Host-related carcinoembryonic antigen cell adhesion molecule 1 promotes metastasis of colorectal cancer.

Liver metastasis is the predominant cause of colorectal cancer (CRC)-related mortality in developed countries. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a cell adhesion molecule with reduced expression in early phases of CRC development and thus functions as a tumor growth inhibitor. However, CEACAM1 is upregulated in metastatic colon cancer, suggesting a bimodal role in CRC progression. To investigate the role of this protein in the host metastatic environment, Ceacam1(-/-) mice were injected intrasplenically with metastatic MC38 mouse CRC cells. A significant reduction in metastatic burden was observed in Ceacam1(-/-) compared with wild-type (WT) livers. Intravital microscopy showed decreased early survival of MC38 cells in Ceacam1(-/-) endothelial environment. Metastatic cell proliferation within the Ceacam1(-/-) livers was also diminished. Bone marrow-derived cell recruitment, attenuation of immune infiltrates and diminished CCL2, CCL3 and CCL5 chemokine production participated in the reduced Ceacam1(-/-) metastatic phenotype. Transplantations of WT bone marrow (BM) into Ceacam1(-/-) mice fully rescued metastatic development, whereas Ceacam1(-/-) BM transfer into WT mice showed reduced metastatic burden. Chimeric immune cell profiling revealed diminished recruitment of CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSCs) to Ceacam1(-/-) metastatic livers and adoptive transfer of MDSCs confirmed the involvement of these immune cells in reduction of liver metastasis. CEACAM1 may represent a novel metastatic CRC target for treatment.

Comparison of GATE/GEANT4 with EGSnrc and MCNP for electron dose calculations at energies between 15 keV and 20 MeV.

The GATE Monte Carlo simulation platform based on the GEANT4 toolkit has come into widespread use for simulating positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging devices. Here, we explore its use for calculating electron dose distributions in water. Mono-energetic electron dose point kernels and pencil beam kernels in water are calculated for different energies between 15 keV and 20 MeV by means of GATE 6.0, which makes use of the GEANT4 version 9.2 Standard Electromagnetic Physics Package. The results are compared to the well-validated codes EGSnrc and MCNP4C. It is shown that recent improvements made to the GEANT4/GATE software result in significantly better agreement with the other codes. We furthermore illustrate several issues of general interest to GATE and GEANT4 users who wish to perform accurate simulations involving electrons. Provided that the electron step size is sufficiently restricted, GATE 6.0 and EGSnrc dose point kernels are shown to agree to within less than 3% of the maximum dose between 50 keV and 4 MeV, while pencil beam kernels are found to agree to within less than 4% of the maximum dose between 15 keV and 20 MeV.

HOPE, an open platform for medical data management on the grid.

The paper describes a platform developed for the secure management and analysis of medical data and images in a grid environment. Designed for telemedicine and built upon the EGEE gLite middleware and particularly the metadata catalogue AMGA as well as the GridSphere web portal, the platform provides to healthcare professionals the capacity to upload and query medical information stored over distributed servers. A job submission environment is also available for data analysis. Security features include authentication and authorization by grid certificates, anonymization of medical data and image encryption. The platform is currently deployed on several sites in Europe and Asia and is being customized for applications in the field of telemedicine and medical physics.

The SHARE road map: Healthgrids for biomedical research and healthcare.

The HealthGrid White Paper was published at the third annual conference in Oxford in 2005. Starting from the conclusions of the White Paper, the EU funded SHARE project (http://www.eu-share.org) has aimed at identifying the most important steps and significant milestones towards wide deployment and adoption of healthgrids in Europe. The project has defined a strategy to address the issues identified in the action plan for European e-Health (COM(2004).356) and has devised a roadmap for the major technological and ethical and legal developments and social and economic investments needed for successful take up of healthgrids in the next 10 years. A "beta" version of the road map underwent full review by a panel of 25 prominent European experts at a workshop in December 2007. The present document is an executive policy summary of the final draft road map. It has sought to reconcile likely conflicts between technological developments and regulatory frameworks by bringing together the project's technical road map and conceptual map of ethical and legal issues and socio-economic prospects. A key tool in this process was a collection of case studies of healthgrid applications.

Validation of a dose deposited by low-energy photons using GATE/GEANT4.

