Molecular Interaction Between the Microenvironment and FLT3/ITD+ AML Cells Leading to the Refractory Phenotype

Internal tandem duplication mutations in the FLT3 gene (FLT3/ITD) are detected in 10–15% of children and 30% of adult patients with AML and are associated with an extremely poor prognosis. Although several antagonists against FLT3/ITD have been developed, few of them are effective for the treatment of FLT3/ITD+ AML because of the emergence of drug-resistant cells. The mechanisms responsible for drug resistance include the acquisition of additional mutations in the FLT3 gene and/or activation of other prosurvival pathways such as microenvironment-mediated resistance. Recent studies have strongly suggested that the reciprocal interaction between the microenvironment and AML cells generates specific machinery that leads to chemoresistance. This chapter describes the molecular mechanism responsible for the refractory phenotype of FLT3/ITD+ AML cells resulting from the communication between the microenvironment and FLT3/ITD+ leukemia cells. Understanding this mechanism enables the discovery of novel and innovative therapeutic interventions for resistant FLT3/ITD+ AML

Facile synthesis of > 99% phase-pure brookite TiO 2 by hydrothermal conversion from Mg 2 TiO 4

The synthesis of pure brookite is generally much more difficult than that of pure anatase. The hydrothermal conversion, recently developed by Kozawa et al., is a facile method to synthesize brookite TiO2 from inverse spinel-type Mg2TiO4 under a mild hydrothermal condition e.g. in 1 M HCl solution at 100 °C. However, slight rutile TiO2 is usually co-existed under the reported conditions. The aim of this study is to prepare a high-purity brookite TiO2 powder by the hydrothermal conversion from Mg2TiO4. We investigated the conditions of Mg2TiO4 preparation and hydrothermal conversion, and it was found that the most important factor for the high-purity brookite synthesis, i.e. decreasing the co-existing rutile TiO2, was to prepare the Mg2TiO4 precursor without MgTiO3. Using an MgO-rich composition and adding a second calcination step for the Mg2TiO4 preparation yielded a high-purity (99.3 wt%) brookite powder with a surface area of 27.7 m2/g. Under the current experimental conditions, addition of a surfactant or an alcohol for the hydrothermal treatment was not apparently effective for the high-purity brookite synthesis

第2言語熟達度テストとしてのOxford Placement Test とMichigan English Placement Test の分析

The purpose of this study was to analyze two second language (L2) English placement tests, the Oxford Placement Test and the Michigan English Placement Test, to evaluate the degree to which the tests function as L2 proficiency tests. Descriptive statistics, normality tests, and correlation coefficients were calculated for the two tests. Factor analytic methods and Rasch scaling were also applied to the data set. The results suggest that both tests can function as proficiency tests for Japanese learners of English. However, the distribution of the Michigan English Placement Test scores deviated from normality, and the reliability estimates of the scores on some of the subsections of that test were low. The implications of the results are that researchers need to choose a testing instrument that measures the aspect of proficiency that is related to a particular study, and that subsection scores may not be reliable enough to use as a unidimensional scale

Long-term effect of metformin on blood glucose control in non-obese patients with type 2 diabetes mellitus

<p>Abstract</p> <p>Background</p> <p>We aimed to investigate the long-term effect of metformin on the blood glucose control in non-obese patients with type 2 diabetes mellitus.</p> <p>Methods</p> <p>A retrospective study was performed in 213 patients with type 2 diabetes mellitus under the administration of metformin for more than one year. The clinical parameters were investigated for 3 years. The obese and non-obese individuals were defined as a body mass index (BMI) of 25 kg/m²or over (<it>n </it>= 105) and a BMI of less than 25 kg/m²(<it>n </it>= 108), respectively.</p> <p>Results</p> <p>HbA1c levels were significantly decreased compared with those at the baseline time. The course of HbA1c was similar between the non-obese and the obese groups, while the dose of metformin required to control blood glucose was significantly lower in the non-obese group than in the obese group. The reductions in HbA1c were 1.2% and 1.1% at 12 months, 0.9% and 0.9% at 24 months, and 0.8% and 1.0% at 36 months in the non-obese and obese groups, respectively. BMI did not change during the observation periods. Approximately half of all patients required no additional antidiabetic agents or a reduction in other treatments after the initiation of metformin in either of the two groups.</p> <p>Conclusions</p> <p>The present study demonstrated the long-term beneficial effect of metformin in non-obese (BMI < 25 kg/m²) diabetic patients. This effect appears to be maintained even after the observation period of this study, because metformin was limited to a relatively low dose in the non-obese group and the observed worsening in glycemic control over time can probably be attenuated by increasing the dose of metformin.</p

