bluuebunny/crossref_metadata_2025 huggingface dataset:
A reduction technique of large‐scale RCG interconnects in the complex frequency domain
Authors: Yamagami Y. , Tanji Y. , Hattori A. , Nishio Y. , Ushida A.
Published: November 2004

High‐speed digital LSI chips usually consist of many sub‐circuits coupled with multi‐conductor interconnects embedded in the substrate. They sometimes cause serious problems of the fault switching operations due to the time‐delays, crosstalks, reflections, etc. In order to solve these problems, it is very important to develop a user‐friendly simulator for the analysis of LSIs coupled with interconnects. In this paper, we consider a large‐scale gate‐array circuit coupled with multi‐conductor RCG interconnects. At first, we propose a new method for calculating the dominant poles of the impedance matrix, which give the large effects to the transient response. The corresponding residues are estimated by the least squares method. Using these poles and residues, the input–output relation of each interconnect can be described by the partial fractions. After then, the interconnect is replaced by the equivalent circuit realizing the partial fractions. In this way, we can easily develop a user‐friendly simulator familiar with SPICE. We found from many examples that the good results can be obtained using only few dominant poles around the origin. Furthermore, the reduction ratio of our method is very large especially for large scale interconnects. Copyright © 2004 John Wiley & Sons, Ltd.
Concurrent analogue fault simulation, the equation formulation aspect
Authors: Litovski Vančo B. , Litovski Ivan V. , Zwoliński Mark
Published: November 2004

Fault simulation is an essential tool for developing test patterns for circuits. Because the potential number of faults in a circuit is potentially very large, computational efficiency is an important consideration. In the digital domain, concurrent fault simulation is well‐established as an efficient tool. For analogue circuits, fault simulation is often performed by repeated insertion of possible faults and resimulation of the circuit. Consequently, methods for efficient concurrent analogue fault simulation are attracting attention. A review of existing methods of concurrent analogue fault simulation shows that most are based on a similar fundamental perturbation of the original fault‐free circuit equations, although the methods differ in the procedure applied after the circuit equations are formulated. We develop here a comprehensive set of element stamps, describing faulty elements, enabling effective and routine equation formulation for faulty circuits. These may be used no matter what method of fault simulation is later applied. These stamps are used in a new technique for concurrent analogue fault simulation, based on modified nodal analysis. A significant improvement in efficiency, compared with other methods, is demonstrated. Copyright © 2004 John Wiley & Sons, Ltd.
On state equations of two‐level quantum systems in a thermal environment
Authors: Civalleri Pier Paolo , Gilli Marco
Published: November 2004

The state equations of open two‐level quantum systems, which form the building blocks of quantum cellular neural networks, are studied in arbitrary representations. It is shown that the dissipation matrix, that under the usual assumptions is diagonal in the energy representation, such remains if and only if the coupling between the states induced by an external field is real and infinitesimal. Copyright © 2004 John Wiley & Sons, Ltd.
Monte Carlo Simulations of the Electron Currents Collected by Electrostatic Probes
Authors: Trunec D. , Holík M. , Kudrna P. , Bilyk O. , Marek A. , Hippler R. , Tichý M.
Published: November 2004

We have carried out Monte Carlo simulation of the motion of electrons in the space charge sheath surrounding a cylindrical Langmuir (electrostatic) probe. The electron currents to the probe have been calculated from these simulations for different conditions (pressure of neutral gas, presence of magnetic field). The results of the simulations have been compared with recent Langmuir probe measurements made in cylindrical DC magnetron plasmas. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Angular Resolved Energy and Particle Flux Measurements in a Magnetized Plasma
Authors: Koch B. , Bohmeyer W. , Fussmann G.
Published: November 2004

A flat probe allowing simultaneous energy flux and current density measurements as functions of an applied voltage was rotated in a homogeneous plasma. The probe dimensions (a) were larger or comparable to the ion gyro radius (ri).

Current density (ji), floating potential (Uf ), energy flux density (q), ion energy reflection coefficient RE and the sheath energy transmission coefficient γ were determined as functions of the angle α between the probe surface normal and the magnetic field. For normal incidence conditions (α = 0) all measured quantities do agree well with the theoretical predictions. With |α| approaching 90°, finite gyro‐radii effects of the ions become important. To lowest order the angular variations can be understood by assuming Γe,i ∝ cos α + 2re,i/a for the ion particle flux density.

Most remarkably, a pronounced reduction of the floating potential and the ion impact energy was found experimentally at shallow angles. In contrast, relatively small angular dependencies were found for γ and RE. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
The Effect of a transverse Magnetic Field on Glow‐Discharge created Electron Beams investigated by Electrical Probes
Authors: Biborosch D.‐L. , Toma M.
Published: November 2004

As known, the hollow cathode discharge has two modes of operation: the usual radial one with low impedance and a high impedance mode in which an axial electron beam is produced. This beam mode occurs at low gas pressures and low discharge currents and the applied discharge voltage determines the energy of the beam electrons. The beam electrons do not suffer collisions with the gas atoms so that they can carry up to 20% of the whole discharge current. In spite of the spatial compression the beam generation does not lead to the pinching of the background discharge.

