Close correlation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate, an intracellular active metabolite, to the therapeutic efficacy of N(4)-behenoyl-1-beta-D-arabinofuranosylcytosine therapy for acute myelogenous leukemia.

N(4)-Behenoyl-1-beta-D-arabinofuranosylcytosine (BHAC), a prodrug of 1-beta-D-arabinofuranosylcytosine, is used effectively for the treatment of leukemia in Japan. BHAC therapy may be more effective if it is delivered in conjunction with monitoring of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP), the intracellular active metabolite of ara-C derived from BHAC. However, previous monitoring methods for ara-CTP were insufficiently sensitive. Here, using our new sensitive method, we evaluated the ara-CTP pharmacokinetics in relation to the therapeutic response in 11 acute myelogenous leukemia patients who received a 2-h infusion of BHAC (70 mg / m(2)) in combination remission induction therapy. ara-CTP could be monitored at levels under 1 mM. BHAC maintained effective levels of plasma ara-C and intracellular ara-CTP for a longer time, even compared with historical values of high-dose ara-C. The area under the concentration-time curve of ara-CTP was significantly greater in the patients with complete remission than in the patients without response. This greater amount of ara-CTP was attributed to the higher ara-CTP concentrations achieved in the responding patients. There was no apparent difference of plasma ara-C pharmacokinetics between the two groups. Thus, for the first time, the ara-CTP pharmacokinetics was evaluated in relation to the therapeutic effect of BHAC, and the importance of ara-CTP was proven. Administration of optimal BHAC therapy may require monitoring of the ara-CTP pharmacokinetics in each individual patient.othe

TIME-DEPENDENT VARIATIONS IN SKY EMISSION TEMPERATURES AT MILLIMETER WAVELENGTHS. ANOMALOUS SKY TEMPERATURE VARIATION WITH ZENITH DISTANCE MEASURED AT A CALM NIGHT AT A WAVELENGTH OF 3.2 MM. MEASUREMENTS OF LINEAR POLARIZATION OF THE MOON AT MILLIMETER WAVELENGTHS.

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(A) Cdc14B-GFP fusion proteins were induced by DOX for 72 h in U2OS Tet-On stable cell lines carrying different Cdc14B-GFP constructs as indicated

Centrosomes were visualized by γ-tubulin staining (red) and overlaid with Cdc14B-GFP (green) and DAPI-stained DNA (blue). Cdc14B-GFP was not detectable at interphase or mitotic centrosomes (arrows). Insets represent magnified images of centrosomes. Bar, 5 μm. (B) Histogram shows the percentage of interphase and mitotic cells with the indicated Cdc14B-GFP at centrosomes 72 h after DOX addition. The interphase data represent the means ± SD of three independent experiments and at least 500 cells were counted in each experiment. The mitotic experiment was performed in triplicates and a total of 113 Cdc14B-GFP– and 374 Cdc14B-GFP–positive cells were counted.<p><b>Copyright information:</b></p><p>Taken from "Cdc14B depletion leads to centriole amplification, and its overexpression prevents unscheduled centriole duplication"</p><p></p><p>The Journal of Cell Biology 2008;181(3):475-483.</p><p>Published online 5 May 2008</p><p>PMCID:PMC2364701.</p><p></p

(A) Overlay images depict partial colocalization of endogenous Cdc14B (red) with centrin (green) in U2OS cells during different stages of the cell cycle

Stages of the cell cycle were determined by centrin-labeled centrioles and DAPI-stained DNA (blue). Arrows indicate centrin and Cdc14B-labeled centrioles. Magnified images of centrioles are shown in the insets. Bar, 5 μm. (B, top) Cdc14B cofractionates with γ-tubulin. Lysates of asynchronized HeLa cells were fractionated on a 50–70% sucrose gradient. Fractions 4–22 were analyzed by Western blotting with γ-tubulin and Cdc14B antibodies. (bottom) Cdc14B but not nucleolin (a noncentrosomal protein) costains with γ-tubulin on purified centrosomes (top, fraction 15).<p><b>Copyright information:</b></p><p>Taken from "Cdc14B depletion leads to centriole amplification, and its overexpression prevents unscheduled centriole duplication"</p><p></p><p>The Journal of Cell Biology 2008;181(3):475-483.</p><p>Published online 5 May 2008</p><p>PMCID:PMC2364701.</p><p></p

