c-Jun N-terminal kinase phosphorylation is a biomarker of plitidepsin activity

This is an open access article distributed under the Creative Commons Attribution License.-- et al.Plitidepsin is an antitumor drug of marine origin currently in Phase III clinical trials in multiple myeloma. In cultured cells, plitidepsin induces cell cycle arrest or an acute apoptotic process in which sustained activation of c-Jun N-terminal kinase (JNK) plays a crucial role. With a view to optimizing clinical use of plitidepsin, we have therefore evaluated the possibility of using JNK activation as an in vivo biomarker of response. In this study, we show that administration of a single plitidepsin dose to mice xenografted with human cancer cells does indeed lead to increased phosphorylation of JNK in tumors at 4 to 12 h. By contrast, no changes were found in other in vitro plitidepsin targets such as the levels of phosphorylated-ERK, -p38MAPK or the protein p27KIP1. Interestingly, plitidepsin also increased JNK phosphorylation in spleens from xenografted mice showing similar kinetics to those seen in tumors, thereby suggesting that normal tissues might be useful for predicting drug activity. Furthermore, plitidepsin administration to rats at plasma concentrations comparable to those achievable in patients also increased JNK phosphorylation in peripheral mononuclear blood cells. These findings suggest that changes in JNK activity provide a reliable biomarker for plitidepsin activity and this could be useful for designing clinical trials and maximizing the efficacy of plitidepsin.This work has been partially supported by grants (Programa Cenit, CEN-20091016, SAF2010-18302 and Fondo Europeo de Desarrollo Regional-Instituto de Salud Carlos III, RD12/0036/0021) from Ministerio de Economía y Competitividad of Spain.Peer Reviewe

Determinants of Satisfaction with an Urban Tourism Destination: The Case of Barcelona

Conscious of the central role of satisfaction in the success of a destination we examine the relationship between a destination's attributes and overall satisfaction. Based on the information about 19 destination attributes and using a principal factor analysis, we identified 5 relevant dimensions, with “Accommodation and restaurant services†as the key factor to explain overall satisfaction. Next, we explore the potential moderating effects of tourist and trip characteristics on that relationship. Our results suggest that the estimated relationship is very stable across types of tourists, trip features or purpose of travel. We use a survey of 2,484 interviews conducted with international tourists that visited Barcelona throughout 2013. Empirical findings allow an efficient allocation of resources in order to achieve maximum satisfaction. Therefore, they are useful to help policy makers and entrepreneurs select targets for promotion, and attain high destination competitiveness

Forest Ecosystem Services: An Analysis of Worldwide Research

The relevance of forests to sustain human well-being and the serious threats they face have led to a notable increase of research works on forest ecosystem services during the last few years. This paper analyses the worldwide research dynamics on forest ecosystem services in the period from 1998 to 2017. A bibliometric analysis of 4284 articles was conducted. The results showed that the number of published research articles has especially increased during the last five years. In total, 68.63% of the articles were published in this period. This research line experiences a growing trend superior to the general publishing trend on forest research. In spite of this increase, its relative significance within the forest research is still limited. The most productive subject areas corresponded to Environmental Science, Agricultural and Biological Sciences and Social Sciences Economic topics are understudied. The scientific production is published in a wide range of journals. The three first publishing countries are United States, China and the United Kingdom. The most productive authors are attached to diverse research centres and their contributions are relatively recent. A high level of international cooperation has been observed between countries, institutions and authors. The findings of this study are useful for researchers since they give them an overview of the worldwide research trends on forest ecosystem services

The Sustainable Management of Metals: An Analysis of Global Research

The objective of this study was to analyze research trends in the field of sustainable management of metals on a global level between 1993 and 2017. To do so, a bibliometric analysis was carried out on a total of 6967 articles. The results revealed the growing interest in this research field, particularly over the last five year-period during which 63% of all articles were published. The three journals in which most articles had been published were the Journal of Cleaner Production, ACS Sustainable Chemistry and Engineering, and Chemsuschem. The countries that published the most articles were China, the United States, India, Germany, and the United Kingdom. A sizeable network of collaboration has been established between countries for the joint publication of studies. The main lines of research have been focused on metal decontamination in water and soil, waste management oriented towards reuse and recycling, and the innovation of processes for cleaner and more efficient production. The results revealed the need for comprehensive studies that integrate different disciplines within the same analytical framework, and to promote research that contributes to the different dimensions of sustainability (environmental, economic, and social)

Neocortical tissue recovery in severe congenital obstructive hydrocephalus after intraventricular administration of bone marrow-derived mesenchymal stem cells

BACKGROUND: In obstructive congenital hydrocephalus, cerebrospinal fluid accumulation is associated with high intracranial pressure and the presence of periventricular edema, ischemia/hypoxia, damage of the white matter, and glial reactions in the neocortex. The viability and short time effects of a therapy based on bone marrow-derived mesenchymal stem cells (BM-MSC) have been evaluated in such pathological conditions in the hyh mouse model. METHODS: BM-MSC obtained from mice expressing fluorescent mRFP1 protein were injected into the lateral ventricle of hydrocephalic hyh mice at the moment they present a very severe form of the disease. The effect of transplantation in the neocortex was compared with hydrocephalic hyh mice injected with the vehicle and non-hydrocephalic littermates. Neural cell populations and the possibility of transdifferentiation were analyzed. The possibility of a tissue recovering was investigated using 1H High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance (1H HR-MAS NMR) spectroscopy, thus allowing the detection of metabolites/osmolytes related with hydrocephalus severity and outcome in the neocortex. An in vitro assay to simulate the periventricular astrocyte reaction conditions was performed using BM-MSC under high TNFα level condition. The secretome in the culture medium was analyzed in this assay. RESULTS: Four days after transplantation, BM-MSC were found undifferentiated and scattered into the astrocyte reaction present in the damaged neocortex white matter. Tissue rejection to the integrated BM-MSC was not detected 4 days after transplantation. Hyh mice transplanted with BM-MSC showed a reduction in the apoptosis in the periventricular neocortex walls, suggesting a neuroprotector effect of the BM-MSC in these conditions. A decrease in the levels of metabolites/osmolytes in the neocortex, such as taurine and neuroexcytotoxic glutamate, also indicated a tissue recovering. Under high TNFα level condition in vitro, BM-MSC showed an upregulation of cytokine and protein secretion that may explain homing, immunomodulation, and vascular permeability, and therefore the tissue recovering. CONCLUSIONS: BM-MSC treatment in severe congenital hydrocephalus is viable and leads to the recovery of the severe neurodegenerative conditions in the neocortex. NMR spectroscopy allows to follow-up the effects of stem cell therapy in hydrocephalus.España Instituto Carlos III , PI15/00619 (to AJJ), PI19/00778 (to AJJ and PPG), PI15/00796, and PI18/01557España Ministerio de Educación, Cultura y Deporte FPU13/02906España, Ministerio de Economía y Competitividad RYC-2014-16980España, FEDER Andalucía y Universidad de Málaga UMA18-FEDERJA-27

Diversification decisions among family firms: the role of family involvement and generational stage

While prior literature has focused on whether family firms are more or less inclined to diversification than non-family firms, the examination of differences in diversification among family firms has received much less attention. We analyze how family involvement (in ownership, control, and management) and the generational stage in the company (first versus later generations) influence diversification among family firms. The empirical evidence is provided by a sample of publicly listed family firms from the EU. Our results show that larger levels of family involvement in the firm are associated with lower diversification. Furthermore, first-generation family firms are found to be less diversified than their later-generation counterparts