For advanced technologies it is important to investigate whether or not a relatively narrow and weak magnetic field applied transversely to the electric field at the exit of the hollow cathode (like in a magnetron dc discharge) can control the created electron beam. Indeed, it was found that this transverse magnetic field could have an important effect on the breakdown of the high impedance mode and on the corresponding spatial distribution of the generated electron beam. Some new data about this effect which are obtained under these conditions by using electrical probes are discussed in the present contribution. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Radially scanned probe measurements in front of the CASTOR lower hybrid antenna
Authors: Žáček F. , Petržílka V. , Goniche M. , Devynck P. , Nanobashvili S.
Published: November 2004

Lower hybrid waves (LHW) are used for non‐inductive generation of the electrical current in many tokamaks. However, in addition to the current drive, a parasitic acceleration of particles in front of the antennas takes place if the power is high enough. The small tokamak CASTOR allows to carry out measurements directly in the waves‐plasma interaction region, using movable Langmuir probes. This paper investigates fluctuations of the plasma parameters and electrical fields in the radially narrow layer in front of the CASTOR antenna, where a significant drop of floating potential has been observed recently [1]. Significant changes in these quantities have been found during LHW discharge phase. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Langmuir Probe Measurements in the WEGA Stellarator
Authors: Horvath K. , Lingertat J. , Laux M. , Wagner F.
Published: November 2004

Langmuir probe measurements have been performed in weakly magnetized (0.06T < B0 ≤ 0.1T), lowpressure (6.× 10–4Pa ≤ p ≤ 1.0 × 10–2Pa) helium, hydrogen and argon plasmas of the WEGA stellarator. A simple cylindrical graphite probe as well as a double probe were used. The observed characteristics do not show saturation of the ion current. The reason for this anomaly can be the presence of a fast electron component in the plasma caused by the heating method ( ECRH at 2.45 GHz ). Using the model from [5] for derivation of the current to the probe for a two‐temperature Maxwellian electron distribution the characteristics were successfully fitted. Radial profiles of the electron temperature, density and plasma potential as a function of heating power, neutral gas pressure, magnetic field and rotational transform have been obtained. The plasma potential values were compared to results from emissive probe measurements. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Design of a thermal probe for the plasma diagnostics
Authors: Matsuura H. , Michimoto K.
Published: November 2004

When a solid material is inserted into plasma, it receives heat flux and electrical current according to its bias voltage. The heat flux‐voltage characteristic is more complicated than the current‐voltage characteristic and depend on ion temperature as well as electron temperature. Thermal probe method uses this characteristic to determine plasma parameter. We propose here to use it to deduce ion temperature and show the results on related work. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Measurements of the Parallel and Perpendicular Ion Temperatures by Means of an Ion‐sensitive Segmented Tunnel Probe
Authors: Balan P. , Schrittwieser R. , Adámek J. , Bařina O. , De Beule P. , Ďuran I. , Gunn J. P. , Hrach R. , Hron M. , Ioniţă C. , Martines E. , Pánek R. , Stöckel J. , Van Den Berge G. , Van Oost G. , Van Rompuy T. , Vicher M.
Published: November 2004

Localised ion temperature measurements can only be performed with special electric probes where the electron component of the current is kept off from the collector. In a strong magnetic field the effect can be utilised that the electron gyro‐radius is much smaller than that of the ions. This method was developed by Katsumata and Okazaki (Japan J. Appl. Phys. 6, 123 (1967)). We have used a so‐called tunnel probe (which consists of a conductive tunnel, terminated by an isolated back plate) by adding a diaphragm in front. Thereby the tunnel is prevented from incident electrons at any potential of both electrodes. By sweeping the potential across the tunnel, the perpendicular ion temperature can be inferred. By segmenting the tunnel axially in two parts also the parallel ion temperature can be determined. When the electrodes are biased to ion saturation, the ratio between the ion currents, which reach the first and the second segment, respectively, is a measure for the parallel ion temperature. The dependence of the ratio of the currents has to be determined by a PIC simulation. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Utility of a Baffled Probe for Measurements of Oscillations in Magnetized Plasma
Authors: Demidov V. I. , Finnegan S. M. , Koepke M. E. , Reynolds E. W.
Published: November 2004

A baffled probe for distinguishing the oscillations of space potential and temperature in magnetized plasma is tested. The probe consists of a tungsten wire tip, oriented perpendicular to the magnetic field, that is partially shielded by ceramic baffles (masks). The probe works under the condition that the electron Larmor radius is much smaller than the probe radius, and the ion Larmor radius is comparable to or larger than the probe radius. The probe uses the same principles as Katsumata and plug probes, but has the advantage of convenient, realtime controllability of the ratio between electron and ion current while electrically floating, and insensitivity to uncertainties in the orientation of the probe tip relative to the direction of the magnetic field. By rotating the baffle configuration around the probe tip, the ratio between electron and ion probe current and consequently the relative sensitivity of the probe to oscillations of space potential and electron/ion temperature, can be adjusted. Thus, measurements of ac floating potential with different ratio of electron and ion currents allow us to distinguish oscillations of space potential from electron/ion temperature fluctuations. Experiments have been conducted in a fully ionized, barium plasma in the West Virginia University Q‐machine. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Selective Deposition of Ultrathin Poly(p‐xylene) Films on Dielectrics Versus Copper Surfaces
Authors: Senkevich J.J. , Wiegand C.J. , Yang G.‐R. , Lu T.‐M.
Published: November 2004

Ultrathin films of poly(p‐xylylene) are selectively deposited on oxide surfaces but not on air exposed copper. The polymers are deposited under conditions favorable for forming highly conformal ultrathin films appropriate for ‘pore sealing’ the surface of ultra‐low κ dielectrics. Variable angle spectroscopic ellipsometry is used to measure the polymer deposit on SiO2, and shows the lack of deposition on air‐exposed copper. X‐ray photoelectron spectroscopic analysis of the copper samples shows deposition of adventitious carbon on the metal surface, and confirms that no polymer deposition occurs.
Comparison of three different staining techniques for intraoperative assessment of nodal metastasis in breast cancer
Authors: Anand Mona , Kumar Rajive , Jain Paresh , Asthana Sonal , Deo S.V.S. , Shukla N.K. , Karak Asis
Published: November 2004

