Immunoselection of breast and ovarian cancer cells with trastuzumab and natural killer cells:selective escape of CD44high/CD24low/HER2low breast cancer stem cells

Although trastuzumab (Herceptin) has substantially improved the overall survival of patients with mammary carcinomas, even initially well-responding tumors often become resistant. Because natural killer (NK) cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) is thought to contribute to the therapeutic effects of trastuzumab, we have established a cell culture system to select for ADCC-resistant SK-OV-3 ovarian cancer and MCF7 mammary carcinoma cells. Ovarian cancer cells down-regulated HER2 expression, resulting in a more resistant phenotype. MCF7 breast cancer cells, however, failed to develop resistance in vitro. Instead, treatment with trastuzumab and polyclonal NK cells resulted in the preferential survival of individual sphere-forming cells that displayed a CD44(high)CD24(low) "cancer stem cell-like" phenotype and expressed significantly less HER2 compared with non-stem cells. Likewise, the CD44(high)CD24(low) population was also found to be more immunoresistant in SK-BR3, MDA-MB231, and BT474 breast cancer cell lines. When immunoselected MCF7 cells were then re-expanded, they mostly lost the observed phenotype to regenerate a tumor cell culture that displayed the initial HER2 surface expression and ADCC-susceptibility, but was enriched in CD44(high)CD24(low) cancer stem cells. This translated into increased clonogenicity in vitro and tumorigenicity in vivo. Thus, we provide evidence that the induction of ADCC by trastuzumab and NK cells may spare the actual tumor-initiating cells, which could explain clinical relapse and progress. Moreover, our observation that the "relapsed" in vitro cultures show practically identical HER2 surface expression and susceptibility toward ADCC suggests that the administration of trastuzumab beyond relapse might be considered, especially when combined with an immune-stimulatory treatment that targets the escape variants.

Macrophage migration inhibitory factor contributes to the immune escape of ovarian cancer by down-regulating NKG2D

The proinflammatory cytokine macrophage migration inhibitory factor (MIF) stimulates tumor cell proliferation, migration, and metastasis; promotes tumor angiogenesis; suppresses p53-mediated apoptosis; and inhibits antitumor immunity by largely unknown mechanisms. We here describe an overexpression of MIF in ovarian cancer that correlates with malignancy and the presence of ascites. Functionally, we find that MIF may contribute to the immune escape of ovarian carcinoma by transcriptionally down-regulating NKG2D in vitro and in vivo which impairs NK cell cytotoxicity toward tumor cells. Together with the additional tumorigenic properties of MIF, this finding provides a rationale for novel small-molecule inhibitors of MIF to be used for the treatment of MIF-secreting cancers.

Rapid climate change did not cause population collapse at the end of the European Bronze Age

The impact of rapid climate change on contemporary human populations is of global concern. To contextualize our understanding of human responses to rapid climate change it is necessary to examine the archeological record during past climate transitions. One episode of abrupt climate change has been correlated with societal collapse at the end of the northwestern European Bronze Age. We apply new methods to interrogate archeological and paleoclimate data for this transition in Ireland at a higher level of precision than has previously been possible. We analyze archeological 14C dates to demonstrate dramatic population collapse and present high-precision proxy climate data, analyzed through Bayesian methods, to provide evidence for a rapid climatic transition at ca. 750 calibrated years B.C. Our results demonstrate that this climatic downturn did not initiate population collapse and highlight the nondeterministic nature of human responses to past climate change.

Genetic Background and Light-Dependent Progression of Photoreceptor Cell Degeneration in Prominin-1 Knockout Mice

PURPOSE: Mutations in the Prominin-1 (Prom1) gene are known to cause retinitis pigmentosa and Stargardt disease, both of which are associated with progressive photoreceptor cell death. There are no effective therapies for either disorder. The aim of this study was to investigate the mechanism of the retinal degeneration in Prom1-deficient mouse models.

METHODS: We constructed Prom1 knockout mice with two distinct genetic backgrounds of C57BL/6 and C57BL/6xCBA/NSlc, and investigated the photoreceptor degeneration by means of histology and functional tests.. In addition, we examined the effect of light on the Prom1(-/-) retina by rearing the mice in the normal light/dark cycle and completely dark conditions. Finally, we investigated if the retinoic-acid derivative Fenretinide slowed the pace of retinal degeneration in these mouse models.

RESULTS: The Prom1(-/-)-knockout mice with both backgrounds developed photoreceptor degeneration after eye opening, but the CB57/BL6-background mice developed photoreceptor cell degeneration much faster than the C57BL/6xCBA/NSlc mice, demonstrating genetic background dependency.. Interestingly, our histologic and functional examination showed that the photoreceptor cell degeneration of Prom1-knockout mice was light-dependent, and was almost completely inhibited when the mutant mice were kept in the dark. The Prom1-knockout retina showed strong downregulation of expression of the visual cycle components, Rdh12 and Abca4. Furthermore, administration of Fenretinide, which lowers the level of the toxic lipofuscin, slowed the degeneration of photoreceptor cells.

