bluuebunny/crossref_metadata_2025 huggingface dataset:
Temperature Dependence of Domain Structure in Strontium Alumino-Ferrites Single Crystals
Authors: Florescu V. , Rosenberg M.
Published: November 2005

The temperature dependence of the domain structure of the single crystals of SrO(6-x)Fe2O3·xAl2O3 with x=1.8; 1.9; 2 and 2.2 was investigated and the dependence of the domain wall energy, σ
w
(T), for the case x=1.8 was computed. A high degree of irreversibility of the domain structure of the crystals with x=2 and 2.2 after heating in the temperature range of the Curie point was observed and related to structural inhomogenities. A sharp maximum in the temperature dependence of coercive field for single crystals with x=2 was observed in the vicinity of the Curie point.
Anomalous Diffusion of Phosphorus into Silicon
Authors: Yagi Kunihiro , Miyamoto Nobuo , Nishizawa Jun-ichi
Published: November 2005

Lattice strains induced by diffusion of phosphorus, arsenic, antimony and tin into silicon are studied through an X-ray double crystal spectrometer. This quantitative experiment gives that the amount of lattice strain induced by diffusion of impurity depends both on the size of impurity atoms diffused into silicon and on the impurity concentration, which agrees with the equation by S. Prussin et al. It also leads to the result as follows; the lattice strain in the diffused layer is compensated in the case of the phosphorus content less than 4×1020 atoms/cm3 by diffusing both tin, whose atomic radius is larger than that of silicon, and phosphorus with smaller radius.
Anomaly in the diffraction pattern is also observed in the case of anomalous diffusion of phosphorus under high vapor pressure of phosphorus.
Domain Etch Patterns on the Faces Parallel to the Ferroelectric Axis of NaNO2
Authors: Morimoto Setsu , Hamano Katsumi
Published: November 2005

Ferroelectric domain boundaries are delineated by etching on the (100), (001) and especially (101) cleaved faces of sodium nitrite crystals, using water or water containing alcohol as an etchant. These faces are parallel to the ferroelectric b-axis, and it has been believed that domain patterns should not be observed on such faces by etching. The observation is possible because the domain boundaries are etched more rapidly than the remaining part of the crystal. This etching process has been ascertained by examining the etched faces under an interference microscope. Some new aspects of domain structures have been disclosed. The effect of a dc field has been studied also.
Mode-Locking of Lasers by Feedback of “Self-Beat” between Cavity-Modes
Authors: Kobayashi Tetsuro , Cho Yoshio , Matsuo Yukito
Published: November 2005

A beat signal between longitudinal modes of the laser cavity is detected, amplified and fed back to an electro-optic element inserted in the laser cavity. In this case, if the gain of the beat amplifier is large, this element should have a large equivalent third order nonlinearity. Since this nonlinearity make the modes couple, many types of mode-looking phenomena are expected. In this paper, a theoretical analysis is presented and compared with experiments using a He-Ne 6328 Å laser.
The Numerical Analyses of the Solid-Liquid Interface Shapes during the Crystal Growth by the Czochralski Method
Authors: Kobayashi Nobuyuki , Arizumi Tetsuya
Published: November 2005

The problem of thermal conduction during the crystal growth process is solved computationally using a model simplified to involve the essential features of the Czochralski crystal growth system. In the crystal the Laplace equation is solved, while in the melt the modified Laplace equation taking account of the fluid motion and the Navier-Stokes equations with the bouyant force being considered are solved simultaneously. The solid-liquid interface shapes are calculated as a function of the crystal rotation rate. Without the crystal rotation, the solid-liquid interface shape is concave to the melt and it becomes more concave as the crystal rotation rate increases. This dependence of the solid-liquid interface shape on the crystal rotation rate is explained by taking the fluid motion into account.
Stacking Disorder in Martensites of Cobalt and Its Alloys
Authors: Kajiwara Setsuo
Published: November 2005

Stacking disorder in the h.c.p. martensites of the pure Co, Co-10.2at%Be and Co-19.5at.%Ni alloys has been studied by electron diffraction, utilizing the selected-area diffraction technique of an electron microscope. The shifts of diffraction spots along [00.1] direction due to stacking faults are observed with these martensites. The shifts are analyzed by Kakinoki theory with Reichweite
s=2, and the corresponding stacking fault probabilities are found to be α=0.03∼0.3. It is considered that these stacking faults are introduced due to the constraints imposed by the surrounding matrix crystal.
Crystalline Morphology and Electrical Properties of Selenium Epitaxilly Grown on Tellurium
Authors: Fukuda Hideki , Sakai Yoshio
Published: November 2005

Trigonal selenium single crystal was grown epitaxially on (0001) and (101̄0) tellurium substrates by evaporation. The dependence of the crystalline morphology on the substrate temperature and the growth rate has been studied. In the case of (0001) substrate, four kinds of selenium film were obtained: of amorphous, polycrystal of large grain, polycrystal of small grain, and single crystal. The electrical properties of single crystal formed by this method depend on the growth condition. In the best sample obtained in this experiment, the conductivity is 1.5×10-5 Ω-1 cm-1, acceptor density 5×1014 cm-3, and mobility 0.2 cm2 V-1 sec-1. These values are almost equal to those of single crystals grown from vapor or liquid phase. This paper also describes the result of study of the effects of doped bromine and thallium on the crystal growth and electrical properties.
Acceleration of Multicharged Heavy Ions in IPCR (Riken) Ordinary 160 cm Cyclotron
Authors: Miyazawa Yoshitoshi , Tonuma Tadao , Kohno Isao , Nakajima Shunji , Inoue Toshihiko , Shimamura Akira , Yoshida Kisaku , Karasawa Takashi
Published: November 2005

