Positron emission tomography imaging of endometrial cancer using engineered anti-EMP2 antibody fragments.

PurposeAs imaging of the cell surface tetraspan protein epithelial membrane protein-2 (EMP2) expression in malignant tumors may provide important prognostic and predictive diagnostic information, the goal of this study is to determine if antibody fragments to EMP2 may be useful for imaging EMP2 positive tumors.ProceduresThe normal tissue distribution of EMP2 protein expression was evaluated by immunohistochemistry and found to be discretely expressed in both mouse and human tissues. To detect EMP2 in tumors, a recombinant human anti-EMP2 minibody (scFv-hinge-C(H)3 dimer; 80 kDa) was designed to recognize a common epitope in mice and humans and characterized. In human tumor cell lines, the antibody binding induced EMP2 internalization and degradation, prompting the need for a residualizing imaging strategy. Following conjugation to DOTA (1,4,7,10-tetraazacyclododecane-N,N',N',N'″-tetraacetic acid), the minibody was radiolabeled with (64)Cu (t (1/2) = 12.7 h) and evaluated in mice as a positron emission tomography (PET) imaging agent for human EMP2-expressing endometrial tumor xenografts.ResultsThe residualizing agent, (64)Cu-DOTA anti-EMP2 minibody, achieved high uptake in endometrial cancer xenografts overexpressing EMP2 (10.2 ± 2.6, percent injected dose per gram (%ID/g) ± SD) with moderate uptake in wild-type HEC1A tumors (6.0 ± 0.1). In both cases, precise tumor delineation was observed from the PET images. In contrast, low uptake was observed with anti-EMP2 minibodies in EMP2-negative tumors (1.9 ± 0.5).ConclusionsThis new immune-PET agent may be useful for preclinical assessment of anti-EMP2 targeting in vivo. It may also have value for imaging of tumor localization and therapeutic response in patients with EMP2-positive malignancies

Velocity Distributions of Granular Gases with Drag and with Long-Range Interactions

We study velocity statistics of electrostatically driven granular gases. For two different experiments: (i) non-magnetic particles in a viscous fluid and (ii) magnetic particles in air, the velocity distribution is non-Maxwellian, and its high-energy tail is exponential, P(v) ~ exp(-|v|). This behavior is consistent with kinetic theory of driven dissipative particles. For particles immersed in a fluid, viscous damping is responsible for the exponential tail, while for magnetic particles, long-range interactions cause the exponential tail. We conclude that velocity statistics of dissipative gases are sensitive to the fluid environment and to the form of the particle interaction.Comment: 4 pages, 3 figure

Two-dimensional Granular Gas of Inelastic Spheres with Multiplicative Driving

We study a two-dimensional granular gas of inelastic spheres subject to multiplicative driving proportional to a power $|v(\vec{x})|^{\delta}$ of the local particle velocity $v(\vec{x})$. The steady state properties of the model are examined for different values of $\delta$, and compared with the homogeneous case $\delta=0$. A driving linearly proportional to $v(\vec{x})$ seems to reproduce some experimental observations which could not be reproduced by a homogeneous driving. Furthermore, we obtain that the system can be homogenized even for strong dissipation, if a driving inversely proportional toComment: 4 pages, 5 figures (accepted as Phys. Rev. Lett.

Evaluation of Two Internalizing Carcinoembryonic Antigen Reporter Genes for Molecular Imaging

PurposeThe objective of this article is to develop internalizing positron emission tomography (PET) reporter genes for tracking genetically modified T cells in vivo.ProceduresThe transmembrane and cytoplasmic domains of the human transferrin receptor (TfR) and CD5 were each fused to the carcinoembryonic (CEA) minigene N-A3 and expressed in Jurkat T cells. Internalization was evaluated by confocal microscopy or by intracellular uptake of ¹²⁵I-labeled anti-CEA scFv-Fc. Reporter gene-transfected Jurkat xenografts in mice were analyzed by immunohistochemistry (IHC) and imaged by PET using ¹²⁴I- or ⁶⁴Cu-scFv-Fc as tracers.ResultsSurface expression of TR(1-99)-NA3 was lower than that of NA3-CD5. Both reporter genes were internalized following binding of the anti-CEA antibody fragment. IHC of tumors showed strong staining of NA3-CD5, whereas TR(1-99)-NA3 stained weakly. Specific targeting of TR(1-99)-NA3 or NA3-CD5 was shown by PET in xenografted mice.ConclusionsThe in vivo imaging studies suggest a potential application of the internalizing form of CEA (N-A3) as a PET reporter gene

Knots and Random Walks in Vibrated Granular Chains

We study experimentally statistical properties of the opening times of knots in vertically vibrated granular chains. Our measurements are in good qualitative and quantitative agreement with a theoretical model involving three random walks interacting via hard core exclusion in one spatial dimension. In particular, the knot survival probability follows a universal scaling function which is independent of the chain length, with a corresponding diffusive characteristic time scale. Both the large-exit-time and the small-exit-time tails of the distribution are suppressed exponentially, and the corresponding decay coefficients are in excellent agreement with the theoretical values.Comment: 4 pages, 5 figure

Granular Collapse as a Percolation Transition

Inelastic collapse is found in a two-dimensional system of inelastic hard disks confined between two walls which act as an energy source. As the coefficient of restitution is lowered, there is a transition between a state containing small collapsed clusters and a state dominated by a large collapsed cluster. The transition is analogous to that of a percolation transition. At the transition the number of clusters n_s of size s scales as $n_s \sim s^{-\tau}$ with $\tau \approx 2.7$.Comment: 10 pages revtex, 5 figures, accepted by Phys Rev E many changes and corrections from previous submissio

Shocks in supersonic sand

We measure time-averaged velocity, density, and temperature fields for steady granular flow past a wedge and calculate a speed of granular pressure disturbances (sound speed) equal to 10% of the flow speed. The flow is supersonic, forming shocks nearly identical to those in a supersonic gas. Molecular dynamics simulations of Newton's laws and Monte Carlo simulations of the Boltzmann equation yield fields in quantitative agreement with experiment. A numerical solution of Navier-Stokes-like equations agrees with a molecular dynamics simulation for experimental conditions excluding wall friction.Comment: 4 pages, 5 figure

Clustering transitions in vibro-fluidized magnetized granular materials

We study the effects of long range interactions on the phases observed in cohesive granular materials. At high vibration amplitudes, a gas of magnetized particles is observed with velocity distributions similar to non-magnetized particles. Below a transition temperature compact clusters are observed to form and coexist with single particles. The cluster growth rate is consistent with a classical nucleation process. However, the temperature of the particles in the clusters is significantly lower than the surrounding gas, indicating a breakdown of equipartition. If the system is quenched to low temperatures, a meta-stable network of connected chains self-assemble due to the anisotropic nature of magnetic interactions between particles.Comment: 4 pages, 5 figure

Bifurcations of a driven granular system under gravity

Molecular dynamics study on the granular bifurcation in a simple model is presented. The model consists of hard disks, which undergo inelastic collisions; the system is under the uniform external gravity and is driven by the heat bath. The competition between the two effects, namely, the gravitational force and the heat bath, is carefully studied. We found that the system shows three phases, namely, the condensed phase, locally fluidized phase, and granular turbulent phase, upon increasing the external control parameter. We conclude that the transition from the condensed phase to the locally fluidized phase is distinguished by the existence of fluidized holes, and the transition from the locally fluidized phase to the granular turbulent phase is understood by the destabilization transition of the fluidized holes due to mutual interference.Comment: 35 pages, 17 figures, to be published in PR