Granular materials and ordinary fluids react differently to shear stresses. Rather than deforming uniformly, materials such as dry sand or cohesionless powders develop shear bands--narrow zones of large relative particle motion, with essentially rigid adjacent regions. Because shear bands mark areas of flow, material failure and energy dissipation, they are important in many industrial, civil engineering and geophysical processes. They are also relevant to lubricating fluids confined to ultrathin molecular layers. However, detailed three-dimensional information on motion within a shear band, including the degree of particle rotation and interparticle slip, is lacking. Similarly, very little is known about how the microstructure of individual grains affects movement in densely packed material. Here we combine magnetic resonance imaging, X-ray tomography and high-speed-video particle tracking to obtain the local steady-state particle velocity, rotation and packing density for shear flow in a three-dimensional Couette geometry. We find that key characteristics of the granular microstructure determine the shape of the velocity profile.

The evolution of granular shear flow is investigated as a function of height in a split-bottom Couette cell. Using particle tracking, magnetic-resonance imaging, and large-scale simulations we find a transition in the nature of the shear as a characteristic height H * is exceeded. Below H * there is a central stationary core; above H * we observe the onset of additional axial shear associated with torsional failure. Radial and axial shear profiles are qualitatively different: the radial extent is wide and increases with height while the axial width remains narrow and fixed.PACS numbers: 45.70. Mg, 83.50.Ax Shear bands in dense granular materials are localized regions of large velocity gradients; they are the antithesis of the broad uniform flows seen in slowly-sheared Newtonian fluids [1,2,3,4,5,6]. Until recently it was generally assumed that all granular shear bands were narrow. However, in 2003 Fenistein et al. [7] discovered that in modified Couette cells granular shear bands can be made arbitrarily broad. In this geometry, the bottom of a cylindrical container is split at radius r = R s and shear is produced by rotating both the outer ring and the cylindrical boundary of the container while keeping the central disk (r < R s ) stationary. For very shallow packs, the shear band measured at the top surface is narrow and located at r = R s so that the inner region directly above the central disk is stationary while the remaining part rotates as a solid. As the filling height of the material, H, increases, the shear band increases in radial width and moves toward the cylinder axis. For sufficiently large H, the shear band overlaps the axis at r = 0 and one might expect qualitatively new behavior. Indeed, Unger et al. [8] predicted that the shape of the boundary between moving and stationary material would undergo a first-order transition as H is increased past a threshold value H * : the shearing region which for H < H * is open at the top and intersects the free surface abruptly collapses to a closed cupola completely buried inside the bulk.Previous experiments focused primarily on the surface flows in shallow containers and left unexplored many questions about the shape and evolution of the shear profiles for large H. Here, we combine magnetic resonance imaging (MRI) and high-speed video observations with large-scale simulations to explore shear flow both for shallow and tall packs. In addition to monitoring the evolution of the flow profiles in the radial direction, we also examine shear in the vertical direction. Instead of a first order collapse of the shear zone as proposed by Unger et al.[8], we find that above H * ≃ 0.6R s , the inner core of immobile material disappears gradually as shear along the central axis of the cylinder sets in. Our setup is similar to that of Fenistein et al. [7] except that we rotate the inner disk instead of the outer ring and cylinder (Fig.1b inset). In the absence of inertial effects, this makes no difference to the results. For surface observations with high-speed video ...

Vibrations in a granular material can spontaneously produce convection rolls reminiscent of those seen in fluids. Magnetic resonance imaging provides a sensitive and noninvasive probe for the detection of these convection currents, which have otherwise been difficult to observe. A magnetic resonance imaging study of convection in a column of poppy seeds yielded data about the detailed shape of the convection rolls and the depth dependence of the convection velocity. The velocity was found to decrease exponentially with depth; a simple model for this behavior is presented here.

The c-Met receptor tyrosine kinase is emerging as a novel target in many solid tumors, including lung cancer. PHA-665752 was identified as a small molecule, ATP competitive inhibitor of the catalytic activity of the c-Met kinase. Here, we show that treatment with PHA665752 reduced NCI-H69 (small cell lung cancer) and NCI-H441 (non-small cell lung cancer) tumorigenicity in mouse xenografts by 99% and 75%, respectively. Reduction in tumor size was also observed by magnetic resonance imaging of tumors in mice. PHA665752 inhibited c-Met phosphorylation at the autophosphorylation and c-Cbl binding sites in mouse xenografts derived from non-small cell lung cancer cell lines (NCI-H441 and A549) and small cell lung cancer cell line (NCI-H69). PHA665752 also inhibited angiogenesis by >85% in all the abovementioned cell lines and caused an angiogenic switch which resulted in a decreased production of vascular endothelial growth factor and an increase in the production of the angiogenesis inhibitor thrombospondin-1. These studies show the feasibility of selectively targeting c-Met with ATP competitive small molecule inhibitors and suggest that PHA665752 may provide a novel therapeutic approach to lung cancer. [Cancer Res 2007;67(8):3529-34]

Purpose:To evaluate variability of a simplified method for measuring semiquantitative DCE-MRI parameters in patients with cancer and to explore effects of treatment with a putative anti-angiogenic compound. Materials and Methods:A total of 19 patients enrolled on treatment trials with the putative anti-angiogenic agent SU5416 underwent contrast enhanced examinations, and 11 had a second examination eight weeks post therapy. Contrast media concentration as a function of time was calculated using changes in signal and literature baseline T 1 values in normal muscle or liver reference tissue. Semiquantitative DCE-MRI parameters, including the area under the contrast concentration vs. time curve (AUC), were calculated for regions-of-interest in normal liver and muscle, and in tumors. Results:The coefficients of variation for pretherapy parameters in normal tissue were 11% to 37%. No significant changes were detected in normal liver over two months of therapy. In tumors and muscle, a significant decrease in the AUC and maximum contrast concentration was observed. Conclusion:Variability of semiquantitative DCE-MRI parameters utilizing a method based on known T 1 values in a reference tissue is low enough to detect changes in tumors during therapy. Use of this method as a pharmacodynamic marker should be further investigated.

