No abstract

Chromosomal instability in human breast cancer is known to take place before mammary neoplasias display morphological signs of invasion. We describe here the unexpected finding of a tumor cell population with normal karyotypes isolated from bone marrow of breast cancer patients. By analyzing the same single cells for chromosomal aberrations, subchromosomal allelic losses, and gene amplifications, we confirmed their malignant origin and delineated the sequence of genomic events during breast cancer progression. On this trajectory of genomic progression, we identified a subpopulation of patients with very early HER2 amplification. Because early changes have the highest probability of being shared by genetically unstable tumor cells, the genetic characterization of disseminated tumor cells provides a novel rationale for selecting patients for targeted therapies.

The increasing use of primary tumors as surrogate markers for prognosis and therapeutic decisions neglects evolutionary aspects of cancer progression. To address this problem, we studied the precursor cells of metastases directly for the identification of prognostic and therapeutic markers and prospectively analyzed single disseminated cancer cells from lymph nodes and bone marrow of 107 consecutive esophageal cancer patients. Whole-genome screening revealed that primary tumors and lymphatically and hematogenously disseminated cancer cells diverged for most genetic aberrations. However, we identified chromosome 17q12-21, the region comprising HER2, as the most frequent gain in disseminated tumor cells that were isolated from both ectopic sites. Survival analysis demonstrated that HER2 gain in a single disseminated tumor cell but not in primary tumors conferred high risk for early death.

This study demonstrates a highly significant sex-related difference in CO2-induced cerebral vasomotor reactivity. The relation between altered carbon dioxide tensions and blood flow velocities of both middle cerebral arteries in 60 healthy volunteers was found to be exponential.

Salivarian trypanosomes are extracellular parasites of mammals that are transmitted by tsetse flies. The procyclic acidic repetitive proteins (PARPs) are the major surface glycoproteins of the form of Trypanosoma brucei that replicates in the fly. The abundance of PARP mRNA and protein is very strongly regulated, mostly at the post-transcriptional level. The 3'-untranslated regions of two PARP genes are of similar lengths, but are dissimilar in sequence apart from a 16mer stem-loop that stimulates translation and a 26mer polypyrimidine tract. Addition of either of these PARP 3'-untranslated regions immediately downstream of a reporter gene resulted in developmental regulation mimicking that of PARP. We show that the PARP 3'-UTR reduces RNA stability and translation in bloodstream forms and that the 26mer polypyrimidine tract is necessary for both effects.