bluuebunny/crossref_metadata_2025 huggingface dataset:
Reactions of 5-Methylphenanthridinium Iodide with Nucleophiles and Reaction Products Conversion
Authors: Dostál Jiří , Potáček Milan , Nechvátal Miloslav
Published: April 2003

Reactions of 5-methylphenanthridinium iodide (I) with oxygen, nitrogen, and carbon nucleophiles, respectively, were studied. 5-Methylphenanthridinium iodide (I) yielded in the basic aqueous medium 5-methyl-6-phenanthridone (II) and 5,6-dihydro-5-methylphenanthridine (III). By NMR spectroscopy in the D2O-CD3CN solution 5,6-dihydro-6-deuteroxy-5-methylphenanthridine (IVb) (pseudobase) was observed as an immediate unstable product. 5-Methylphenanthridinium iodide (I) gave the corresponding adducts with methoxide and ethoxide anions, morpholine, piperidine, pyrrolidine, cyanide anion and acetone. Their structure was determined by IR, 1H and 13C NMR spectroscopy. Reactions of 5,6-dihydro-5-methyl-6-morpholinophenanthridine (VII) were followed by NMR spectroscopy. Morpholino adduct VII gave in the CD3CN-D2O solution pseudobase (IVb) and its products of disproportionation: oxophenanthridine II and dihydrophenanthridine III. Treatment of 5,6-dihydro-5-methyl-6-morpholinophenanthridine (VII) with H2O/D2O in (CH3)2CO/(CD3)2CO led to CH3COCH2-/CD3COCD2- adduct XIa/XIb formation, respectively.
Influence of Partial Blocking of the Electrode Surface on the Transfer Coefficients
Authors: Wein Ondřej
Published: April 2003

Partial blocking of the transport surface under the stagnant (nerst) layer is simulated by periodically alternating bands of perfectly insulating zones and active zones with a constant potential of driving force. The numeric solution of the corresponding two-dimensional elliptic problem is represented by a simple empirical correlation for the transfer coefficients. The result is interpreted in terms of a simple electrochemical problem about limiting diffusion currents at electrodes with non-uniform surface activity.
Radical Reduction of C-Cl Bonds in Chlorofluoro Ethers
Authors: Liška František , Fikar Jiří , Kuzmič Petr
Published: April 2003

Reduction of C-Cl bonds in 2,2-dichloro-1,1,2-trifluoroethyl trichloromethyl ether (I), 2-chloro-1,1,2-trifluoroethyl trichloromethyl ether (II), and 2,2-dichloro-1,1,2-trifluoroethyl dichloromethyl ether (III) with 2-propanol, 2-butanol, cyclohexanol, tetrahydrofurane, diethyl ether, and 1,3-dioxolane initiated photochemically and by radiation has been investigated. Beside the main reduction products - 2-chloro-1,1,2-difluoroethyl trichloromethyl ether (IV) and 2-chloro-1,1,2-difluoroethyl chloromethyl ether (V) - it was also possible to prove the formation of 1,2-dichloro-1,2-bis(2-chloro-1,1,2-trifluoroethoxy)ethane (VI), 1-chloro-1,2-bis(2-chloro-1,1,2-trifluoroethoxy)ethane (VII), and 1,2-dichloro-1,2-bis(2-chloro-1,1,2-trifluoroethoxy)ethene (VIII). The structure of products was confirmed by elemental analysis, MS, IR, 1H NMR and 19F NMR spectra and by GLC comparison of the elution times with those of standards. The relative reduction ability of the solvents used in the reduction rate order of C-Cl bonds in the compounds (CCl3 > CFCl2 > CHCl2 and CFClH) are given.
Extraction of Complexes of Some Metals with 1,1-Disubstituted 3-Diphenoxythiophosphorylthioureas
Authors: Navrátil Oldřich , Herrmann Eckhard , Chau Nguyen Thi Thu , Tea Channy , Smola Jiří
Published: April 2003

The extraction of complexes of silver, mercury, cadmium, cobalt, zinc, scandium and some rare earth elements (Ln) into benzene solutions of 1,1-disubstituted 3-diphenoxythiophosphorylthioureas (HA) containing alkyl and aryl substituents was examined using the radiotracer technique. The complexes AgA(HA), HgA2, CdA2 and LnA3 are extracted into the organic phase, and the extraction increases in order Co, Zn, Cd ≈ Ln << Hg < Ag. The extraction constants were calculated. During the extraction process using medium acidic aqueous phases (1 M HNO3), the reagents decompose into the corresponding amines and (PhO)2P(S)NCS.
New Preparation of 2-N-Alkyl(aryl)amino-5-methyl-4H-1,3-thiazin-4-ones and 3,4-Dihydro-5-methyl-2,4-dioxo-2H-1,3-thiazine
Authors: Koščík Dušan , Dzurilla Milan , Kutschy Peter
Published: April 2003

