Activation of p53 by nutlin-3a induces apoptosis and cellular senescence in human glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. Despite concerted efforts to improve current therapies and develop novel clinical approaches, patient survival remains poor. As such, increasing attention has focused on developing new therapeutic strategies that specifically target the apoptotic pathway in order to improve treatment responses. Recently, nutlins, small-molecule antagonists of MDM2, have been developed to inhibit p53-MDM2 interaction and activate p53 signaling in cancer cells. Glioma cell lines and primary cultured glioblastoma cells were treated with nutlin-3a. Nutlin-3a induced p53-dependent G1- and G2-M cell cycle arrest and apoptosis in glioma cell lines with normal TP53 status. In addition, nutlin-arrested glioma cells show morphological features of senescence and persistent induction of p21 protein. Furthermore, senescence induced by nutlin-3a might be depending on mTOR pathway activity. In wild-type TP53 primary cultured cells, exposure to nutlin-3a resulted in variable degrees of apoptosis as well as cellular features of senescence. Nutlin-3a-induced apoptosis and senescence were firmly dependent on the presence of functional p53, as revealed by the fact that glioblastoma cells with knockdown p53 with specific siRNA, or cells with mutated or functionally impaired p53 pathway, were completely insensitive to the drug. Finally, we also found that nutlin-3a increased response of glioma cells to radiation therapy. The results provide a basis for the rational use of MDM2 antagonists as a novel treatment option for glioblastoma patients.

Impacto de las proliferaciones de medusas en la valoración económica ambiental de las playas de Denia (Sudoeste Mediterráneo), Alicante, España

El actual incremento de medusas en las costas mediterráneas, percibido como un factor negativo en la calidad de las playas, supone un factor reductor de la demanda turística en las ubicaciones costeras, sobre todo en aquellas más afectadas por éstas proliferaciones. Debido a que la época de mayor presencia de fitoplacton disponible (principal fuente de alimento de las medusas), relacionada a la alta incidencia lumínica, coincide con la temporada alta de turismo en el verano; las notificaciones de incidencias por picaduras de medusa en esta época son frecuentes. Ejemplo de ello, es el caso de Denia (Alicante, España) donde, desde 2008, se ha detectado un considerable aumento de incidencias sanitarias a causa de picaduras de medusa, paralela a la aparición de la especie invasora de cubomedusa Carybdea marsupialis (Bordehore et al, 2011). En este estudio se ha realizado una valoración económica de la playa como un bien ambiental recreativo, mediante encuestas semi-estructuradas elaboradas por Paulo Nunes (CIESM), aplicadas a una muestra inicial de 300 individuos; y evaluado cual sería el impacto social y económico en la valoración ambiental de Denia, si las proliferaciones de medusa no se estabilizaran. Se ha estimado el valor económico del impacto sicial causado por las bioinvasiones marinas en las playas recreacionistas según Nunes and Van den Bergh (2004) y Nunes and Markandya (2008); el método que también ha sido aplicado en el mismo estudio aplicado en Israel (B. Galil, J. Gowdy and P. Nunes 2012) y en Cataluña (2013, Paulo Nunes, M. Loureiro, L. Piñol, S. Sastre, L. Voltaire). En ambos casos los resultados en el impacto económico son considerables pero menores a los esperados, al igual que en los resultados obtenidos en Denia (Alicante).

Acute Infection in Total Knee Arthroplasty: Diagnosis and Treatment

Infection is one of the most serious complications after total knee arthroplasty (TKA). The current incidence of prosthetic knee infection is 1-3%, depending on the series(.) For treatment and control to be more cost effective, multidisciplinary groups made up of professionals from different specialities who can work together to eradicate these kinds of infections need to be assembled. About the microbiology, Staphylococcus aureus and coagulase-negative staphylococcus were among the most frequent microorganisms involved (74%). Anamnesis and clinical examination are of primary importance in order to determine whether the problem may point to a possible acute septic complication. The first diagnosis may then be supported by increased CRP and ESR levels. The surgical treatment for a chronic prosthetic knee infection has been perfectly defined and standardized, and consists in a two-stage implant revision process. In contrast, the treatment for acute prosthetic knee infection is currently under debate. Considering the different surgical techniques that already exist, surgical debridement with conservation of the prosthesis and polythene revision appears to be an attractive option for both surgeon and patient, as it is less aggressive than the two-stage revision process and has lower initial costs. The different results obtained from this technique, along with prognosis factors and conclusions to keep in mind when it is indicated for an acute prosthetic infection, whether post-operative or haematogenous, will be analysed by the authors.

