDXs), RANKL inhibition reduced tumor cell proliferation and stemness, regulated tumor immunity and metabolism, and improved response to chemotherapy. Intriguingly, tumor RANK protein expression associated with poor prognosis in postmenopausal breast cancer patients, activation of NFKB signaling, and modulation of immune and metabolic pathways, suggesting that RANK signaling increases after menopause. Our results demonstrate that RANK protein expression is an independent biomarker of poor prognosis in postmenopausal and ER- breast cancer patients and support the therapeutic benefit of RANK pathway inhibitors, such as denosumab, in breast cancer patients with RANK+ ER- tumors after menopause.

Predictive and Prognostic Brain Metastases Assessment in Luminal Breast Cancer Patients: FN14 and GRP94 from Diagnosis to Prophylaxis.

FN14 has been implicated in many intracellular signaling pathways, and GRP94 is a well-known endoplasmic reticulum protein regulated by glucose. Recently, both have been associated with metastasis progression in breast cancer patients. We studied the usefulness of FN14 and GRP94 expression to stratify breast cancer patients according their risk of brain metastasis (BrM) progression. We analyzed FN14 and GRP94 by immunohistochemistry in a retrospective multicenter study using tissue microarrays from 208 patients with breast carcinomas, of whom 52 had developed BrM. Clinical and pathological characteristics and biomarkers expression in Luminal and non-Luminal patients were analyzed using a multivariate logistic regression model adjusted for covariates, and brain metastasis-free survival (BrMFS) was estimated using the Kaplan-Meier method and the Cox proportional hazards model. FN14 expression was associated with BrM progression mainly in Luminal breast cancer patients with a sensitivity (53.85%) and specificity (89.60%) similar to Her2 expression (46.15 and 89.84%, respectively). Moreover, the likelihood to develop BrM in FN14-positive Luminal carcinomas increased 36.70-fold (3.65-368.25, p = 0.002). Furthermore, the worst prognostic factor for BrMFS in patients with Luminal carcinomas was FN14 overexpression (HR = 8.25; 95% CI: 2.77-24.61; p = 0.00015). In these patients, GRP94 overexpression also increased the risk of BrM (HR = 3.58; 95% CI: 0.98-13.11; p = 0.054-Wald test). Therefore, FN14 expression in Luminal breast carcinomas is a predictive/prognostic biomarker of BrM, which combined with GRP94 predicts BrM progression in non-Luminal tumors 4.04-fold (1.19-8.22, p = 0.025), suggesting that both biomarkers are useful to stratify BrM risk at early diagnosis. We propose a new follow-up protocol for the early prevention of clinical BrM of breast cancer patients with BrM risk.

FN14 and GRP94 expression are prognostic/predictive biomarkers of brain metastasis outcome that open up new therapeutic strategies.

Brain metastasis is a devastating problem in patients with breast, lung and melanoma tumors. GRP94 and FN14 are predictive biomarkers over-expressed in primary breast carcinomas that metastasized in brain. To further validate these brain metastasis biomarkers, we performed a multicenter study including 318 patients with breast carcinomas. Among these patients, there were 138 patients with metastasis, of whom 84 had brain metastasis. The likelihood of developing brain metastasis increased by 5.24-fold (95%CI 2.83-9.71) and 2.55- (95%CI 1.52-4.3) in the presence of FN14 and GRP94, respectively. Moreover, FN14 was more sensitive than ErbB2 (38.27 vs. 24.68) with similar specificity (89.43 vs. 89.55) to predict brain metastasis and had identical prognostic value than triple negative patients (p < 0.0001). Furthermore, we used GRP94 and FN14 pathways and GUILD, a network-based disease-gene prioritization program, to pinpoint the genes likely to be therapeutic targets, which resulted in FN14 as the main modulator and thalidomide as the best scored drug. The treatment of mice with brain metastasis improves survival decreasing reactive astrocytes and angiogenesis, and down-regulate FN14 and its ligand TWEAK. In conclusion our results indicate that FN14 and GRP94 are prediction/prognosis markers which open up new possibilities for preventing/treating brain metastasis.

Los estereotipos étnicos en los profesionales del deporte / Ethnic stereotypes in sports and physical activity professionals / Os estereótipos étnicos nos profissionais do esporte

Resumen: El objetivo del artículo es conocer si los actuales y futuros profesionales del deporte poseen estereotipos étnicos respecto a los deportistas negros. Entrevistamos a 38 entrenadores profesionales y estudiantes de Educación Física y aplicamos un cuestionario a 272 estudiantes de tres Facultades de Ciencias Motoras de la región italiana del Lacio. Los resultados muestran que, entre los entrenadores y estudiantes de Educación Física, existen estereotipos étnicos, ligados a la pertenencia étnica y en relación con el rendimiento deportivo, tales como la creencia de superioridad y la predisposición biológico-genética de los deportistas negros para el baloncesto o para la carrera de velocidad, así como una menor predisposición para la natación. Esto supone elaborar una propuesta formativo-pedagógica sobre las implicaciones educativas de ciertos estereotipos entre los escolares. (AU)

Abstract: The main aim of this paper is to know whether current and future sports professionals hold ethnic stereotypes about black athletes. We interviewed a group of 38 professional coaches and Physical Education students, and administered a questionnaire to a sample of 272 students from three Movement and Health Science departments in the Italian region of Lazio. The results show that both coaches and sport science students hold ethnic stereotypes on ethnic belonging and connected to concepts of sports performance, such as the belief in biological superiority and genetic predisposition of black athletes for basketball or sprinting and their lower inclination to swimming. The study highlights the need for a pedagogical proposal on the educational implications of certain stereotypes for young students. (AU)

