The molecular pathology of p53 in primitive neuroectodermal tumours of the central nervous system

One hundred and one pre-treatment primary central primitive neuroectodermal tumours were analysed for the expression of p53 protein by immunohistochemistry using the monoclonal antibody DO-7. The staining intensity was classified into four groups: strong, medium, weak and negative and strong staining intensity was associated with the poorest survival. DNA sequencing of the p53 gene was performed in 28 cases representing all four staining groups. Mutations were found in only three of the strong staining tumours suggesting that DNA mutations were not common events and that in the majority of the tumours with over-expressed p53, the protein was likely to be wild-type. Results of immunohistochemistry showed a significantly positive relationship between the expression of p53 and Bax and Bcl-2 proteins, but not Waf-1. Multivariate analyses supported the prognostic value of p53 immunostaining in central primitive neuroectodermal tumours and also of age and gender of patients

Organism-sediment interactions govern post-hypoxia recovery of ecosystem functioning

Hypoxia represents one of the major causes of biodiversity and ecosystem functioning loss for coastal waters. Since eutrophication-induced hypoxic events are becoming increasingly frequent and intense, understanding the response of ecosystems to hypoxia is of primary importance to understand and predict the stability of ecosystem functioning. Such ecological stability may greatly depend on the recovery patterns of communities and the return time of the system properties associated to these patterns. Here, we have examined how the reassembly of a benthic community contributed to the recovery of ecosystem functioning following experimentally-induced hypoxia in a tidal flat. We demonstrate that organism-sediment interactions that depend on organism size and relate to mobility traits and sediment reworking capacities are generally more important than recovering species richness to set the return time of the measured sediment processes and properties. Specifically, increasing macrofauna bioturbation potential during community reassembly significantly contributed to the recovery of sediment processes and properties such as denitrification, bedload sediment transport, primary production and deep pore water ammonium concentration. Such bioturbation potential was due to the replacement of the small-sized organisms that recolonised at early stages by large-sized bioturbating organisms, which had a disproportionately stronger influence on sediment. This study suggests that the complete recovery of organism-sediment interactions is a necessary condition for ecosystem functioning recovery, and that such process requires long periods after disturbance due to the slow growth of juveniles into adult stages involved in these interactions. Consequently, repeated episodes of disturbance at intervals smaller than the time needed for the system to fully recover organism-sediment interactions may greatly impair the resilience of ecosystem functioning.

Integrated Genomics Identifies Five Medulloblastoma Subtypes with Distinct Genetic Profiles, Pathway Signatures and Clinicopathological Features

BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements in cure rates, prediction of disease outcome remains a major challenge and survivors suffer from serious therapy-related side-effects. Recent data showed that patients with WNT-activated tumors have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects. This illustrates the potential benefits of a robust classification of medulloblastoma patients and a detailed knowledge of associated biological mechanisms. METHODS AND FINDINGS: To get a better insight into the molecular biology of medulloblastoma we established mRNA expression profiles of 62 medulloblastomas and analyzed 52 of them also by comparative genomic hybridization (CGH) arrays. Five molecular subtypes were identified, characterized by WNT signaling (A; 9 cases), SHH signaling (B; 15 cases), expression of neuronal differentiation genes (C and D; 16 and 11 cases, respectively) or photoreceptor genes (D and E; both 11 cases). Mutations in beta-catenin were identified in all 9 type A tumors, but not in any other tumor. PTCH1 mutations were exclusively identified in type B tumors. CGH analysis identified several fully or partly subtype-specific chromosomal aberrations. Monosomy of chromosome 6 occurred only in type A tumors, loss of 9q mostly occurred in type B tumors, whereas chromosome 17 aberrations, most common in medulloblastoma, were strongly associated with type C or D tumors. Loss of the inactivated X-chromosome was highly specific for female cases of type C, D and E tumors. Gene expression levels faithfully reflected the chromosomal copy number changes. Clinicopathological features significantly different between the 5 subtypes included metastatic disease and age at diagnosis and histology. Metastatic disease at diagnosis was significantly associated with subtypes C and D and most strongly with subtype E. Patients below 3 yrs of age had type B, D, or E tumors. Type B included most desmoplastic cases. We validated and confirmed the molecular subtypes and their associated clinicopathological features with expression data from a second independent series of 46 medulloblastomas. CONCLUSIONS: The new medulloblastoma classification presented in this study will greatly enhance the understanding of this heterogeneous disease. It will enable a better selection and evaluation of patients in clinical trials, and it will support the development of new molecular targeted therapies. Ultimately, our results may lead to more individualized therapies with improved cure rates and a better quality of life

Wnt/β-catenin Signalling Is Active in a Highly Dynamic Pattern during Development of the Mouse Cerebellum

The adult cerebellum is composed of several distinct cell types with well defined developmental origins. However, the molecular mechanisms that govern the generation of these cell types are only partially resolved. Wnt/β-catenin signalling has a wide variety of roles in generation of the central nervous system, though the specific activity of this pathway during cerebellum development is not well understood. Here, we present data that delineate the spatio-temporal specific pattern of Wnt/β-catenin signaling during mouse cerebellum development between E12.5 and P21. Using the BAT-gal Wnt/β-catenin reporter mouse, we found that Wnt/β-catenin activity is present transiently at the embryonic rhombic lip but not at later stages during the expansion of cell populations that arise from there. At late embryonic and early postnatal stages, Wnt/β-catenin activity shifts to the cerebellar ventricular zone and to cells arising from this germinal centre. Subsequently, the expression pattern becomes progressively restricted to Bergmann glial cells, which show expression of the reporter at P21. These results indicate a variety of potential functions for Wnt/β-catenin activity during cerebellum development