The GATE Monte Carlo simulation platform based on the Geant4 toolkit has now become a diffused tool for simulating PET and SPECT imaging devices. In this paper, we explore its relevance for dosimetry of low-energy 125I photon brachytherapy sources used to treat prostate cancers. To that end, three 125-iodine sources widely used in prostate cancer brachytherapy treatment have been modelled. GATE simulations reproducing dosimetric reference observables such as radial dose function g(r), anisotropy function F(r, theta) and dose-rate constant (Lambda) were performed in liquid water. The calculations were splitted on the EGEE grid infrastructure to reduce the computing time of the simulations. The results were compared to other relevant Monte Carlo results and to measurements published and fixed as recommended values by the AAPM Task Group 43. GATE results agree with consensus values published by AAPM Task Group 43 with an accuracy better than 2%, demonstrating that GATE is a relevant tool for the study of the dose induced by low-energy photons.

Grid-added value to address malaria.

Through this paper, we call for a distributed, Internet-based collaboration to address one of the worst plagues of our present world, malaria. The spirit is a nonproprietary peer-production of information-embedding goods. And we propose to use the grid technology to enable such a worldwide "open-source" like collaboration. The first step toward this vision has been achieved during the summer 2005 on the enabling grids for E-scienceE (EGEE) grid infrastructure where 42 million ligands were docked for a total amount of 80 CPU years in 6 weeks in the quest for new drugs. The impact of this first deployment has significantly raised the interest of the research community so that several laboratories all around the world expressed interest to propose targets for a second large-scale deployment against malaria.

Replication and update of molecular biology databases.

Update of molecular biology databases is a growing burden on the biomedical research community. As the grid allows to share and replicate data, we propose a service to automatically update the molecular biology databases from a single changing reference using Web services. In this paper we report the components, the architecture, and the deployment of the update service on the french RUGBI grid infrastructure. RUGBI is a computing grid infrastructure based on existing middleware and technologies for the community of scientists in bioinformatics.

Grid-enabling medical image analysis.

Grids have emerged as a promising technology to handle the data and compute intensive requirements of many application areas. Digital medical image processing is a promising application area for grids. Given the volume of data, the sensitivity of medical information, and the joint complexity of medical datasets and computations expected in clinical practice, the challenge is to fill the gap between the grid middleware and the requirements of clinical applications. The research project AGIR (Grid Analysis of Radiological Data) presented in this paper addresses this challenge through a combined approach: on one hand, leveraging the grid middleware through core grid medical services which target the requirements of medical data processing applications; on the other hand, grid-enabling a panel of applications ranging from algorithmic research to clinical applications.

Fully 3D Monte Carlo reconstruction in SPECT: a feasibility study.

In single photon emission computed tomography (SPECT) with parallel hole collimation, image reconstruction is usually performed as a set of bidimensional (2D) analytical or iterative reconstructions. This approach ignores the tridimensional (3D) nature of scatter and detector response function that affects the detected signal. To deal with the 3D nature of the image formation process, iterative reconstruction can be used by considering a 3D projector modelling the 3D spread of photons. In this paper, we investigate the value of using accurate Monte Carlo simulations to determine the 3D projector used in a fully 3D Monte Carlo (F3DMC) reconstruction approach. Given the 3D projector modelling all physical effects affecting the imaging process, the reconstruction problem is solved using the maximum likelihood expectation maximization (MLEM) algorithm. To validate the concept, three data sets were simulated and F3DMC was compared with two other 3D reconstruction strategies using analytical corrections for attenuation, scatter and camera point spread function. Results suggest that F3DMC improves spatial resolution, relative and absolute quantitation and signal-to-noise ratio. The practical feasibility of the approach on real data sets is discussed.

Partitioning medical image databases for content-based queries on a Grid.

OBJECTIVES: In this paper we study the impact of executing a medical image database query application on the grid. For lowering the total computation time, the image database is partitioned into subsets to be processed on different grid nodes. METHODS: A theoretical model of the application complexity and estimates of the grid execution overhead are used to efficiently partition the database. RESULTS: We show results demonstrating that smart partitioning of the database can lead to significant improvements in terms of total computation time. CONCLUSIONS: Grids are promising for content-based image retrieval in medical databases.

Empowering humanitarian medical development using grid technology.