Addition-cyclization reactions of 3-bromo- and 3-chloro-2-methylpropenoylisothiocyanates with primary and secondary amines and alcohols have been studied. The formed addition products, thioureas, underwent cyclization of heating with ethanolic KOH or in dimethylformamide in the presence of lithium hydride. This method represents a new approach to 2-dialkyl(aryl)amino-5-methyl-4H-1,3-thiazin-4-ones. Addition reactions with alcohols afforded 3,4-dihydro-5-methyl-2,4-dioxo-2H-1,3-thiazine as the sole product. The structure of the synthesized compounds was confirmed by 1H NMR, 13C NMR, IR and mass spectroscopy.
Crystal Structure of the Native Sesquiterpene Lactone Arctolide
Authors: Rychłewska Urszula , Szczepanska Beata , Buděšínský Miloš , Šaman David , Vašíčková Soňa , Drożdż Bohdan , Grabarczyk Halina , Holub Miroslav
Published: April 2003

X-Ray structure analysis of the native sesquiterpenic arctolide (I) was performed. The results gave evidence that the relative configuration of the hydroxy group at C(3) in the initially suggested arctolide formula (II) has to be corrected to β. Related to this modification, formulas of some other native lactones and derivatives which had been corelated with arctolide before were also corrected.
Synthesis of 5α-Cholestane Type Glycoside Sulfates
Authors: Arnoštová Libuše , Černý Ivan , Pouzar Vladimír , Drašar Pavel
Published: April 2003

Synthesis of steroid glycoside sulfates sulfated both on the steroid skeleton and in sugar part are presented. Sodium salts of 5α-cholestane-3β,6α-diol 6-β-D-glucoside 3-sulfate V and 3-β-D-glucoside 6-sulfate XI were prepared from 3β-(2-tetrahydropyranyloxy)-5α-cholestan-6α-ol (I) using acetyl and methoxymethyl groups for temporary protection. Sulfation in the sugar part was at first checked in pregnane series and triethylammonium salts of 3β-(β-D-glucopyranosyloxy)pregn-5-en-20-one 6'-sulfate (XXVI) and 4'-sulfate 2',3'-diacetate XXVII were prepared. Application of the method on cholestane derivatives gave triethylammonium salt of 5α-cholestan-3β-yl β-D-glucopyranoside-6-sulfate (XXXI).
Pitzer and Thermodynamic Parameters of Triethanolamine and Glycine in Aqueous Saline Solutions
Authors: Herrero Roberto , Brandariz Isabel , Fiol Sarah , Sastre de Vicente Manuel
Published: April 2003

On the basis of the ionic strength dependence of the equilibrium constant (pK*) of thriethanolamine (TEA) and glycine, the ionic interaction parameters of the species involved in the equilibria TEAH+ ↔ TEA + H+ (for TEA), AH2+ ↔ AH + H+ and AH ↔ A- + H+ (for glycine) in aqueous solutions of KCl and KNO3, respectively, were determined using the Pitzer equations. Values of pK* were expressed on both the molarity and the molality scale at various temperatures and values of thermodynamic quantities ∆G0, ∆H0 and ∆S0 ascertained, for TEA.
1H and 13C NMR Spectra of Technically Important Sodium 1- and 2-Aminonaphthalenesulfonates
Authors: Jirman Josef
Published: April 2003

The 1H and 13C NMR spectra of twenty-one technically important sulfonated 1- and 2-naphthylamines have been measured in deuterium oxide. The substituent chemical shifts (SCS) of a sulfonic acid group on naphthylamine skeleton have been calculated from the chemical shifts assigned.
Oxidation of α-Hydroxy Acids with Quinolinium Dichromate - A Kinetic Study
Authors: Aruna Kailasa , Manikyamba Prerepa , Sundaram Embar Venkatachari
Published: April 2003

Oxidation of lactic acid, α-hydroxyphenyllacetic acid and its 4-chloro derivative with quinolinium dichromate (QDC) in 30% (v/v) aqueous acetic acid at 303 K are first order in QDC and first-order in hydroxy acids. The reactions are acid-catalyzed and a medium of low dielectric constant favours the oxidation. The products are the corresponding aldehydes. Thermodynamic parameters are evaluated and a mechanism involving a C-C bond cleavage is proposed.
Thermodynamic Interactions in Binary Mixtures of 2-Methoxyethanol with Alkyl and Aryl Esters at 298.15, 303.15 and 308.15 K
Authors: Aminabhavi Tejraj M. , Raikar Shrinivas K.
Published: April 2003

