A role for eukaryotic initiation factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma.

Dysregulated expression of factors that control protein synthesis is associated with poor prognosis of many cancers, but the underlying mechanisms are not well defined. Analysis of the diffuse large B-cell lymphoma (DLBCL) translatome revealed selective upregulation of mRNAs encoding anti-apoptotic and DNA repair proteins. We show that enhanced synthesis of these proteins in DLBCL is mediated by the relief of repression that is normally imposed by structure in the 5'-untranslated regions of their corresponding mRNAs. This process is driven by signaling through mammalian target of rapamycin, resulting in increased synthesis of eukaryotic initiation factor (eIF) 4B complex (eIF4B), a known activator of the RNA helicase eIF4A. Reducing eIF4B expression alone is sufficient to decrease synthesis of proteins associated with enhanced tumor cell survival, namely DAXX, BCL2 and ERCC5. Importantly, eIF4B-driven expression of these key survival proteins is directly correlated with patient outcome, and eIF4B, DAXX and ERCC5 are identified as novel prognostic markers for poor survival in DLBCL. Our work provides new insights into the mechanisms by which the cancer-promoting translational machinery drives lymphomagenesis

Asteroseismology of red giants as a tool for studying stellar populations: first steps

The detection of solar-like oscillations in G and K giants with the CoRoT and Kepler space-based satellites allows robust constraints to be set on the mass and radius of such stars. The availability of these constraints for thousands of giants sampling different regions of the Galaxy promises to enrich our understanding on the Milky Way's constituents. In this contribution we briefly recall which are the relevant constraints that red-giant seismology can currently provide to the study of stellar populations. We then present, for a few nearby stars, the comparison between radius and mass determined using seismic scaling relations and those obtained by other methods.Comment: Proc. of the workshop "Red Giants as Probes of the Structure and Evolution of the Milky Way" (Roma, 15-17 Nov 2010), Astrophysics and Space Science Proceedings, ISBN 978-3-642-18417-8 (eds. A. Miglio, J. Montalban, A. Noels). Part of RedGiantsMilkyWay/2011/ proceedings available at http://arxiv.org/html/1108.4406v

Human monoclonal antibodies targeting carbonic anhydrase IX for the molecular imaging of hypoxic regions in solid tumours

BACKGROUND: Hypoxia, which is commonly observed in areas of primary tumours and of metastases, influences response to treatment. However, its characterisation has so far mainly been restricted to the ex vivo analysis of tumour sections using monoclonal antibodies specific to carbonic anhydrase IX (CA IX) or by pimonidazole staining, after the intravenous administration of this 2-nitroimidazole compound in experimental animal models.METHODS: In this study, we describe the generation of high-affinity human monoclonal antibodies (A3 and CC7) specific to human CA IX, using phage technology.RESULTS: These antibodies were able to stain CA IX ex vivo and to target the cognate antigen in vivo. In one of the two animal models of colorectal cancer studied (LS174T), CA IX imaging closely matched pimonidazole staining, with a preferential staining of tumour areas characterised by little vascularity and low perfusion. In contrast, in a second animal model (SW1222), distinct staining patterns were observed for pimonidazole and CA IX targeting. We observed a complementary pattern of tumour regions targeted in vivo by the clinical-stage vascular-targeting antibody L19 and the anti-CA IX antibody A3, indicating that a homogenous pattern of in vivo tumour targeting could be achieved by a combination of the two antibodies.CONCLUSION: The new human anti-CA IX antibodies are expected to be non-immunogenic in patients with cancer and may serve as broadly applicable reagents for the non-invasive imaging of hypoxia and for pharmacodelivery applications. British Journal of Cancer (2009) 101, 645-657. doi: 10.1038/sj.bjc.6605200 www.bjcancer.com Published online 21 July 2009 (C) 2009 Cancer Research U

The American Astronomical Society, find out more The Institute of Physics, find out more The Sixth Data Release of the Radial Velocity Experiment (Rave). II. Stellar Atmospheric Parameters, Chemical Abundances, and Distances