Imprint cytology has increasingly been used for intraoperative assessment of nodal status in breast cancer. We carried out this study to compare the efficacy of Jenner Giemsa (JG), hematoxylin‐eosin (H&E), and Papanicolaou (Pap) stains for intraoperative lymph node imprint cytology (IIC) in breast cancer. One hundred and seven cases of stage I–III breast cancer were studied. Overall, IIC was accurate in 95.3% cases and had a sensitivity and specificity of 98.5% and 90.0%, respectively. The accuracy of JG (95.3%) was better than that of H&E (90.6%) and Pap (94.0%), although the differences were not statistically significant. Problems encountered included cell loss and drying artifacts with H&E and Pap and the inability to distinguish between tumor cells and histiocytes confidently in tight cellular clusters that were occasionally seen. Opinion was possible in all JG cases, but not in five and four cases by H&E and Pap, respectively. Although the choice of the stain would vary depending on the experience of the pathologist, our work suggests that JG, because of fewer technical problems and superior accuracy, may be preferable over H&E and Pap. Diagn. Cytopathol. 2004;31:423–426. © 2004 Wiley‐Liss, Inc.
Erdheim‐Chester disease of the brain: Cytological features and differential diagnosis of a challenging case
Authors: Rushing Elisabeth J. , Kaplan Keith J. , Mena Hernando , Sandberg Glenn D. , Koeller Kelly , Bouffard John‐Paul
Published: November 2004

Erdheim‐Chester disease (ECD) is an uncommon, systemic xanthogranulomatous disorder, with distinct clinicopathological features, that is rarely expected preoperatively. We describe a case that presented in the brain of a 26‐yr‐old male patient and clinically mimicked the appearance of a neoplasm. The final diagnosis was a surprise. In retrospect, the diagnosis was suggested by the intraoperative “squash” preparations, which demonstrated a mixed cellular proliferation of lymphohistiocytic elements and large, multinucleated cells with vesicular nuclei, prominent nucleoli, and abundant cytoplasm. To the best of our knowledge, this is the first report detailing the cytopathological features of ECD. Diagn. Cytopathol. 2004;31:420–422. © 2004 Wiley‐Liss, Inc.
Evidence of a right‐shift factor affecting infant hand‐use preferences from 7 to 11 months of age as revealed by latent class analysis
Authors: Michel George F. , Sheu Ching‐Fan , Brumley Michele R.
Published: November 2004

Infant hand‐use preferences for apprehending objects were assessed three times at 7, 9, and 11 months of age for 154 infants (79 males) using a reliable and valid procedure. Two classification procedures (differing in Type I classification error rates) were used to identify an infant's preference (right, left, no preference) at each age, and these data were examined using two‐ and three‐group latent class analysis models. These analyses revealed the importance of using a handedness classification procedure with low Type I error rates and evidence of a right‐shift factor similar to that expressed in child and adult handedness. Thus, infant hand‐use preferences for apprehending objects are likely a developmental precursor of adult handedness. The relation of the right‐shift factor to increased susceptibility to social influences during development and the evolution of human abilities also is discussed. © 2002 John Wiley & Sons, Inc. Dev Psychobiol 40: 1–13, 2002
Diurnal cycle in salivary cortisol levels in common marmosets
Authors: Cross Nicola , Rogers Lesley J.
Published: November 2004

A noninvasive method of saliva sampling was used to assess the diurnal cortisol rhythm from 0900 to 1700 hr in the common marmoset (Callithrix jacchus). The levels of cortisol were highest in the morning and declined significantly over the day. Individual marmosets varied in the magnitude of the cycle, and the greatest individual variability occurred in the morning levels. The decrease in cortisol levels was more rapid after than before the midday feeding period in subordinate marmosets (aged 53–63 months) compared to dominant marmosets (aged 79–80 months), and overall, the levels of cortisol were higher in the subordinate marmosets. We found no effect of sex on cortisol levels across the cycle. © 2004 Wiley Periodicals, Inc. Dev Psychobiol 45: 134‐139, 2004.
Gene expression in the axolotl germ line: Axdazl, Axvh, Axoct‐4, and Axkit
Authors: Bachvarova Rosemary F. , Masi Thomas , Drum Matthew , Parker Nathan , Mason Ken , Patient Roger , Johnson Andrew D.
Published: November 2004

Primordial germ cells (PGCs) in embryos of mammals and urodele amphibians are formed by induction in the absence of germ plasm. We describe expression of four germ cell‐related genes through the germ cell cycle of the axolotl. The orthologs of vasa and daz‐like are up‐regulated in PGCs of tail bud embryos before the gonad forms and are expressed throughout the female germ cell cycle. Mammalian Oct‐4 is a marker of pluripotency in embryonic cells. Axolotl Oct‐4 has higher homology to Oct‐4 than that found in other vertebrates. It is expressed in the equivalent of the mouse epiblast, in the posterior mesoderm of late gastrulae that gives rise to PGCs, and in diplotene growing oocytes, but not in presumptive PGCs after gastrulation. Finally, a c‐kit homolog is expressed in gonadal oogonia and growing oocytes as in mice but is also not found in PGCs. The expression pattern in urodele gonadal germ cells is similar to that of other vertebrates, although the pattern in pregonadal PGCs is distinctly different from that of mice. We conclude that PGCs are restricted to the germ line later in urodeles than in mice or lack migration and proliferation programs. Developmental Dynamics 231:871–880, 2004. © 2004 Wiley‐Liss, Inc.
FGF‐2 signaling is sufficient to induce dermal condensations during feather development
Authors: Song Hee‐Kyung , Lee So‐Hyung , Goetinck Paul F.
Published: November 2004

