The proto-oncogene proviral integration site for moloney murine leukemia virus (PIM) kinases (PIM-1, PIM-2, and PIM-3) are serine/threonine kinases that are involved in a number of signaling pathways ...important to cancer cells. PIM kinases act in downstream effector functions as inhibitors of apoptosis and as positive regulators of G
1
-S phase progression through the cell cycle. PIM kinases are upregulated in multiple cancer indications, including lymphoma, leukemia, multiple myeloma, and prostate, gastric, and head and neck cancers. Overexpression of one or more PIM family members in patient tumors frequently correlates with poor prognosis. The aim of this investigation was to evaluate PIM expression in low- and high-grade urothelial carcinoma and to assess the role PIM function in disease progression and their potential to serve as molecular targets for therapy. One hundred thirty-seven cases of urothelial carcinoma were included in this study of surgical biopsy and resection specimens. High levels of expression of all three PIM family members were observed in both noninvasive and invasive urothelial carcinomas. The second-generation PIM inhibitor, TP-3654, displays submicromolar activity in pharmacodynamic biomarker modulation, cell proliferation studies, and colony formation assays using the UM-UC-3 bladder cancer cell line. TP-3654 displays favorable human ether-à-go-go-related gene and cytochrome P450 inhibition profiles compared with the first-generation PIM inhibitor, SGI-1776, and exhibits oral bioavailability.
In vivo
xenograft studies using a bladder cancer cell line show that PIM kinase inhibition can reduce tumor growth, suggesting that PIM kinase inhibitors may be active in human urothelial carcinomas.
First of all, there is our government: no longer merely dysfunctional, it has now entirely ceased to operate in a coherent manner. As with ancient Rome, the signs were already present: the barbarians ...at the gates (9/11 was months away); the demographic implosion of populations of European descent; the cultural decadence; and, worst of all, the drastic loss of national self-confidence and self-direction. ... the statistics everywhere you look are ghastly: an unemployment rate of 9.1 percent; all-time-record-setting foreclosures; a 40-percent out-of-wedlock birthrate; uncontrollable illegal immigration (12 million illegals currently living in the United States, compared with 5 million in 1996); a Federal Reserve that seems to be aiming at Weimar Republic-level inflation; swollen, immovable unionized bureaucracies at every level of government; a K-12 education system that is one of the worst in the industrialized world; and an entitlement burden that eats up half the federal budget.
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