In the IPCR (Riken) 160 cm ordinary cyclotron the operation ranges of electromagnet and radio frequency system are 0.5 to 2.0 wb/m2 and 5.0 to 12.0 MH
Z
respectively, and various particles of different mass to charge ratios from proton to Ne5+ ion can be accelerated with variable energy.
Multicharged heavy ion sources of electron bombarded hot cathode type for this cyclotron have been developed to produce C4+, N4+, O4+, N5+ and O5+ ions. At present these ions are produced in sufficient quantities under arc power of 2.0 to 2.5 kW. The source life is mainly limited by the erosion of tungsten cathode at about 20 hours.
The attenuation of beam current by charge exchange collision with residual molecules and the spectra of various ions accelerated in the cyclotron are discussed.
C4+, N4+ and O4+ ions are accelerated up to 39 to 120 MeV, 45 to 100 MeV and 52 to 100 MeV respectively and used for several experiments.
Polypropylene-Window Proportional Counter for the Cosmic Soft X-Ray Measurement
Authors: Hayakawa Satio , Kato Takako , Makino Fumiyoshi , Ogawa Hideo , Tanaka Yasuo , Yamashita Koujun
Published: November 2005

Polypropylene-window proportional counters have been developed and successfully flown on board a sounding rocket for the soft X-ray measurement. Biaxially-oriented thin polypropylene film is found to have remarkable strength and particular advantage in the transmission of soft X-rays, for this material is composed of only carbon and hydrogen. The four-micron thick film which we used transmits 43% of the fluorescent K X-rays of carbon (0.28 KeV) and 79% of K X-rays of aluminium (1.49 KeV).
Phase Forming Processes in Tantalum Films through Sputtering
Authors: Nakamura Masashi , Fujimori Masatoshi , Nishimura Yasuro
Published: November 2005

For the formation of tantalum films by sputtering at a lower gas pressure, α-tantalum is deposited in a contaminative atmosphere, while β-tantalum is deposited in a clean atmosphere. The latter phenomenon can be thought of as the quenching of sputtered tantalum atoms by direct collision with the substrate when no layers of adsorbed impurity gas exist. At a higher pressure, the phase transition to β-Ta can be caused by the incorporation of discharge gas and thermal effect.
For tantalum nitride, there is a certain region where the characteristics of the films are insensitive to the nitrogen partial pressure. The extent of nitrization is considered to be determined by the density ratio between the number of nitrogen molecules on the substrate and that of the incoming tantalum atoms. Within this region, the ratio is constant, so a stable film with a low energy state and stoichiometric structure whose main content is Ta2N is formed.
Structural and Dielectric Studies of Ferroelectric K3Li2(TaxNb1-x)5O15
Authors: Fukuda Tsuguo
Published: November 2005

X-ray, dielectric and optical studies on single crystals of the ferroelectric K3Li2(Ta
x
Nb1-x
)5O15 (0≤x≤1, designated KLTN) were carried out and the effect of the substitution of Ta ions for Nb in K3Li2Nb5O15 on the crystal structure and ferroelectric properties was investigated.
As x is increased from 0 to 1 in KLTN, the lattice constant c decreases from 4.039 to 3.931 Å and the Curie temperature from 480°C to -266°C while the ferroelectric polar axis remains parallel to [001]. A discontinuous point is observed in those variations at approximately 0.55. At room temperature KLTN crystal is tetragonal for x\lesssim0.55 but orthorhombic for x\gtrsim0.55, and has a “completely filled” tungsten bronze type structure for x=1, that is, for K3Li2Ta5O15. High temperature X-ray and optical studies showed that the orthorhombic KLTN transforms into tetragonal phase at about 250°C, and also revealed an interesting thermal behavior in structure of the crystal.
The relation between structure and ferroelectric properties of the KLTN is discussed.
Piezoelectric Properties of Se Film Deposited on Te Crystal
Authors: Shiosaki Tadashi , Kawabata Akira , Tanaka Tetsuro
Published: November 2005

Se films deposited on Te crystals were studied as an ultrasonic transducer of a delay line and as a driver of a composite resonator. The values of electromechanical coupling factors k
11 and k
26 of Se were deduced as 0.15 and 0.27 respectively from the experimental and theoretical characteristics of the insertion loss of the delay line, and the value of the piezoelectric constant e
11 was obtained as 0.17C/m2 from these coupling factors.
Liquid Materials and Their Figures of Merit as Acoustooptical Deflector
Authors: Fukumoto Akira , Watanabe Akinori
Published: November 2005

Three figures of merit defined by Dixon for acoustooptical deflectors are reconsidered using combinations which include scattering efficiency, sound frequency bandwidth, number of resolvable spots and sound attenuation constant. A fourth figure of merit is proposed which is applicable to materials with non-negligible acoustic losses. Liquid materials were evaluated according to the proposed criteria and some were selected as good for use as acoustooptical deflectors. Experiments showed that the scattering efficiency and the fourth figure of merit of n-propyl iodide were 7.7 and 2.5 times those of water.
Barium-Strontium Ferrite with Admixtures of Elements of the III-rd Group
Authors: Wolski Włodzimierz , Kowalewska Jadwiga
Published: November 2005

Influence of the admixtures of group III elements of the periodic table upon magnetic properties of the barium–strontium ferrite has been investigated. The ferrites of BaO0.75SrO0.25·6Fe2O3 containing following admixtures of the group III oxides: B2O3 from 0.032 to 1.26 mole, Al2O3 from 0.054 to 2.59 mole, Ga2O3 from 0.012 to 0.76 mole were synthetised. Chemical analysis, X-ray identifications and matallographic obsevations were performed. Saturation Magnetization, remanence, coercive force and Curie temperature were measured.
CuxS-CdS Junction Cell for the C-Plane of the CdS Single Crystal
Authors: Miya Noriaki
Published: November 2005