In a previous report, we showed that fibroblast growth factor‐2 (FGF‐2) is a signal produced by epidermal placode cells during feather development and that this growth factor can induce feathers in scaleless mutant skins that fail to form feathers due to a defective epidermis (Song et al., [1996] Proc Natl Acad Sci USA 93:10246–10249). Here, we test whether FGF‐2 is sufficient to induce dermal condensations, structures that normally form under the control of signals from the epidermal placode and are identified on the basis of aggregation of cells, the expression of FGF receptor‐1 and bone morphogenetic protein‐2 transcripts and the cessation of proliferation of the condensed cells. By using denuded 8‐day scaleless dermis as a test system, we have established that FGF‐2 is sufficient to induce dermal condensation. We suggest that the primary effect of FGF‐2 is an increase in cellular density mediated through cell migration, followed by the expression of dermal condensation‐specific genes and cessation of cell proliferation. The FGF‐2 effect can be abolished by heparin, suggesting the involvement of heparan sulfate proteoglycans (HSPGs) in growth factor signaling. The spatiotemporal expression of syndecan‐3 during feather development suggests that this cell‐surface HSPG may be involved in the response of competent embryonic skin dermis to FGF‐2. Developmental Dynamics 231:741–749, 2004. © 2004 Wiley‐Liss, Inc.
Fgf signaling induces posterior neuroectoderm independently of Bmp signaling inhibition
Authors: Rentzsch Fabian , Bakkers Jeroen , Kramer Carina , Hammerschmidt Matthias
Published: November 2004

Whereas according to the neural default model, neural specification is induced by extracellular inhibitors of bone morphogenetic proteins (Bmps), the role of fibroblast growth factors (Fgfs) during neural induction is heavily debated. Here, we show that, in zebrafish embryos, Bmps and Fgfs play differential roles during the induction and patterning of the anterior vs. the posterior neuroectoderm. Induction of anterior neuroectoderm, giving rise to fore‐ and midbrain, is accomplished by Bmp inhibition, with Fgfs playing a moderate posteriorizing/patterning role, possibly by blocking Bmp signaling at the level of Smad proteins. In contrast, in the posterior‐most neuroectoderm, which is located in marginal regions of the early gastrula embryo to give rise to spinal cord and hindbrain, Fgfs play a neural‐inducing rather than a neural‐patterning role. This Fgf‐dependent posterior neural induction takes place during late blastula and early gastrula stages, after mesoderm has been induced and cannot be blocked by Bmps or the Bmp target gene and downstream effector ΔNp63α, indicating that here, Fgfs act independently of Bmp signaling inhibition. Developmental Dynamics 231:750–757, 2004. © 2004 Wiley‐Liss, Inc.
Dioxovanadium(V) Complexes of ONO Donor Ligands Derived from Pyridoxal and Hydrazides: Models of Vanadate‐Dependent Haloperoxidases
Authors: Maurya Mannar R. , Agarwal Shalu , Bader Cerstin , Rehder Dieter
Published: November 2004

[VO(acac)2] reacts with H2L [H2L are the hydrazones H2pydx‐inh (I), H2pydx‐nh (II), or H2pydx‐bhz (III); pydx = pyridoxal, inh = isonicotinohydrazide, nh = nicotinohydrazide, bhz = benzohydrazide] in dry methanol to yield the oxovanadium(IV) complexes [VOL] (H2L = I: 1; H2L = II: 4) or [VO(pydx‐bhz)]. These complexes, when exposed to air, convert into the corresponding dioxovanadium(V) complexes [VO2HL] (H2L = I: 2; H2L = II: 5; H2L = III: 7). Aqueous solutions of vanadate and the ligands at pH = 7.5 give rise to the formation of [K(H2O)3][VO2(pydx‐inh)] (3), [K(H2O)2][VO2(pydx‐nh)] (6) and [K(H2O)2][VO2(pydx‐bhz)] (8). Treatment of 6 and 8 with H2O2 generates the oxo(peroxo)vanadium complexes [VO(O2)L] (H2L = II: 9; H2L = III: 10). Complexes 9 and 10 are capable of transferring an oxo group to PPh3. Acidification of 8 with HCl afforded a hydroxo(oxo) complex. The crystal and molecular structures of ligand I and complex 3 have been solved by single‐crystal X‐ray diffraction. In the anion 3, the vanadium atom is in a distorted tetragonal‐pyramidal environment (τ = 0.23). The K+ ion is coordinated to four water molecules (two of which bridge to a neighbouring K+ ion), the pyridine nitrogen atom of an isonicotinic moiety, the equatorial oxo group of the VO2+ fragment, and the alcoholic group of the pyridoxal moiety, which links adjacent layers in the three‐dimensional lattice network. In the presence of KBr/H2O2, the anionic complexes 3, 6 and 8 catalyse the oxidative bromination of salicylaldehyde in water to 5‐bromosalicylaldehyde in ca. 40% yields with ca. 87% selectivity. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)
History and rationale of genetic toxicity testing: An impersonal, and sometimes personal, view
Authors: Zeiger Errol
Published: November 2004