Resumo: O objetivo do artigo é saber se os atuais e futuros profissionais do esporte têm estereótipos étnicos a respeito dos desportistas negros. Entrevistamos 38 treinadores profissionais e estudantes de Educação Física e aplicamos um questionário a 272 estudantes de três Faculdades de Ciências Motoras da região italiana de Lácio. Os resultados mostram que, dentre os treinadores e estudantes de Educação Física, existem estereótipos étnicos ligados à procedência étnica e em relação ao rendimento desportivo, tais como a crença de superioridade e a predisposição biológico-genética dos desportistas negros para o basquete e para a corrida de velocidade, assim como uma menor predisposição para a natação. Isto supõe elaborar uma proposta formativopedagógica sobre as implicações educativas de certos estereótipos dentre os escolares. (AU)

Minimising mortality in endangered raptors due to power lines: the importance of spatial aggregation to optimize the application of mitigation measures.

Electrocution by power lines is one of the main causes of non-natural mortality in birds of prey. In an area in central Spain, we surveyed 6304 pylons from 333 power lines to determine electrocution rates, environmental and design factors that may influence electrocution and the efficacy of mitigation measures used to minimise electrocution cases. A total of 952 electrocuted raptors, representing 14 different species, were observed. Electrocuted raptors were concentrated in certain areas and the environmental factors associated with increased electrocution events were: greater numbers of prey animals; greater vegetation cover; and shorter distance to roads. The structural elements associated with electrocutions were shorter strings of insulators, one or more phases over the crossarm, cross-shaped design and pylon function. Of the 952 carcasses found, 148 were eagles, including golden eagle (Aquila chrysaetos), Spanish imperial eagle (Aquila adalberti) and Bonelli's eagle (Aquila fasciata). Electrocuted eagles were clustered in smaller areas than other electrocuted raptors. The factors associated with increased eagle electrocution events were: pylons function, shorter strings of insulators, higher slopes surrounding the pylon, and more numerous potential prey animals. Pylons with increased string of insulators had lower raptor electrocution rates than unimproved pylons, although this technique was unsuccessful for eagles. Pylons with cable insulation showed higher electrocution rates than unimproved pylons, both for raptors and eagles, despite this is the most widely used and recommended mitigation measure in several countries. To optimize the application of mitigation measures, our results recommend the substitution of pin-type insulators to suspended ones and elongating the strings of insulators.

Aprendizaje cooperativo en Educación Física / Cooperative learning in Physical Education / Aprendizagem cooperativa na Educação Física

La finalidad del estudio es conocer y analizar la concepción que tienen del aprendizaje cooperativo (AC) un grupo de docentes de Educación Física españoles que son reconocidos como referentes en esta metodología, así como el modo en que lo implementan en sus clases. Se trata de un estudio de caso múltiple, a través de entrevistas, observación no participante y análisis documental. Los resultados indican que todos los docentes participantes conocen los principios generales del AC y lo utilizan, lo conciben como una importante metodología para avanzar en diferentes ámbitos de aprendizaje, consideran que cualquier contenido puede ser enseñado con AC y valoran la importancia de la evaluación formativa y compartida

The purpose of the study is to know and analyze the concept of cooperative learning (CL) of a group of Spanish teachers of Physical Education who are recognized as references in this methodology, as well as the way they implement it in the classroom. It is a multiple case study that utilized interviews, not participant observation and documental analysis. The results indicate that all the participant teachers know the general principles of CL, utilize and consider them as an important methodology to develop the different aspects of learning. Besides, the teachers consider that any content can be taught using the CL and value the importance of the formative and shared evaluation

A finalidade do estudo é conhecer e analisar a concepção de aprendizagem cooperativa (AC) de um grupo de docentes espanhóis de Educação Física, reconhecidos como referência nesta metodologia, assim como o modo que adotam para implementá-la em suas aulas. Trata-se de um estudo de caso múltiplo que utilizou entrevistas, observação não participante e análise documental. Os resultados indicam que todos os docentes participantes conhecem os princípios gerais da AC e os utilizam, concebendo-os como uma importante metodologia para avançar nos diferentes âmbitos da aprendizagem. Além disso, consideram que qualquer conteúdo pode ser ensinado por meio da AC e valorizam a importância da avaliação formativa e compartilhada

Training needs among sport technicians / Estudio de las necesidades formativas de los técnicos deportivos

Despite the fact that during the last ten years ongoing training has become usual among Spanish workers, some labour fields are still out of this trend. Our study analyses training needs of 507 Sport Technicians classified in eight different sport specialities: Rhythmical Gymnastics (58), Athletics (70), Swimming (68), Handball (76), Volleyball (81), Football (74), Basketball (80). The results show some vital structural shortages: the initial training they receive is general and lacks specific content. The programs are weak, obsolete and far from these workers needs. For those reasons the study concludes with some basic recommendations for the development of the range of professions that Sport Technicians can carry out (AU)

A pesar del hecho de que durante los últimos diez años la formación continua ha llegado a ser habitual entre los trabajadores españoles, algunos campos profesionales han quedado al margen de esta tendencia. Nuestro estudio se centra en las necesidades de formación de 507 técnicos deportivos clasificados en ocho especialidades diferentes: Gimnasia rítmica (58), Atletismo (70), Natación (68), Handball (76), Voleibol (81), Fútbol (74) y Baloncesto (80). Los resultados muestran algunas deficiencias estructurales vitales: la formación inicial que reciben es general y carece de contenido específico. Los programas son débiles, obsoletos y alejados de las necesidades de estos trabajadores. Por esas razones el estudio concluye con algunas recomendaciones básicas para el desarrollo profesional dentro del marco de tareas que los técnicos pueden desarrollar (AU)