AURKA overexpression accompanies dysregulation of DNA-damage response genes in invasive urothelial cell carcinoma

Invasive urothelial cell carcinoma (UCC) is characterized by increased chromosomal instability and follows an aggressive clinical course in contrast to non-invasive disease. To identify molecular processes that confer and maintain an aggressive malignant phenotype, we used a high-throughput genome-wide approach to interrogate a cohort of high and low clinical risk UCC tumors. Differential expression analyses highlighted cohesive dysregulation of critical genes involved in the G(2)/M checkpoint in aggressive UCC. Hierarchical clustering based on DNA Damage Response (DDR) genes separated tumors according to a pre-defined clinical risk phenotype. Using array-comparative genomic hybridization, we confirmed that the DDR was disrupted in tumors displaying high genomic instability. We identified DNA copy number gains at 20q13.2-q13.3 (AURKA locus) and determined that overexpression of AURKA accompanied dysregulation of DDR genes in high risk tumors. We postulated that DDR-deficient UCC tumors are advantaged by a selective pressure for AURKA associated override of M phase barriers and confirmed this in an independent tissue microarray series. This mechanism that enables cancer cells to maintain an aggressive phenotype forms a rationale for targeting AURKA as a therapeutic strategy in advanced stage UCC.

Language Experience Affects Grouping of Musical Instrument Sounds

Language experience clearly affects the perception of speech, but little is known about whether these differences in perception extend to non-speech sounds. In this study, we investigated rhythmic perception of non-linguistic sounds in speakers of French and German using a grouping task, in which complexity (variability in sounds, presence of pauses) was manipulated. In this task, participants grouped sequences of auditory chimeras formed from musical instruments. These chimeras mimic the complexity of speech without being speech. We found that, while showing the same overall grouping preferences, the German speakers showed stronger biases than the French speakers in grouping complex sequences. Sound variability reduced all participants' biases, resulting in the French group showing no grouping preference for the most variable sequences, though this reduction was attenuated by musical experience. In sum, this study demonstrates that linguistic experience, musical experience, and complexity affect rhythmic grouping of non-linguistic sounds and suggests that experience with acoustic cues in a meaningful context (language or music) is necessary for developing a robust grouping preference that survives acoustic variability.