Hypoxia-inducible factor-1 is a known cancer progression factor, promoting growth, spread, and metastasis. However, in selected contexts HIF-1 is a tumor suppressor coordinating hypoxic cell cycle suppression and apoptosis. Prior studies focused on HIF-1 function in established malignancy, however little is known about its role during the entire process of carcinogenesis from neoplasia induction to malignancy. Here we tested HIF-1 gain of function during multistage murine skin chemical carcinogenesis in K14-HIF-1αPro402A564G (K14-HIF-1αDPM) transgenic mice. Transgenic papillomas appeared earlier and were more numerous, 6±3 transgenic versus 2±1.5 nontransgenic papillomas per mouse, yet they were more differentiated, their proliferation was lower, and their malignant conversion was profoundly inhibited, 7% in transgenic versus 40% in non transgenic mice. Moreover, transgenic cancers maintained squamous differentiation whereas epithelial mesenchymal transformation was frequent in nontransgenic malignancies. Transgenic basal keratinocytes upregulated the HIF-1 target N-myc downstream regulated gene-1, a known tumor suppressor gene in human malignancy, and its expression was maintained in transgenic papillomas and cancer. We also discovered a novel HIF-1 target gene, selenium binding protein-1 (selenbp1), a gene of unknown function whose expression is lost in human cancer. Thus, HIF-1 can function as a tumor suppressor through transactivation of genes that are themselves targets for negative selection in human cancers.

Qualitative and quantitative properties of the finite part, H(f), of the Shannon entropy of a continuous waveform f(t) in the continuum limit are derived in order to illuminate its use for waveform characterization. Simple upper and lower bounds on H(f), based on features of f(t), are defined. Quantitative criteria for a priori estimation of the average-case variation of H(f) and log E(f), where E(f) is the signal energy of f(t) are also derived. These provide relative sensitivity estimates that could be used to prospectively choose optimal imaging strategies in real-time ultrasonic imaging machines, where system bandwidth is often pushed to its limits. To demonstrate the utility of these sensitivity relations for this application, a study designed to assess the feasibility of identification of angiogenic neovasculature targeted with perfluorocarbon nanoparticles that specifically bind to alpha(v)beta3-integrin expression in tumors was performed. The outcome of this study agrees with the prospective sensitivity estimates that were used for the two receivers. Moreover, these data demonstrate the ability of entropy-based signal receivers when used in conjunction with targeted nanoparticles to elucidate the presence of alpha(v)beta3 integrins in primordial neovasculature, particularly in acoustically unfavorable environments.

Real-time detection of targeted contrast agent binding is challenging due to background signal from unbound agent. 19

There are two main techniques used to manufacture investment castings depending on the type of mould used. These are either block moulds or shell moulds:(1) Block moulds -this was the main technique used until the mid-1950s, and involves pouring a refractory ceramic around a wax pattern assembly contained in a flask. One of the main disadvantages of this technique is that the cast metal is surrounded by a very thick ceramic shell. This is an insulator and causes slow cooling and, therefore, poor metallurgical structures. Another problem is that the solid ceramic block inhibits contraction of the metal as it cools and this can lead to failure of the casting.(2) Shell moulds -these are produced by "investing" a wax assembly with several ceramic layers. The first layer is normally a fine coating so that a good surface finish on the casting will be obtained. Subsequent layers are made up of a ceramic slurry and refractory granules. The shell will normally be made up of between five and eight layers depending on the cooling rate required and the subsequent metallurgical properties.Once the ceramic has dried, the wax is removed by placing the block or shell in a steam autoclave at 150-200°C and 6-7 bar.The wax can be reclaimed and used for moulding the runner systems. Although the coefficient of thermal expansion for wax is much greater than the ceramic, the shells do not usually crack. This is because initially the heat melts the outer layer of wax and this acts as a "buffer zone" which allows expansion of the main body of wax. After dewaxing, the moulds are fired in a furnace to give full strength and to bring them nearer to the melt temperature of the metal. Using rapid prototype models for investment castingInvestment casting [1,2] and rapid prototyping[3] have the potential for an ideal marriage in that they are both techniques suited to complex parts. Two of the main commercial rapid prototyping systems, selective laser sintering (SLS) and fused deposition modelling (FDM), are capable of producing wax models which can be used almost directly in investment casting [4,5]. However, these 4

Previous work has demonstrated that a signal receiver based on a limiting form of the Shannon entropy is, in certain settings, more sensitive to subtle changes in scattering architecture than conventional energy-based signal receivers ͓M. S. Hughes et al., J. Acoust. Soc. Am. 121, 3542-3557 ͑2007͔͒. In this paper new results are presented demonstrating further improvements in sensitivity using a signal receiver based on the Renyi entropy.