CONCLUSIONS: These findings improve our understanding of the mechanism of cell death in Prominin-1-related disease and provide evidence that fenretinide may be worth studying in human disease.

Variation in DNA repair genes XRCC3, XRCC4, XRCC5 and susceptibility to myeloma

Cytogenetic analysis in myeloma reveals marked chromosomal instability. Both widespread genomic alterations and evidence of aberrant class switch recombination, the physiological process that regulates maturation of the antibody response, implicate the DNA repair pathway in disease pathogenesis. We therefore assessed 27 SNPs in three genes (XRCC3, XRCC4 and XRCC5) central to DNA repair in patients with myeloma and controls from the EpiLymph study and from an Irish hospital registry (n = 306 cases, 263 controls). For the haplotype-tagging SNP (htSNP) rs963248 in XRCC4, Allele A was significantly more frequent in cases than in controls (86.4 versus 80.8%; odds ratio 1.51; 95% confidence interval 1.10-2.08; P = 0.0133), as was the AA genotype (74 versus 65%) (P = 0.026). Haplotype analysis was performed using Unphased for rs963248 in combination with additional SNPs in XRCC4. The strongest evidence of association came from the A-T haplotype from rs963248-rs2891980 (P = 0.008). For XRCC5, the genotype GG from rs1051685 was detected in 10 cases from different national populations but in only one control (P = 0.015). This SNP is located in the 3'-UTR of XRCC5. Overall, these data provide support for the hypothesis that common variation in the genes encoding DNA repair proteins contributes to susceptibility to myeloma.

Old World megadroughts and pluvials during the Common Era

Climate model projections suggestwidespread drying in the Mediterranean Basin and wetting in Fennoscandia in the coming decades largely as a consequence of greenhouse gas forcing of climate. To place these and other “Old World” climate projections into historical perspective based on more complete estimates of natural hydroclimatic variability, we have developed the “Old World Drought Atlas” (OWDA), a set of year-to-year maps of tree-ring reconstructed summer wetness and dryness over Europe and the Mediterranean Basin during the Common Era.
The OWDA matches historical accounts of severe drought and wetness with a spatial completeness not previously available. In addition, megadroughts reconstructed over north-central Europe in the 11th and mid-15th centuries
reinforce other evidence from North America and Asia that droughts were more severe, extensive, and prolonged over Northern Hemisphere land areas before the 20th century, with an inadequate understanding of their causes. The OWDA provides new data to determine the causes of Old World drought and wetness and attribute past climate variability to forced and/or internal variability.

Introducing the CTA concept

The Cherenkov Telescope Array (CTA) is a new observatory for very high-energy (VHE) gamma rays. CTA has ambitions science goals, for which it is necessary to achieve full-sky coverage, to improve the sensitivity by about an order of magnitude, to span about four decades of energy, from a few tens of GeV to above 100 TeV with enhanced angular and energy resolutions over existing VHE gamma-ray observatories. An international collaboration has formed with more than 1000 members from 27 countries in Europe, Asia, Africa and North and South America. In 2010 the CTA Consortium completed a Design Study and started a three-year Preparatory Phase which leads to production readiness of CTA in 2014. In this paper we introduce the science goals and the concept of CTA, and provide an overview of the project. © 2013 Elsevier B.V. All rights reserved.

Local object gist: meaningful shapes and spatial layout at a very early stage of visual processing

In his introduction, Pinna (2010) quoted one of Wertheimer’s observations: “I stand at the window and see a house, trees, sky. Theoretically I might say there were 327 brightnesses and nuances of color. Do I have ‘327’? No. I have sky, house, and trees.” This seems quite remarkable, for Max Wertheimer, together with Kurt Koffka and Wolfgang Koehler, was a pioneer of Gestalt Theory: perceptual organisation was tackled considering grouping rules of line and edge elements in relation to figure-ground segregation, i.e., a meaningful object (the figure) as perceived against a complex background (the ground). At the lowest level – line and edge elements – Wertheimer (1923) himself formulated grouping principles on the basis of proximity, good continuation, convexity, symmetry and, often forgotten, past experience of the observer. Rubin (1921) formulated rules for figure-ground segregation using surroundedness, size and orientation, but also convexity and symmetry. Almost a century of research into Gestalt later, Pinna and Reeves (2006) introduced the notion of figurality, meant to represent the integrated set of properties of visual objects, from the principles of grouping and figure-ground to the colour and volume of objects with shading. Pinna, in 2010, went one important step further and studied perceptual meaning, i.e., the interpretation of complex figures on the basis of past experience of the observer. Re-establishing a link to Wertheimer’s rule about past experience, he formulated five propositions, three definitions and seven properties on the basis of observations made on graphically manipulated patterns. For example, he introduced the illusion of meaning by comics-like elements suggesting wind, therefore inducing a learned interpretation. His last figure shows a regular array of squares but with irregular positions on the right side. This pile of (ir)regular squares can be interpreted as the result of an earthquake which destroyed part of an apartment block. This is much more intuitive, direct and economic than describing the complexity of the array of squares.