Medulloblastoma outcome is adversely associated with overexpression of EEF1D, RPL30, and RPS20 on the long arm of chromosome 8

BACKGROUND: Medulloblastoma is the most common malignant brain tumor of childhood. Improvements in clinical outcome require a better understanding of the genetic alterations to identify clinically significant biological factors and to stratify patients accordingly. In the present study, we applied cytogenetic characterization to guide the identification of biologically significant genes from gene expression microarray profiles of medulloblastoma. METHODS: We analyzed 71 primary medulloblastomas for chromosomal copy number aberrations (CNAs) using comparative genomic hybridization (CGH). Among 64 tumors that we previously analyzed by gene expression microarrays, 27 were included in our CGH series. We analyzed clinical outcome with respect to CNAs and microarray results. We filtered microarray data using specific CNAs to detect differentially expressed candidate genes associated with survival. RESULTS: The most frequent lesions detected in our series involved chromosome 17; loss of 16q, 10q, or 8p; and gain of 7q or 2p. Recurrent amplifications at 2p23-p24, 2q14, 7q34, and 12p13 were also observed. Gain of 8q is associated with worse overall survival (p = 0.0141), which is not entirely attributable to MYC amplification or overexpression. By applying CGH results to gene expression analysis of medulloblastoma, we identified three 8q-mapped genes that are associated with overall survival in the larger group of 64 patients (p < 0.05): eukaryotic translation elongation factor 1D (EEF1D), ribosomal protein L30 (RPL30), and ribosomal protein S20 (RPS20). CONCLUSION: The complementary use of CGH and expression profiles can facilitate the identification of clinically significant candidate genes involved in medulloblastoma growth. We demonstrate that gain of 8q and expression levels of three 8q-mapped candidate genes (EEF1D, RPL30, RPS20) are associated with adverse outcome in medulloblastoma

Metal-macrofauna interactions determine microbial community structure and function in copper contaminated sediments

Peer reviewedPublisher PD

Experimental study of dense pyroclastic density currents using sustained, gas-fluidized granular flows

© 2014, Springer-Verlag Berlin Heidelberg. We present the results of laboratory experiments on the behaviour of sustained, dense granular flows in a horizontal flume, in which high-gas pore pressure was maintained throughout the flow duration by continuous injection of gas through the flume base. The flows were fed by a sustained (0.5–30 s) supply of fine (75 ± 15 μm) particles from a hopper; the falling particles impacted an impingement surface at concentrations of ~3 to 45 %, where they densified rapidly to generate horizontally moving, dense granular flows. When the gas supplied through the flume base was below the minimum fluidization velocity of the particles (i.e. aerated flow conditions), three flow phases were identified: (i) an initial dilute spray of particles travelling at 1–2 m s−1, followed by (ii) a dense granular flow travelling at 0.5–1 m s−1, then by (iii) sustained aggradation of the deposit by a prolonged succession of thin flow pulses. The maximum runout of the phase 2 flow was linearly dependent on the initial mass flux, and the frontal velocity had a square-root dependence on mass flux. The frontal propagation speed during phase 3 had a linear relationship with mass flux. The total mass of particles released had no significant control on either flow velocity or runout in any of the phases. High-frequency flow unsteadiness during phase 3 generated deposit architectures with progradational and retrogradational packages and multiple internal erosive contacts. When the gas supplied through the flume base was equal to the minimum fluidization velocity of the particles (i.e. fluidized flow conditions), the flows remained within phase 2 for their entire runout, no deposit formed and the particles ran off the end of the flume. Sustained granular flows differ significantly from instantaneous flows generated by lock-exchange mechanisms, in that the sustained flows generate (by prolonged progressive aggradation) deposits that are much thicker than the flowing layer of particles at any given moment. The experiments offer a first attempt to investigate the physics of the sustained pyroclastic flows that generate thick, voluminous ignimbrites

Stem cells of ependymoma

Ependymomas are tumours that arise throughout the central nervous system. Little is known regarding the aberrant cellular and molecular processes that generate these tumours. This lack of knowledge has hampered efforts to reduce the significant mortality and morbidity that are associated with ependymoma. Here, we review recent data that suggest that radial glia are cells of origin of ependymoma, and discuss the processes that might transform these neural progenitors into ependymoma cancer stem cells

Curcumin-induced HDAC inhibition and attenuation of medulloblastoma growth in vitro and in vivo

<p>Abstract</p> <p>Background</p> <p>Medulloblastoma is the most common brain tumor in children, and its prognosis is worse than for many other common pediatric cancers. Survivors undergoing treatment suffer from serious therapy-related side effects. Thus, it is imperative to identify safer, effective treatments for medulloblastoma. In this study we evaluated the anti-cancer potential of curcumin in medulloblastoma by testing its ability to induce apoptosis and inhibit tumor growth <it>in vitro </it>and <it>in vivo </it>using established medulloblastoma models.</p> <p>Methods</p> <p>Using cultured medulloblastoma cells, tumor xenografts, and the Smo/Smo transgenic medulloblastoma mouse model, the antitumor effects of curcumin were tested <it>in vitro </it>and <it>in vivo</it>.</p> <p>Results</p> <p>Curcumin induced apoptosis and cell cycle arrest at the G2/M phase in medulloblastoma cells. These effects were accompanied by reduced histone deacetylase (HDAC) 4 expression and activity and increased tubulin acetylation, ultimately leading to mitotic catastrophe. In <it>in vivo </it>medulloblastoma xenografts, curcumin reduced tumor growth and significantly increased survival in the Smo/Smo transgenic medulloblastoma mouse model.</p> <p>Conclusions</p> <p>The <it>in vitro </it>and <it>in vivo </it>data suggest that curcumin has the potential to be developed as a therapeutic agent for medulloblastoma.</p