(A, top) Cdc14B-GFP fusion proteins were induced by 4 μg/ml DOX in the presence of 2 mM HU for 72 h in U2OS Tet-On stable cell lines carrying different Cdc14B-GFP constructs as indicated

Centrioles were visualized by anti-centrin staining (red) and overlaid with Cdc14B-GFP (green) and DAPI (blue). Note that Cdc14B-GFP was not detectable at centrioles (arrow). Insets show magnified images of centrioles. Bar, 5 μm. (bottom) The percentage of cells with more than four centrioles was calculated from both induced (+DOX) and uninduced (−DOX) Cdc14B-GFP stable clones as indicated. Data shown represent the means ± SD of three independent experiments from two individual Cdc14B-GFP stable clones. At least 500 cells were counted in each experiment. (B, top) U2OS Tet-On cells were transfected as indicated. 16 h after transfection, cells were incubated with (+HU) or without (−HU) 2 mM HU and 4 μg/ml DOX for 72 h. Centrosomes were visualized by γ-tubulin staining (red). Representative centrosome amplification was detected in mock-transfected cells after HU treatment but not in pBI-tet-Cdc14B-GFP transfected cells where Cdc14B-GFP (green) associated with centrosomes. Insets show magnified images of centrosomes. DAPI (blue), DNA. Bar, 5 μm. (bottom) The percentage of cells with the indicated centrosome numbers was calculated from the experiments shown in the top panel. Centrosomes were counted in both mock and Cdc14B-GFP–transfected cells (Cdc14B-GFP–positive at centrosomes). All the data are shown as the means ± SD of three independent experiments. At least 500 cells were counted in each experiment. (C) Representative fluorescence-activated cell sorting profile on cell cycle distribution of DOX-inducible Cdc14B-GFP U2OS Tet-On stable clones. Cells were cultivated in the presence or absence of 4 μg/ml DOX for 72 h. Positions of cells with 2 N and 4 N DNA contents are labeled with arrowheads.<p><b>Copyright information:</b></p><p>Taken from "Cdc14B depletion leads to centriole amplification, and its overexpression prevents unscheduled centriole duplication"</p><p></p><p>The Journal of Cell Biology 2008;181(3):475-483.</p><p>Published online 5 May 2008</p><p>PMCID:PMC2364701.</p><p></p

(A) Representative confocal images of BJ and MRC-5 cells with clustered supernumerary centrioles are shown

Centrioles were labeled by anti-centrin antibody. Insets show magnified images of centrioles. Bar, 10 μm. (B) The percentage of cells with more than four centrioles was calculated from the experiments shown in A. Data shown represent the means ± SD of three independent experiments. At least 300 cells were counted in each experiment.<p><b>Copyright information:</b></p><p>Taken from "Cdc14B depletion leads to centriole amplification, and its overexpression prevents unscheduled centriole duplication"</p><p></p><p>The Journal of Cell Biology 2008;181(3):475-483.</p><p>Published online 5 May 2008</p><p>PMCID:PMC2364701.</p><p></p

(A) Dox-inducible U2OS Tet-On cell lines carrying the indicated Cdc14B-GFPs and mock controls were treated with 1 μM Z-L-VS in the presence or absence of 4 μg/ml Dox for 48 h

Representative centrioles (red) were visualized by an anti-centrin antibody and DNA (blue) was visualized by DAPI. Bar, 5 μM. (B) The percentage of cells with more than four centrioles was calculated from the experiments shown in A and as indicated. Centrioles were counted in mock, uninduced controls (−Dox) and Cdc14B-GFP–induced (+Dox) cells (Cdc14B-GFP–positive at centrioles). All the data are shown as the means ± SD of three independent experiments. At least 400 cells were counted in each experiment.<p><b>Copyright information:</b></p><p>Taken from "Cdc14B depletion leads to centriole amplification, and its overexpression prevents unscheduled centriole duplication"</p><p></p><p>The Journal of Cell Biology 2008;181(3):475-483.</p><p>Published online 5 May 2008</p><p>PMCID:PMC2364701.</p><p></p