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Data from the clinical absolute bioavailability (F) study with cobimetinib suggested that F was lower than predicted based on its low hepatic extraction and good absorption. The CYP3A4 transgenic (Tg) mouse model with differential expression of CYP3A4 in the liver (Cyp3aTg-3A4Hep) or intestine (Cyp3a Tg-3A4Int) and both liver and intestine (Cyp3aTg-3A4Hep/Int) were used to study the contributio...
In 15% to 30% of patients with acute myeloid leukemia (AML), aberrant proliferation is a consequence of a juxtamembrane mutation in the FLT3 gene (FMS-like tyrosine kinase 3-internal tandem duplication [FLT3-ITD]), causing constitutive kinase activity. ABT-869 (a multitargeted receptor tyrosine kinase inhibitor) inhibited the phosphorylation of FLT3, STAT5, and ERK, as well as Pim-1 expression ...
Tyrosine Kinase Inhibitors (TKI) have significantly changed the landscape of current cancer therapy. Understanding of mechanisms of aberrant TK signaling and strategies to inhibit TKs in cancer, further promote the development of novel agents.ABT-869, a novel ATP-competitive receptor tyrosine kinase inhibitor is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and ...
Phenethylisothiocyanate (PEITC), a naturally occurring isothiocyanate and potent cancer chemopreventive agent, works by multiple mechanisms, including the inhibition of cytochrome P450 (P450) enzymes, such as CYP2E1, that are involved in the bioactivation of carcinogens. PEITC has been reported to be a mechanismbased inactivator of some P450s. We describe here the possible mechanism for the ina...
ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families (e.g., KDR IC50 = 4 nmol/L) but has much less activity (IC50s > 1 micromol/L) against unrelated RTKs, soluble tyrosine kinases, or serine/threonine kinases. The inhibition prof...
AIM The TGF-β gene participates in the development of chronic kidney disease. We investigated whether the 869 T > C, 915 G > C and -800 G > A polymorphisms of TGF-β1 are associated with diabetic nephropathy (DN). METHODS Polymorphisms were genotyped in 439 type 2 diabetes mellitus patients, 233 with diabetic nephropathy (DN+) and 206 without (DN-). The sample was characterized for relevant cl...
Authors' A Pediatrics Comprehen University o and 3Path Medicine a Biology Ins California Research, Laboratorie
The Ewing Sarcoma (EWS) family of tumors is one of the most common tumors diagnosed in children and adolescents and is characterized by a translocation involving the EWS gene. Despite advances in chemotherapy, the prognosis of metastatic EWS is poor with an overall survival of <30% after 5 years. EWS tumor cells express the receptor tyrosine kinases, platelet-derived growth factor receptor (PDG...
This study investigated interactions between dietary fat intake and IL-6 polymorphisms on obesity and serum lipids in black and white South African (SA) women. Normal-weight and obese, black and white women underwent measurements of body composition, serum lipids and dietary fat intake, and were genotyped for the IL-6 -174 G>C, IVS3 +281 G>T and IVS4 +869 A>G polymorphisms. In black women the I...
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862 Hepatopulmonary syndrome . . . . . . . . . . . . . . . . . . 862 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862 Staging of severity . . . . . . . . . . . . . . . . . . . . . . . 863 Natural history and outcome . . . . . . . . . . . . . . . . 863 Pathophysiology . . . . . . . . . . . . . . . . . . ...
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