David Brasse

Effect of prior treatment with resveratrol on density and structure of rat long bones under tail-suspension.

Physical inactivity during space flight or prolonged bed rest causes rapid and marked loss of bone mass in humans. Resveratrol, a red wine polyphenol that is currently under study for its therapeutic antioxidant properties, has been shown to significantly modulate biomarkers of bone metabolism, i.e., to promote osteoblast differentiation and to prevent bone loss induced by estrogen deficiency. However, there is no direct evidence supporting its inhibitory effect toward bone loss during physical inactivity. In the present study, effects of resveratrol on bone mineral density (BMD), bone mineral content, and bone structure were examined in the femora and tibiae of tail-suspended and unsuspended rats using X-ray micro-computed tomography (micro-CT). Rats were treated with 400xa0mg/kg/day of resveratrol for 45xa0days and half of them were suspended during the last 2xa0weeks of treatment. Suspension caused a decrease in tibial and femoral BMD and deterioration of trabecular and cortical bone. Bone deterioration during suspension was paralleled by increased bone marrow area, which could be caused by an increase in stromal cells with osteoclastogenic potential or in adipocytes. Resveratrol had a preventive effect against bone loss induced by hindlimb immobilization. In particular, trabecular bone in the proximal tibial metaphysis was totally preserved in rats treated with resveratrol before tail-suspension.

Transmembrane domain targeting peptide antagonizing ErbB2/Neu inhibits breast tumor growth and metastasis.

Breast cancer is still a deadly disease despite major achievements in targeted therapies designed to block ligands or ligand-binding subunits of major tyrosine kinase receptors. Relapse is significant and metastases deleterious, which demands novel strategies for fighting this disease. Here, we report a proof-of-concept experiment demonstrating that small peptides interfering with the transmembrane domain of the tyrosine kinase epidermal growth factor receptor ErbB2 exhibit anticancer properties when used at micromolar dosages in a genetically engineered mouse model of breast cancer. Different assays demonstrate the specificity of the ErbB2-targeting peptide, which induces long-term reduction of ErbB2 phosphorylation and Akt signaling consistent with reduced tumor cell proliferation and increased survival. Microcomputed tomography analysis established the antimetastatic activity of the peptide and its impact on primary tumor growth. This reveals the interior of the cell membrane as an unexplored dimension for drug design.

Matrix metalloproteinase 11/stromelysin-3 exerts both activator and repressor functions during the hematogenous metastatic process in mice

MMP11 expression is a poor prognosis factor in human carcinomas. Although it has been shown to favor primary tumor development, its role in metastatic processes remains unclear. We studied the hematogenous metastatic activity of C26 mouse colon cancer cells injected into the tail vain of wild‐type or MMP11‐deficient mice during 2 months. Using X‐ray computed tomography to image metastasis development in recipient living mice, lung metastases were found to occur earlier and to grow faster in wild‐type mice. Histological analyses of the lung, liver, kidney, adrenal gland, mammary gland, ovary and salivary gland, performed at the end of experiment, also showed lower numbers of metastases in wild‐type mice, regardless of organ. Lung metastases showed similar Factor VIII‐positive vascular networks regardless of the mouse MMP11 status. However, those found in MMP11‐deficient mice also exhibited vessel‐like structures that did not express Factor VIII, Lyve‐1 and vimentin, and were not stained with PAS. Consequently, they did not correspond to vascular or lymphatic vessels or to vascular mimicry channels. Collectively, these results revealed significant spatio‐temporal variability that is dependent on host MMP11 status. Furthermore, they point‐out the paradoxical role of MMP11 in favoring the onset and growth of lung metastases but limiting lung foci number, and inhibiting the cancer cell dissemination to other organs. These data highlight the complexity of the metastatic process in which the same factor can play activator or repressor functions depending on the metastatic step.

A detector response function design in pinhole SPECT including geometrical calibration

Clinical single photon emission computed tomography (SPECT) equipped with pinhole collimators have a magnification factor that results in high spatial resolution images for small animal imaging. Using Monte Carlo simulations to model the acquisition process and the propagation of the photons from their point of emission to their detection point then integrating the model into an iterative reconstruction algorithm improves the signal-to-noise ratio, the contrast and the spatial resolution in the reconstructed images. However, pinhole SPECT systems are known to be very sensitive to geometrical misalignments. Geometrical misalignments are defined as the radial or axial shift of the collimator pinhole and/or twist and tilt of the detector heads and are introduced in the system each time the collimation device is changed (pinhole to parallel holes or vice versa). In this work, we present a flexible detector response function table (DRFT) design that takes into account the geometrical misalignments and avoids performing new Monte Carlo simulations for each exam in order to calculate a geometrical study-dependent system matrix. The utilization of the DRFT for the calculation of the system matrix speeds up its computation time by two orders of magnitude making it acceptable for preclinical and clinical applications.

