Minimal hepatic toxicity of Onyx-015: spatial restriction of coxsackie-adenoviral receptor in normal liver.

We administered an adenoviral vector, Onyx-015, into the hepatic artery of patients with metastatic colorectal cancer involving the liver. Thirty-five patients enrolled in this multi-institutional phase I/II trial received up to eight arterial infusions of up to 2 x 10(12) viral particles. Hepatic toxicity was the primary dose-limiting toxicity observed in preclinical models. However, nearly 200 infusions of this adenoviral vector were administered directly into the hepatic artery without significant toxicity. Therefore, we undertook this analysis to determine the impact of repeated adenoviral exposure on hepatic function. Seventeen patients were treated at our institution, providing a detailed data set on the changes in hepatic function following repeated exposure to adenovirus. No changes in hepatic function occurred with the first treatment of Onyx-015 among these patients. Transient increases in transaminase levels occurred in one patient starting with the second infusion and transient increases in bilirubin was observed in two patients starting with the fifth treatment. These changes occurred too early to be explained by viral-mediated lysis of hepatocytes. In addition, viremia was observed starting 3-5 days after the viral infusion in half of the patient, but was not associated with hepatic toxicity. To further understand the basis for the minimal hepatic toxicity of adenoviral vectors, we evaluated the replication of adenovirus in primary hepatocytes and tumor cells in culture and the expression of the coxsackie-adenoviral receptor (CAR) in normal liver and colon cancer metastatic to the liver. We found that adenovirus replicates poorly in primary hepatocytes but replicates efficiently in tumors including tumors derived from hepatocytes. In addition, we found that CAR is localized at junctions between hepatocytes and is inaccessible to hepatic blood flow. CAR is not expressed on tumor vasculature but is expressed on tumor cells. Spatial restriction of CAR to the intercellular space in normal liver and diminished replication of adenovirus in hepatocytes may explain the minimal toxicity observed following repeated hepatic artery infusions with Onyx-015

Anwendung des öffentlichen Vergaberechts auf moderne IT-Softwareentwicklungsverfahren

Die öffentliche Hand ist der größte Auftraggeber in Deutschland, Europa und wohl auch in anderen Ländern der Welt wie USA und England. Nach der ?International Market Scoreboard-Statistik July 2009? betrug das Gesamtvolum aller EU-weit ausgeschriebenen öffentlichen Aufträge 2 Billionen Euro. Damit besitzt die öffentliche Hand eine beträchtliche Marktmacht, die geeignet ist, massiven Einfluss auf die Wettbewerbsverhältnisse auf den Märkten zu nehmen. Angesichts dieser Gefahr für den Wettbewerb hat das öffentliche Vergaberecht (§§ 100 f GWB, VOB/A,VOL/A usw.) die Aufgabe, diese Marktmacht der öffentlichen Auftraggeber in Grenzen zu halten und den Wettbewerb auf den Beschaffungsmärkten zu schützen. Absolute Priorität der Vergabeordnungen (§ 101 GWB) hat daher die öffentlichen Vergabe im Wettbewerb. Besondere Vergabeprobleme zeigen sich immer wieder bei der öffentlichen Vergabe von IT Anwendungsentwicklungen. Hierbei werden aus betriebswirtschaftlichen Gründen zunehmend Technologiekonzepte (iterative Verfahren) verwandt, bei denen die wirtschaftlichen und technischen Ziele erst in Form eines iterativen Prozesses zwischen Anbieter und Kunde erarbeitet und realisiert werden. Der nachfolgende Beitrag gibt einen Überblick über die öffentlichen Vergabearten und behandelt die Frage, ob und in welcher Weise Software-Entwicklungsprozesse mit den Vergabearten der öffentlichen Hand in Einklang stehen oder gebracht werden können

Anwendung des öffentlichen Vergaberechts auf moderne IT Softwareentwicklungsverfahren

Das öffentliche Vergaberecht, die UFAB und das V Modell XT schließen kein Vorgehensmodell bei der IT Beschaffung aus. Falls bei komplexen IT Beschaffungen keine geeignete Lösungsmöglichkeit vom Auftraggeber aufgezeigt werden kann, bieten das Verhandlungsverfahren und der wettbewerbliche Dialog eine Alternative, dass der öffentlichen Auftraggeber und die Anbieter unterschiedliche Lösungsmöglichkeiten und Vorgehensverfahren in einem Dialog zu erörtern bzw. suchen, die eine wirtschaftlichste Beschaffung auf der Grundlage von angemessenen Vertragsbedingungen und Vergütungsarten ermöglichen. --

