National accounting rules in a globalized world (Pro and contra) ; contra - the best of both worlds

Grundsätze ordnungsmäßiger Buchführung, Bilanztheorie, Globalisierung, GAAP (Generally Accepted Accounting Principles), Accounting theory, Globalization

PHLPP phosphatase regulation of growth factor signaling

Over the last several years, the PHLPP protein phosphatases have emerged as critical regulators of cell signaling. The two PHLPP genes, PHLPP1 and PHLPP2 were originally characterized as hydrophobic motif phosphatases for Akt and PKC. By dephosphorylating these kinases, PHLPP1 and PHLPP2 suppress their proliferative and anti- apoptotic activities. Here, we expand the PHLPP family of enzymes with the cloning of a third member, PHLPP1[Beta]. In addition, we identify the Ras/ERK pathway as a novel target of PHLPP activity, and reveal that PHLPP regulation of this pathway is mediated through control of EGF receptor levels. Finally, we explore the role of PHLPP as a tumor suppressor by sequencing PHLPP1 in CLL patient samples. Together, these studies further our knowledge of the PHLPP family of phosphatases and provide additional evidence in support of a prominent role for PHLPP in controlling growth factor signaling and suppressing tumor growt

PHLPP phosphatase regulation of growth factor signaling

Over the last several years, the PHLPP protein phosphatases have emerged as critical regulators of cell signaling. The two PHLPP genes, PHLPP1 and PHLPP2 were originally characterized as hydrophobic motif phosphatases for Akt and PKC. By dephosphorylating these kinases, PHLPP1 and PHLPP2 suppress their proliferative and anti- apoptotic activities. Here, we expand the PHLPP family of enzymes with the cloning of a third member, PHLPP1[Beta]. In addition, we identify the Ras/ERK pathway as a novel target of PHLPP activity, and reveal that PHLPP regulation of this pathway is mediated through control of EGF receptor levels. Finally, we explore the role of PHLPP as a tumor suppressor by sequencing PHLPP1 in CLL patient samples. Together, these studies further our knowledge of the PHLPP family of phosphatases and provide additional evidence in support of a prominent role for PHLPP in controlling growth factor signaling and suppressing tumor growt

EGF816, an irreversible mutant-selective EGFR inhibitor, is effective in NSCLC with both primary activating and T790M-mediated resistant EGFR mutations

NSCLC patients carrying oncogenic EGFR mutations initially respond to EGFR targeted therapy. However, duration of the response is limited due to dose limiting toxicities and acquired resistance. EGF816 is a novel, irreversible mutant-selective EGFR inhibitor that specifically targets both primary activating and the T790M acquired resistant EGFR mutations, while sparing wild-type (WT) EGFR. EGF816 potently inhibits the most common EGFR mutations L858R, Ex19del and T790M in vitro which translating into strong tumor regressions in vivo in several patient-derived xenografts (PDX). Of note, EGF816 also demonstrated antitumor activity in an exon 20 insertion mutant model. At levels above efficacious doses, EGF816 showed minimal inhibition of WT EGFR receptor and was well-tolerated. In single dose studies, EGF816 showed sustained inhibition of pEGFR, consistent with its irreversible binding mechanism. In addition, EGF816 in combination with a cMET inhibitor demonstrated durable efficacy in a model that became resistant to first generation EGFR inhibitors via cMET activation. EGF816 has shown promising clinical efficacy in phase I trials