The acid-mediated tumor invasion hypothesis proposes altered glucose metabolism and increased glucose uptake, observed in the vast majority of clinical cancers by fluorodeoxyglucose-positron emission tomography, are critical for development of the invasive phenotype. In this model, increased acid production due to altered glucose metabolism serves as a key intermediate by producing H + flow along concentration gradients into adjacent normal tissue. This chronic exposure of peritumoral normal tissue to an acidic microenvironment produces toxicity by: (a) normal cell death caused by the collapse of the transmembrane H + gradient inducing necrosis or apoptosis and (b) extracellular matrix degradation through the release of cathepsin B and other proteolytic enzymes. Tumor cells evolve resistance to acidinduced toxicity during carcinogenesis, allowing them to survive and proliferate in low pH microenvironments. This permits them to invade the damaged adjacent normal tissue despite the acid gradients. Here, we describe theoretical and empirical evidence for acid-mediated invasion. In silico simulations using mathematical models provide testable predictions concerning the morphology and cellular and extracellular dynamics at the tumor-host interface. In vivo experiments confirm the presence of peritumoral acid gradients as well as cellular toxicity and extracellular matrix degradation in the normal tissue exposed to the acidic microenvironment. The acid-mediated tumor invasion model provides a simple mechanism linking altered glucose metabolism with the ability of tumor cells to form invasive cancers.

We demonstrate precise linearization of ultrabroadband laser frequency chirps via a fiber-based self-heterodyne technique to enable extremely high-resolution, frequency-modulated cw laser-radar (LADAR) and a wide range of other metrology applications. Our frequency chirps cover bandwidths up to nearly 5 THz with frequency errors as low as 170 kHz, relative to linearity. We show that this performance enables 31-mum transform-limited LADAR range resolution (FWHM) and 86 nm range precisions over a 1.5 m range baseline. Much longer range baselines are possible but are limited by atmospheric turbulence and fiber dispersion.

As the bandwidth and linearity of frequency modulated continuous wave chirp ladar increase, the resulting range resolution, precisions, and accuracy are improved correspondingly. An analysis of a very broadband (several THz) and linear (<1 ppm) chirped ladar system based on active chirp linearization is presented. Residual chirp nonlinearity and material dispersion are analyzed as to their effect on the dynamic range, precision, and accuracy of the system. Measurement precision and accuracy approaching the part per billion level is predicted.

Deformable membrane mirrors are promising MOEMS devices for focus control and aberration correction in vital microscopy, offering high speed focus adjustment in an optical system that can be miniaturized for in vivo use. This paper describes mirrors comprising metalized polymer membranes suspended over three concentric circular electrodes for electrostatic actuation. The membranes are 2-μm thick and 3 mm in diameter, made from the fully cross-linked photoset epoxy SU-8 2002. A layer of SU-8 2025 is used to establish a 30-μm thick air gap between the electrodes and the membrane mirror. The membranes are actuated by applying voltage to each electrode individually to achieve displacement as large as 12 μm while minimizing spherical aberration. Surface deflection is studied using phase-shift interferometry under both static and dynamic excitation. Using the deformable MOEMS mirror for focus control in an optical microscope we demonstrate the ability to adjust the location of the focal plane by 85 μm using an N.A. = 0.75 optical system. C 2011 Society of Photo-Optical Instrumentation Engineers (SPIE).