Greg S. Karczmar

Signatures of granular microstructure in dense shear flows

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.

Granular convection observed by magnetic resonance imaging

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.

A Selective Small Molecule Inhibitor of c-Met, PHA665752, Inhibits Tumorigenicity and Angiogenesis in Mouse Lung Cancer Xenografts

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.

Semiquantitative analysis of dynamic contrast enhanced MRI in cancer patients: Variability and changes in tumor tissue over time†

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.

Phase II study of the Flk-1 tyrosine kinase inhibitor SU5416 in advanced melanoma.

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/m2) was administered via a central catheter twice weekly for 8 weeks. Premedication with dexamethasone, diphenhydramine, and a H2 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.

Three-Dimensional Shear in Granular Flow

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.

Effect of air on granular size separation in a vibrated granular bed

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 nonmonotonic 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 risetime. 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.

Magnetic resonance measurement of response to hyperoxia differentiates tumors from normal tissue and may be sensitive to oxygen consumption.

Karczmar GS, Kupertnan VY, River JN, Lewis MZ, Lipton MJ. MR measurement of response to hyperoxia differentiates tumors from normal tissue and may be sensitive to oxygen consumption. Invest Radiol 1994;29:S161–S163.

Intruders in the Dust: Air-Driven Granular Size Separation

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, nonmonotonic 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 shows how the two regimes are connected by considering pressure gradients across the granular bed during a shaking cycle.

A new technique for differentiating between diffusion and flow in granular media using magnetic resonance imaging

We have shown that a simple nuclear magnetic resonance spin‐tagging sequence for spatial encoding of the longitudinal magnetization, combined with an imaging sequence, can be used to measure flow and diffusion in granular materials. Using this technique, experiments have been performed to study flow and diffusion profiles during convection induced by the vertical shaking of a container (39 mm diameter) filled with a granular medium. We have shown that maximum diffusion and displacements occur in a thin boundary layer near the container’s walls. The observed flow profiles are predominantly flat with relatively small positive displacements across the container with the exception of the boundary layer, where increasingly negative displacements are observed as the container’s edges are approached.