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Professor and Frau Dr. Staudinger made an epoch-making visit to Japan in the cherry blossom time in 1957, 4 years after his Nobel Prize. Japan was gradually recovering from the damage of World War II. In accordance with the strong demand from industry, research activities on polymeric substances became popular in major national universities. Through various contacts, including two major lectures in Tokyo and Osaka, they left an impressive lesson on “what science is all about” for young researchers in this new field.

The physical picture of the nematic conformation has been discussed on the basis of the rotational isomeric state analysis for segmented liquid-crystal (LC)-forming molecules, comprising mesogenic units on both sides of a flexible spacer. The disorientation angles (θ) of the two terminal mesogenic units are calculated for given spatial configurations of the spacer. The observed odd-even character of the thermodynamic quantities at the nematic (N)–isotropic (I) phase transition T NI = ΔH NI/ΔS NI has been interpreted in terms of the profiles of the calculated distribution curves P(θ) − θ. Combined use of rotational isomeric state and 2H NMR techniques has led to an estimate of the conformer fraction in the nematic state. The transition entropies derived on this basis are favorably compared with the constant–volume transition entropies obtained from the pressure–volume–temperature measurement. The observed V–T relation indicates that the expansivity of the nematic LC phase is higher relative to that of the isotropic melt. It has been pointed out that the nematic conformation might possibly gain extra stability from the free volume effect in the LC state. These considerations offer an explanation why amazingly long flexible chain segments can be accommodated in the nematic fluid.

Technology and Development of Self-Reinforced Polymer Composites, by Ben Alcock und Ton Peijs.- Recent Advances in High-Temperature Fractionation of Polyolefins, by Harald Pasch, Muhammad Imran Malik und Tibor Macko.- Antibacterial Peptidomimetics: Polymeric Synthetic Mimics of Antimicrobial Peptides, by Karen Lienkamp, Ahmad E. Madkour und Gregory N. Tew.- Collagen in Human Tissues: Structure, Function, and Biomedical Implications from a Tissue Engineering Perspective, by Molamma P. Prabhakaran.

Mainchain liquid crystals having a regularly alternating rigid-flexible repeating structure often exhibit distinct odd-even oscillation in their thermodynamic quantities with respect to the number of methylene units in the spacer. The effect has been widely observed from dimer (DLC) to polymer liquid crystals (PLC), but not in the monomer liquid crystals (MLC) which comprise a mesogenic unit carrying one or two tails. The degree of oscillation varies depending on the chemical structure of the linking group used to join the spacer with mesogenic units. In our previous work, we have suggested that such characteristics are mainly due to the geometrical arrangement of the linkage. In this work, we have prepared a series of carbonate-type MLCs NC ? ?OCOO(CH 2 ) n-1 CH 3 , where ? is a phenyl group, as well as DLCs NC ? ?OOCO(CH 2 ) n O-COO??CN. The thermodynamic behaviors at the nematic-isotropic NI transition have been compared with those previously reported for the ether-type DLCs. For the dimer series, the molecular orientation and the spacer conformation were investigated by using 2 H NMR technique. The origin of the difference in the odd-even behaviors has been traced back to the geometrical characteristics of the linking groups, which affect the relative orientation of the terminal mesogenic cores, thus leading to modification of the conformational distribution in the nematic state. The analysis has yielded the nematic conformation which satisfactorily reproduces the observed values of the dipolar and quadrupolar couplings. The bond conformation vs. bond order plots are shown for the n odd and n even systems together with the corresponding results derived previously for the ether-type DLCs. Although the numbers of bonds of the flexible spacer are not exactly comparable with each other, the conformational ordering along the spacer tends to be pronounced in both DLC systems.

In this work, we wish to report the results of conformational analysis of poly(β-phenethyl L-aspartate) (PPLA) and poly(γ-benzyl L-glutamate) (PBLG) in two opposite α-helical screw sense. Variously deuterated PPLA samples were prepared, and 2H NMR measurements were carried out in tetrachloroethane at two different temperatures: one for the right-handed and the other for the left-handed α-helical state. The rotational isomeric state (RIS) analysis of the 2H NMR quadrupolar splitting data was carried out, and the sidechain conformations were estimated. The results of the analysis for the right-handed α-helical PBLG have been reported previously. In the right-handed α-helix regime, i.e., r-PPLA and r-PBLG, the preferred form of the first two bonds was found to be χ1χ2=tt, leading to an extended sidechain conformation in the direction perpendicular to the α-helical axis. The corresponding arrangements in the l-form (1-PPLA) are more or less evenly distributed among three states, g−t, tt, and g−g+. MD simulations were performed for the side chain flanking the right- and left-handed α-helical backbone by using Biosym’s Discover program. An α-helix fragment consisting of 18 aminoacid residues, Ac-X18-NHMe with X= Asp(OPhe) or Glu(OBzl), was adopted as a model for the polymers in the simulation. The preferred sidechain conformations were elucidated as an average over an interval 100—200 ps. The simulations were performed in vacuo as well as in the presence of solvent molecules (chloroform). The agreement was found to be quite reasonable in all three polymer systems for which relevant experimental data are available.