Epithelial-to-mesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer

Molecular characterization of radical prostatectomy specimens after systemic therapy may identify a gene expression profile for resistance to therapy. This study assessed tumor cells from patients with prostate cancer participating in a phase II neoadjuvant docetaxel and androgen deprivation trial to identify mediators of resistance. Transcriptional level of 93 genes from a docetaxel-resistant prostate cancer cell lines microarray study was analyzed by TaqMan low-density arrays in tumors from patients with high-risk localized prostate cancer (36 surgically treated, 28 with neoadjuvant docetaxel þ androgen deprivation). Gene expression was compared between groups and correlated with clinical outcome. VIM, AR and RELA were validated by immunohistochemistry. CD44 and ZEB1 expression was tested by immunofluorescence in cells and tumor samples. Parental and docetaxel-resistant castration-resistant prostate cancer cell lines were tested for epithelial-to-mesenchymal transition (EMT) markers before and after docetaxel exposure. Reversion of EMT phenotype was investigated as a docetaxel resistance reversion strategy. Expression of 63 (67.7%) genes differed between groups (P < 0.05), including genes related to androgen receptor, NF-k B transcription factor, and EMT. Increased expression of EMT markers correlated with radiologic relapse. Docetaxel-resistant cells had increased EMT and stem-like cell markers expression. ZEB1 siRNA transfection reverted docetaxel resistance and reduced CD44 expression in DU-145R and PC-3R. Before docetaxel exposure, a selected CD44 þ subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic docetaxel resistance; ZEB1/CD44 þ subpopulations were found in tumor cell lines and primary tumors; this correlated with aggressive clinical behavior. This study identifies genes potentially related to chemotherapy resistance and supports evi-dence of the EMT role in docetaxel resistance and adverse clinical behavior in early prostate cancer.

Temperature-Specific Competition between Invasive Mosquitofish and an Endangered Cyprinodontid Fish

Condition-specific competition is widespread in nature. Species inhabiting heterogeneous environments tend to differ in competitive abilities depending on environmental stressors. Interactions between these factors can allow coexistence of competing species, which may be particularly important between invasive and native species. Here, we examine the effects of temperature on competitiveinteractions between invasive mosquitofish, Gambusia holbrooki, and an endemic Iberian toothcarp, Aphanius iberus. We compare the tendency to approach heterospecifics and food capture rates between these two species, and examine differences between sexes and species in aggressive interactions, at three different temperatures (19, 24 and 29uC) in three laboratory experiments. Mosquitofish exhibit much more aggression than toothcarp. We show that mosquitofish have the capacity to competitively displace toothcarp through interference competition and this outcome is more likely at higher temperatures. We also show a reversal in the competitive hierarchy through reduced food capture rate by mosquitofish at lower temperatures and suggest that these two types of competition may act synergistically to deprive toothcarp of food at higher temperatures. Males of both species carry out more overtly aggressive acts than females, which is probably related to the marked sexual dimorphism and associated mating systems of these two species. Mosquitofish may thus impact heavily on toothcarp, and competition from mosquitofish, especially in warmer summer months, may lead to changes in abundance of the native species and displacement to non-preferred habitats. Globally increasing temperatures mean that highly invasive, warm-water mosquitofish may be able to colonize environments from which they are currently excluded through reduced physiological tolerance to low temperatures. Research into the effects of temperature on interactions between native and invasive species is thus of fundamental importance

Cytoplasmic accumulation of NCoR in malignant melanoma: Consequences of altered gene repression and prognostic significance

Invasive malignant melanoma (MM) is an aggressive tumor with no curative therapy available in advanced stages. Nuclear corepressor (NCoR) is an essential regulator of gene transcription, and its function has been found deregulated in different types of cancer. In colorectal cancer cells, loss of nuclear NCoR is induced by Inhibitor of kappa B kinase (IKK) through the phosphorylation of specific serine residues. We here investigate whether NCoR function impacts in MM, which might have important diagnostic and prognostic significance. By IHC, we here determined the subcellular distribution of NCoR in a cohort of 63 primary invasive MM samples, and analyzed its possible correlation with specific clinical parameters. We therefore used a microarray-based strategy to determine global gene expression differences in samples with similar tumor stage, which differ in the presence of cytoplasmic or nuclear NCoR. We found that loss of nuclear NCoR results in upregulation of a specific cancer-related genetic signature, and is significantly associated with MM progression. Inhibition of IKK activity in melanoma cells reverts NCoR nuclear distribution and specific NCoR-regulated gene transcription. Analysis of public database demonstrated that inactivating NCoR mutations are highly prevalent in MM, showing features of driver oncogene.