Synergistic induction of apoptosis by the Bcl-2 inhibitor ABT-737 and imatinib mesylate in gastrointestinal stromal tumor cells.

Background: Although imatinib mesylate has revolutionized the management of patients with gastrointestinal stromal tumor (GIST), resistance and progression almost inevitably develop with long-term monotherapy. To enhance imatinib-induced cytotoxicity and overcome imatinib-resistance in GIST cells, we examined the antitumor effects of the pro-apoptotic Bcl-2/Bcl-x(L) inhibitor ABT-737, alone and in combination with imatinib.

Methods: We treated imatinib-sensitive, GIST-T1 and GIST882, and imatinib-resistant cells with ABT-737 alone and with imatinib.

Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics.

Metaplastic breast cancers (MBC) are aggressive, chemoresistant tumors characterized by lineage plasticity. To advance understanding of their pathogenesis and relatedness to other breast cancer subtypes, 28 MBCs were compared with common breast cancers using comparative genomic hybridization, transcriptional profiling, and reverse-phase protein arrays and by sequencing for common breast cancer mutations. MBCs showed unique DNA copy number aberrations compared with common breast cancers.

An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer.

Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy-based sequencing and reverse-phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of PIK3CA, AKT, and PTEN mutations and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor-positive (34.

Atypical PKCiota contributes to poor prognosis through loss of apical-basal polarity and cyclin E overexpression in ovarian cancer.

We show that atypical PKCiota, which plays a critical role in the establishment and maintenance of epithelial cell polarity, is genomically amplified and overexpressed in serous epithelial ovarian cancers. Furthermore, PKCiota protein is markedly increased or mislocalized in all serous ovarian cancers. An increased PKCiota DNA copy number is associated with decreased progression-free survival in serous epithelial ovarian cancers.

Prolonged controlled hemorrhagic shock in a swine model: is there a role for mechanical circulatory assistance?

Outcomes of mechanical circulatory assistance during hemorrhagic shock were evaluated in a swine model. Pigs were bled to a mean arterial pressure of 35 mm Hg (group I, n = 3) or 40 mm Hg (group II, n = 5; group III, n = 5), maintained there for 30 minutes, and then resuscitated with fluids alone (groups I and II) or fluids plus mechanical circulatory assistance (group III). Mean blood loss was greater in group I than in groups II or III (1,037 +/- 212 vs.