Genetic toxicity testing is a necessary and pivotal component of product development and registration. This article traces the historical development and evolution of genetic toxicity testing, and the rationale for such testing, and identifies some of the individuals who played key roles in this process. The evolution of the present test batteries and some of the research and rationales behind the decisions to accept or reject tests are described. Environ. Mol. Mutagen., 2004. © 2004 Wiley‐Liss, Inc.
Modelling error and constitutive relations in simulation of flow and transport
Authors: Carey Graham F. , Barth William , Woods Juliette A. , Kirk Benjamin S. , Anderson Michael L. , Chow Sum , Bangerth Wolfgang
Published: November 2004

The main theme of this paper is the modelling error associated with the choice of constitutive equations and associated parameter sensitivity. These key concepts are first discussed in a general way and explored in detail subsequently for three flow application problems which share certain similarities not only in the finite element formulation but also in the nature of the non‐linear constitutive laws that are investigated. The specific flow problems involve: density driven flow in porous media, the Powell–Eyring model for generalized Newtonian flows, and the related Glen's flow type of constitutive relations for glacier modelling. Copyright © 2004 John Wiley & Sons, Ltd.
A fractal forecasting model for financial time series
Authors: Richards Gordon R.
Published: November 2004

Financial market time series exhibit high degrees of non‐linear variability, and frequently have fractal properties. When the fractal dimension of a time series is non‐integer, this is associated with two features: (1) inhomogeneity—extreme fluctuations at irregular intervals, and (2) scaling symmetries—proportionality relationships between fluctuations over different separation distances. In multivariate systems such as financial markets, fractality is stochastic rather than deterministic, and generally originates as a result of multiplicative interactions. Volatility diffusion models with multiple stochastic factors can generate fractal structures. In some cases, such as exchange rates, the underlying structural equation also gives rise to fractality. Fractal principles can be used to develop forecasting algorithms. The forecasting method that yields the best results here is the state transition‐fitted residual scale ratio (ST‐FRSR) model. A state transition model is used to predict the conditional probability of extreme events. Ratios of rates of change at proximate separation distances are used to parameterize the scaling symmetries. Forecasting experiments are run using intraday exchange rate futures contracts measured at 15‐minute intervals. The overall forecast error is reduced on average by up to 7% and in one instance by nearly a quarter. However, the forecast error during the outlying events is reduced by 39% to 57%. The ST‐FRSR reduces the predictive error primarily by capturing extreme fluctuations more accurately. Copyright © 2004 John Wiley & Sons, Ltd.
Identification of new translocations involving ETV6 in hematologic malignancies by fluorescence in situ hybridization and spectral karyotyping
Authors: Odero María D. , Carlson Katrin , Calasanz María J. , Lahortiga Idoya , Chinwalla Vandana , Rowley Janet D.
Published: November 2004

TEL/ETV6 is the first transcription factor identified that is specifically required for hematopoiesis within the bone marrow. This gene has been found to have multiple fusion partners; 35 different chromosome bands have been involved in ETV6 translocations, of which 13 have been cloned. To identify additional ETV6 partner genes and to characterize the chromosomal abnormalities more fully, we studied bone marrow samples from patients known to have rearrangements of 12p, using fluorescence in situ hybridization (FISH) and spectral karyotyping (SKY). FISH analysis was done with 14 probes located on 12p12.1 to 12p13.3. Nine ETV6 rearrangements were identified using FISH. The aberrations include t(1;12)(p36;p13), t(4;12)(q12;p13) (two patients), t(4;12)(q22;p13), t(6;12)(p21;p13), der(6)t(6;21)(q15;q?)t(12;21)(p13;q22), t(6;12)(q25;p13), inv(12)(p13q24), and t(2;2;5;12;17)(p25;q23;q31;p13;q12). Six new ETV6 partner bands were identified: 1p36, 4q22, 6p21, 6q25, 12q24, and 17q12. Our present data as well previous data from us and from other researchers suggest that ETV6 is involved in 41 translocations. The breakpoints in ETV6 were upstream from the exons coding for the HLH (helix‐loop‐helix) domain in six cases. Although cytogenetic analysis identified 12p abnormalities in all cases, FISH and SKY detected new and unexpected chromosomal rearrangements in many of them. Thus, complete characterization of the samples was achieved by using all three techniques in combination. © 2001 Wiley‐Liss, Inc.
Multivariate analyses of genomic imbalances in solid tumors reveal distinct and converging pathways of karyotypic evolution
Authors: Höglund Mattias , Gisselsson David , Mandahl Nils , Johansson Bertil , Mertens Fredrik , Mitelman Felix , Säll Torbjörn
Published: November 2004