Conformation of 1,3-dimethoxypropane has been studied in the gas phase (approximately 120–180°C). Vicinal coupling constants 3JHH and 3JCH determined by 1H and 13C NMR were analysed within the rotational isomeric state approximation. The trans and gauche couplings required in this analysis were set equal to JG = 2.8 Hz and JT = 13.7 Hz for 1HCC1H, and JG = 2.0 Hz and JT + J′G = 16.0 Hz for 13COC1H. The conformational energy parameters of the chain were conventionally defined as Eσ and Eϱ for the gauche state around the CH2CH2 and OCH2 bond, respectively, and Eω for the repulsive second-order interaction (g±g∓) for the OCH2CH2CH2O fragment. The experimental values of the coupling constants were found to be reproduced by a variety of combinations of Eσ and Eω, Eϱ being kept at 1.03 kcal mol−1. Adoption of Eω = 1.97 kcal mol−1, as calculated by a molecular mechanics method, led to Eσ = −0.84 kcal mol−1. Alternatively, by setting Eσ = −0.58 kcal mol−1 as calculated, Eω = 0.40 kcal mol−1. Assuming Eω > 1 kcal mol−1 for the gas phase, a value of Eσ from −0.7 to approximately −0.9 kcal mol−1 was proposed. The conformation, and thus conformational energies, varied quite sensitively with the polarity of the medium. The results were compared with those observed in solution.

RIS analysis of the deuterium quadrupolar splitting data was performed for dimer liquid crystals CNPhPhO(CH 2 ) m OPhPhCN (m=9 (CBA-9) and m=10 (CBA-10)). The analysis indicates that most of the conformers involved in the range 0< ψ 1 ,ψ 2 < 45° adopt spatial configurations reasonably consistent with the nematic arrangement of mesogenic cores in both dimer LC systems, where ψ 1 and ψ 2 denote the inclination angles of the terminal mesogenic cores with respect to the molecular axis. The conformational entropy changes at the crystal-nematic (CN) and nematic-isotropic (NI) interphases estimated on this basis are as follows: CBA-9, ΔS cn cibf = 59.6, ΔS ni conf = 13.3; CBA-10, ΔS cn conf = 64.2, ΔS ni conf = 15.6 (J mol -1 K -1 units). The values of the entropies ΔS tr conf thus derived were compared with the constant-volume transition entropies (ΔS ni ) υ determined by the PVT measurements reported in the accompanying paper: CBA-9, (ΔS cn ) υ = 53.9, (ΔS ni ) υ = 7.9; CBA-10, (ΔS cn ) υ = 62.4, (ΔS ni ) υ = 13.3 (J mol -1 K -1 units). In view of the uncertainties involved in the estimation of the entropies both in theory and in experiments, the correspondence is quite favorable. The conformation of the spacer undoubtedly plays an important role in determining the phase behaviors of these main chain liquid crystals. It is pointed out that the discrepancy between the calculation and experiment may be further improved by considering other contributions such as (1) the entropy changes due to the orientation of the anisotropic molecules in the liquid crystalline state and (2) the possibility of the entropy loss during the compression to achieve constant-volume transitions. It is concluded that the observed increase in the quadrupolar and dipolar splittings with decreasing temperature arises mainly from the variation of the order parameter of the molecular axis

Pressure-volume-temperature (PVT) measurements were performed on α,ω-bis[(4,4'-cyanobiphenylyl)oxy]alkane (CBA-n) dimer liquid crystals having -O(CH 2 ) n O- flexible spacers (n=9, 10) between the 4,4'-cyanobiphenylyl ends. Both samples exhibit crystalline↔nematic (CN) and nematic↔isotropic (NI) transitions. The contribution in entropy ΔS V caused by the volume change has been estimated by using the standard thermodynamic relation ΔS V =-(α/β)ΔV tr , where ΔV tr represents the transition volume, α the thermal expansion coefficient, and β the isothermal compressibility. The transition entropy (ΔS tr ) υ at constant volume was elucidated by subtracting ΔS υ from the entropy change (ΔS tr ) p observed under constant pressure. By using the (ΔS ni ) p values derived from the Clapeyron equation, the constant-volume entropies (ΔS ni ) υ at the NI transition were found to be 7.9 and 13.3 J mol -1 K -1 , respectively, for CBA-9 and -10. The values of (ΔS cn ) υ for the CN transition were estimated on the basis of DSC data: 53.9 (CBA-9) and 62.4 J mol -1 K -1 (CBA-10). For both transitions, the correction for the basis volume change was found to be significant, ranging from 40 to 60% of the total transition entropy observed under constant pressure. Nevertheless, the odd-even character of the NI transition remains unaltered. As shown by comparison of (ΔS cn ) υ and (ΔS cn ) υ the major change (85%) takes place at the CN transition the liberation of entropy at the NI interphase being much smaller (15%)