The p-layers (Cu
x
S) are made by the chemical deposit method on the Cd-plane and S-plane, [E. P. Ware Kois et al: J. appl. Phys. 33 (1962) 690] respectively, for the C-planes of CdS single crystals. The concentration ratio of Cu, S and Cd atoms near the boundary are determined by an electron probe X-ray micro analyzer. The energy band model of the junction cell is proposed on the basis of measurements of voltage-current, voltage-capacitance characteristics and photovoltaic effect. From the results obtained, the junction between the p-layer on the Cd-plane and the CdS crystal forms a graded junction; on the other hand, the junction on the S-plane forms an abrupt junction. The formation of the p-layer does not depend on Cu thermal diffusion, [R. L. Clarke: J. appl. Phys. 30 (1959) 957] but on dissolution of Cd ions and deposition of Cu ions.
Effect of Lubricant Inertia on Squeeze Film in Spherical Bearing
Authors: Agrawal V. K.
Published: November 2005

A theoretical investigation of inertia effects on squeeze film in a spherical bearing is presented. It is shown that inertia forces make a significant contribution to the time of approach.
Magnetohydrodynamical Supersonic Flow of a Slightly Conducting Fluid Past a Slender Body of Revolution Placed in a Circular Wind Tunnel
Authors: Suwa Shigeaki
Published: November 2005

The wind tunnel interference problem in magnetohydrodynamics, in which an inviscid compressible fluid with small electrical conductivity flows steadily past a slender axisymmetric pointed body of revolution in a cylindrical perfectly insulated wind tunnel, in the presence of an applied slightly inclined magnetic field, is considered. The interference is found to induce electric field even if Rm≈0. The lift of the body changes its sign according to the direction of the angle between the applied magnetic field and the direction of the uniform flow at infinity.
ESR Studies on Pyrolyzed and Irradiated Polyacrylonitrile
Authors: Hasegawa Seiichi , Shimizu Tatsuo
Published: November 2005

ESR studies are carried out at temperatures from 77 to -196°C for polyacrylonitrile (PAN) pyrolyzed in the temperature up to 700°C and for the one irradiated with ultraviolet light and γ-ray. The ESR spectra for PAN pyrolyzed below 600°C are considered to be due to a free radical because they are independent of the measurement temperature. The g-values are found to decrease with increasing pyrolysis temperature and a possible explanation is proposed. The ESR spectra for PAN pyrolyzed above 650°C are sensitively affected by being exposed to air and change with the measurement temperature in a complicated way; the broad and narrow lines are observed and it may be speculated that the former and latter are, respectively, due to a conduction electron and a free radical. For PAN irradiated with ultraviolet light and the one with γ-ray, hyperfine structure (hfs) is observed in the ESR spectra in contrast with those for pyrolyzed PAN. The hfs lines are well explained by two types of free radical likely to be produced.
Meal feeding enhances formation of eIF4F in skeletal muscle: role of increased eIF4E availability and eIF4G phosphorylation
Authors: Vary Thomas C. , Lynch Christopher J.
Published: November 2005

Feeding promotes protein accretion in skeletal muscle through a stimulation of the mRNA translation initiation phase of protein synthesis either secondarily to nutrient-induced rises in insulin or owing to direct effects of nutrients themselves. The present set of experiments establishes the effects of meal feeding on potential signal transduction pathways that may be important in accelerating mRNA translation initiation. Gastrocnemius muscle from male Sprague-Dawley rats trained to consume a meal consisting of rat chow was sampled before, during, and after the meal. Meal feeding enhanced the assembly of the active eIF4G·eIF4E complex, which returned to basal levels within 3 h of removal of food. The increased assembly of the active eIF4G·eIF4E complex was associated with a marked 10-fold rise in phosphorylation of eIF4G(Ser1108) and a decreased assembly of inactive 4E-BP1·eIF4E complex. The reduced assembly of 4E-BP1·eIF4E complex was associated with a 75-fold increase in phosphorylation of 4E-BP1 in the γ-form during feeding. Phosphorylation of S6K1 on Ser789was increased by meal feeding, although the extent of phosphorylation was greater at 0.5 h after feeding than after 1 h. Phosphorylation of mammalian target of rapamycin (mTOR) on Ser2448or Ser2481, an upstream kinase responsible for phosphorylating both S6K1 and 4E-BP1, was increased at all times during meal feeding, although the extent of phosphorylation was greater at 0.5 h after feeding than after 1 h. Phosphorylation of PKB, an upstream kinase responsible for phosphorylating mTOR, was elevated only after 0.5 h of meal feeding for Thr308, whereas phosphorylation Ser473was significantly elevated at only 0.5 and 1 h after initiation of feeding. We conclude from these studies that meal feeding stimulates two signal pathways in skeletal muscle that lead to elevated eIF4G·eIF4E complex assembly through increased phosphorylation of eIF4G and decreased association of 4E-BP1 with eIF4E.
Synergistic effects of PDGF-BB and cAMP-elevating agents on expression of connexin43 in mesangial cells
Authors: Yao Jian , Kitamura Masanori , Zhu Ying , Meng Yiman , Kasai Ayumi , Hiramatsu Nobuhiko , Morioka Tetsuo , Takeda Masayuki , Oite Takashi
Published: November 2005

