MicroRNAs have essential functional roles in brain development and neuronal specification but their roles in neurodegenerative diseases such as Alzheimer's disease (AD) is unknown. Using a sensitive qRT-PCR platform we identified regional and stage-specific deregulation of miRNA expression in AD patient brains. We used experimental validation in addition to literature to reveal how the deregulated brain microRNAs are biomarkers for known and novel pathways in AD pathogenesis related to amyloid processing, neurogenesis, insulin resistance, and innate immunity. We additionally recovered miRNAs from cerebrospinal fluid and discovered AD-specific miRNA changes consistent with their role as potential biomarkers of disease.

These results support the proposed mechanism of action of ipilimumab, suggesting that cell-mediated immune responses play an important role in the antitumor activity of ipilimumab.

The p53 tumor suppressor controls multiple cell cycle checkpoints regulating the mammalian response to DNA damage. To identify the mechanism by which p53 regulates G 2 , we have derived a human ovarian cell that undergoes p53-dependent G 2 arrest at 32°C. We have found that p53 prevents G 2 ͞M transition by decreasing intracellular levels of cyclin B1 protein and attenuating the activity of the cyclin B1 promoter. Cyclin B1 is the regulatory subunit of the cdc2 kinase and is a protein required for mitotic initiation. The ability of p53 to control mitotic initiation by regulating intracellular cyclin B1 levels suggests that the cyclin Bdependent G 2 checkpoint has a role in preventing neoplastic transformation.

The transcription factor NF-B is a pivotal regulator of inf lammatory responses. While the activation of NF-B in the arthritic joint has been associated with rheumatoid arthritis (RA), its significance is poorly understood. Here, we examine the role of NF-B in animal models of RA. We demonstrate that in vitro, NF-B controlled expression of numerous inf lammatory molecules in synoviocytes and protected cells against tumor necrosis factor ␣ (TNF␣) and Fas ligand (FasL) cytotoxicity. Similar to that observed in human RA, NF-B was found to be activated in the synovium of rats with streptococcal cell wall (SCW)-induced arthritis. In vivo suppression of NF-B by either proteasomal inhibitors or intraarticular adenoviral gene transfer of super-repressor IB␣ profoundly enhanced apoptosis in the synovium of rats with SCW-and pristane-induced arthritis. This indicated that the activation of NF-B protected the cells in the synovium against apoptosis and thus provided the potential link between inf lammation and hyperplasia. Intraarticular administration of NF-kB decoys prevented the recurrence of SCW arthritis in treated joints. Unexpectedly, the severity of arthritis also was inhibited significantly in the contralateral, untreated joints, indicating beneficial systemic effects of local suppression of NF-B. These results establish a mechanism regulating apoptosis in the arthritic joint and indicate the feasibility of therapeutic approaches to RA based on the specific suppression of NF-B.