Using high-speed video and magnetic resonance imaging (MRI) we study the motion of a large sphere in a vertically vibrated bed of smaller grains. As previously reported we find a non-monotonic density dependence of the rise and sink time of the large sphere. We show that air drag causes relative motion between the intruder and the bed during the shaking cycle and is ultimately responsible for the observed density dependence of the rise time. We investigate in detail how the motion of the intruder sphere is influenced by size of the background particles, initial vertical position in the bed, ambient pressure and convection. We explain our results in the framework of a simple model and find quantitative agreement in key aspects with numerical simulations to the model equations.

Using MRI and high-speed video we investigate the motion of a large intruder particle inside a vertically shaken bed of smaller particles. We find a pronounced, non-monotonic density dependence, with both light and heavy intruders moving faster than those whose density is approximately that of the granular bed. For light intruders, we furthermore observe either rising or sinking behavior, depending on intruder starting height, boundary condition and interstitial gas pressure. We map out the phase boundary delineating the rising and sinking regimes. A simple model can account for much of the observed behavior and show how the two regimes are connected by considering pressure gradients across the granular bed during a shaking cycle.PACS numbers: 45.70. Mg, 64.75.+g, 83.80.Fg Unlike thermal systems which favor mixing to increase entropy, granular systems tend to separate under an external driving mechanism such as vibrations [1,2]. This is commonly known as the Brazil Nut Effect, in which a large particle, the "intruder", rises to the top of a bed of smaller background particles [3,4,5]. More recently, new behavior was discovered for the limit of very small bed particles ("dust"), in particular the sinking of light intruders [6,7], and a non-monotonic dependence of the rise time on density [8,9,10]. A number of theory and experimental papers explored different aspects of this surprising behavior [11,12,13,14,15,16], but so far there has been no consensus about either the underlying mechanisms or the relative importance of various system parameters in driving the intruder motion.Here we present results from a systematic investigation of both the intruder motion and the bed particle flow. Our central finding is that there is a phase diagram which delineates rising and sinking behavior of the intruder as a function of interstitial gas pressure, intruder density, and initial intruder height within the container. Our results lead to a physical model that provides a unifying framework to describe both rising and sinking regimes. In this way, the work presented here connects previously disjointed pieces of a puzzle that pointed to the importance of pressure gradients [7,8,9] but approached the two regimes as separate phenomena. As a consequence, our findings directly contrast with the mechanisms proposed in Refs. [6,10,14,16] that neglect interstitial gas flow.We placed granular material inside an acrylic cylinder (inner diameter 8.2 cm) mounted on a shaker and used individual, well-spaced sine wave cycles ("taps") of frequency f and amplitude A to vibrate the vessel vertically. The cell could be evacuated to a gas pressure, P . Both smooth and rough cells (created by gluing glass beads to the interior walls of an otherwise smooth cell) were used to study the effect of wall friction. A large intruder sphere of diameter D was buried in the bed of background spheres (diameter d) at a height h s measured from the vessel bottom to the intruder top (See Fig. 1(a)). A range of diameter ratios D/d, shaking parameters, and bac...

Purpose: Vascular endothelial growth factor (VEGF) expression is prognostic in melanoma, and the activity of VEGF is mediated in part through the receptor tyrosine kinase Flk-1. A Phase II study of SU5416, a preferential inhibitor of Flk-1, was carried out in patients with metastatic melanoma to determine clinical response, tolerability, and changes in tumor vascular perfusion.Experimental Design: Patients with documented progressive disease and <1 prior therapy were eligible. Central nervous system metastases were allowed if stable off medication. SU5416 (145 mg/m 2 ) was administered via a central catheter twice weekly for 8 weeks. Premedication with dexamethasone, diphenhydramine, and a H 2 blocker was required because of the Cremophor vehicle. Tumor vascular perfusion was assessed before treatment and during week 8 by dynamic contrast magnetic resonance imaging, and plasma was analyzed for VEGF.Results: Thirty-one patients were enrolled. Two-thirds had received prior therapy, 21 had visceral metastasis, and 14 had an elevated lactate dehydrogenase. Mean absolute lymphocyte counts were decreased (P ‫؍‬ 0.002), and glucose levels were increased (P ‫؍‬ 0.001) posttherapy, presumably because of steroid premedication. Four vascular adverse events were observed. Of 26 evaluable patients, 1 experienced a partial response, 1 had stable disease, and 5 had a mixed response. Dynamic contrast magnetic resonance imaging in 5 evaluable patients showed decreased tumor perfusion at week 8 (P ‫؍‬ 0.024), and plasma VEGF levels were elevated compared with pretherapy (P ‫؍‬ 0.008).Conclusions: SU5146 appears to be relatively well tolerated in this population. Although the modest clinical activity and potential effects on tumor vascularity may support additional exploration of VEGF as a target in melanoma, effects from steroid premedication limit further investigation of this agent.