BACKGROUND: The training of local clinicians is the best way to raise the standard of medical knowledge in developing countries. This requires transferring skills, techniques and resources. OBJECTIVES: Grid technology opens new perspectives for preparation and follow-up of medical missions in developing countries as well as support to local medical centers in terms of teleconsulting, telediagnosis and patient follow-up. Indeed, grids allow to hide the complexity of handling distributed data in such a way that physicians will be able to access patient data while ignoring where these data are stored. METHODS: To meet requirements of a development project of the French NPO Chain of Hope in China, we propose to deploy a grid-based federation of databases. FIRST RESULTS AND CONCLUSIONS: A first protocol was established for describing the patients' pathologies and their pre- and post-surgery states through a web interface in a language-independent way. This protocol was evaluated by French and Chinese clinicians during medical missions in the fall of 2003. The first sets of medical patients recorded in the databases will be used to evaluate grid implementation of services.

GATE: a simulation toolkit for PET and SPECT.

Monte Carlo simulation is an essential tool in emission tomography that can assist in the design of new medical imaging devices, the optimization of acquisition protocols and the development or assessment of image reconstruction algorithms and correction techniques. GATE, the Geant4 Application for Tomographic Emission, encapsulates the Geant4 libraries to achieve a modular, versatile, scripted simulation toolkit adapted to the field of nuclear medicine. In particular, GATE allows the description of time-dependent phenomena such as source or detector movement, and source decay kinetics. This feature makes it possible to simulate time curves under realistic acquisition conditions and to test dynamic reconstruction algorithms. This paper gives a detailed description of the design and development of GATE by the OpenGATE collaboration, whose continuing objective is to improve, document and validate GATE by simulating commercially available imaging systems for PET and SPECT. Large effort is also invested in the ability and the flexibility to model novel detection systems or systems still under design. A public release of GATE licensed under the GNU Lesser General Public License can be downloaded at http:/www-lphe.epfl.ch/GATE/. Two benchmarks developed for PET and SPECT to test the installation of GATE and to serve as a tutorial for the users are presented. Extensive validation of the GATE simulation platform has been started, comparing simulations and measurements on commercially available acquisition systems. References to those results are listed. The future prospects towards the gridification of GATE and its extension to other domains such as dosimetry are also discussed.

Measurement of the generalized polarizabilities of the proton in virtual Compton scattering at Q2=0.92 and 1.76 GeV2.

We report a virtual Compton scattering study of the proton at low c.m. energies. We have determined the structure functions P(LL)-P(TT)/epsilon and P(LT), and the electric and magnetic generalized polarizabilities (GPs) alpha(E)(Q2) and beta(M)(Q2) at momentum transfer Q(2)=0.92 and 1.76 GeV2. The electric GP shows a strong falloff with Q2, and its global behavior does not follow a simple dipole form. The magnetic GP shows a rise and then a falloff; this can be interpreted as the dominance of a long-distance diamagnetic pion cloud at low Q2, compensated at higher Q2 by a paramagnetic contribution from piN intermediate states.

Validation of the GATE Monte Carlo simulation platform for modelling a CsI(Tl) scintillation camera dedicated to small-animal imaging.

Monte Carlo simulations are increasingly used in scintigraphic imaging to model imaging systems and to develop and assess tomographic reconstruction algorithms and correction methods for improved image quantitation. GATE (GEANT4 application for tomographic emission) is a new Monte Carlo simulation platform based on GEANT4 dedicated to nuclear imaging applications. This paper describes the GATE simulation of a prototype of scintillation camera dedicated to small-animal imaging and consisting of a CsI(Tl) crystal array coupled to a position-sensitive photomultiplier tube. The relevance of GATE to model the camera prototype was assessed by comparing simulated 99mTc point spread functions, energy spectra, sensitivities, scatter fractions and image of a capillary phantom with the corresponding experimental measurements. Results showed an excellent agreement between simulated and experimental data: experimental spatial resolutions were predicted with an error less than 100 microns. The difference between experimental and simulated system sensitivities for different source-to-collimator distances was within 2%. Simulated and experimental scatter fractions in a [98-182 keV] energy window differed by less than 2% for sources located in water. Simulated and experimental energy spectra agreed very well between 40 and 180 keV. These results demonstrate the ability and flexibility of GATE for simulating original detector designs. The main weakness of GATE concerns the long computation time it requires: this issue is currently under investigation by the GEANT4 and the GATE collaborations.

Synergy between medical informatics and bioinformatics: facilitating genomic medicine for future health care.

