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

Geoid undulations and gravity anomalies over the Aral Sea, the Black Sea and the Caspian Sea from a combined GEOS-3/SEASAT/GEOSAT altimeter data set

Satellite-based altimetric data taken by GOES-3, SEASAT, and GEOSAT over the Aral Sea, the Black Sea, and the Caspian Sea are analyzed and a least squares collocation technique is used to predict the geoid undulations on a 0.25x0.25 deg. grid and to transform these geoid undulations to free air gravity anomalies. Rapp's 180x180 geopotential model is used as the reference surface for the collocation procedure. The result of geoid to gravity transformation is, however, sensitive to the information content of the reference geopotential model used. For example, considerable detailed surface gravity data were incorporated into the reference model over the Black Sea, resulting in a reference model with significant information content at short wavelengths. Thus, estimation of short wavelength gravity anomalies from gridded geoid heights is generally reliable over regions such as the Black Sea, using the conventional collocation technique with local empirical covariance functions. Over regions such as the Caspian Sea, where detailed surface data are generally not incorporated into the reference model, unconventional techniques are needed to obtain reliable gravity anomalies. Based on the predicted gravity anomalies over these inland seas, speculative tectonic structures are identified and geophysical processes are inferred

User's guide: Programs for processing altimeter data over inland seas

The programs described were developed to process GEODYN-formatted satellite altimeter data, and to apply the processed results to predict geoid undulations and gravity anomalies of inland sea areas. These programs are written in standard FORTRAN 77 and are designed to run on the NSESCC IBM 3081(MVS) computer. Because of the experimental nature of these programs they are tailored to the geographical area analyzed. The attached program listings are customized for processing the altimeter data over the Black Sea. Users interested in the Caspian Sea data are expected to modify each program, although the required modifications are generally minor. Program control parameters are defined in the programs via PARAMETER statements and/or DATA statements. Other auxiliary parameters, such as labels, are hard-wired into the programs. Large data files are read in or written out through different input or output units. The program listings of these programs are accompanied by sample IBM job control language (JCL) images. Familiarity with IBM JCL and the TEMPLATE graphic package is assumed

Analysis of altimetry over inland seas

Satellite-based altimetric data taken by GEOS-3 and SEASAT over the Black Sea and Caspian Sea are analyzed and a least squares collocation technique is used to predict the geoid undulation on a .25-degree by .25-degree grid and to transform these geoid undulations to free air gravity anomalies. This project entailed processing satellite altimeter data over inland seas for recovery of area mean gravity information. Gravity information in this area of the world is not readily available, so the possibility of obtaining it from the processing of altimeter observations is attractive. The principal objective was to complete and extend analyses done in a previous study, verify those results, and document the results and techniques. A secondary objective was to improve the algorithms and results, if possible. The approach used involved editing geoid height data to remove overland data; evaluating geoid height differences at crossover points; removing orbit errors from geoid heights using crossover differences; gridding geoid height data at .25-degree by .25-degree intervals; and estimating the gravity anomalies from gridded geoid heights using the collocation technique

Analysis of altimetry over the Aral Sea

Satellite based altimetric data taken by GEOS-3, SEASAT, and GEOSAT over the Aral Sea are analyzed and a least squares collocation technique is used to predict the geoid undulations on a 0.25 by 0.25 degree grid and to transform these geoid undulations to free air gravity anomalies. Rapp's 180 by 180 geopotential model is taken as the empirical model. The collocation procedure is performed with a set of local residual empirical covariance functions. For comparison, Rapp's global covariance functions and Jordan's self-consistent theoretical covariance functions based on Jordan's formulation and on locally derived parameters are also used to grid geoid undulations and to predict gravity anomalies. The sensitivity of the collocation results to the choice of covariance functions is discussed

SHOP2: An HTN Planning System

The SHOP2 planning system received one of the awards for distinguished performance in the 2002 International Planning Competition. This paper describes the features of SHOP2 which enabled it to excel in the competition, especially those aspects of SHOP2 that deal with temporal and metric planning domains

Solicitor-Client Privilege and Litigation Privilege in Civil Litigation

This paper examines the nature and scope of solicitor-client privilege and litigation privilege. Contrary to a recent article suggesting that there are no real differences between them, it is argued that the two privileges are distinct in terms of both their underlying purposes and the requisite conditions to invoke them. Most importantly, confidentiality is a requirement of solicitor-client privilege but not of litigation privilege. Moreover, extending solicitor-client privilege to communications from third parties (as proposed in the recent article) would be dangerous. It would stretch the scope of that privilege beyond its justification of necessity, and open the way for lawyers to develop and offer a new product line : namely, confidentiality. Whatever third party communications a client desires to keep secret could conveniently be clothed with privilege simply by having lawyers act as a conduit for such communications and asking them for their legal opinion thereon (as it now appears the tobacco industry has been doing for some time with research data). A strong policy reason for confining solicitor-client privilege to direct communications between lawyer and client is to limit the potential abuse of the privilege. Further, since the assertion of privilege inevitably impedes the truth finding process, the public interest is best served by confining the scope of solicitor-client privilege within narrow limits. For the same reason, the concept of agents must be accorded a narrow meaning in the context of solicitor-client privilege, so as not to render agency a back-door through which third party communications attract solicitor-client privilege