The gap junction plays an important role in the regulation of cell growth, migration, and differentiation. Platelet-derived growth factor (PDGF) is reported to be a potent inhibitor of gap junctional intercellular communication (GJIC). Short-term exposure of cells to PDGF causes rapid and transient disruption of GJIC without altering connexin43 (Cx43) protein level. In this study, we investigated long-term effects of PDGF-BB on Cx43 expression in mesangial cells (MCs). Exposure of MCs to PDGF-BB affected neither the Cx43 protein level nor GJIC. However, in the presence of cAMP-elevating agents, PDGF-BB dramatically increased the expression of Cx43, which was accompanied by obviously augmented membrane distribution of Cx43 and functional GJIC. The increased expression of Cx43 was closely correlated with reduction in α-actin, a dedifferentiation marker of MCs. The effect of PDGF on Cx43 was largely prevented by inhibitors of phosphatidylinositol 3′-kinase or mitogen-activated protein kinase, but not by inhibition of protein kinase C. Exposure of MCs to PDGF-BB caused elevation in intracellular cAMP, and it was abolished by indomethacin, a cyclooxygenase inhibitor. However, indomethacin did not affect the synergistic effect. In addition, PDGF-BB also did not affect the degradation of Cx43. With the use of MCs transfected with a Cx43 promoter-luciferase vector, cooperative activation of Cx43 promoter by PDGF and cAMP was found. Together, our data reveal, for the first time, unexpected synergy between PDGF-BB and cAMP-elevating agents in the induction of Cx43 and MC differentiation. Regulation of GJIC could be an important mechanism via which PDGF modulates MC phenotypes.
Immunolocalization of anion transporter Slc26a7 in mouse kidney
Authors: Dudas Paul L. , Mentone SueAnn , Greineder Colin F. , Biemesderfer Daniel , Aronson Peter S.
Published: November 2005

Previous studies have indicated that a major fraction of the filtered Cl−is reabsorbed via apical membrane Cl−/base exchange in the proximal tubule. Recent studies in Slc26a6 null mice have suggested that this transporter mediates only a portion of proximal tubule Cl−/base exchange, raising the possibility that one or more unidentified apical membrane transporters may additionally contribute. Recent studies have identified Slc26a7 as another Cl−/base exchanger expressed in the kidney. We therefore generated Slc26a7-specific polyclonal and monoclonal antibodies to examine cellular and subcellular sites of expression in mouse kidney. The specificity of each antibody was verified by immunoblotting and immunofluorescence of COS-7 cells transiently transfected with mouse Slc26a7. Immunofluorescence microscopy of mouse kidney detected the expression of Slc26a7 subapically in proximal tubule cells, and on the basolateral surface of thick ascending limb cells. Similar staining patterns were demonstrated with two antibodies shown to react with different epitopes on Slc26a7. Immunolocalization of Slc26a7 to proximal tubule and thick ascending limb was also observed in rat kidney. We conclude that Slc26a7 is expressed in the proximal tubule and thick ascending limb of the loop of Henle, and it may therefore contribute to anion transport in these nephron segments.
Effects of ACE inhibition on proximal tubule sodium transport
Authors: Leong Patrick K. K. , Devillez Angela , Sandberg Monica B. , Yang Li E. , Yip Daniel K. P. , Klein Jon B. , McDonough Alicia A.
Published: November 2005

Angiotensin-converting enzyme (ACE) inhibitors such as captopril, which block ANG II formation, are commonly used for treatment of hypertension. There is substantial evidence that the proximal tubule (PT) is a primary target site for captopril but the molecular mechanisms for its action in PT are not well defined. The aim of this study was to determine the physiological and molecular changes in PT provoked by acute captopril treatment in the absence of changes in blood pressure or glomerular filtration rate (GFR). Captopril (infused at 12 μg/min for 20 min) did not change blood pressure or GFR but induced an immediate (<10 min) increase in PT flow measured with a nonobstructive optical method (to 117 ± 14% of baseline) along with a rapid diuresis from 2.1 ± 0.6 mg/min (baseline) to 3.7 ± 0.9 mg/min (captopril). Captopril also provoked a significant retraction of PT Na+/H+exchanger isoform 3 (NHE3), NHE regulatory factor (NHERF)-1, myosin-VI, and Na+-Picotransporter type 2 (NaPi2), but not ACE, out of apical microvillus-enriched membranes. Proteomic analysis with MALDI-TOF MS revealed an additional eight abundant membrane-associated proteins that redistributed out of the microvillus-enriched membrane during captopril treatment: megalin, myosin II-A, clathrin, aminopeptidase N, DPPIV, ezrin, moesin, and vacuolar H+-ATPase subunit β2. In summary, captopril can rapidly depress PT reabsorption in the absence of a change in GFR or BP and provokes the redistribution of a set of transporters and transporter-associated proteins that likely participate in the decrease in PT reabsorption and may also contribute to the blood pressure-lowering effect of ACE inhibitors.
Assessment of Low Linear Energy Transfer Radiation–Induced Bystander Mutagenesis in a Three-Dimensional Culture Model
Authors: Persaud Rudranath , Zhou Hongning , Baker Sarah E. , Hei Tom K. , Hall Eric J.
Published: November 2005