A total of 3,016 malignant solid tumors (kidney, colorectal, breast, head and neck, ovarian, and lung carcinomas, neuroglial tumors, malignant melanoma, and testicular germ cell tumors) were selected for statistical analyses regarding karyotypic evolution. Genomic imbalances, i.e., net gains and losses, present in more than 5% of each tumor type were identified. Individual tumors were then classified with respect to absence or presence of these imbalances. To analyze for possible patterns of correlated imbalances, principal component analyses (PCA) were performed. Furthermore, algorithms were developed to analyze the temporal order of the imbalances, as well as the possible selection for early or late appearance in the karyotypic evolution. By analyzing the temporal order of imbalances common to many tumor types, a general order for nine of these emerged, namely, +7, −3p, −6q, −1p, −8p, −17p, −9p, −18, and −22. The distributions of the number of imbalances per case revealed a geometrical distribution, ranging from one to nine imbalances per tumor, in the majority of the tumor types. In tumor types in which cases with a high number of imbalances per case were frequent, notably head and neck, ovarian, and lung carcinomas, the overall distributions were bimodal, indicating the presence of two modes of chromosome evolution. By combining data from the PCA with the temporal analyses, it was possible to identify karyotypic pathways. It was found that the majority of the tumor types displayed more than one cytogenetic route, but, as the karyotypic evolution continued, these converged to a common pathway. © 2001 Wiley‐Liss, Inc.
Spectral karyotyping reveals 17;22 fusions in a cytogenetically atypical dermatofibrosarcoma protuberans with a large marker chromosome as a sole abnormality
Authors: Mrózek Krzysztof , Iliszko Mariola , Ryś Janusz , Babińska Małgorzata , Niezabitowski Aleksander , Bloomfield Clara D. , Limon Janusz
Published: November 2004

The presence of an extra ring chromosome containing material from 17q and 22q, or, less frequently, a t(17;22)(q22;q13), is a cytogenetic hallmark of dermatofibrosarcoma protuberans (DFSP). However, occasionally tumors with other, atypical karyotypes are encountered. We describe a case of recurrent DFSP without a ring chromosome or a t(17;22) on standard cytogenetic analysis. In all cells analyzed by G‐banding, an additional, large marker chromosome was present as a sole abnormality. This chromosome apparently included chromosome 8 or the 8q arm, but the origin of its remaining part could not be determined with certainty. To characterize further the abnormal chromosome, we applied spectral karyotyping (SKY). SKY confirmed the presence of an extra chromosome 8 or arm 8q in the marker and showed that its remaining part was composed of segments from chromosomes 7, 17, 21, and 22, with two copies of a 17;22 fusion. Our results and the literature data suggest that, in addition to a specific 17;22 fusion, amplification of material from chromosomes 17, 22, 8, 5, 7, and 21 may play a role in DFSP development and/or progression. Furthermore, our case demonstrates the usefulness of SKY in detection of a diagnostically relevant 17;22 fusion in DFSP patients who have unusual karyotypic features. © 2001 Wiley‐Liss, Inc.
Coduplication of the MLL and FLT3 genes in patients with acute myeloid leukemia
Authors: Jamal Rahman , Taketani Takeshi , Taki Tomohiko , Bessho Fumio , Hongo Teruaki , Hamaguchi Hiroyuki , Horiike Shigeo , Taniwaki Masafumi , Hanada Ryoji , Nakamura Hideo , Hayashi Yasuhide
Published: November 2004

Tandem duplication (TD) of the MLL or FLT3 gene in acute myeloid leukemia (AML) has been reported. We examined whether TD of these two genes occurs simultaneously. We analyzed 13 AML and 2 myelodysplastic syndrome patients, including 6 adult patients with trisomy 11 and 9 pediatric patients with TD of the FLT3 gene, using RT‐PCR followed by sequencing. Among these, TD of the MLL and FLT3 genes was found in 5 and 10 patients, respectively. Notably, TD of both the MLL and FLT3 genes (coduplication) was detected in two AML patients, who died 6 and 14 months after diagnosis. TD of these two genes in AML is rare; thus, coduplication of these genes in the same patient is predicted to be very rare. Although the mechanisms of TD of both genes are different, development of TD of both genes may be related to an unknown similar etiology in leukemia because the frequency of coduplication of these genes in a single patient is considered to be very low. Further studies of the coduplication of these genes in AML patients may lead to the clarification of its mechanism and clinical implications. © 2001 Wiley‐Liss, Inc.
Lymphoid gene expression as a predictor of risk of secondary brain tumors
Authors: Edick Mathew J. , Cheng Cheng , Yang Wenjian , Cheok Meyling , Wilkinson Mark R. , Pei Deqing , Evans William E. , Kun Larry E. , Pui Ching‐Hon , Relling Mary V.
Published: November 2004

Gene expression profiles are tissue‐specific but may also reflect germ‐line‐driven expression patterns across tissue types. Previously, using a targeted pharmacologic approach, we identified germ‐line polymorphisms in a single gene (thiopurine methyltransferase) associated with the risk of irradiation‐ and chemotherapy‐induced secondary brain tumors in children with acute lymphoblastic leukemia (ALL). To identify additional candidate genetic risk factors, in identically treated patients, we compared the gene expression profiles of diagnostic ALL blasts of those who did develop irradiation‐associated brain tumors (n = 9) with the profiles from those who did not (n = 33). Weighted rank regression was used to identify 33 probe sets associated with the time‐dependent development of brain tumors; k‐means clustering (k = 2) identified 2 groups that differed significantly in cumulative incidence of brain tumors (P = 0.012). Permutation analysis was used to estimate the probability (P = 0.18) of obtaining 2 such clusters by chance. Linear discriminant analysis (time‐independent categorization of outcome) was used to identify 70 probe sets whose expression differentiated between the 2 groups of patients. Permutation analyses (n = 1,000) was used to estimate the probability of selecting these probe sets by chance (P = 0.055). Five probe sets were in common between the time‐independent and time‐dependent methods. The distinguishing genes are involved in neural growth (FGFR1) and in nuclear trafficking (HNRPL, KPNB1). These data suggest that gene expression profiling from accessible tissues may identify targets involved in therapy‐related malignancies in unrelated tissues. (
). © 2004 Wiley‐Liss, Inc.
Formation of der(19)t(1;19)(q23;p13) in acute lymphoblastic leukemia
Authors: Paulsson Kajsa , Horvat Andrea , Fioretos Thoas , Mitelman Felix , Johansson Bertil
Published: November 2004