We present part 2 of the 6th and final Data Release (DR6 or FDR) of the Radial Velocity Experiment (RAVE), a magnitude-limited (9<I<12) spectroscopic survey of Galactic stars randomly selected in the southern hemisphere. The RAVE medium-resolution spectra (R~7500) cover the Ca-triplet region (8410-8795A) and span the complete time frame from the start of RAVE observations on 12 April 2003 to their completion on 4 April 2013. In the second of two publications, we present the data products derived from 518387 observations of 451783 unique stars using a suite of advanced reduction pipelines focussing on stellar atmospheric parameters, in particular purely spectroscopically derived stellar atmospheric parameters (Teff, log(g), and the overall metallicity), enhanced stellar atmospheric parameters inferred via a Bayesian pipeline using Gaia DR2 astrometric priors, and asteroseismically calibrated stellar atmospheric parameters for giant stars based on asteroseismic observations for 699 K2 stars. In addition, we provide abundances of the elements Fe, Al, and Ni, as well as an overall [alpha/Fe] ratio obtained using a new pipeline based on the GAUGUIN optimization method that is able to deal with variable signal-to-noise ratios. The RAVE DR6 catalogs are cross matched with relevant astrometric and photometric catalogs, and are complemented by orbital parameters and effective temperatures based on the infrared flux method. The data can be accessed via the RAVE Web site (http://rave-survey.org) or the Vizier database

Microenvironmental adaptation of experimental tumours to chronic vs acute hypoxia

This study investigated long-term microenvironmental responses (oxygenation, perfusion, metabolic status, proliferation, vascular endothelial growth factor (VEGF) expression and vascularisation) to chronic hypoxia in experimental tumours. Experiments were performed using s.c.-implanted DS-sarcomas in rats. In order to induce more pronounced tumour hypoxia, one group of animals was housed in a hypoxic atmosphere (8% O2) for the whole period of tumour growth (chronic hypoxia). A second group was acutely exposed to inspiratory hypoxia for only 20 min prior to the measurements (acute hypoxia), whereas animals housed under normal atmospheric conditions served as controls. Acute hypoxia reduced the median oxygen partial pressure (pO2) dramatically (1 vs 10 mmHg in controls), whereas in chronically hypoxic tumours the pO2 was significantly improved (median pO2=4 mmHg), however not reaching the control level. These findings reflect the changes in tumour perfusion where acutely hypoxic tumours show a dramatic reduction of perfused tumour vessels (maybe the result of a simultaneous reduction in arterial blood pressure). In animals under chronic inspiratory hypoxia, the number of perfused vessels increased (compared to acute hypoxia), although the perfusion pattern found in control tumours was not reached. In the chronically hypoxic animals, tumour cell proliferation and tumour growth were significantly reduced, whereas no differences in VEGF expression and vascular density between these groups were observed. These results suggest that long-term adaptation of tumours to chronic hypoxia in vivo, while not affecting vascularity, does influence the functional status of the microvessels in favour of a more homogeneous perfusion

Nitric oxide production by tumour tissue: impact on the response to photodynamic therapy

The role of nitric oxide (NO) in the response to Photofrin-based photodynamic therapy (PDT) was investigated using mouse tumour models characterized by either relatively high or low endogenous NO production (RIF and SCCVII vs EMT6 and FsaR, respectively). The NO synthase inhibitors Nω-nitro- L -arginine (L-NNA) or Nω-nitro- L -arginine methyl ester (L-NAME), administered to mice immediately after PDT light treatment of subcutaneously growing tumours, markedly enhanced the cure rate of RIF and SCCVII models, but produced no obvious benefit with the EMT6 and FsaR models. Laser Doppler flowmetry measurement revealed that both L-NNA and L-NAME strongly inhibit blood flow in RIF and SCCVII tumours, but not in EMT6 and FsaR tumours. When injected intravenously immediately after PDT light treatment, L-NAME dramatically augmented the decrease in blood flow in SCCVII tumours induced by PDT. The pattern of blood flow alterations in tumours following PDT indicates that, even with curative doses, regular circulation may be restored in some vessels after episodes of partial or complete obstruction. Such conditions are conducive to the induction of ischaemia-reperfusion injury, which is instigated by the formation of superoxide radical. The administration of superoxide dismutase immediately after PDT resulted in a decrease in tumour cure rates, thus confirming the involvement of superoxide in the anti-tumour effect. The results of this study demonstrate that NO participates in the events associated with PDT-mediated tumour destruction, particularly in the vascular response that is of critical importance for the curative outcome of this therapy. The level of endogenous production of NO in tumours appears to be one of the determinants of sensitivity to PDT. © 2000 Cancer Research Campaig

In vitro hypoxia-conditioned colon cancer cell lines derived from HCT116 and HT29 exhibit altered apoptosis susceptibility and a more angiogenic profile in vivo