Severe disseminated varicella zoster virus (VZV) infection rarely occurs in patients who are not recipients of hematopoietic stem cell transplantation. This report concerns severe disseminated VZV infection in a diffuse large B cell lymphoma (DLBCL) patient treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). The patient was an 82-year-old male with DLBCL who had a history of type II diabetes mellitus. He incurred VZV infection with severe hepatitis and disseminated intravascular coagulopathy after three courses of R-CHOP. When the VZV infection occurred, anti-VZV IgG was not detected and lymphopenia was observed. We initiated treatment with acyclovir, immunoglobulin, and thrombomodulin alpha, and rescued this patient. We suggest that the use of chemotherapy for immune-suppressed elderly lymphoma patients may involve the risk of severe VZV infection.

Participatory GIS (PGIS) is used in regional urban development and in solving regional problems that affect local communities. Accordingly, the widespread adoption of PGIS is important. In this paper, the development of a Web GIS-based regional social networking service (SNS) is presented. The SNS focuses on PGIS and takes into account user activity support. The system has three functions: information extraction by user activity area, GPS location referencing, and location based information posting function. The proposed SNS is evaluated in Takizawa Village, Japan. Furthermore, a PGIS usage model is proposed for actively utilizing PGIS. Local governments, nonprofit organizations, and universities each have a role in this model.

The conformations of flexible chain molecules incorporated in a nematic environment have been investigated. The phase behaviours and orientational characteristics of 1,2-dimethoxyethane (DME) dissolved in 4′-methoxybenzylidene-4-n-butylaniline at low solute mol fraction have been reported in our previous paper. In this work, proton–proton and carbon–carbon dipolar coupling constant measurements were attempted in addition to 2H NMR observations of quadrupolar splittings. These conformation-dependent properties were analysed according to the rotational isometric state (RIS) simulation scheme previously proposed. Our treatment rests on the assumption that the molecular axis of the chain should tend to align along the nematic field. Studies were further extended to a mixture of 1,2-diphenyloxyethane (DPE) with a nematic liquid crystal, 4,4′-azoxyanisole. Replacement of the terminal methyl groups in DME by phenyl groups leads to DPE. The results of the analysis indicate that the fraction of elongated ...

ネマチック液晶状態を取る多くの化合物について, NMRの磁場中 (～12 T) では液晶場の配向ベクトルが磁場の方向と一致することが知られている. 液晶の一部に重水素ラベルをして2H NMR測定を行うと, 核四極子相互作用による分裂を示し, 分裂巾からラベルを施した結合の配向秩序度が求まる. 分子内回転が許されている鎖状分子の四極子分裂は, 分子全体としての配向に加えて, コンホメーションに関する平均にも依存する. 二つの寄与を適当な理論モデルまたは統計的シミュレーション・モデルを用いて分離することにより, 液晶などの異方性場に置かれた鎖状分子のコンホメーションを推定することが可能である. 本論文では, 回転異性状態 (RIS) シミュレーション法により, (1) リオトロピック液晶を形成するポリ (γ-ベンジルL-グルタメート) (PBLG) α-ヘリックスの側鎖コンボメーションと (2) サーモトロピック液晶となるα, ω-ビス [ (4, 4′-シアノビフェニル) オキシ] アルカン (CBA-n) に含まれるスペーサー-O (CH2) nO-のネマチック・コンボメーションを解析した. いずれの例においても, 鎖に沿って結合コンボメーションに長距離の相関が見られることを指摘した. これらの結果を踏まえて, 鎖状部分のコンホメーションと系の熱力学的性質との関わり合いについて考察した. さらに, MDシミュレーションの現状についても言及した.

FMS-related tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase that plays important roles in hematopoiesis, including early progenitors and dendritic cell development. FLT3 is expressed at high levels in 70–100% of cases of AML and in virtually all cases of B-lineage acute lymphoblastic leukemia. FLT3 is regarded as a molecular target in the development of novel therapies for acute leukemia patients. Currently, many small-molecule FLT3 inhibitors have been developed, but clinical trials have resulted in limited antileukemia effects because of off-target toxicities and drug resistance. The development of anti-FLT3 Abs might overcome these difficulties and enhance the antileukemia efficacy of FLT3 inhibitors. In the present study, we demonstrate the isolation of novel human mAbs against FLT3 with antagonistic or agonistic activities. An antagonistic Ab, designated A2, continuously inhibits FLT3 ligand (FL)-induced phosphorylation of FLT3 and MAPK. A2 cooperatively induces apoptosis with daunorubicin, even in the presence of FL. An agonistic Ab, designated 3E6, surprisingly induces the phosphorylation of FLT3 and MAPK, and supports the growth of a factor-dependent cell line independently of FL addition. In addition, A2 showed complement-dependent cytotoxicity activity, but was devoid of Ab-dependent cell mediated cytotoxicity. Finally, we evaluated Ab internalization in a cell line. Immunofluorescence and flow cytometry analyses revealed that A2 is efficiently internalized. Collectively, these data demonstrate that A2 is a potent human Ab that might be capable of delivering cytotoxic reagents and that has antagonistic effects on FLT3 signaling. In addition, 3E6 might be a potential scaffold for novel dendritic cell-based immunotherapies. (Cancer Sci 2012; 103: 350–359)