A three-dimensional cell culture model composed of human-hamster hybrid (AL) and Chinese hamster ovary (CHO) cells in multicellular clusters was used to investigate low linear energy transfer (LET) radiation–induced bystander genotoxicity. CHO cells were mixed with AL cells in a 1:5 ratio and briefly centrifuged to produce a spheroid of 4 × 106 cells. CHO cells were labeled with tritiated thymidine ([3H]dTTP) for 12 hours and subsequently incubated with AL cells for 24 hours at 11°C. The short-range β-particles emitted by [3H]dTTP result in self-irradiation of labeled CHO cells; thus, biological effects on neighboring AL cells can be attributed to the bystander response. Nonlabeled bystander AL cells were isolated from among labeled CHO cells by using a magnetic separation technique. Treatment of CHO cells with 100 μCi [3H]dTTP resulted in a 14-fold increase in bystander mutation incidence among neighboring AL cells compared with controls. Multiplex PCR analysis revealed the types of mutants to be significantly different from those of spontaneous origin. The free radical scavenger DMSO or the gap junction inhibitor Lindane within the clusters significantly reduced the mutation incidence. The use of AL cells that are dominant negative for connexin 43 and lack gap junction formation produced a complete attenuation of the bystander mutagenic response. These data provide evidence that low LET radiation can induce bystander mutagenesis in a three-dimensional model and that reactive oxygen species and intercellular communication may have a modulating role. The results of this study will address the relevant issues of actual target size and radiation quality and are likely to have a significant effect on our current understanding of radiation risk assessment.
Induction of Early Post-Transplant Graft-versus-Leukemia Effects Using Intentionally Mismatched Donor Lymphocytes and Elimination of Alloantigen-Primed Donor Lymphocytes for Prevention of Graft-versus-Host Disease
Authors: Yung Iris , Weiss Lola , Abdul-Hai Ali , Kasir Judith , Reich Shoshana , Slavin Shimon
Published: November 2005

Graft-versus-leukemia (GVL) effects can be induced in tolerant mixed chimeras prepared with nonmyeloablative conditioning. GVL effects can be amplified by post-grafting donor lymphocyte infusion (DLI). Unfortunately, DLI is frequently associated with graft-versus-host disease (GVHD). We investigated the feasibility of induction of potent GVL effects by DLI using intentionally mismatched lymphocytes followed by elimination of alloreactive donor T cells by cyclophosphamide for prevention of lethal GVHD following induction of very short yet most potent GVL effects. Mice inoculated with B-cell leukemia (BCL1) and mismatched donor lymphocytes were treated 2 weeks later with low-dose or high-dose cyclophosphamide. All mice receiving cyclophosphamide 2 weeks after DLI survived GVHD, and no residual disease was detected by PCR; all control mice receiving DLI alone died of GVHD. Analysis of host (female) and donor (male) DNA showed that cyclophosphamide treatment eradicated most alloreactive donor cells, yet mixed chimerism was converted to full donor chimerism following transient self-limited GVHD. Our working hypothesis suggests that short-term yet effective and safe adoptive immunotherapy of leukemia may be accomplished early post-transplantation using alloreactive donor lymphocytes, with prevention of GVHD by elimination of GVL effector cells.
Mammalian Target of Rapamycin, a Molecular Target in Squamous Cell Carcinomas of the Head and Neck
Authors: Amornphimoltham Panomwat , Patel Vyomesh , Sodhi Akrit , Nikitakis Nikolaos G. , Sauk John J. , Sausville Edward A. , Molinolo Alfredo A. , Gutkind J. Silvio
Published: November 2005

Emerging knowledge on how the dysregulated function of signaling networks contributes to the malignant growth of squamous cell carcinoma of the head and neck (HNSCC) can now be exploited to identify novel mechanism-based anticancer treatments. In this regard, we have observed that persistent activation of the serine/threonine kinase Akt is a frequent event in HNSCC, and that blockade of its upstream kinase, 3′-phosphoinositide-dependent kinase 1, potently inhibits tumor cell growth. Akt promotes cell proliferation by its ability to coordinate mitogenic signaling with energy- and nutrient-sensing pathways that control protein synthesis through the atypical serine/threonine kinase, mammalian target of rapamycin (mTOR). This kinase, in turn, phosphorylates key eukaryotic translation regulators, including p70-S6 kinase and the eukaryotic translation initiation factor, 4E binding protein 1. Indeed, we show here that aberrant accumulation of the phosphorylated active form of S6, the most downstream target of the Akt-mTOR-p70-S6 kinase pathway, is a frequent event in clinical specimens from patients with HNSCC and their derived cell lines. Of interest, this enhanced level of the phosphorylated active form of S6 was rapidly reduced in HNSCC cell lines and HNSCC xenograft models at clinically relevant doses of rapamycin, which specifically inhibits mTOR. Furthermore, we observed that rapamycin displays a potent antitumor effect in vivo, as it inhibits DNA synthesis and induces the apoptotic death of HNSCC cells, ultimately resulting in tumor regression. These findings identify the Akt-mTOR pathway as a potential therapeutic target for HNSCC, and may provide the rationale for the early clinical evaluation of rapamycin and its analogues in patients with HNSCC.
High Frequencies of Functional Tumor-Reactive T Cells in Bone Marrow and Blood of Pancreatic Cancer Patients
Authors: Schmitz-Winnenthal Friedrich H. , Volk Christine , Z'graggen Kaspar , Galindo Luis , Nummer Daniel , Ziouta Yvonne , Bucur Marianna , Weitz Jürgen , Schirrmacher Volker , Büchler Markus W. , Beckhove Philipp
Published: November 2005

