Carcinogenesis and tumor progression are multistage processes involving genetic and epigenetic aberrations that dysregulate signal transduction and gene expression. Chemical, physical and viral agents can increase the frequency of both genetic and epigenetic lesions including those in proto- oncogenes and tumor suppressor genes. The molecular mechanisms controlling genomic stability and fidelity of DNA synthesis and DNA repair are of intrinsic importance in development, differentiation, evolution, and mutational diseases such as cancer. The conference will focus on the basic mechanisms responsible for maintaining genomic stability, aberrations in these mechanisms mediated by chemical, physical and viral carcinogenic agents, and strategies to improve cancer diagnosis and therapy. grant=r01dk42290 Ultrasonically imageable bubbles have now been generated in excised canine bladders under conditions which acoustically mimic the in vivo state of the urine. Based on anticipated in vivo bubble generation and a theoretical model for enhanced bubble growth, new approaches to the production and control of bubbles in vivo will be studied to determine methods for controlled generation and detection of bubbles for use as contrast agents and potentially for therapy. Initial studies will be directed toward rapid bubble generation and size assessment in water, with control of cavitation nuclei and gas saturation. We have recently described new techniques utilizing frequency-modulated ultrasound pulses, that should, at relatively low intensities, cause rapid growth of small, resonant bubbles to facilitate their detection at small concentrations within stronger reflections from blood and surrounding tissues. One approach, of superimposing the higher frequency FM pulses with negative pressures from very low frequency waves, may increase bubble growth rates even further by providing quasi-static decompression of the liquid. Growth of a short bolus of encapsulated microbubbles will also be investigated. Creation, growth and maintenance of bubbles will be evaluated extensively in water. Prom3ising techniques will be tried in urine and blood, contained in freshly-excised organs to maintain in vivo properties. Strategically interwoven with the generation and growth studies will be development of methods for detecting and analyzing the bubble generation and growth, while minimizing the chance of bubble collapse. Most detection methods will be specific for echoes from bubbles. Experimental apparatus developed initially will be modified for limited demonstrations of controlled generation of bubbles in vivo. Bubbles will be generated in the renal artery, parenchyma, collecting system, ureter, vena cava and in the urinary bladder (a relatively easy site suitable for evaluation of reflux and as part of a possible diagnostic test for interstitial cystitis). Current medical marketing estimates are that ultrasound sales in dollars and numbers of procedures will exceed those of any other imaging modality in the early to mid 1990's. Short boluses of bubbles produced at will, or regrown from orally-induced or intravenously injected cavitation nuclei, should comprise a relatively low cost, but very diverse and powerful new tool for medical care. There should be indirect benefits as well in terms of increased knowledge of methods to suppress undesired cavi-tation in routine and other enhanced ultrasound diagnostic procedures. While selective generation and tracking of bubbles throughout the urinary and vascular systems, as a hopefully noninvasive, dynamic, ultrasound contrast agent, is an impressive goal, the list of potential applications from this project is even broader than might be expected.