Roads should be safe and kept in good condition. In order to carry out effective road maintenance, the use of spatial and temporal information is necessary. As research in this field, a web-based road maintenance support system has been in long-term operation. However, in the existing system, the accumulated data is not intended for use in future work. The maintenance information produced over the life cycle of a road is instead distributed among multiple computers and management offices. In this paper, a prototype of information portal system using Web GIS is proposed and evaluated in terms of its practicality for project participants to retrieve and to share information. Road data models containing structural and work information are constructed for use in the system. The system includes functions for data analysis from the viewpoint of budget and maintenance, provides aerial views on Web GIS, and contains spatial analysis results using GIS.

PAX5 is a transcription factor required for B-cell development and maintenance. PML is a tumor suppressor and a pro-apoptotic factor. A fusion gene, PAX5-PML, was found in acute lymphoblastic leukemia (ALL) with chromosomal translocation t(9;15)(p13;q24), but no functional analysis has been reported. Here, we demonstrate that PAX5-PML had a dominant-negative effect on both PAX5 and PML. PAX5-PML dominant negatively inhibited PAX5 transcriptional activity in the luciferase reporter assay and suppressed the expression of the PAX5 transcriptional targets in B-lymphoid cell line. Surprisingly, PAX5-PML hardly showed DNA-binding activity in vitro although it retained the DNA-binding domain of PAX5. Additional experiments, including chromatin immunoprecipitation (ChIP) assay, suggested that PAX5-PML bound to the promoter through the association with PAX5 on the promoter. On the other hand, coexpression of PAX5-PML inhibited PML sumoylation, disrupted PML nuclear bodies (NBs), and conferred apoptosis resistance on HeLa cells. Furthermore, treatment with arsenic trioxide (ATO) induced PML sumoylation and reconstitution of PML NBs, and overcame the anti-apoptotic effect of PAX5-PML in HeLa cells. These data suggest the possible involvement of this fusion protein in the leukemogenesis of B-ALL in a dual dominant-negative manner and the possibility that ALL with PAX5-PML can be treated with ATO.

Phase diagrams were reported for binary mixtures comprising a series of dimethyl ethyleneglycol ethers CH3O(CH2CH2O)xCH3 (x=1−3) (DMEG) and a nematogenic solvent 4′-methoxybenzylidene-4-n-butylaniline (MBBA) at low solute mole fraction. For a comparison purpose, measurements were also carried out for n-hexane hosted in the same solvent. Following Martire et al., the slopes, βN and βI, of the nematic and isotropic phase boundary lines have been used as a measure of the compatibility of nonmesomorphic solutes with the nematic phase. The β values of the DMEG series were found to increase rapidly with the chain length in contrast to those reported for n-alkanes CH3(CH2)n−2CH3. The 2H NMR technique was extensively employed to elucidate the orientational order of the individual components in the mixture. In accordance with the trend observed in the phase behavior, the DMEG series exhibit a greater reduction of nematic order when compared at the same solute concentration of hydrocarbon analogs. The deuterium quadrupolar splittings Δv were observed for the methylene and methyl deuterons of the solute molecule. The ratio of quadrupolar splittings Δvi/Δvj which represents the relative orientation of the CD bonds at sites i and j, were found to remain nearly invariant over a wide range of concentration and temperature. It has been concluded from the RIS analysis that the fiexible chain molecules examined prefer to take somewhat more elongated forms to facilitate alignment in the nematic field as compared with those in the conventional isotropic solution.

SAXS intensity for the lamellar structure of polymeric materials has been formulated with consideration of structural defects such as the finiteness of the lamellar stack, the lamellar bend, and the paracrystalline distortions. In particular, the effects of the lamellar bend on the SAXS profile have been elucidated on the basis of Vonk's formula γ 1 (x)=γ 1 0 (x)exp(-2x/d). Here, the scattering profile due to the lamellar bend is shown to be expressed by a Cauchy function. The integral breadth is equal to 2π/d, being independent of the order of scattering. As an example of the SAXS analysis based on the theory, the characterization of the lamellar structure in the «hard» elastic polypropylene films is reported

To investigate the possibility of killing tumor cells by the expression of an exogenously introduced toxic gene, we have constructed a novel retroviral vector (LTRNL) which has the polyA signal deleted herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene. The vector becomes toxic by treating cells expressing HSV1-tk with the antiherpetic drugs acyclovir or ganciclovir (GCV). Cells of the human leukemia lines (K562, MEG-01) were infected with this vector and two transduced cell lines (K562/LTRNL, MEG-01/LTRNL) were established. Southern blot analysis confirmed the integration of the HSV1-tk transgene in these cells and Northern blot analysis exhibited the expression of 4.8-kb viral mRNA containing the HSV1-tk gene. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay for the in vitro cytotoxic effects of GCV to these cells demonstrated that concentrations of about 2.5 microM for K562/LTRNL and 1.25 microM for MEG-01/LTRNL cells resulted in 50% inhibition of cell growth after 72 hr. Subcutaneous tumors of MEG-01/LTRNL in KSN nude mice, but not those of uninfected MEG-01 cells, showed durable regressions after exposure of the mice to 40 mg/kg of GCV given subcutaneously once a day for 15 days. This study indicates that the LTRNL-infected human leukemia cells exhibit inducible susceptibility to GCV.