Pancreatic cancer is characterized by aggressive growth and treatment resistance. New approaches include immunotherapeutic strategies but the type and extent of spontaneous immune responses against tumor antigens remains unclear. A dominance of TH2 cytokines in patients' sera reported previously suggests systemic tumor-induced immunosuppression, potentially inhibiting the induction of tumor-reactive T cells. We characterized the localization, frequencies, and functional potential of spontaneously induced memory T cells specific for individual tumor antigens or the tumor-associated antigen mucin-1 in the peripheral blood and bone marrow of 41 pancreatic cancer patients. We found high numbers of tumor-reactive T cells in all bone marrow samples and in 50% of the blood samples. These cells secreted the TH1 cytokine IFN-γ rather than TH2 cytokines upon stimulation with tumor antigens. Although consistently induced during pancreatic cancer, T cells specific for pancreatic antigens were not detected during chronic pancreatitis, suggesting that their evaluation may be of diagnostic use in both diseases. Freshly isolated T cells from cancer patients recognized autologous tumor cells and rejected them in vitro and in a xenotransplant model in vivo, suggesting their therapeutic potential. Thus, tumor antigen–specific T cell responses occur regularly during pancreatic cancer disease and lead to enrichment of tumor cell–reactive memory T cells in the bone marrow. The bone marrow can therefore be considered an important organ for antitumor immune responses in pancreatic cancer.
Loss of Heterozygosity and Somatic Mutations of the Glucocorticoid Receptor Gene Are Rarely Found at Relapse in Pediatric Acute Lymphoblastic Leukemia but May Occur in a Subpopulation Early in the Disease Course
Authors: Irving Julie A.E. , Minto Lynne , Bailey Simon , Hall Andy G.
Published: November 2005

Glucocorticoids are pivotal in the treatment of children with acute lymphoblastic leukemia (ALL) and have significant antileukemic effects in the majority of children. However, clinical resistance is a significant problem. Although cell line models implicate somatic mutations and loss of heterozygosity (LOH) of the glucocorticoid receptor (GR) gene as a mechanism of in vitro glucocorticoid resistance, the relevance of this mechanism as a cause of clinical resistance in children with ALL is not known. Mutational screening of all coding exons of the GR gene and LOH analyses were done in a large cohort of relapsed ALL. We show that somatic mutations and LOH of the GR rarely contribute to relapsed disease in children with ALL. However, we report the second case of ALL with a somatic mutation of the GR involving a 29-bp deletion in exon 8 and resulting in a truncated protein with loss of part of the ligand-binding domain. There was no evidence of a remaining wild-type allele. Allele-specific PCR detected the mutated clone at day 28 after presentation, which persisted at a low level throughout the disease course before relapse several years later. We hypothesize that the mutated allele present in a leukemic subclone at initial diagnosis was selected for during remission induction with glucocorticoids and contributed to the emergence of a glucocorticoid-resistant cell population.
Application of Embryonic Lethal or Other Obvious Phenotypes to Characterize the Clinical Significance of Genetic Variants Found in Trans with Known Deleterious Mutations
Authors: Judkins Thaddeus , Hendrickson Brant C. , Deffenbaugh Amie M. , Eliason Kristilyn , Leclair Benoît , Norton Michael J. , Ward Brian E. , Pruss Dmitri , Scholl Thomas
Published: November 2005

This work describes an approach to characterize the clinical significance of genetic variants detected during the genetic testing of BRCA1 in patients from hereditary breast/ovarian cancer families. Results from transgenic mice and extensive clinical testing support the hypothesis that biallelic BRCA1 mutations result in embryonic lethality. Therefore, it is reasonable to conclude that variants of uncertain clinical significance found to reside in trans with known deleterious mutations impart reduced risk for cancer. This approach was applied to a large data set of 55,630 patients who underwent clinical BRCA1 screening by whole gene direct DNA sequencing. Fourteen common single nucleotide polymorphisms (SNPs) were used to assign 10 previously defined common, recurrent, or canonical haplotypes in 99% of these cases. From a total of 1,477 genetic variants detected in these patients, excluding haplotype-tagging SNPs, 877 (59%) could be unambiguously assigned to one or more haplotypes. In 41 instances, variants previously classified as being of uncertain clinical significance, mostly missense variants, were excluded as fully penetrant mutations due to their coincidence in trans with known deleterious mutations. From a total of 1,150 patients that harbored these 41 variants, 956 carried one as the sole variant of uncertain clinical significance reported. This approach could have widespread application to other disease genes where compound heterozygous mutations are incompatible with life or result in obvious phenotypes. This largely computational technique is advantageous because it relies upon existing clinical data and is likely to prove informative for prevalent genetic variants in large data sets.
Retinol Inhibits the Growth of All-Trans-Retinoic Acid–Sensitive and All-Trans-Retinoic Acid–Resistant Colon Cancer Cells through a Retinoic Acid Receptor–Independent Mechanism
Authors: Park Eun Young , Dillard Alice , Williams Elizabeth A. , Wilder Erik T. , Pepper M. Reese , Lane Michelle A.
Published: November 2005

Retinol (vitamin A) is thought to exert its effects through the actions of its metabolite, all-trans-retinoic acid (ATRA), on gene transcription mediated by retinoic acid receptors (RAR) and retinoic acid response elements (RARE). However, retinoic acid resistance limits the chemotherapeutic potential of ATRA. We examined the ability of retinol to inhibit the growth of ATRA-sensitive (HCT-15) and ATRA-resistant (HCT-116, SW620, and WiDR) human colon cancer cell lines. Retinol inhibited cell growth in a dose-responsive manner. Retinol was not metabolized to ATRA or any bioactive retinoid in two of the cell lines examined. HCT-116 and WiDR cells converted a small amount of retinol to ATRA; however, this amount of ATRA was unable to inhibit cell growth. To show that retinol was not inducing RARE-mediated transcription, each cell line was transfected with pRARE-chloramphenicol acetyltransferase (CAT) and treated with ATRA and retinol. Although treatment with ATRA increased CAT activity 5-fold in ATRA-sensitive cells, retinol treatment did not increase CAT activity in any cell line examined. To show that growth inhibition due to retinol was ATRA, RAR, and RARE independent, a pan-RAR antagonist was used to block RAR signaling. Retinol-induced growth inhibition was not alleviated by the RAR antagonist in any cell line, but the antagonist alleviated ATRA-induced growth inhibition of HCT-15 cells. Retinol did not induce apoptosis, differentiation or necrosis, but affected cell cycle progression. Our data show that retinol acts through a novel, RAR-independent mechanism to inhibit colon cancer cell growth.
Epigenetic Regulation of WTH3 in Primary and Cultured Drug-Resistant Breast Cancer Cells
Authors: Tian Kegui , Jurukovski Vladimir , Wang Xue-Ping , Kaplan Mark H. , Xu Haopeng
Published: November 2005