The t(1;19)(q23;p13), which results in a fusion of TCF3 (previously E2A) at 19p13 with PBX1 at 1q23, is one of the most common translocations in acute lymphoblastic leukemia (ALL). It is seen either as a balanced t(1;19) or as an unbalanced der(19)t(1;19); occasional cases with coexisting t(1;19)‐ and der(19)‐positive clones also have been described. Although it generally has been assumed that the unbalanced form arises from the balanced t(1;19) through loss of the derivative chromosome 1 followed by duplication of the normal homologue, this has never been proved. At least two other mechanisms are possible for the formation of the der(19): an initial trisomy 1 followed by translocation and subsequent loss of the der(1) or a rearrangement during the G2 phase of the cell cycle, with the derivative chromosomes 1 and 19 ending up in separate daughter cells. The different alternatives may be distinguished by investigation of markers proximal to the breakpoint in 1q23 because they would be expected to lead to different allelic patterns. Thus, loss of heterozygosity as a result of the presence of uniparental disomy (UPD)—both copies of a chromosome being derived from only one parent—for chromosome 1 would be present in all der(19)‐harboring cases arising via the duplication pathway and in one‐third of cases arising via the trisomy pathway, but in none of the der(19) formed via the G2 pathway. In this study, we used quantitative fluorescence PCR with polymorphic microsatellite markers to investigate chromosomes 1 and 19 in two t(1;19)‐ and four der(19)‐positive ALLs. None of the der(19) cases displayed UPD for chromosome 1, excluding that this aberration arises through the duplication pathway. Because previous findings of cases with coexisting t(1;19) and der(19) clones are difficult to explain if the translocation originated in G2, the present results suggest that an unbalanced der(19) may arise from an initial trisomy 1 followed by t(1;19) translocation and loss of the derivative chromosome 1. © 2004 Wiley‐Liss, Inc.
Evaluating associations of haplotypes with traits
Authors: Schaid Daniel J.
Published: November 2004

Haplotypes have played a major role in the study of highly‐penetrant single‐gene disorders, and recent evidence that the human genome has hot‐spots and cold‐spots for recombination have suggested that haplotype‐based methods may play a key role in the study of common complex traits. This report reviews the motivation of using haplotypes for the study of the genetic basis of human traits, ranging from biologic function, to statistical power advantages of haplotypes, to linkage disequilibrium fine‐mapping. Recent developments of regression models for haplotype analyses are reviewed, offering a synthesis of current methods, as well as their limitations and areas that require further research. Regression models provide significant advantages, such as the ability to control for non‐genetic covariates, the effects of the haplotypes can be modeled, step‐wise selection can be used to screen for a subset of markers that explain most of the association, haplotype × environment interactions can be evaluated, and regression diagnostics are well developed. Despite these strengths, the current regression methods tend to lack the sophisticated population genetic perspectives offered by coalescent and other similar approaches. Future work that links regression methods with population genetic models may prove beneficial.Genet. Epidemiol. © 2004 Wiley‐Liss, Inc.
SNPs, haplotypes, and model selection in a candidate gene region: The SIMPle analysis for multilocus data
Authors: Conti David V. , Gauderman W. James
Published: November 2004

Modern molecular techniques make discovery of numerous single nucleotide polymorphims (SNPs) in candidate gene regions feasible. Conventional analysis relies on either independent tests with each variant or the use of haplotypes in association analysis. The first technique ignores the dependencies between SNPs. The second, though it may increase power, often introduces uncertainty by estimating haplotypes from population data. Additionally, as the number of loci expands for a haplotype, ambiguity in interpretation increases for determining the underlying genetic components driving a detected association. Here, we present a genotype‐level analysis to jointly model the SNPs via a SNP interaction model with phase information (SIMPle) to capture the underlying haplotype structure. This analysis estimates both the risk associated with each variant and the importance of phase between pairwise combinations of SNPs. Thus, rather than selecting between genotype‐ or haplotype‐level approaches, the SIMPle method frames the analysis of multilocus data in a model selection paradigm, the aim to determine which SNPs, phase terms, and linear combinations best describe the relation between genetic variation and a trait of interest. To avoid unstable estimation due to sparse data and to incorporate both the dependencies among terms and the uncertainty in model selection, we propose a Bayes model averaging procedure. This highlights key SNPs and phase terms and yields a set of best representative models. Using simulations, we demonstrate the utility of the SIMPle model to identify crucial SNPs and underlying haplotype structures across a variety of causal models and genetic architectures. Genet. Epidemiol. © 2004 Wiley‐Liss, Inc.
Isolated polycystic liver disease as a distinct genetic disease, unlinked to polycystic kidney disease 1 and polycystic kidney disease 2
Authors: Pirson Y , Lannoy N , Peters D , Geubel A , Gigot J , Breuning M , Verellen-Dumoulin C
Published: November 2004

Polycystic liver disease (PLD) is proven to occur either sporadically or in association with autosomal dominant polycystic kidney disease (ADPKD), whereas the existence of an isolated (i.e., without any kidney cyst) familial form is disputed. We describe a family with definitely isolated PLD transmitted through three generations and exclude the linkage of the disease to the genetic markers of PKD1 and PKD2, the two main loci responsible for ADPKD. These findings strongly support the existence of PLD as a genetic disease distinct from the known forms of ADPKD.
The antiandrogen cyproterone acetate induces synthesis of transforming growth factor β1 in the parenchymal cells of the liver accompanied by an enhanced sensitivity to undergo apoptosis and necrosis without inflammation
Authors: Oberhammer F , Nagy P , Tiefenbacher R , Froschl G , Bouzahzah B , Thorgeirsson S S , Carr B
Published: November 2004