One of the recent strategies for gene therapy as a cancer control is the targeted introduction of a drug-sensitivity gene into tumor cells. We investigated the gene transfer of herpes simplex virus type I thymidine kinase (HSV-TK) gene as a drug-sensitivity gene into human lung cancer cell lines. We used a recombinant retroviral vector derived from Moloney murine leukemia virus (MuLV) as one of potential vectors for gene therapy. The amphotropic retroviral vector consisted of the HSV-TK gene and the neomycin-resistant gene under Rous sarcoma virus (RSV) promoter control. The antiherpes drugs, acyclovir (ACV) and ganciclovir (GCV), were chosen for testing the activity of HSV-TK that was transferred into human lung cancer cell lines. ACV and GCV are nucleoside analogs specifically converted by HSV-TK to a toxic form capable of inhibiting DNA synthesis. The cytotoxicity was determined by using a tetrazolium-based colorimetric assay (MTT assay). The results obtained from our experiments demonstrated that the retroviral vector-mediated HSV-TK gene transfer leads to ACV- and GCV-dependent cytotoxicity in human lung cancer cell lines, which were both small cell carcinoma and non-small cell carcinoma established from human specimens. These findings suggest that the gene transfer of HSV-TK gene into tumor cells would be one of the models for the use of gene therapy to control lung cancer.

For a ternary system of sodium octanoate, 1-decanol, and water, conformational and orientational characteristics of the amphiphilic molecules octanoate (C 8 OO) and decanol (C 10 OH) incorporated in the hexagonal, lamellar, and reversed hexagonal aggregates have been investigated. Deuterium NMR quadrupolar splittings observed for these compounds were analyzed according to the scheme employed in our previous studies on main-chain thermotropic liquid crystals and flexible chains dissolved in nematic solvents; the orientational order parameters, the bond conformations and the average chain extensions were evaluated. In addition, the aggregate sizes and the area per polar head were estimated by small-angle X-ray diffraction

Internal tandem duplication of FMS-like receptor tyrosine kinase 3 (FLT3/ITD) within its juxtamembrane domain is a frequent mutation in adult acute myeloid leukaemia (AML). This mutation causes constitutive activation of FLT3 and is associated with poor prognosis. The high relapse rate of FLT3/ITD-positive AML might be partly because of insufficient eradication of slow-cycling leukaemic stem cells in the bone marrow microenvironment. β1 integrin mediates haematopoietic stem and progenitor cell homing along with their retention in the bone marrow and also inhibits haematopoietic proliferation and differentiation. Here, we demonstrate that inhibition of FLT3/ITD kinase activity by a FLT3 selective inhibitor named FI-700 decreases affinity of α4β1 integrin to soluble VCAM-1. α4β1 integrin deactivation by FI-700 is independent of Rap1, which is the critical regulator of integrin inside-out signalling. In addition, selective inhibition of FLT3/ITD induces Pyk2 dephosphorylation together with the inhibition of phosphatidylinositol-3-kinase (PI3K)/Akt pathway. Both wild-type and ITD-FLT3 proteins co-immunoprecipitated with β1 integrin and Pyk2 indicating the signal crosstalk between FLT3, β1 integrin and Pyk2. These results collectively indicated that the inhibition of FLT3 kinase might contribute not only to the induction of apoptosis, but also to the leukaemia cell detachment from the bone marrow microenvironment in the treatment of AML.

The 13 C− 1 H NMR vicinal coupling constant 3 J C H 3 OC H 2 was measured for dimethoxymethane CH 3 OCH 2 OCH 3 in the gas phase as well as in various solvents. The observed values tend to decrease slightly with temperature. The energy difference E σ between the gg and tg forms was estimated to be −2.5 ± 0.2 kcal mol −1 in the gas phase. The coupling constant parameters determined concomitantly are as follows: ( J T + J G− )/2 = 6.7 ± 0.1 and J G = 2.0 Hz. Values of E σ observed in nonpolar solvents were found to fall in the same range. A somewhat smaller value (ca. −2.2 kcal mol −1 ) was derived from the measurements in (CD 3 ) 2 SO. These values are reasonably consistent with the results of recent MO calculations by Wiberg and Murcko. A similar 13 C NMR analysis of 1,1-dimethoxyethane CH 3 OCH(CH 3 )OCH 3 indicates that the g− g and tg conformers exists in nearly equal amounts, i.e. E τ = E g− g − E tg ≅ 0 kcal mol −1 . In the latter compound, the anomeric conformation ( g − ) involves unfavorable steric interactions around the g− bond.

