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. --

Targeted Neuronal Death Affects Neuronal Replacement and Vocal Behavior in Adult Songbirds

AbstractIn the high vocal center (HVC) of adult songbirds, increases in spontaneous neuronal replacement correlate with song changes and with cell death. We experimentally induced death of specific HVC neuron types in adult male zebra finches using targeted photolysis. Induced death of a projection neuron type that normally turns over resulted in compensatory replacement of the same type. Induced death of the normally nonreplaced type did not stimulate their replacement. In juveniles, death of the latter type increased recruitment of the replaceable kind. We infer that neuronal death regulates the recruitment of replaceable neurons. Song deteriorated in some birds only after elimination of replaceable neurons. Behavioral deficits were transient and followed by variable degrees of recovery. This raises the possibility that induced neuronal replacement can restore a learned behavior

Dentin sialoprotein, dentin phosphoprotein, enamelysin and ameloblastin, tooth- specific molecules that are distinctively expressed during murine dental differentiation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73260/1/j.0909-8836.1998.eos106510.x.pd

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

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

Who Drives the Market? Estimating a Heterogeneous Agent-based Financial Market Model Using a Neural Network Approach

Introduction. The objects of investigation of this work are micro-level behaviors in stock markets. We aim at better understanding which strategies of market participants drive stock markets. The problem is that micro-level data from real stock markets are largely unobservable. We take an estimation perspective to obtain daily time series of fractions of chartists and fundamentalists among market participants. We estimate the heterogeneous agent-based financial market model introduced by Lux and Marchesi [1] to the S&P 500. This model has more realistic time series properties compared to less complex econometric and other agent-based models. Such kinds of models have a rather complex dependency between micro and macro parameters that have to be mapped to empirical data by the estimation method. This poses heavy computational burdens. Our contribution to this field is a new method for indirectly estimating time-varying micro-parameters of highly complex agent-based models at high frequency. Related work. Due to the high complexity, few authors have published on this topic to date (e.g., [2], [3], and [4]). Recent approaches in directly estimating agent-based models are restricted to simpler models, make simplifying assumptions on the estimation procedure, estimate only non-time varying parameters, or estimate only low frequency time series. Approach and computational methods. The indirect estimation method we propose is based on estimating the inverse model of a rich agent-based model that derives realistic macro market behavior from heterogeneous market participants’ behaviors. Applying the inverse model, which maps macro parameters back to micro parameters, to widely available macro-level financial market data, allows for estimating time series of aggregated real world micro-level strategy data at daily frequency. To estimate the inverse model in the first place, a neural network approach is used, as it allows for a large degree of freedom concerning the structure of the mapping to be represented by the neural network. As basis for learning the mapping, micro and macro time series of the market model are generated artificially using a multi-agent simulation based on RePast [5]. After applying several pre-processing and smoothing methods to these time series, a feed-forward multilayer perceptron is trained using a variant of the Levenberg-Marquardt algorithm combined with Bayesian regularization [6]. Finally, the trained network is applied to the S&P 500 to estimate daily time series of fractions of strategies used by market participants. Results. The main contribution of this work is a model-free indirect estimation approach. It allows estimating micro-parameter time series of the underlying agent-based model of high complexity at high frequency. No simplifying assumptions concerning the model or the estimation process have to be applied. Our results also contribute to the understanding of theoretical models. By investigating fundamental depen¬den¬cies in the Lux and Marchesi model by means of sensitivity analysis of the resulting neural network inverse model, price volatility is found to be a major driver. This provides additional support to findings in [1]. Some face validity for concrete estimation results obtained from the S&P 500 is shown by comparing to results of Boswijk et al. [3]. This is the work which comes closest to our approach, albeit their model is simpler and estimation frequency is yearly. We find support for Boswijk et al.’s key finding of a large fraction of chartists during the end of 1990s price bubble in technology stocks. Eventually, our work contributes to understanding what kind of micro-level behaviors drive stock markets. Analyzing correlations of our estimation results to historic market events, we find the fraction of chartists being large at times of crises, crashes, and bubbles. See also http://www.whodrivesthemarket.com for some continuously updated and derived live-results

A Vibrio cholerae Classical TcpA Amino Acid Sequence Induces Protective Antibody That Binds an Area Hypothesized To Be Important for Toxin-Coregulated Pilus Structure

Vibrio cholerae is a gram-negative bacterium that has been associated with cholera pandemics since the early 1800s. Whole-cell, killed, and live-attenuated oral cholera vaccines are in use. We and others have focused on the development of a subunit cholera vaccine that features standardized epitopes from various V. cholerae macromolecules that are known to induce protective antibody responses. TcpA protein is assembled into toxin-coregulated pilus (TCP), a type IVb pilus required for V. cholerae colonization, and thus is a strong candidate for a cholera subunit vaccine. Polypeptides (24 to 26 amino acids) in TcpA that can induce protective antibody responses have been reported, but further characterization of their amino acid targets relative to tertiary or quaternary TCP structures has not been done. We report a refinement of the TcpA sequences that can induce protective antibody. One sequence, TcpA 15 (residues 170 to 183), induces antibodies that bind linear TcpA in a Western blot as well as weakly bind soluble TcpA in solution. These antibodies bind assembled pili at high density and provide 80 to 100% protection in the infant mouse protection assay. This is in sharp contrast to other anti-TcpA peptide sera (TcpA 11, TcpA 13, and TcpA 17) that bind very strongly in Western blot and solution assays yet do not provide protection or effectively bind TCP, as evidenced by immunoelectron microscopy. The sequences of TcpA 15 that induce protective antibody were localized on a model of assembled TCP. These sequences are centered on a site that is predicted to be important for TCP structure