Enhancement of vaccinia virus based oncolysis with histone deacetylase inhibitors

Histone deacetylase inhibitors (HDI) dampen cellular innate immune response by decreasing interferon production and have been shown to increase the growth of vesicular stomatitis virus and HSV. As attenuated tumour-selective oncolytic vaccinia viruses (VV) are already undergoing clinical evaluation, the goal of this study is to determine whether HDI can also enhance the potency of these poxviruses in infection-resistant cancer cell lines. Multiple HDIs were tested and Trichostatin A (TSA) was found to potently enhance the spread and replication of a tumour selective vaccinia virus in several infection-resistant cancer cell lines. TSA significantly decreased the number of lung metastases in a syngeneic B16F10LacZ lung metastasis model yet did not increase the replication of vaccinia in normal tissues. The combination of TSA and VV increased survival of mice harbouring human HCT116 colon tumour xenografts as compared to mice treated with either agent alone. We conclude that TSA can selectively and effectively enhance the replication and spread of oncolytic vaccinia virus in cancer cells. © 2010 MacTavish et al

Geographical information retrieval with ontologies of place

Geographical context is required of many information retrieval tasks in which the target of the search may be documents, images or records which are referenced to geographical space only by means of place names. Often there may be an imprecise match between the query name and the names associated with candidate sources of information. There is a need therefore for geographical information retrieval facilities that can rank the relevance of candidate information with respect to geographical closeness of place as well as semantic closeness with respect to the information of interest. Here we present an ontology of place that combines limited coordinate data with semantic and qualitative spatial relationships between places. This parsimonious model of geographical place supports maintenance of knowledge of place names that relate to extensive regions of the Earth at multiple levels of granularity. The ontology has been implemented with a semantic modelling system linking non-spatial conceptual hierarchies with the place ontology. An hierarchical spatial distance measure is combined with Euclidean distance between place centroids to create a hybrid spatial distance measure. This is integrated with thematic distance, based on classification semantics, to create an integrated semantic closeness measure that can be used for a relevance ranking of retrieved objects

An upper limit on the electron-neutrino flux from the HiRes detector

Air-fluorescence detectors such as the High Resolution Fly's Eye (HiRes) detector are very sensitive to upward-going, Earth-skimming ultrahigh energy electron-neutrino-induced showers. This is due to the relatively large interaction cross sections of these high-energy neutrinos and to the Landau-Pomeranchuk-Migdal (LPM) effect. The LPM effect causes a significant decrease in the cross sections for bremsstrahlung and pair production, allowing charged-current electron-neutrino-induced showers occurring deep in the Earth's crust to be detectable as they exit the Earth into the atmosphere. A search for upward-going neutrino-induced showers in the HiRes-II monocular dataset has yielded a null result. From an LPM calculation of the energy spectrum of charged particles as a function of primary energy and depth for electron-induced showers in rock, we calculate the shape of the resulting profile of these showers in air. We describe a full detector Monte Carlo simulation to determine the detector response to upward-going electron-neutrino-induced cascades and present an upper limit on the flux of electron-neutrinos.Comment: 13 pages, 3 figures. submitted to Astrophysical Journa

Search for Point Sources of Ultra-High Energy Cosmic Rays Above 40 EeV Using a Maximum Likelihood Ratio Test

We present the results of a search for cosmic ray point sources at energies above 40 EeV in the combined data sets recorded by the AGASA and HiRes stereo experiments. The analysis is based on a maximum likelihood ratio test using the probability density function for each event rather than requiring an a priori choice of a fixed angular bin size. No statistically significant clustering of events consistent with a point source is found.Comment: 7 pages, 7 figures. Accepted for publication in The Astrophysical Journa

A Measurement of Time-Averaged Aerosol Optical Depth using Air-Showers Observed in Stereo by HiRes

Air fluorescence measurements of cosmic ray energy must be corrected for attenuation of the atmosphere. In this paper we show that the air-showers themselves can yield a measurement of the aerosol attenuation in terms of optical depth, time-averaged over extended periods. Although the technique lacks statistical power to make the critical hourly measurements that only specialized active instruments can achieve, we note the technique does not depend on absolute calibration of the detector hardware, and requires no additional equipment beyond the fluorescence detectors that observe the air showers. This paper describes the technique, and presents results based on analysis of 1258 air-showers observed in stereo by the High Resolution Fly's Eye over a four year span.Comment: 7 pages, 3 figures, accepted for publication by Astroparticle Physics Journa