In this work we wish to report preliminary results of the gas phase NMR studies on 1,2-dimethoxyethane. The conformation of the compound has been previously studied in solution using the same NMR technique [9]. The results obtained compare favorably with those observed in nonpolar solvent

T315I mutation of the ABL-kinase domain in chronic myeloid leukemia (CML) confers resistance to imatinib (IM) as well as second-generation tyrosine kinase inhibitors (TKIs). We report a chronic-phase CML patient undergoing IM treatment, who showed the overt existence of the T315I mutation after 15 months. We retrospectively analyzed the distribution of the T315I mutation using the invader assay and direct DNA sequencing among FACSAria-sorted populations from bone marrow cells: total mononuclear cells (TMC), hematopoietic stem cells (HSC)/Thy-1(+), HSC/Thy-1⁻, common myeloid progenitors (CMP), granulocyte macrophage progenitors (GMP), and megakaryocyte erythroid progenitors (MEP), at 0, 3, 6, 9, and 12 months after IM treatment. T315I was barely detectable by 12 months in TMC, but detectable in 19.2% of HSC/Thy-1⁻ and 46.4% of MEP at diagnosis, and finally expanded into all populations. These results suggest that the monitoring of gene mutations in HSC and progenitors at diagnosis might be helpful for the early detection of TKI-resistant CML patients and facilitate appropriate therapeutic decision.

The conformation of the ethoxy tail flanking the cyanobiphenyl core has been studied in the liquid-crystalline phase as well as in the isotropic solution. In solution, the vicinal coupling constant 3JCH for the moiety CphOCH (Cph: phenyl carbon) provided the information regarding the rotation around the OC bond. Phenetole was mostly used as a model compound. The conventional rotational isomeric state (RIS) analysis yielded the energy difference between the gauche and trans state to be of the order of 1,6 to 1,4 kcal/mol in CDCl3, C6D6 and dimethyl-d6 sulfoxide. In this treatment, the rotational state around the neighboring bond (CphO) was taken to occur at 0 or π. The deuterated compound, 4-ethoxy-4′-biphenylyl-d7 cyanide, was prepared and studied in the liquid-crystalline state by 2H NMR. The orientational order parameters of the mesogenic core were determined by the analysis of dipolar and quadrupolar splitting data due to aromatic deuterons. The quadrupolar splitting data were also obtained for the deuterated ethoxy tail. The conformation of the tail was elucidated according to the RIS simulation scheme previously proposed. The fraction of the trans conformation ft was estimated to be 0,79 around the nematic-isotropic transition temperature (TNI = 91,9°C). It was suggested that the conformation of the ethoxy tail remains nearly unaffected by the phase transition in the immediate vicinity of TNI. The fraction ft increases moderately toward an asymptotic value as temperature decreases.

Conformational characteristics of 1,2-dimethoxyethane (DME) in the gas phase have been studied by the NMR method, Observed 1 H- 1 H and 13 C- 1 H NMR vicinal coupling constants are compared with those previously determined in nonpolar solvents. The values observed in the gas phase and in solution do not exhibit any appreciable discontinuity at the transition

Conformation of the ethoxy tail flanking the cyanobiphenyl core has been studied in the liquid-crystalline state. The compound exhibits a monotropic nematic phase at 91.9 °C. The2H NMR analysis indicates that the fraction of the trans conformer around the O−CH2 bond amounts to 0.79 at the temperature slightly below the isotropic-to-nematic transition point. The result was found to be consistent with those reported for some related compounds by Celebre et al.

Deuterium NMR studies have been performed to elucidate orientational characteristics of some ether-type main-chain liquid crystals. Spacers used are of the type -O(CH2)nO- with n = 9 and 10. Dimers, homopolymers as well as copolymers in which spacers n = 9 and 10 are arranged in an alternative fashion were investigated. The quadrupolar splitting data obtained from the deuterium-labeled mesogenic core and spacer have been studied within the rotational isomeric state (RIS) approximation. The ordering characteristics thus estimated were found to be consistent with the magnetic susceptibility data obtained by using superconducting quantum interference device (SQUID) for the same polymers.

