In this paper, we developed a detailed mathematical model of dual action pneumatic actuators controlled with proportional spool valves. Effects of nonlinear flow through the valve, air compressibility in cylinder chambers, leakage between chambers, end of stroke inactive volume, and time delay and attenuation in the pneumatic lines were carefully considered. We performed system identification, numerical simulation, and model validation experiments for two types of air cylinders and different connecting tubes length. The mathematical model of the present article is used in a sequel article to develop high performance nonlinear pneumatic force controllers. [S0022-0434(00)00503-7]

SUMMARY Medullary thyroid carcinoma (MTC) is a neuroendocrine cancer that originates from calcitonin-secreting parafollicular cells, or C cells. We found that Cdk5 and its cofactors, p35 and p25, are highly expressed in human MTC and that Cdk5 activity promotes MTC proliferation. A conditional MTC mouse model was generated and corroborated the role of aberrant Cdk5 activation in MTC. C cell-specific overexpression of p25 caused rapid C cell hyperplasia leading to lethal MTC, which was arrested by repressing p25 overexpression. A comparative phosphoproteomic screen between proliferating and arrested MTC identified the retinoblastoma protein (Rb) as a crucial Cdk5 downstream target. Prevention of Rb phosphorylation at Ser807/811 attenuated MTC proliferation. These findings implicate Cdk5 signaling via Rb as critical to MTC tumorigenesis and progression.

In this article we present two nonlinear force controllers based on the sliding mode control theory. For this purpose we use the detailed mathematical model of the pneumatic system developed in the first part of the paper. The first controller is based on the complete model, and exhibits superior performance both in the numerical simulation and experiments, but requires complex online computations for the control law. The second controller neglects the valve dynamics and the time delay due to connecting tubes. The performance of this controller exhibits slight degradation for configurations with relatively short tubes, and at frequencies up to 20 Hz. At higher frequencies or when long connecting tubes are used, however, the performance exhibits significant degradation compared to the one provided by the full order controller. [S0022-0434(00)00703-6]

Bioluminescent imaging (BLI) has found significant use in evaluating long-term cancer therapy in small animals. We have now tested the feasibility of using BLI to assess acute effects of the vascular disrupting agent Combretastatin A4 phosphate (CA4P) on luciferase expressing MDA-MB-231 human breast tumor cells growing as xenografts in mice. Following administration of luciferin substrate, there is a rapid increase in light emission reaching a maximum after about six minutes, which gradually decreases over the following 20 min. The kinetics of light emission are highly reproducible, however, following IP administration of CA4P (120 mg/kg), the detected light emission was decreased between 50 and 90 percent and time to maximum was significantly delayed. Twenty-four hours later, there was some recovery of light emission following further administration of luciferin substrate. Comparison with dynamic contrast-enhanced MRI based on the paramagnetic contrast agent Omniscan showed comparable changes in the tumors consistent with the previous literature. Histology also confirmed shutdown of tumor vascular perfusion. We believe this provides an important novel application for BLI, which could have widespread application in screening novel therapeutics expected to cause acute vascular changes in tumors.

Bioluminescence imaging (BLI) is a highly sensitive tool for visualizing tumors, neoplastic development, metastatic spread, and response to therapy. Although BLI has engendered much excitement due to its apparent simplicity and ease of implementation, few rigorous studies have been presented to validate the measurements. Here, we characterize the nature of bioluminescence output from mice bearing subcutaneous luciferase-expressing tumors over a 4-week period. Following intraperitoneal or direct intratumoral administration of luciferin substrate, there was a highly dynamic kinetic profile of light emission. Although bioluminescence was subject to variability, strong correlations (r >.8, p <.001) between caliper measured tumor volumes and peak light signal, area under light signal curve and light emission at specific time points were determined. Moreover, the profile of tumor growth, as monitored with bioluminescence, closely resembled that for caliper measurements. The study shows that despite the dynamic and variable nature of bioluminescence, where appropriate experimental precautions are taken, single time point BLI may be useful for noninvasive, high-throughput, quantitative assessment of tumor burden.