Acceleration of Fully 3D Monte Carlo Based System Matrix Computation for Image Reconstruction in Small Animal SPECT

It has already been proved that Fully Three Dimensional Monte Carlo (F3DMC) is a robust image reconstruction algorithm that can be applied in Single Photon Emission Computed Tomgraphy (SPECT) and small animal Positron Emission Tomography (PET). F3DMC has still not yet been validated on real data in small animal SPECT application. The advantage of such image reconstruction technique is that all the physical processes occuring within the detector and its geometrical parameters can be precisely modelled within the system matrix thanks to powerful Monte Carlo Simulation toolkit. Once the system matrix is computed, it can be integrated within an iterative reconstruction algorithm such as Maximum Likelihood Estimation Maximization (MLEM) in order to resolve the inverse image reconstruction problem. However, such reconstruction technique is penalized by the huge time consumption required for the computation of the system matrix since the accuracy of this latter requires the simulation of large number of photons tracks from the imaged subject to the detector. In this study, we proposed two main solutions to tackle the problem of time consumption. The first has already been proposed in anterior works and consists in parallelizing the Monte Carlo simulations performed with the Geant4 toolkit on a Computing Grid (CG) and the second suggests to apply a Forced Detection (FD) technique in order to accelerate the convergence of the system matrix elements. Results show that an accelerated version of a F3DMC technique is feasible in a reasonable delay and leads to reconstructed images with good spatial resolution and a good capability of restoring relative quantification. Hence, it has been proven that F3DMC is an applicable reconstruction technique in small animal SPECT.

Optimizing PET DOI Resolution With Crystal Coating and Length

In the last few years, one of the main research programs for PET systems has been the improvement of spatial resolution using Depth Of Interaction (DOI) information. In the context of developing a new PET system dedicated to small animals with axially oriented LYSO crystals and DOI capability, we have investigated the influence of the crystal coating and its length on the DOI resolution. The proposed PET system is composed of four detection modules arranged around the animal. Each module consists in 768 LYSO crystals read at both ends by multichannel plate photodetectors. The particular geometry combined with an inner diameter of 61.2 mm, lead to high detection efficiency close to the system solid angle. The LYSO crystal is chosen for its light yield of 33 ph/keV and its attenuation length of 11.2 mm at 511 keV. To obtain a transverse spatial resolution of 1 mm, the section of the crystal was fixed to 1.5 mm. To achieve a DOI resolution close to 1 mm, measurements have been performed on different LYSO crystal coatings with a length ranging from 25 mm to 35 mm. Each crystal is positioned on an xy translation stage and read out at both ends by H3164-10 Hamamatsu PMTs. The DOI information is then derived every 0.5 mm along the crystal extent. The use of an electronic collimation leads to a 22Na source beam size of (1.58 ± 0.04) mm reaching the crystal. The optimized coating in terms of packing fraction and DOI resolution is found to be a mixture made with 30% TiO2 powder in a PMMA binder. With this appropriate coating, an average DOI resolution of (0.82 ± 0.13) mm can be achieved with a 25 mm crystal length using a 20% photopeak energy window. The resolution degrades to (1.39 ± 0.16) mm when a wide-open energy window is used. Those values are corrected for the source beam size. Using this experimental proposal, a matrix of LYSO crystals has been built reaching a packing fraction of 93%. In this study, we demonstrate that using a 1.5 × 1.5 × 25 mm3 LYSO crystal, a DOI resolution of less than a millimeter can be achieved while keeping a high packing fraction for a system detection efficiency close to 15%.

The impact of tracking system properties on the most likely path estimation in proton CT.

Proton CT nowadays aims at improving hadron therapy treatment planning by mapping the stopping power of materials. In order to optimize a spatial resolution of the reconstructed images, the most likely path (MLP) of each proton can be computed. We investigated the errors in the computation of this path due to the configuration of the system, i.e. the spatial resolution of the tracking planes, their material budget, and their positioning. A method for computing the uncertainty in the estimated paths for a given system was derived. The uncertainties upon the entrance and exit of the object were propagated analytically in the path computation. This procedure was then used to evaluate the impact of each parameter, and to compare different systems. We show that the intrinsic characteristics of the system generate an uncertainty in the positions and directions of the particles propagated during the MLP computation. The spatial resolution and material budget of the trackers in particular may affect the path estimation, and thus the spatial resolution of an image.

