Revised Abstract: "Molecular/Cellular Pathways of Bladder Cancer Progression", is led by Dr. Richard J. Cote who will determine how the altered expression of cell-cycle regulatory and apoptosis related genes plays a role during bladder carcinogenesis. Additional studies will examine the expression of proteins encoded by genes studied in Projects 1 and 2, with the long-term goal of developing better techniques for predicting and for establishing better, more rational treatment. The strengths of this project are the leadership ability of the project leader, who has made significant contributions to the field of bladder cancer biology and clinical management, the strong translational potential of the research, and the likelihood that the data generated will enhance the understanding of bladder cancer progression. Deficiencies identified in the previous review included an inadequate description by the project leader of the significance of the p53 mutations that they were studying, the fact that there were apparently limited quantities of fresh tissue available for the Western immunoblot assays that were proposed and that there were some instances where there were inadequate descriptions of some of the preliminary data regarding the novel competitive RT-PCR assays. In response to these concerns, the applicants have now provided greater details that successfully address all of these issues. The investigators described data, which demonstrate that specific p53 exons have been shown to be relevant to different cellular and clinical responses. Therefore, the exon-based analysis that they will conduct will be important in determining the relationship of p53 alterations to bladder cancer. The investigators will focus on the use of two important cohorts, which are uniquely suited to conduct these studies. They will also relate these to other effectors that they have proposed in this project. In regard to the availability of "fresh" tissue for immunoblot analysis, the investigators provide additional information that they have more than the necessary 100 frozen samples already in their bank and collect more than 40 cases/year. Therefore, this frozen material is more than sufficient to conduct these analyses. Finally, in response to the question of the RT-PCR technology, the investigators now indicate that they have made even further refinements to this approach and are now able to demonstrate that it can be standardized and may even be more consistent than Taq Man PCR. The project leader has adequately addressed a previous concern about the ambitious nature of the proposed studies by emphasizing the unique resources available to him through his integration in the program project. In summary, although the critiques raised in the previous review were relatively minor, the investigators have addressed each of them thoughtfully. No deficiencies went unanswered and the investigators have done an outstanding job in addressing the comments raised in the previous review. This project is much improved and received an average merit rating of 1.3.