The antiproliferative activity of kinase inhibitors in chronic myeloid leukemia cells is mediated by FOXO transcription factors

Chronic myeloid leukemia (CML) is initiated and maintained by the tyrosine kinase BCR-ABL which activates a number of signal transduction pathways, including PI3K/AKT signaling and consequently inactivates FOXO transcription factors. ABL-specific tyrosine kinase inhibitors (TKIs) induce minimal apoptosis in CML progenitor cells, yet exert potent antiproliferative effects, through as yet poorly understood mechanisms. Here, we demonstrate that in CD34+ CML cells, FOXO1 and 3a are inactivated and relocalized to the cytoplasm by BCR-ABL activity. TKIs caused a decrease in phosphorylation of FOXOs, leading to their relocalization from cytoplasm (inactive) to nucleus (active), where they modulated the expression of key FOXO target genes, such as Cyclin D1, ATM, CDKN1C, and BCL6 and induced G1 arrest. Activation of FOXO1 and 3a and a decreased expression of their target gene Cyclin D1 were also observed after 6 days of in vivo treatment with dasatinib in a CML transgenic mouse model. The over-expression of FOXO3a in CML cells combined with TKIs to reduce proliferation, with similar results seen for inhibitors of PI3K/AKT/mTOR signaling. While stable expression of an active FOXO3a mutant induced a similar level of quiescence to TKIs alone, shRNA-mediated knockdown of FOXO3a drove CML cells into cell cycle and potentiated TKI-induced apoptosis. These data demonstrate that TKI-induced G1 arrest in CML cells is mediated through inhibition of the PI3K/AKT pathway and reactivation of FOXOs. This enhanced understanding of TKI activity and induced progenitor cell quiescence suggests that new therapeutic strategies for CML should focus on manipulation of this signaling network

Project 17233 : intellectual disability (Compulsory Care) legislation : a thesis presented in partial fulfilment of the requirements for the degree of Master in Philosophy in Sociology at Massey University

This study presents an exploration of the history of people who have an intellectual disability and the proposed Compulsory Care legislation that is currently before Parliament. The hypothesis posed is that the legislation is the result of a moral panic. An analysis of the components of a moral panic were identified and examined. The history of the 'eugenics' era is outlined. This era involved the systematic marginalisation of intellectually disabled people on the basis that they posed a 'serious' threat to Western society. This period of history spanning the years 1880 to 1930 is examined for evidence of a moral panic. The 1950's to the present day are briefly reviewed for evidence of a continuation of eugenic thinking. The process and progress of the Compulsory Care legislation is documented and analysed. The findings show there is some evidence to support the hypothesis but that it is insufficient to confirm the view that the legislation resulted from a moral panic

Роль совершенствования бухгалтерского учета в управлении производственными запасами

Целью проведения исследования является обоснование направлений повышения эффективности использования материальных производственных запасов на предприятии в условиях рыночной экономики

Potential Role of Protein Kinase B in Insulin-induced Glucose Transport, Glycogen Synthesis, and Protein Synthesis

Various biological responses stimulated by insulin have been thought to be regulated by phosphatidylinosi-tol 3-kinase, including glucose transport, glycogen syn-thesis, and protein synthesis. However, the molecular link between phosphatidylinositol 3-kinase and these biological responses has been poorly understood. Re-cently, it has been shown that protein kinase B (PKB/c-Akt/ Rac) lies immediately downstream from phosphati-dylinositol 3-kinase. Here, we show that expression of a constitutively active form of PKB induced glucose up-take, glycogen synthesis, and protein synthesis in L6 myotubes downstream of phosphatidylinositol 3-kinase and independent of Ras and mitogen-activated protein kinase activation. Introduction of constitutively active PKB induced glucose uptake and protein synthesis but not glycogen synthesis in 3T3L-1 adipocytes, which lack expression of glycogen synthase kinase 3 different from L6 myotubes. Furthermore, we show that deactivation of glycogen synthase kinase 3 and activation of rapamy-cin- sensitive serine/threonine kinase by PKB in L6 myo-tubes might be involved in the enhancement of glycogen synthesis and protein synthesis, respectively. These re-sults suggest that PKB acts as a key enzyme linking phosphatidylinositol 3-kinase activation to multiple bi-ological functions of insulin through regulation of downstream kinases in skeletal muscle, a major target tissue of insulin

Возможность прогнозирования клеточного типа увеальных меланом без использования инвазивных методов диагностики

Резюме. С помощью дискриминантного анализа установлена возможность определения клеточного типа меланомы увеального тракта в процессе проведения комбинированного (фотокоагуляция + брахитерапия) лечения. Разработана высокозначимая (l = 0,08; р = 0,002) дискриминантная модель, включающая ряд клинических (степень пигментации, пол, скорость роста меланомы) и иммунологических (количество Т- и В-лимфоцитов, процент Т-хелперов и др.) показателей. Особое место в модели занимают признаки, в наибольшей степени отражающие биологические особенности увеальных меланом различного клеточного состава, а именно — скорость изменения размера опухоли в процессе лечения и изменение показателей клеточного иммунитета. Ключевые слова: увеальная меланома, клеточный тип, клинико-морфологические, иммунологические показатели, дискриминантный анализ.Summary. Application of the discriminant analysis shows that it is possible to define the cell type of melanoma of uveal tract of the eye in the process of combined (photocoagulation + brachytherapy) treatment. A highly reliable (l= 0,08; р = 0,002) discriminant model was elaborated, involving a number of both clinical (pigmentation level, gender, melanoma growth rate) and immunological (number of T and B lymphocytes, T helper rate, etc.) indicators. In this model, especially important are those traits that most pronouncedly reflect the biological peculiarities of uveal melanomas of various cellular compositions, namely — the pace of tumor size growth in the process of treatment and changes in cell immunity indicators. Key Words: uveal melanoma, cell type, clinical and morphological, immunological indicators, discriminant analysis