Previous studies showed that the WTH3 gene functioned as a negative regulator during multidrug resistance (MDR) development in vitro. To understand whether this gene is also involved in clinical drug resistance, hypermethylation at its promoter region observed in cultured MDR MCF7/AdrR cells was examined in primary drug-resistant breast cancer epithelial cells isolated from effusions of breast cancer patients. The results showed that this event also occurred in drug-resistant breast cancer epithelial cells and a newly induced drug-resistant cell line, MCF7/inR. Interestingly, we found that a CpG (CpG 23) that was close to the TATA-like box was constantly methylated in the WTH3 promoter of drug-resistant breast cancer epithelial and cultured MDR cells. Mutagenic study suggested that this CpG site had a functional effect on promoter activity. We also discovered that MCF7/AdrR cells treated with trichostatin A, a histone deacetylase inhibitor, exhibited higher WTH3, but lower MDR1, expression. A reverse correlation between WTH3 and MDR1 gene expression was also observed in MCF7/AdrR, and its non-MDR parental cell line, MCF7/WT. This result indicated that both DNA methylation and histone deacetylase could act in concert to inhibit WTH3 and consequently stimulate MDR1 expression. This hypothesis was supported by data obtained from introducing the WTH3 transgene into MDR cell lines, which reduced endogenous MDR1 expression. Therefore, our studies suggested that the behavior of WTH3 in primary drug-resistant breast cancer epithelial cells was similar to that in a model system where epigenetic regulation of the WTH3 gene was linked to the MDR phenotype.
‘Mixing’ the Registers: Glottal Source or Vocal Tract?
Authors: Miller Donald G. , Schutte Harm K.
Published: November 2005

Electroglottograph and microphone signals are examined of scale passages crossing the boundary between chest and middle registers in the female singing voice. From a protocol executed by professional classical singers, the examples are selected to illustrate differing approaches to the chest-middle transition, as well as to illuminate varying theories on the female middle register, specifically the question of ‘mixing’ the primary registers, chest and falsetto. The results suggest that the skillful tuning of the resonances of the vocal tract contributes more toward the pedagogical goal of smoothing the register transition than does a presumed mixing of the registers at the glottal source.
An Appropriate Indication for the Initiation of Beta-Blocker Therapy in Dilated Cardiomyopathy
Authors: Morooka Toshifumi , Inoue Teruo , Kotooka Norihiko , Fujimatsu Daisuke , Komatsu Aiko , Uchida Fumi , Yoshida Kazuyo , Hashimoto Shigemasa , Hikichi Yutaka , Kato Toru , Node Koichi
Published: November 2005

Backgrounds: Although long-term treatment with beta-blockers has been shown to improve morbidity and mortality in dilated cardiomyopathy (DCM), patient re- sponses are heterogeneous. Methods: To establish the appropriate indication for the initiation of beta-blocker therapy, we retrospectively analyzed 38 DCM patients treated with beta-blockers (metoprolol or carvedilol) and examined differences in baseline profiles between patients who could continue the therapy (responders) and those who could not (non-responders). Results: In 13 non-responders, the duration from onset of symptoms to beta-blocker initiation was longer (p < 0.05), systolic blood pressure was lower (p < 0.001), serum sodium concentration was lower (p < 0.05), left ventricular posterior wall thickness was thinner (p < 0.05), left ventricular end-diastolic pressure was higher (p < 0.05) and left ventricular wall stress was lower (p < 0.05) than in 25 responders. In 19 patients receiving carvedilol, 5 non-responders showed higher levels of human atrial natriuretic peptide (p < 0.05) and brain natriuretic peptide (p < 0.01) than 13 responders. Discriminant analysis with a linear discriminant function showed the following equation predicted response to beta-blocker therapy: h = 0.004 × systolic blood pressure – 0.002 × brain natriuretic peptide + 0.667 (R2 = 0.67, p < 0.001). The probability of predicting the response was 94.1% with h ≧0.5. Conclusion: We conclude that h≧0.5 is the appropriate indication for the initiation of beta-blocker therapy in DCM.
Lipid Peroxidation and Ca-ATPase Activity of Basal Plasma Membranes of Syncytiotrophoblast from Normotensive Pregnant Women
Authors: Borrego Emma , Proverbio Teresa , Marín Reinaldo , Proverbio Fulgencio
Published: November 2005