Hypoxia is an important selective force in the clonal evolution of tumours. Through HIF-1 and other transcription factors combined with tumour-specific genetic alterations, hypoxia is a dominant factor in the angiogenic phenotype. Cellular adaptation to hypoxia is an important requirement of tumour progression independent of angiogenesis. The adaptive changes, insofar as they alter hypoxia-induced apoptosis, are likely to determine responsiveness to antiangiogenic strategies. To investigate this adaptation of tumour cells to hypoxia, we recreated in vitro the in vivo situation of chronic intermittent exposure to low-oxygen levels. The colon carcinoma cell lines HT29 and HCT116 were subjected to 40 episodes of sublethal hypoxia (4 h) three times a week. The resulting two hypoxia-conditioned cell lines have been maintained in culture for more than 2 years. In both cell lines changes in doubling times occurred: in HT29 an increase, and in HCT116 a decrease. Cell survival in response to hypoxia and to DNA damage differed strikingly in the two cell lines. The HT29 hypoxia-conditioned cells were more resistant than the parental line to a 24 h hypoxic challenge, while those from HCT116 surprisingly were more sensitive. Sensitivity to cisplatin in vitro was also significantly different for the hypoxia-conditioned compared with the parental lines, suggesting a change in pathways leading to apoptosis following DNA damage signaling. The growth of both conditioned cell lines in vivo as xenografts in immunodeficient (SCID) mice was more rapid than their parental lines, and was accompanied in each by evidence of enhanced vascular proliferation as a consequence of the hypoxia-conditioning. Thus the changes in apoptotic susceptibility were independent of altered angiogenesis. The derivation of these lines provides a model for events within hypoxic regions of colon cancers, and for the acquisition of resistance and sensitivity characteristics that may have therapeutic implications for the use of antiangiogenesis drugs

Distinctive Patterns of MicroRNA Expression Associated with Karyotype in Acute Myeloid Leukaemia

Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults; however, the genetic aetiology of the disease is not yet fully understood. A quantitative expression profile analysis of 157 mature miRNAs was performed on 100 AML patients representing the spectrum of known karyotypes common in AML. The principle observation reported here is that AMLs bearing a t(15;17) translocation had a distinctive signature throughout the whole set of genes, including the up regulation of a subset of miRNAs located in the human 14q32 imprinted domain. The set included miR-127, miR-154, miR-154*, miR-299, miR-323, miR-368, and miR-370. Furthermore, specific subsets of miRNAs were identified that provided molecular signatures characteristic of the major translocation-mediated gene fusion events in AML. Analysis of variance showed the significant deregulation of 33 miRNAs across the leukaemic set with respect to bone marrow from healthy donors. Fluorescent in situ hybridisation analysis using miRNA-specific locked nucleic acid (LNA) probes on cryopreserved patient cells confirmed the results obtained by real-time PCR. This study, conducted on about a fifth of the miRNAs currently reported in the Sanger database (microrna.sanger.ac.uk), demonstrates the potential for using miRNA expression to sub-classify cancer and suggests a role in the aetiology of leukaemia

Herbivore-Mediated Effects of Glucosinolates on Different Natural Enemies of a Specialist Aphid

The cabbage aphid Brevicoryne brassicae is a specialist herbivore that sequesters glucosinolates from its host plant as a defense against its predators. It is unknown to what extent parasitoids are affected by this sequestration. We investigated herbivore-mediated effects of glucosinolates on the parasitoid wasp Diaeretiella rapae and the predator Episyrphus balteatus. We reared B. brassicae on three ecotypes of Arabidopsis thaliana that differ in glucosinolate content and on one genetically transformed line with modified concentrations of aliphatic glucosinolates. We tested aphid performance and the performance and behavior of both natural enemies. We correlated this with phloem and aphid glucosinolate concentrations and emission of volatiles. Brevicoryne brassicae performance correlated positively with concentrations of both aliphatic and indole glucosinolates in the phloem. Aphids selectively sequestered glucosinolates. Glucosinolate concentration in B. brassicae correlated negatively with performance of the predator, but positively with performance of the parasitoid, possibly because the aphids with the highest glucosinolate concentrations had a higher body weight. Both natural enemies showed a positive performance-preference correlation. The predator preferred the ecotype with the lowest emission of volatile glucosinolate breakdown products in each test combination, whereas the parasitoid wasp preferred the A. thaliana ecotype with the highest emission of these volatiles. The study shows that there are differential herbivore-mediated effects of glucosinolates on a predator and a parasitoid of a specialist aphid that selectively sequesters glucosinolates from its host plant