Empfehlungen für die Gestaltung schriftlicher Arbeiten in Studiengängen der Abteilung Information und Kommunikation der Fakultät III der Fachhochschule Hannover

Die für die Abteilung Information und Kommunikation der Fakultät III, Medien, Information und Design – MID (im Folgenden: Abteilung IK) der Fachhochschule Hannover erarbeiteten „Empfehlungen für die Gestaltung schriftlicher Arbeiten“ bieten Anregungen und Erläuterungen zur formalen Gestaltung von schriftlichen Arbeiten, die von den Studierenden im Laufe ihres Studiums an der Abteilung IK als Studien- oder Prüfungsleistungen zu erbringen sind. Sie bringen teilweise ausführliche Beispiele und legen beson-deres Gewicht auf eine Darstellung der Zitiertechnik und der Zitierregeln (auch von Internet-Dokumenten). Weitere Schwerpunkte dieser Empfehlungen sind besondere Richtlinien für die Gestaltung von Diplom- oder Bachelorarbeiten, eine Auflistung der diesen Empfehlungen zugrunde gelegten Literatur und Anhänge (mit Beispielen zur Gestaltung von Titelseiten und Inhaltsverzeichnissen).

Makerspace in der Stadtbibliothek Göttingen : Machbarkeitsstudie und Risikoanalyse

Bei dem Konzept Makerspace handelt es sich um ein niedrigschwelliges Angebot, das für alle Besucher Anreize, Ideen und Unterstützung bieten kann. Durch den Faktor des gemeinsamen Lernens werden soziale Grenzen überbrückt und neue Netzwerke gebildet, implizites Wissen wird ausgetauscht und Lernen neu erfahren. Der Makerspace bietet eine Bühne, um eigene Erfahrungen auszutauschen, Wissen an Interessierte weiterzugeben oder gemeinschaftlich an einem kreativen Projekt zu arbeiten. Als Ort des Lernens und der Information, aber auch als Treffpunkt bieten öffentliche Bibliotheken einen idealen Rahmen für ein entsprechendes Angebot. Das modulare Makerspace-Konzept ermöglicht ihnen, die Angebote ganz nach ihren Bedürfnissen und Ansprüchen auszurichten. Vorhandene Medienbestände können in die Makerspace-Aktivitäten eingebunden werden. Makerspaces sind vielversprechende Zukunftsmodelle kollektiver Erfahrungsräume und bieten Platz für eine inklusive Lernwerkstatt für die Gemeinschaft. Aufgrund der vorliegenden Analyse empfiehlt das Projektteam für die Stadtbibliothek Göttingen mit dem Koffermodul zu starten, um die Teilnehmer und Mitarbeiter nicht zu überfordern. Die räumlichen Gegebenheiten lassen aber in einem späteren Stadium auch die Module Schrank und Raum zu. Diese Erweiterungen sollten von der Nutzung und der Nachfrage abhängig gemacht werden.

Der Einsatz von audiovisuellen medien im DAF-Unterricht

Relatório da Prática de Ensino Supervisionada, Mestrado em Ensino de Inglês e de Alemão, Universidade de Lisboa, 2014

Julietta May 12, 14, 15, 1988

Concert Program for Julietta May 12, 14, 15 1988

RadiaLE: A framework for designing and assessing link quality estimators in wireless sensor networks

Stringent cost and energy constraints impose the use of low-cost and low-power radio transceivers in large-scale wireless sensor networks (WSNs). This fact, together with the harsh characteristics of the physical environment, requires a rigorous WSN design. Mechanisms for WSN deployment and topology control, MAC and routing, resource and mobility management, greatly depend on reliable link quality estimators (LQEs). This paper describes the RadiaLE framework, which enables the experimental assessment, design and optimization of LQEs. RadiaLE comprises (i) the hardware components of the WSN testbed and (ii) a software tool for setting-up and controlling the experiments, automating link measurements gathering through packets-statistics collection, and analyzing the collected data, allowing for LQEs evaluation. We also propose a methodology that allows (i) to properly set different types of links and different types of traffic, (ii) to collect rich link measurements, and (iii) to validate LQEs using a holistic and unified approach. To demonstrate the validity and usefulness of RadiaLE, we present two case studies: the characterization of low-power links and a comparison between six representative LQEs. We also extend the second study for evaluating the accuracy of the TOSSIM 2 channel model.