Breast cancer is the second leading cause of cancer death in North American women. There is considerable need for reliable prognostic markers to assist clinicians in making management decisions. Although a variety of factors have been tested, only tumor stage, grade, size, hormone receptor status, and S-phase fraction are used on a routine basis. The cell cycle is governed by a family of cyclin-dependent kinases (cdks), which are regulated by associated cyclins and by phosphorylation. p27Kip1, a cyclin-dependent kinase inhibitor, regulates progression from G1 into S phase by binding and inhibiting cyclin/cdks. p27Kip1 protein levels and/or activity are upregulated by growth inhibitory cytokines including transforming growth factor-beta (TGF-beta) and, thus, provide an important link between extracellular regulators and the cell cycle. Loss of p27Kip1, a negative cell-cycle regulator, may contribute to oncogenesis and tumor progression. However, p27Kip1 mutations in human tumors are extremely rare. We have demonstrated by immunohistochemistry that p27Kip1 protein levels are reduced in primary breast cancers and that this is associated with tumor progression in both in situ and invasive lesions. This was confirmed by western analysis, reflected in increased G1/S-phase cyclin-dependent kinase activities and shown to be regulated posttranscriptionally by in situ hybridization. Furthermore, on multivariate analysis, low p27Kip1 is a predictor of reduced disease-free survival. This simple and reliable immunohistochemical assay may become a routine part of breast cancer evaluation and may influence patient management.

Objective. To investigate the effects of chronic calcium pyrophosphate dihydrate (CPPD) synovitis on the development of osteoarthritic (OA) lesions in an animal model.Methods. OA was induced in the right knees of 30 male New Zealand white rabbits by partial lateral meniscectomy and section of the fibular collateral and sesamoid ligaments (PLWLS), followed by 8 weekly intraarticular (IA) injections of 1 mg (low-dose) or 10 mg (high-dose) of CPPD crystals in 3 sets of experiments (10 rabbits each). The contralateral left knees served as controls: experiment 1 PLMLS alone, experiment 2 8 weekly IA injections of CPPD crystals alone, and experiment 3 sham surgery plus 8 weekly IA injections of CPPD crystals.Results. At 8 weeks, repeated IA injections of low-dose and high-dose CPPD crystals into meniscectomized right knees resulted in more severe OA than in meniscectomized but noninjected left knees (experiment 1) (P = 0.003 and P = 0,001, respectively). One-fourth of the meniscectomized knees (11 of 40), both CPPDinjected and noninjected, showed embedded synovial cartilage shards.Conelusion. The data demonstrate a worsening effect of chronic CPPD crystal-induced synovitis on experimental OA produced in the rabbit knees by

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