No abstract

Colorectal cancers (CRC) with microsatellite instability (MSI) have clinical, pathologic, genetic, and epigenetic features distinct from microsatellite-stable CRC. Examination of epidermal growth factor receptor (EGFR) mRNA and protein expression levels in a panel of colon cancer cell lines identified strong expression of EGFR in multiple cell lines with MSI. Although no relationship between EGFR overexpression and the length of a CA dinucleotide repeat in intron 1 was observed, a variant A13/A14 repeat sequence within the 3 ¶-untranslated region (3 ¶-UTR) of the EGFR gene was identified, which was mutated by either mononucleotide or dinucleotide adenosine deletions in 64% of MSI cell lines and 69% of MSI colon tumors. Using a Tet-Off system, we show that this mutation increases EGFR mRNA stability in colon cancer cells, providing a mechanistic basis for EGFR overexpression in MSI colon cancer cell lines. To determine whether this mutation is a driver or a bystander event in MSI colon cancer, we examined the effect of pharmacologic and molecular inhibition of EGFR in EGFR 3 ¶-UTR mutant MSI cell lines. Cell lines with an EGFR 3 ¶-UTR mutation and that were wild-type (WT) for downstream signaling mediators in the Ras/BRAF and PIK3CA/PTEN pathways were sensitive to EGFR inhibition, whereas those harboring mutations in these signaling mediators were not. Furthermore, in cell lines WT for downstream signaling mediators, those with EGFR 3 ¶-UTR mutations were more sensitive to EGFR inhibition than EGFR 3 ¶-UTR WT cells, suggesting that this mutation provides a growth advantage to this subset of MSI colon tumors.

IBM's logistics management system (LMS) is a real-time imbedded transaction-based integrated decision and knowledge-based expert support system which serves as a dispatcher, monitoring and controlling the manufacturing flow of IBM's semiconductor facility near Burlington, Vermont. Burlington produces various logic and memory micro electronic chips and modules that are used throughout the IBM product line. LMS helps improve manufacturing performance and is critical to running major areas of the manufacturing facility. It was developed by the advanced industrial engineering department.

No abstract