As a critical component in the PI3K/AKT/mTOR pathway, AKT has become an attractive target for therapeutic intervention. ARQ 092 and a next generation AKT inhibitor, ARQ 751 are selective, allosteric, pan-AKT and AKT1-E17K mutant inhibitors that potently inhibit phosphorylation of AKT. Biochemical and cellular analysis showed that ARQ 092 and ARQ 751 inhibited AKT activation not only by dephosph...

A somatic activating mutation in AKT1, c.49G>A, pGlu17Lys, that results in elevated AKT signaling in mutation-positive cells, is responsible for the mosaic overgrowth condition, Proteus syndrome. ARQ 092 is an allosteric pan-AKT inhibitor under development for treatment in cancer. We tested the efficacy of this drug for suppressing AKT signaling in cells and tissues from patients with Proteus s...

BACKGROUND Due to the rapidly increasing number of older people worldwide, the prevalence of frailty among older adults is expected to escalate in coming decades. It is crucial to recognize early onset symptoms to initiate specific preventive care. Therefore, early detection of frailty with appropriate screening instruments is needed. The aim of this study was to evaluate the underlying dimensi...

Gfi-1 also dampens the cells’ tendencies toward the Th17 and T reg cell lineages. Gfi-1 inhibited production of IL-17 and blocked the expression of CD103, which is found on certain T reg cells. In a model of autoimmunity, mice that lacked Gfi-1 developed a preponderance of CD103expressing T reg cells, thus delaying the onset of disease. The protein prevented gene expression by binding to loci i...

The zinc finger transcriptional repressor Gfi-1b is essential for erythroid and megakaryocytic development in the embryo. Its roles in the maintenance of bone marrow erythropoiesis and thrombopoiesis have not been defined. We investigated Gfi-1b's adult functions using a loxP-flanked Gfi-1b allele in combination with a novel doxycycline-inducible Cre transgene that efficiently mediates recombin...

The induction of Bcl-x(L) is critical for the survival of late proerythroblasts. The erythroid-specific transcriptional network that regulates Bcl-x(L) expression in erythropoiesis remains unclear. The activation of the central erythropoietic transcriptional factor, GATA-1, leads to the early, transient induction of a transcription repressor, Gfi-1B, followed by the late induction of Bcl-x(L) d...

Gfi-1 also dampens the cells’ tendencies toward the Th17 and T reg cell lineages. Gfi-1 inhibited production of IL-17 and blocked the expression of CD103, which is found on certain T reg cells. In a model of autoimmunity, mice that lacked Gfi-1 developed a preponderance of CD103expressing T reg cells, thus delaying the onset of disease. The protein prevented gene expression by binding to loci i...

Neutrophil-specific granule deficiency (SGD) is a rare congenital disorder marked by recurrent bacterial infections. Neutrophils from SGD patients lack secondary and tertiary granules and their content proteins and lack normal neutrophil functions. Gene-inactivating mutations in the C/EBPepsilon gene have been identified in 2 SGD patients. Our studies on a third SGD patient revealed a heterozyg...

Session 1 was classified, and began with a presentation by Weatherington on various platforms in use by the US DoD, their signal collection types (described as EO & IR, although IR in general is considered an EO technology, so EO may refer to visible in this case), and growth plans for future capabilities. Fenner Milton then presented on tests by the US Army Night Vision and Electronic Sensors ...

The prognosis of patients with advanced hepatocellular carcinoma (HCC) is very poor. The AKT pathway is activated in almost half of HCC cases and in addition, long term exposure to conventional drug treatment of HCC, sorafenib, often results in over-activation of AKT, leading to HCC resistance. Therefore, it is important to assess the safety and the efficacy of selective allosteric AKT inhibito...