Densities, viscosities, refractive indices, and sound velocities of 2-methoxyethanol + ester mixtures have been measured at 298.15, 303.15 and 308.15 K. These data have been used to calculate excess volume, excess isentropic compressibility, excess refraction, excess viscosity and excess Gibbs energy of activation of flow. These quantities have been fitted to quadratic equations to estimate the parameters and standard errors. The results have been interpreted in term of the intermolecular interactions between the mixing components.
Batch Crystallization with Crystals Attrition
Authors: Nývlt Jaroslav , Žáček Stanislav
Published: April 2003

The dependence of the mean crystal size of the products from batch crystallizers on the batch time occasionally exhibits a maximum, which can be explained by secondary nucleation due to the attrition of crystals. A kinetic equatation of nucleation, comprising a term for crystal attrition, can be used for the theoretical description of such behaviour. A mathematical model of a batch crystallizer with crystal attrition has been verified on the calcium sulfate precipitation.
The Effect of Vapour Space Volume on Vapour-Liquid Equilibrium Measured by Stripping with an Inert Gas Stream
Authors: Surový Július , Ovečková Jana , Graczová Elena
Published: April 2003

The effect of vapour space size when measuring the vapour-liquide equilibrium by a modified saturation method based on the change in the liquid phase concentration with time is studied in this work. The relation was derived for calculating the correction for the vapour space volume. On using some model solutions of different degree of non-ideality and of different concentrations, the magnitude of this correlation and its influence on the calculated vapour-liquid equilibrium data is studied. In case of systems of completely miscible liquids, it is not necessary, as a rule, to expect a more significant effect of the vapour space size on vapor-liquid equilibrium.
Study of the Reactivity of 2-Benzylidene[3]ferrocenophane-1,3-dione with Ethyl Acetoacetate and Some Other C-Nucleophiles
Authors: Sališová Marta , Šebo Ľubomír , Toma Štefan , Solčániová Eva
Published: April 2003

Michael addition of C-nucleophiles to 2-benzylidine[3]ferrocenophane-1,3-dione has been studied. In some cases, (ethyl acetoacetate, acetylacetone and malononitrile as the C-nucleophiles) the addition was followed by intramolecular cyclization leading to pyran derivatives. Addition of malononitrile gave the pyran derivative as a sole product. The Michael adducts of ethyl acetoacetate and acetylacetone can be converted to [7]ferrocenophane-1,7-dione derivatives by refluxing in benzene with triethylamine as catalyst. they also easily react with ammonia, under SiO2 catalysis, to give Hantzsch dihydropyridine derivatives. The 1H NMR spectra of the products are discussed.
Thermodynamic Functions of Pendular Molecules
Authors: Friedrich Břetislav , Herschbach Dudley R.
Published: April 2003

External electric or magnetic fields can hybridize rotational states of individual dipolar molecules and thus create pendular states whose field-dependent eigenproperties differ qualitatively from those of a rotor or an oscilator. The pendular eigenfunctions are directional, so the molecular axis id oriented. Here we use quantum statistical mechanics to evaluate ensamble properties of the pendular states. For linear molecules, the partition function and the averages that determine the thermodynamic functions can be specified by two reduced variables involving the dipole moment, field strength, rotational constant, and temperature. We examine a simple approximation due to Pitzer that employs the classical partition function with quantum corrections. This provides explicit analytic formulas which permit thermodynamic properties to be evaluated to good accuracy without computing energy levels. As applications we evaluate the high-field average orientation of the molecular dipoles and field-induced shifts of chemical equilibria.
Synthesis of 5-Arylidene-2,4,6(1H,3H,5H)pyrimidinetrione Derivatives
Authors: Prousek Josef
Published: April 2003

From the synthetic viewpoint, barbituric acid and its derivatives serve in preparation of acrylidine condensation products. We have now synthesized new derivatives by reaction of barbituric acid with the corresponding heterocyclic aldehydes RCH=O in DMF.
ON KIRBY'S PROBLEM ABOUT SIMPLICATION OF LINKS
Authors: MANCHÓN P. M. G.
Published: April 2003

Totally included framed links are defined and an algorithm for moving these links to Lickorish's framed links is given by means of a refinement of the Fundamental Theorem of Surgery on 3-manifolds. This technique is applied to the simple chains or bracelets.
RACK SPACES AND LOOP SPACES
Authors: Wiest Bert
Published: April 2003

We prove that the rack and quandle spaces of links in 3-manifolds, considered only as topological spaces (disregarding their cubical structure), are closely related to certain subspaces of the loop spaces on the 3-manifold, which we call the vertical and the straight loop space of the link. Using these models we prove that the homotopy type of the non-augmented rack and quandle spaces of a link L in a 3-manifold M depends essentially only on the homotopy type of the pair (M,M -L).
GENERA OF KNOTS AND VASSILIEV INVARIANTS
Authors: Stoimenow A.
Published: April 2003