Background: The Ca-ATPase activity of the plasma membranes of several tissues of preeclamptic pregnant women is significantly reduced when compared with the values of normotensive pregnant women. This has been explained considering the raise in the level of lipid peroxidation of the plasma membranes with preeclampsia. In this work we studied the effect of lipid peroxidation of syncytiotrophoblast basal (fetal facing) plasma membranes from normotensive pregnant women, on their level of Ca-ATPase activity. Methods: The syncytiotrophoblast basal (fetal facing) plasma membranes from normotensive pregnant women were isolated and irradiated with ultraviolet (UV) light (254 nm). The membranes were then assayed for Ca-ATPase activity and lipid peroxidation by TBARS. Results: The UV irradiation raises the level of lipid peroxidation of the membranes, producing a concomitant inhibition of their Ca-ATPase activity. Presence of the antioxidant butylated hydroxytoluene during the UV irradiation of the membranes prevents increase in their level of lipid peroxidation and hence the inhibition of their Ca-ATPase activity. Conclusion: These results give a strong support to the hypothesis that the lowered Ca-ATPase activity already described for plasma membranes of several tissues of preeclamptic women is the consequence of the increased level of lipid peroxidation shown by these membranes.
Magnetic Resonance Assessment of the Substrate for Inducible Ventricular Tachycardia in Nonischemic Cardiomyopathy
Authors: Nazarian Saman , Bluemke David A. , Lardo Albert C. , Zviman Menekhem M. , Watkins Stanley P. , Dickfeld Timm L. , Meininger Glenn R. , Roguin Ariel , Calkins Hugh , Tomaselli Gordon F. , Weiss Robert G. , Berger Ronald D. , Lima João A.C. , Halperin Henry R.
Published: November 2005

Background—

Patients with left ventricular dysfunction have an elevated risk of sudden cardiac death. However, the substrate for ventricular arrhythmia in patients with nonischemic cardiomyopathy remains poorly understood. We hypothesized that the distribution of scar identified by MRI is predictive of inducible ventricular tachycardia.

Methods and Results—

Short-axis cine steady-state free-precession and postcontrast inversion-recovery gradient-echo MRI sequences were obtained before electrophysiological study in 26 patients with nonischemic cardiomyopathy. Left ventricular ejection fraction was measured from end-diastolic and end-systolic cine images. The transmural extent of scar as a percentage of wall thickness (percent scar transmurality) in each of 12 radial sectors per slice was calculated in all myocardial slices. The percentages of sectors with 1% to 25%, 26% to 50%, 51% to 75%, and 76% to 100% scar transmurality were determined for each patient. Predominance of scar distribution involving 26% to 75% of wall thickness was significantly predictive of inducible ventricular tachycardia and remained independently predictive in the multivariable model after adjustment for left ventricular ejection fraction (odds ratio, 9.125;
P
=0.020).

Conclusions—

MR assessment of scar distribution can identify the substrate for inducible ventricular tachycardia and may identify high-risk patients with nonischemic cardiomyopathy currently missed by ejection fraction criteria.
Relationship Between Procedure Indications and Outcomes of Percutaneous Coronary Interventions by American College of Cardiology/American Heart Association Task Force Guidelines
Authors: Anderson H. Vernon , Shaw Richard E. , Brindis Ralph G. , Klein Lloyd W. , McKay Charles R. , Kutcher Michael A. , Krone Ronald J. , Wolk Michael J. , Smith Sidney C. , Weintraub William S.
Published: November 2005

Background—

An American College of Cardiology/American Heart Association (ACC/AHA) Task Force periodically revises and publishes guidelines with evidence-based recommendations for appropriate use of percutaneous coronary intervention (PCI). Some studies have suggested that closer adherence to guidelines can reduce variations in care, can improve quality, and may ultimately result in better outcomes, but this finding is incompletely understood. Guidelines themselves must change to be responsive to continuously evolving clinical practice. Our goal here was to investigate whether any relationship existed between the most recent ACC/AHA recommended indications for PCI and short term in-hospital outcomes.

Methods and Results—

We analyzed the ACC National Cardiovascular Data Registry for the period of January 1, 2001, through March 31, 2004. We excluded PCI procedures performed for acute myocardial infarction (ST-segment elevation myocardial infarction); all others were grouped by their indications according to the standard ACC/AHA scheme: Class I, evidence and/or agreement that PCI is useful and effective; Class IIa, conflicting evidence and/or divergent opinions, weight is in favor; Class IIb, usefulness/efficacy is less well established; and Class III, evidence and/or agreement that PCI is not useful or effective and may be harmful. Clinical success was defined as angiographic success (<20% residual stenosis) at all lesions attempted without the adverse events of myocardial infarction, same-admission bypass surgery, or death. There were 412 617 PCI procedures included in the analysis. Frequency of indications was as follows: Class I, 64%; Class IIa, 21%; Class IIb, 7%; and Class III, 8%. Clinical success declined across the indications classes (92.8%, 91.7%, 89%, and 85.5%, respectively;
P
<0.001), whereas adverse events increased.

Conclusions—

In this large survey of contemporary PCI practice, most procedures were performed for Class I indications. A significant relationship between evidence-based indications recommended by the ACC/AHA Task Force and in-hospital outcomes was noted.
Venture Capital Decision-Making and the Cultures of Risk: An Application of Q Methodology to US and UK Innovation Clusters
Authors: Babcock-Lumish Terry L.
Published: November 2005

This paper presents a comparative perspective on risk perception and decision-making within United States (US) and United Kingdom (UK) entrepreneurial communities since the bursting of the technology, media, and telecommunications (TMT) bubble in 2000. Using an empirical approach drawn from political science literature, this paper relies upon interviews and Q (rather than R) methodology to analyze the experiences and insights of individuals throughout innovation investment communities, including entrepreneurs, investment angels, venture capitalists, and institutional investors. This study sheds light on post-boom behavioral trends and risk propensities, in relation to actors' interrelated decision-making processes. From decision-makers' reported and ranked perceptions, factor analysis in conjunction with additional contextual evidence was used to identify four influential groups of individuals with shared approaches to early-stage innovation investment: American-style managers, junior venture professionals, experienced angel investors, and committed business builders. From this study of the social and economic geography of American and British innovation communities, implications are drawn for understanding the effectiveness of staged-funding networks in the innovation process and subsequently for community and economic development. Furthermore, this analysis represents a foray into application of Q methodology to the study of economic geography generally and innovation clusters specifically.