Distinct signalling pathways mediate insulin and phorbol ester- stimulated eukaryotic initiation factor 4F assembly and protein synthesis in HEK 293 cells

Stimulation of serum-starved human embryonic kidney (HEK) 293 cells with either the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), or insulin resulted in increases in the phosphorylation of 4E-BP1 and p70 S6 kinase, eIF4F assembly, and protein synthesis. All these effects were blocked by rapamycin, a specific inhibitor of mTOR. Phosphatidylinositol 3-kinase and protein kinase B were activated by insulin but not by TPA. Therefore TPA can induce eIF4F assembly, protein synthesis, and the phosphorylation of p70 S6 kinase and 4E-BP1 independently of both phosphatidylinositol 3-kinase and protein kinase B. Using two structurally unrelated inhibitors of MEK (PD098059 and U0126), we provide evidence that Erk activation is important in TPA stimulation of eIF4F assembly and the phosphorylation of p70 S6 kinase and 4E-BP1 and that basal MEK activity is important for basal, insulin, and TPA-stimulated protein synthesis. Transient transfection of constitutively active mitogen-activated protein kinase interacting kinase 1 (the eIF4E kinase) indicated that inhibition of protein synthesis and eIF4F assembly by PD098059 is not through inhibition of eIF4E phosphorylation but of other signals emanating from MEK. This report also provides evidence that increased eIF4E phosphorylation alone does not affect the assembly of the eIF4F complex or general protein synthesis

Identification and characterization of CKLiK, a novel granulocyteCa^(++)/calmodulin-dependent kinase

Human granulocytes are characterized by a variety of specific effector functions involved in host defense. Several widely expressed protein kinases have been implicated in the regulation of these effector functions. A polymerase chain reaction- based strategy was used to identify novel granulocyte-specific kinases.Anovel protein kinase complementary DNA with an open reading frame of 357 amino acids was identified with homology to calciumcalmodulin- dependent kinase I (CaMKI). This has been termed CaMKI-like kinase (CKLiK). Analysis of CKLiK messenger RNA (mRNA) expression in hematopoietic cells demonstrated an almost exclusive expression in human polymorphonuclear leukocytes (PMN). Up-regulation of CKLiK mRNA occurs during neutrophilic differentiation of CD341 stem cells. CKLiK kinase activity was dependent on Ca11 and calmodulin as analyzed by in vitro phosphorylation of cyclic adenosine monophosphate responsive element modulator (CREM). Furthermore, CKLiKtransfected cells treated with ionomycin demonstrated an induction of CREbinding protein (CREB) transcriptional activity compared to control cells. Additionally, CaMK-kinasea enhanced CKLiK activity. In vivo activation of CKLiK was shown by addition of interleukin (IL)-8 to a myeloid cell line stably expressing CKLiK. Furthermore inducible activation of CKLiK was sufficient to induce extracellular signal-related kinase (ERK) mitogen-activated protein (MAP) kinase activity. These data identify a novel Ca11/calmodulin-dependent PMNspecific kinase that may play a role in Ca11-mediated regulation of human granulocyte functions

Fluidity in the perception of auditory speech: Cross-modal recalibration of voice gender and vowel identity by a talking face

Article first published online: January 13, 2020Humans quickly adapt to variations in the speech signal. Adaptation may surface as recalibration, a learning effect driven by error-minimisation between a visual face and an ambiguous auditory speech signal, or as selective adaptation, a contrastive aftereffect driven by the acoustic clarity of the sound. Here, we examined whether these aftereffects occur for vowel identity and voice gender. Participants were exposed to male, female, or androgynous tokens of speakers pronouncing /e/, /ø/, (embedded in words with a consonant-vowel-consonant structure), or an ambiguous vowel halfway between /e/ and /ø/ dubbed onto the video of a male or female speaker pronouncing /e/ or /ø/. For both voice gender and vowel identity, we found assimilative aftereffects after exposure to auditory ambiguous adapter sounds, and contrastive aftereffects after exposure to auditory clear adapter sounds. This demonstrates that similar principles for adaptation in these dimensions are at play.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by Gravitation Grant 024.001.006 of the Language in Interaction Consortium from Netherlands Organization for Scientific Research. The third author was supported by The Netherlands Organization for Scientific Research (NWO: VENI Grant 275-89-027)

Crosstalk between cAMP and MAP Kinase Signaling in the Regulation of Cell Proliferation

Hormonal stimulation of cyclic adenosine monophosphate (cAMP) and the cAMP-dependent protein kinase PKA regulates cell growth by multiple mechanisms. A hallmark of cAMP is its ability to stimulate cell growth in many cell types while inhibiting cell growth in others. In this review, the cell type-specific effects of cAMP on the mitogen-activated protein (MAP) kinase (also called extracellular signal-regulated kinase, or ERK) cascade and cell proliferation are examined. Two basic themes are discussed. First, the capacity of cAMP for either positive or negative regulation of the ERK cascade accounts for many of the cell type-specific actions of cAMP on cell proliferation. Second, there are several specific mechanisms involved in the inhibition or activation of ERKs by cAMP. Emerging new data suggest that one of these mechanisms might involve the activation of the GTPase Rap1, which can activate or inhibit ERK signaling in a cell-specific manner