Endothelial Progenitor Cells Promote Directional Three-Dimensional Endothelial Network Formation by Secreting Vascular Endothelial Growth Factor

Endothelial progenitor cell (EPC) transplantation induces the formation of new blood-vessel networks to supply nutrients and oxygen, and is feasible for the treatment of ischemia and cardiovascular diseases. However, the role of EPCs as a source of proangiogenic cytokines and consequent generators of an extracellular growth factor microenvironment in three-dimensional (3D) microvessel formation is not fully understood. We focused on the contribution of EPCs as a source of proangiogenic cytokines on 3D microvessel formation using an in vitro 3D network model. To create a 3D network model, EPCs isolated from rat bone marrow were sandwiched with double layers of collagen gel. Endothelial cells (ECs) were then cultured on top of the upper collagen gel layer. Quantitative analyses of EC network formation revealed that the length, number, and depth of the EC networks were significantly enhanced in a 3D model with ECs and EPCs compared to an EC monoculture. In addition, conditioned medium (CM) from the 3D model with ECs and EPCs promoted network formation compared to CM from an EC monoculture. We also confirmed that EPCs secreted vascular endothelial growth factor (VEGF). However, networks cultured with the CM were shallow and did not penetrate the collagen gel in great depth. Therefore, we conclude that EPCs contribute to 3D network formation at least through indirect incorporation by generating a local VEGF gradient. These results suggest that the location of EPCs is important for controlling directional 3D network formation in the field of tissue engineering

Survivin Selectively Modulates Genes Deregulated in Human Leukemia Stem Cells

ITD-Flt3 mutations are detected in leukemia stem cells (LSCs) in acute myeloid leukemia (AML) patients. While antagonizing Survivin normalizes ITD-Flt3-induced acute leukemia, it also impairs hematopoietic stem cell (HSC) function, indicating that identification of differences in signaling pathways downstream of Survivin between LSC and HSC are crucial to develop selective Survivin-based therapeutic strategies for AML. Using a Survivin-deletion model, we identified 1,096 genes regulated by Survivin in ITD-Flt3-transformed c-kit+, Sca-1+, and lineageneg (KSL) cells, of which 137 are deregulated in human LSC. Of the 137, 124 genes were regulated by Survivin exclusively in ITD-Flt3+ KSL cells but not in normal CD34neg KSL cells. Survivin-regulated genes in LSC connect through a network associated with the epidermal growth factor receptor signaling pathway and falls into various functional categories independent of effects on apoptosis. Pathways downstream of Survivin in LSC that are distinct from HSC can be potentially targeted for selective anti-LSC therapy

Hypertension resistant to antihypertensive agents commonly occurs with the progression of diabetic nephropathy in Japanese patients with type 2 diabetes mellitus: a prospective observational study

