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The AKT/mamnialian target of rapamycin (AKT/mTOR) and ERK MAPK signaling pathways have been shown to cooperate in prostate cancer progression and the transition to androgen-independent disease. We have now tested the effects of combinatorial inhibition of these pathways on prostate tumorigenicity by performing preclinical studies using a genetically engineered mouse model of prostate cancer. We report here that combination therapy using rapamycin, an inhibitor of mTOR, and PD0325901, an inhibitor of MAPK kinase 1 (MEK; the kinase directly upstream of ERK), inhibited cell growth in cultured prostate cancer cell lines and tumor growth particularly for androgen-independent prostate tumors in the mouse model. We further showed that such inhibition leads to inhibition of proliferation and upregulated expression of the apoptotic regulator Bcl-2-interacting mediator of cell death (Bim). Furthermore, analyses of human prostate cancer tissue microarrays demonstrated that AKT/mTOR and ERK MAPK signaling pathways are often coordinately deregulated during prostate cancer progression in humans. We therefore propose that combination therapy targeting AKT/mTOR and ERK MAPK signaling pathways may be an effective treatment for patients with advanced prostate cancer, in particular those with hormone-refractory disease., Introduction Prostate cancer is one of the most common neoplasms, particularly among aging males in the United States. Like many adenocarcinomas, prostate tumors arise from preinvasive lesions, mainly prostatic intraepithelial [...]

Intracellular calcium concentration ([[[Ca.sup.2+]].sub.i]) signals are central to the mechanisms underlying fluid and protein secretion in pancreatic and parotid acinar cells. Calcium release was studied in natively buffered cells following focal laser photolysis of caged molecules. Focal photolysis of caged-inositol 1,4,5 trisphosphate (Ins[P.sub.3]) in the apical region resulted in [Ca.sup.2+] release from the apical trigger zone and, after a latent period, the initiation of an apical-to-basal [Ca.sup.2+] wave. The latency was longer and the wave speed significantly slower in pancreatic compared with parotid cells. Focal photolysis in basal regions evoked only limited [Ca.sup.2+] release at the photolysis site and never resulted in a propagating wave. Instead, an apical-to-basal wave was initiated following a latent period. Again, the latent period was significantly longer under all conditions in pancreas than parotid. Although slower in pancreas than parotid, once initiated, the apical-to-basal wave speed was constant in a particular cell type. Photo release of caged-[Ca.sup.2+] failed to evoke a propagating [Ca.sup.2+] wave in either cell type. However, the kinetics of the [Ca.sup.2+] signal evoked following photolysis of caged-Ins[P.sub.3] were significantly dampened by ryanodine in parotid but not pancreas, indicating a more prominent functional role for ryanodine receptor (RyR) following Ins[P.sub.3] receptor (Ins[P.sub.3]R) activation. These data suggest that differing expression levels of Ins[P.sub.3]R, RyR, and possibly cellular buffering capacity may contribute to the fast kinetics of [Ca.sup.2+] signals in parotid compared with pancreas. These properties may represent a specialization of the cell type to effectively stimulate [Ca.sup.2+]-dependent effectors important for the differing primary physiological role of each gland. inositol 1,4,5 trisphosphate receptors; ryanodine receptors; imaging

We present two forward-adjoint models for recovering intrinsic fluorescence spectra and hemoglobin oxygen saturation of turbid samples. The first fits measured diffuse reflectance spectra to obtain the absorption and scattering spectra of the medium, and these are then used to correct distortions imposed on the fluorescence spectrum by absorption and scattering. The second fits only the measured fluorescence spectrum to determine simultaneously the amplitudes of absorption and fluorescence basis spectra and scattering parameters. Both methods are validated with Monte Carlo simulations and experimentally in scattering phantoms containing nicotinamide adenine dinucleotide and human erythrocytes. Preliminary measurements from murine tumors in vivo are presented. OCIS codes: 170.3890, 170.6280, 170.6510, 170.7050.

We present a steady-state method for localizing a source of luminescence (i.e., fluorescence or phosphorescence) buried in a semi-infinite turbid medium with unknown optical properties. A diffusion theory expression describing the emittance of an isotropic point source is fit to spatially resolved surface measurements of the diffuse emittance from the luminescent source. The technique reports the location of the center of a 6.0-mm-diameter, fluorophore-containing spherical bulb embedded in a liquid phantom with an accuracy of 1.0 mm or better for source depths as great as 40.0 mm. Monte Carlo data are analyzed to investigate the range and the possible sources of error in the reconstructed source depth.

We present a steady-state radially resolved diffuse reflectance spectrometer capable of measuring the absorption and transport scattering spectra of tissue-simulating phantoms over an adjustable 170-nm wavelength interval in the visible and near infrared. Measurements in a variety of phantoms are demonstrated over the relevant range of tissue optical properties, and the accuracy of the instrument is found to be approximately 10% in both scattering and absorption. Monte Carlo simulations designed to test the accuracy of the instrument are presented that support the experimental findings. Key words: Diffuse reflectance, diffusion theory, Monte Carlo, tissue optics.

The archaeological applications of optimization theory that were applied to resource use are reviewed. A study that modeled agricultural productivity among the 18th-early 19th century Muscogee Creek Indians showed that the residents of Cussetuh were risk minimizers and were not maximizing long-term average rate of corn yield in their gardens.