Stem cells of acute myeloid leukemia (AML) have been identified as immunodeficient mouse-repopulating cells with a Lin(-)CD34(+)38(-) phenotype similar to normal hematopoietic stem cells. To identify the leukemia-propagating stem cell fraction of Philadelphia chromosome-positive (Ph(+)) leukemia, we serially transplanted human leukemia cells from patients with chronic myeloid leukemia blast crisis (n = 3) or Ph(+) acute lymphoblastic leukemia (n = 3) into NOD/SCID/IL-2Rgammac(-/-) mice. Engrafted cells were almost identical to the original leukemia cells as to phenotypes, IGH rearrangements, and karyotypes. CD34(+)CD38(-)CD19(+), CD34(+)38(+)CD19(+), and CD34(-)CD38(+)CD19(+) fractions could self-renew and transfer the leukemia, whereas the CD34(-)CD38(+)CD19(+) fraction did not stably propagate in NOD/SCID mice. These findings suggest that leukemia-repopulating cells in transformed Ph(+) leukemia are included in a lineage-committed but multilayered fraction, and that CD34(+) leukemia cells potentially emerge from CD34(-) populations.

KW-2449, a multikinase inhibitor of FLT3, ABL, ABL-T315I, and Aurora kinase, is under investigation to treat leukemia patients. In this study, we examined its possible modes of action for antileukemic effects on FLT3-activated, FLT3 wild-type, or imatinib-resistant leukemia cells. KW-2449 showed the potent growth inhibitory effects on leukemia cells with FLT3 mutations by inhibition of the FLT3 kinase, resulting in the down-regulation of phosphorylated-FLT3/STAT5, G1 arrest, and apoptosis. Oral administration of KW-2449 showed dose-dependent and significant tumor growth inhibition in FLT3-mutated xenograft model with minimum bone marrow suppression. In FLT3 wild-type human leukemia, it induced the reduction of phosphorylated histone H3, G2/M arrest, and apoptosis. In imatinib-resistant leukemia, KW-2449 contributed to release of the resistance by the simultaneous down-regulation of BCR/ABL and Aurora kinases. Furthermore, the antiproliferative activity of KW-2449 was confirmed in primary samples from AML and imatinib-resistant patients. The inhibitory activity of KW-2449 is not affected by the presence of human plasma protein, such as α1-acid glycoprotein. These results indicate KW-2449 has potent growth inhibitory activity against various types of leukemia by several mechanisms of action. Our studies indicate KW-2449 has significant activity and warrants clinical study in leukemia patients with FLT3 mutations as well as imatinib-resistant mutations.

Although oncogenic functions and the clinical significance of Wilms tumor 1 (WT1) have been extensively studied in acute leukemia, the regulatory mechanism of its transcription still remains to be determined. We found a significant correlation among the amounts of WT1, GATA-1 and GATA-2 mRNAs from leukemia and solid tumor cell lines. Overexpression and small interfering RNA (siRNA) transfection experiments of GATA-1 and GATA-2 showed that these GATA transcription factors could induce WT1 expression. Promoter analysis showed that the 5' promoter did not explain the different WT1 mRNA levels between cell lines. The 3' enhancer, especially the distal sites out of six putative GATA binding sites located within the region, but not the intron 3 enhancer, were essential for the WT1 mRNA level. Electrophoretic mobility shift assay (EMSA) showed both GATA-1 and GATA-2 bound to these GATA sites. Besides acute leukemia cell lines, solid tumor cell lines including, TYK-nu-cPr also showed a high level of WT1 mRNA. We showed that GATA-2 expression is a determinant of WT1 mRNA expression in both TYK-nu-cPr cells and HL60 cells without GATA-1 expression. Taken together, these results suggest that GATA-1 and/or GATA-2 binding to a GATA site of the 3' enhancer of WT1 played an important role in WT1 gene expression.

The orientational characteristics of the polymers [Pt(PBu 3 ) 2 -C≡C-C≡C-Pt(PBu 3 ) 2 -C≡C-Ph-C≡C] n in the lyotropic nematic mesophase (trichloroethylene) were studied in relation to their phase behavior.

The magnetic susceptibilities of the polymers [PhOC-(O)PhO(CH 2 )nOPhC(O)OPhO(CH 2 ) n O] x (Ether-PLC-n) with n=9 and 10 have been measured. The Δχ values estimated for the stable nematic state were analyzed according to the RIS scheme developed in the previous work. The order parameters of the mesogenic core axis S M were elucidated for the nematic conformation derived independently from the 2 H NMR analysis. The same treatment has been extended to include ester-type main-chain liquid crystals such as -[Ph(CH 3 )N(O)NPh(CH 3 )OOC(CH 2 ) n COO] x -(Ester-PLC-n) with n=7 and 10

In this work we wish to report preliminary results of the gas phase NMR studies on 1,2-dimethoxyethane. The conformation of the compound has been previously studied in solution using the same NMR technique [9]. The results obtained compare favorably with those observed in nonpolar solvent

Conformational Anisotropy of n -Alkanes Dissolved in a Nematic Solvent: A Rotational Isomeric State Analysis of Proton–Proton Dipolar Coupling and Deuterium Quadrupolar Splitting Data

Orientational Characteristics of Semiflexible Poly(yne)–Platinum Polymers as Studied by Deuterium NMR