BACKGROUND: We investigated 1) the frequency of hypertension in patients with type 2 diabetes graded by the new classification of chronic kidney disease (CKD) reported by the Kidney Disease: Improving Global Outcomes (KDIGO) and 2) the number of antihypertensive agents needed to achieve treatment goals using a prospective observational study. METHODS: A population of 2018 patients with type 2 diabetes mellitus was recruited for the study. The CKD stage was classified according to the eGFR and the urinary albumin excretion levels. RESULTS: Hypertension was found in 1420 (70%) of the patients, and the proportion of subjects showing a blood pressure < 130/80 mmHg was 31% at the baseline. Although the mean blood pressure was approximately 130/75 mmHg, the rate of patients with a blood pressure of < 130/80 mmHg became limited to 41-50% during the observation period. The number of antihypertensive agents required for treatment was significantly higher at the endpoint (2.0 ± 1.3) than at the baseline (1.6 ± 1.2). Furthermore, it increased with the progression of the CKD stage at both the baseline and the endpoint of the observation. However, the frequency of subjects who did not achieve the blood pressure target was found to increase in the group demonstrating the later stage of CKD. CONCLUSIONS: Hypertension resistant to antihypertensive agents was common in the patients with type 2 diabetes mellitus and increased with the progression of CKD. Although powerful combination therapy using antihypertensive agents is considered necessary for the strict control of blood pressure, this became difficult in individuals who were in advanced stages as graded based on the eGFR and the urinary albumin excretion levels

Internal Tandem Duplication in FLT3 Attenuates Proliferation and Regulates Resistance to the FLT3 Inhibitor AC220 by Modulating p21Cdkn1a and Pbx1 in Hematopoietic Cells

Internal tandem duplication (ITD) mutations in the Fms-related tyrosine kinase 3 (FLT3) gene (FLT3-ITD) are associated with poor prognosis in patients with acute myeloid leukemia (AML). Due to the development of drug resistance, few FLT3-ITD inhibitors are effective against FLT3-ITD+ AML. In this study, we show that FLT3-ITD activates a novel pathway involving p21Cdkn1a (p21) and pre-B cell leukemia transcription factor 1 (Pbx1) that attenuates FLT3-ITD cell proliferation and is involved in the development of drug resistance. FLT3-ITD up-regulated p21 expression in both mouse bone marrow c-kit+-Sca-1+-Lin- (KSL) cells and Ba/F3 cells. The loss of p21 expression enhanced growth factor-independent proliferation and sensitivity to cytarabine as a consequence of concomitantly enriching the S+G2/M phase population and significantly increasing the expression of Pbx1, but not Evi-1, in FLT3-ITD+ cells. This enhanced cell proliferation following the loss of p21 was partially abrogated when Pbx1 expression was silenced in FLT3-ITD+ primary bone marrow colony-forming cells and Ba/F3 cells. When FLT3-ITD was antagonized with AC220, a selective inhibitor of FLT3-ITD, p21 expression was decreased coincident with Pbx1 mRNA up-regulation and a rapid decline in the number of viable FLT3-ITD+ Ba/F3 cells; however, the cells eventually became refractory to AC220. Overexpressing p21 in FLT3-ITD+ Ba/F3 cells delayed the emergence of cells that were refractory to AC220, whereas p21 silencing accelerated their development. These data indicate that FLT3-ITD is capable of inhibiting FLT3-ITD+ cell proliferation through the p21/Pbx1 axis and that treatments that antagonize FLT3-ITD contribute to the subsequent development of cells that are refractory to a FLT3-ITD inhibitor by disrupting p21 expression

A Survey of Skills-Based Integrated English Classes in the New Curriculum

　岡山大学では平成25年度入学者から英語新カリキュラムを導入し、新１年生のスキル別科目の「総合英語１－４」（スピーキング、リーディング、ライティング、リスニング）は習熟度別クラス編成を行っている。本稿は、言語教育センター英語系が前期末の７月に実施した授業満足度に関するアンケート調査結果を分析したものである。入学時４月のTOEIC IP スコア395点以下、400点以上595点以下、600点以上の習熟度別グループに分け て学生の授業満足度の平均値をみると、習熟度の低いグループよりも高いグループの満足度が高い傾向がみられた。また、授業満足度に影響を与える要因は、習熟度別グループおよび担当教員グループによって異なることがわかった