Recently, cases of liver damage and liver tumors have been reported after treatment of prostate cancer patients with the antiandrogen cyproterone acetate (CPA). In rat liver, CPA initiates a wave of DNA synthesis that is accompanied by apoptosis. In apoptotic hepatocytes, a latent form of transforming growth factor β1 (TGF-β1) is detectable by immunohistochemistry. Injection of a single dose of TGF- β1 induces apoptosis in the liver of animals pretreated with CPA but has an insignificant effect in untreated animals. In this study, we show by Northern analysis that there is increased expression of TGF-β1 in the liver after CPA treatment. Detection of TGF-β1 with in situ hybridization showed that TGF-β1 was synthesized in the parenchymal cells. Time course and dose-response experiments performed 48 hours after the last application of CPA showed that apoptotic nuclei with chromatin condensed at the nuclear periphery (AN) were already visible 2 hours after injection (0.13%), and apoptotic bodies (ABs) increased 2 to 9 hours after the injection (from 1.28% to 6.67%) after 25 μg TGF-β1/kg. At 4.5 hours after injection, an induction of apoptosis could be detected with 0.25 microgram TGF-β1/kg and after the maximum dose (250 μg TGF-β1/kg) ANs (0.24%) and ABs (16.74%) were homogeneously distributed throughout the liver lobe. Irrespective of the dose or time after injection of TGF-β1, 82% of the ABs were localized within hepatocytes. Liver enzymes were detected in high amounts in the serum (eightfold elevation of glutamate dehydrogenase, fivefold elevation of alanine transaminase [ALT]) 7 hours after the first visible sign of apoptosis. After an additional 20 hours, the liver contained many necrotic figures. These results suggest that the combination of TGF-β1 expression coupled with a strikingly enhanced sensitivity to the induction of apoptosis could be responsible both for the liver damage and the development of liver tumors observed after treatment with CPA.
Protective effect of S -adenosyl-l-methionine on bromobenzene- and d- galactosamine-induced toxicity to isolated rat hepatocytes
Authors: Wu J , Soderbergh H , Karlsson K , Danielsson Å
Published: November 2004

The protective effect of S-adenosyl-l-methionine (SAMe) on bromobenzene (BB)- or d-galactosamine (GalN)-induced damage to isolated rat hepatocytes and its effect on cellular glutathione (GSH) levels were investigated. SAMe at concentrations of 0.5 to 3.0 mmol/L significantly reduced lactate dehydrogenase leakage from cells exposed to 1.6 mmol/L BB (P < .05 to .001) during 2 hours’ incubation. GalN at 25 to 50 mmol/L induced a marked increase of LDH leakage from the cells during the later stage of 24 hours’ incubation and SAMe at 1.0 mmol/L clearly attenuated the LDH leakage in GalN (25 mmol/L)-exposed cells. The GSH content in the cells exposed to 2.4 mmol/L BB for 150 minutes was markedly decreased, and further decreased during 24 hours’ incubation. SAMe (1.5 mmol/L) both reduced LDH leakage and corrected GSH depletion in cells exposed to 2.4 mmol/L BB. The GSH content in 25 and 50 mmol/L GalN-exposed cells was strikingly diminished to 51.2% and 32.8% of the controls, respectively, during 24 hours’ of exposure. SAMe at 1.5 mmol/L significantly reduced the loss in GSH content in 25 mmol/L GalN-exposed cells. The findings show that SAMe has beneficial effects on both BB- and GalN-induced toxicity to rat hepatocytes. The main mechanism behind the protective effect of SAMe on BB and GalN toxicity seems to be associated with enhancement of GSH synthesis in the cells.
Induction of interleukin-6 by interferon alfa and its abrogation by a serine protease inhibitor in patients with chronic hepatitis C
Authors: Ito N , Kawata S , Tamura S , Kiso S , Tsushima H , Maeda Y , Yamasaki E , Igura T , Matsuzawa Y
Published: November 2004

We investigated short-term alterations in plasma interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor α (TNF-α) levels induced by interferon alfa (IFN-α) injection in 18 patients with chronic hepatitis C. A single intramuscular injection of human recombinant IFN-α 2a (6 million units [MU]) significantly increased the plasma IL-6 level 6 hours after the injection (P < .05). On the other hand, the IFN-α injection did not affect the plasma TNF-α and IL-lβ levels. Polymerase chain reaction (PCR) analysis showed accumulation of IL-6 gene transcripts in peripheral blood mononuclear cells (PBMC) after IFN-α injection, indicating that IFN-α enhances IL-6 production at the messenger RNA level. The induction of IL-6 by IFN-α was completely suppressed by the intravenous administration of gabexate mesilate (GM), a serine protease inhibitor. The mechanism whereby GM suppresses the elevation in circulating IL-6 levels seems to be the inhibition of IL-6 production at the messenger RNA level. Elevations of both serum C-reactive protein (CRP) levels and body temperature after GM-suppressed IFN-α injection suggest that the administration of GM by suppressing IL-6 production, may attenuate the IL-6-related responses induced by IFN-α injection. In conclusion, we found that IL-6 was induced by IFN-α in vivo, and that this induction was completely abrogated by the administration of GM. Our results indicate that serine protease inhibitors may be useful for inhibiting IL-6-relating responses.