In this paper, we review the results of BIOINFOMED, a study funded by the European Commission (EC) with the purpose to analyse the different issues and challenges in the area where Medical Informatics and Bioinformatics meet. Traditionally, Medical Informatics has been focused on the intersection between computer science and clinical medicine, whereas Bioinformatics have been predominantly centered on the intersection between computer science and biological research. Although researchers from both areas have occasionally collaborated, their training, objectives and interests have been quite different. The results of the Human Genome and related projects have attracted the interest of many professionals, and introduced new challenges that will transform biomedical research and health care. A characteristic of the 'post genomic' era will be to correlate essential genotypic information with expressed phenotypic information. In this context, Biomedical Informatics (BMI) has emerged to describe the technology that brings both disciplines (BI and MI) together to support genomic medicine. In recognition of the dynamic nature of BMI, institutions such as the EC have launched several initiatives in support of a research agenda, including the BIOINFOMED study.

DataGrid, prototype of a biomedical grid.

BACKGROUND: The availability of large amounts of data in heterogeneous formats and the rapid progress in fields such as computer based drug design, medical imaging and medical simulations have lead to a growing demand for large computational power and easy accessibility to heterogeneous data sources. OBJECTIVES: The goal is to address these needs by deploying computing grids. Grids provide both large scale and distributed storage facilities and an increased computing power. Moreover, Grids are a promising tool to foster the synergy between bioinformatics and computerised medical imaging. METHODS: A first biomedical grid is being deployed within the framework of the DataGrid IST project (http://www.edg.org). The goal of the project is to provide a novel environment to support globally distributed scientific exploration involving up to multi-Perabyte datasets. RESULTS AND CONCLUSIONS: The first biomedical applications deployed inside the project demonstrate the relevance of the grid paradigm for genomics and medical image processing. They also highlight the specific requirements of the biomedical community.

Hypervariable region 1 quasispecies in hepatitis C virus genotypes 1b and 3 infected patients with normal and abnormal alanine aminotransferase levels.

The role of hepatitis C virus (HCV) heterogeneity in the severity of chronic hepatitis C infection remains unclear. Our aim was to study the hypervariable region 1 (HVR1) heterogeneity in patients with chronic hepatitis C infected with genotype 1b or 3 and with normal or abnormal alanine aminotransferase (ALT). HVR1 quasispecies were assessed by single strand conformational polymorphism (SSCP) in 67 patients with chronic hepatitis C, including 35 with persistently normal ALT and 32 with abnormal ALT. Sixty-two patients underwent a liver biopsy. Among the 67 patients, 40 were infected with genotype 1b and 27 with genotype 3. In univariate analysis, low heterogeneity (

Prospective study on anti-hepatitis C virus-positive patients with persistently normal serum alanine transaminase with or without detectable serum hepatitis C virus RNA.

A significant proportion of patients with detectable antibodies to hepatitis C virus have normal serum alanine transaminase levels. Our aim was to study the outcome of this group. Between 1992 and 1999, 135 consecutive anti-HCV-positive patients with persistently normal ALT were followed for 3.6 +/- 2.3 years (0.5 to 8.5 years), 108 had a liver biopsy at inclusion, and 24 had a second liver biopsy 3.5 +/- 1.0 years later. Serum HCV RNA was detectable with PCR in 94 patients (69%) and not detectable in 41 patients (31%). Patients with and without detectable serum HCV RNA had similar epidemiological characteristics. Serum ALT levels and anti-HCV ratio were lower (P =.001), and histological lesions had lower grade and stage in patients without detectable serum HCV RNA (P =.001). Liver HCV RNA was not detectable with PCR in the 12-serum HCV RNA-negative patients tested. During follow-up, all patients without detectable serum HCV RNA remained HCV RNA-negative and kept normal serum ALT; all patients with detectable serum HCV RNA remained HCV RNA-positive, 20 (21%) had a slight fluctuation of serum ALT above the upper limit of normal. No significant changes were observed in the liver lesions of the 24 patients who underwent a second liver biopsy. In anti-HCV-positive patients with persistently normal serum ALT, histological lesions are significantly lower in HCV RNA-negative than in HCV RNA-positive patients. During follow-up, the HCV RNA status of patients remained unchanged; 21% of the patients with detectable serum HCV RNA had slight increase in serum ALT levels, but histological lesions remained stable.