Proton computed tomography from multiple physics processes.

Proton CT (pCT) nowadays aims at improving hadron therapy treatment planning by mapping the relative stopping power (RSP) of materials with respect to water. The RSP depends mainly on the electron density of the materials. The main information used is the energy of the protons. However, during a pCT acquisition, the spatial and angular deviation of each particle is recorded and the information about its transmission is implicitly available. The potential use of those observables in order to get information about the materials is being investigated. Monte Carlo simulations of protons sent into homogeneous materials were performed, and the influence of the chemical composition on the outputs was studied. A pCT acquisition of a head phantom scan was simulated. Brain lesions with the same electron density but different concentrations of oxygen were used to evaluate the different observables. Tomographic images from the different physics processes were reconstructed using a filtered back-projection algorithm. Preliminary results indicate that information is present in the reconstructed images of transmission and angular deviation that may help differentiate tissues. However, the statistical uncertainty on these observables generates further challenge in order to obtain an optimal reconstruction and extract the most pertinent information.

Evaluation of a 1024 Anodes Micro-Channel Plate PMT for Preclinical PET Imaging

A new generation of flat panel photomultiplier tube (PMT) based on micro-channel plates (MCP) offers characteristics suitable for PET imaging. We are developing a preclinical PET system composed of four detection modules arranged around the animal. Each module consists in 768 LYSO:Ce crystals read at both ends by MCP PMT. The particular geometry combined with an inner diameter of 61.2 mm lead to a high detection efficiency with a volumetric spatial resolution of 1 μl. The purpose of this work is to characterize the 1024 anodes of the MCP-PMT (Planacon XP85023/A1, Photonis Corp.) used in our preclinical PET system. The Planacon has very compact size (58 × 58 × 13.7 mm3) with an active area of 53 × 53 mm2. The anode array consists in a 32 × 32 matrix in which each individual anode is 1.4 × 1.4 mm2 with a pitch of 1.6 mm. Due to the lack of backside connectors and in order to individually readout the anode current, a dedicated connection board has been developed. The dark current, the gain and the timing resolution of one anode are measured as well as the cross talk, the gain uniformity and the intrinsic spatial resolution on the entire active field of view. With a timing resolution below 100 ps, an intrinsic spatial resolution of 400 μm, a low dark current and a high gain, the Planacon XP85023/A1 offers a promising photodetector for PET imaging.

A pencil beam approach to proton computed tomography.

PURPOSEnA new approach to proton computed tomography (pCT) is presented. In this approach, protons are not tracked one-by-one but a beam of particles is considered instead. The elements of the pCT reconstruction problem (residual energy and path) are redefined on the basis of this new approach. An analytical image reconstruction algorithm applicable to this scenario is also proposed.nnnMETHODSnThe pencil beam (PB) and its propagation in matter were modeled by making use of the generalization of the Fermi-Eyges theory to account for multiple Coulomb scattering (MCS). This model was integrated into the pCT reconstruction problem, allowing the definition of the mean beam path concept similar to the most likely path (MLP) used in the single-particle approach. A numerical validation of the model was performed. The algorithm of filtered backprojection along MLPs was adapted to the beam-by-beam approach. The acquisition of a perfect proton scan was simulated and the data were used to reconstruct images of the relative stopping power of the phantom with the single-proton and beam-by-beam approaches. The resulting images were compared in a qualitative way.nnnRESULTSnThe parameters of the modeled PB (mean and spread) were compared to Monte Carlo results in order to validate the model. For a water target, good agreement was found for the mean value of the distributions. As far as the spread is concerned, depth-dependent discrepancies as large as 2%-3% were found. For a heterogeneous phantom, discrepancies in the distribution spread ranged from 6% to 8%. The image reconstructed with the beam-by-beam approach showed a high level of noise compared to the one reconstructed with the classical approach.nnnCONCLUSIONSnThe PB approach to proton imaging may allow technical challenges imposed by the current proton-by-proton method to be overcome. In this framework, an analytical algorithm is proposed. Further work will involve a detailed study of the performances and limitations of this approach in terms of image quality. The paper shows how to account for the MCS in the reconstruction step with this new approach when an analytical reconstruction algorithm is used.