Recently, the administrative and maintenance expenses of superannuated public infrastructure and facilities became unfeasible in Japan. Then, Necessity arose for premeditated and efficient maintenance of public infrastructures like road facilities. However, because controlling the maintenance of road facilities such as bridges and road lights depends on human resources and businesses, therefore the introduction of excessively advanced information systems was avoided. This research proposes a road facility management support system architecture that integrates Radio Frequency IDentification (RFID) and Geographic Information Systems (GIS) and evaluates the effectiveness of such a support system. The design goal of the proposed support system is to enable the efficient inspection of road facilities; it comprises (1) road facilities enabled with RFID tags, (2) mobile phones with built-in RFID readers, (3) ITAG (Integration server of e-Tag Application and GIS) to integrate the RFID functionality with GIS servers, and (4) a database to store road facility inspection data and site photographs. A field experiment prototype system was developed based on the proposed system architecture. The field experimentation of this prototype system was conducted with the Morioka City Office Road Administration Division as the experimental subject. A survey questionnaire administered after the completion of the field experiment showed that the system was effective in enabling the unified administration of inspection history. In conclusion, this paper proposes a new type of system architecture that integrates RFID and GIS for GIS-based applications that will be required for the advanced spatial information societies of the future.

We have previously shown that theanine (=gamma-glutamylethylamide), an ingredient of green tea, has a protective effect against ischemic neuronal death in the hippocampal CA1 region of the gerbil brain without affecting ligand binding to ionotropic receptor subtypes of the neurotransmitter glutamate structurally related to theanine. The neurotransmitter pool of glutamate is thought to be fueled by the entry of the other structural analog glutamine (Gln) and subsequent cleavage by glutaminase. Although theanine did not inhibit [3H]glutamate accumulation, [3H]theanine was actively accumulated in a temperature-dependent and saturable manner in rat brain synaptosomal fractions. The accumulation of [3H]theanine was markedly inhibited by Gln in a concentration-dependent manner, whereas [3H]Gln accumulation was inhibited by theanine vice versa. Both [3H]theanine and [3H]Gln accumulations were decreased after the replacement of sodium chloride with choline chloride, along with similarly high distribution profiles in telencephalic structures. A similar equilibrium was observed within 30 min at 30 degrees C for the accumulations of both [3H]theanine and [3H]Gln in cultured rat neocortical astroglia as well as neurons, whereas theanine inhibited [3H]Gln accumulation in a concentration-dependent manner at 0.1-10 mM. Furthermore, sustained exposure to 10 mM theanine led to a significant decrease in the level of extracellular glutamate released from cultured neurons. These results suggest that the green tea ingredient theanine would be an inhibitor of different transporters capable of transporting Gln across plasma membranes toward the modulation of the glutamate/Gln cycle required for the neurotransmitter pool of glutamate in neurons.

Aleukemic leukemia cutis has been rarely reported in infant leukemia. This report describes a 6-month-old boy with aleukemic leukemia cutis, which regressed without any treatments within 6 months. Interestingly, a cytogenetic analysis disclosed a leukemia clone with the karyotype of 46, XY, t(5;17)(q35;q12), which generated nucleophosmin (NPM)-retinoic acid receptor alpha fusion (RARA) fusion transcripts. The patient simultaneously had cutaneous mastocytosis, which also disappeared with the leukemia cutis. He shows no physical or laboratory abnormalities without any treatments after 12 months, although the NPM/RARA transcripts remain faintly in the bone marrow. The present case is partially compatible with systemic mastocytosis with an associated clonal hematologic non-mast cell lineage disorder, proposed by the WHO classification, and it is also suggestive of the initiation or early stage of acute promyelocytic leukemia.

The 13 C− 1 H NMR vicinal coupling constant 3 J C H 3 OC H 2 was measured for dimethoxymethane CH 3 OCH 2 OCH 3 in the gas phase as well as in various solvents. The observed values tend to decrease slightly with temperature. The energy difference E σ between the gg and tg forms was estimated to be −2.5 ± 0.2 kcal mol −1 in the gas phase. The coupling constant parameters determined concomitantly are as follows: ( J T + J G− )/2 = 6.7 ± 0.1 and J G = 2.0 Hz. Values of E σ observed in nonpolar solvents were found to fall in the same range. A somewhat smaller value (ca. −2.2 kcal mol −1 ) was derived from the measurements in (CD 3 ) 2 SO. These values are reasonably consistent with the results of recent MO calculations by Wiberg and Murcko. A similar 13 C NMR analysis of 1,1-dimethoxyethane CH 3 OCH(CH 3 )OCH 3 indicates that the g− g and tg conformers exists in nearly equal amounts, i.e. E τ = E g− g − E tg ≅ 0 kcal mol −1 . In the latter compound, the anomeric conformation ( g − ) involves unfavorable steric interactions around the g− bond.

La susceptibilite magnetique des composes cristaux liquides NC-Ph-Ph-O(CH 2 ) n -O-Ph-Ph-EN (n=9, 10) est mesuree en fonction de la temperature. Les parametres d'ordre orientationnel de la mesophase nematique deduits sont en accord avec les valeurs obtenues par RMN 2 H