We prove that there is no non-constant Vassiliev invariant which is constant on alternating knots of Infinitely many genera (contrasting the existence of the Conway Vassiliev invariants, which vanish on any finite set of genera) and that a (non-constant) knot invariant with values bounded by a funciton of the genus, in particular any invariant depending just on genus, signature and maximal degree of the Alexander polynomial, is not a Vassiliev invariant.
UNDERSTANDING THE KAUFFMAN BRACKET SKEIN MODULE
Authors: BULLOCK DOUG , FROHMAN CHARLES , KANIA-BARTOSZYŃSKA JOANNA
Published: April 2003

The Kauffman bracket skein module K(M) of a 3-manifold M is defined over formal power series in the variable h by letting A = eh/4. For a compact oriented surface F, it is shown that K(F×I) is a quantization of the [Formula: see text]-characters of the fundamental group of F corresponding to a geometrically defined Poisson bracket. Finite type invariants for unoriented knots and links are defined and obtained from topologically free Kauffman bracket modules. A structure theorem for K(M) is given in terms of the affine [Formula: see text]-characters of π1(M). It follows for compact M that K(M) can be generated as a module by cables on a finite set of knots. Moreover, if M contains no incompressible surfaces, the module is topologically finitely generated.
AN OBSTRUCTION TO EMBEDDING 4-TANGLES IN LINKS
Authors: KREBES DAVID A.
Published: April 2003

We consider the ways in which a 4-tangle T inside a unit cube can be extended outside the cube into a knot or link L. We present two links n(T) and d(T) such that the greatest common divisor of the determinants of these two links always divides the determinant of the link L.

In order to prove this result we give a two-integer invariant of 4-tangles. Calculations are facilitated by viewing the determinant as the Kauffman bracket at a fourth root of -1, which sets the loop factor to zero. For rational tangles, our invariant coincides with the value of the associated continued fraction.
BILLIARD KNOTS IN A CYLINDER
Authors: LAMM C. , OBERMEYER D.
Published: April 2003

We define cylinder knots as billiard knots in a cylinder. We present a necessary condition for cylinder knots: after dividing cylinder knots by possible rotational symmetries we obtain ribbon knots. We obtain an upper bound for the number of cylinder knots with two fixed parameters (out of three). In addition we prove that rosette knots are cylinder knots.
A HOMFLY-PT POLYNOMIAL OF LINKS IN A SOLID TORUS
Authors: KIM JAEHOO PARK
Published: April 2003

In this paper a Homfly-pt type Laurant polynomial1 for links in S1 × D2 is defined. This invariant is defined by giving an algebra and a trace, analogous to the Hecke algebra construction of the Homfly-pt polynomial for links in S3.
DIAGRAMMATICS OF BRAIDED GROUP GAUGE THEORY
Authors: MAJID SHAHN
Published: April 2003

We develop a gauge theory or theory of bundles and connections on them at the level of braids and tangles. Extending recent algebraic work, we provide now a fully diagrammatic treatment of principal bundles, a theory of global gauge transformations, associated braided fiber bundles and covariant derivatives on them. We describe the local structure for a concrete ℤ3-graded or 'anyonic' realization of the theory.
FINITE TYPE LINK HOMOTOPY INVARIANTS
Authors: MELLOR BLAKE
Published: April 2003

In [2], Bar-Natan used unitrivalent diagrams to show that finite type invariants classify string links up to homotopy. In this paper, I will construct the correct spaces of chord diagrams and unitrivalent diagrams for links up to homotopy. I will use these spaces to show that, far from classifying links up to homotopy, the only rational finite type invariants of link homotopy are the linking numbers of the components.
VIRTUAL TANGLES AND A THEOREM OF KREBES
Authors: SILVER DANIEL S. , WILLIAMS SUSAN G.
Published: April 2003

Let t be a virtual tangle embedded in a virtual knot or link k. If a prime p divides the determinants of both the numerator and the denominator closure of t, then p divides the determinant of k.
LOCATION GAME ON THE PLANE
Authors: MAZALOV VLADIMIR , SAKAGUCHI MINORU
Published: April 2003

We analyze Hotelling's duopoly model on the plane. There are two players (firms) located in different points inside a circle and the customers are distributed with some density in it. The solution of two game-theoretic problems is derived. The first problem is to find the equilibrium prices for the homogeneous goods, and the second problem is to find the equilibrium allocation of the players inside the circle. The equilibrium in location game is constructed for uniform and non-uniform case.
DISCRETE TIME DYNAMIC GAMES WITH CONTINUUM OF PLAYERS II: SEMI-DECOMPOSABLE GAMES
Authors: WISZNIEWSKA-MATYSZKIEL AGNIESZKA
Published: April 2003

In this paper we consider dynamic games with continuum of players which can constitute a framework to model large financial markets. They are called semi-decomposable games.

In semi-decomposable games the system changes in response to a (possibly distorted) aggregate of players' decisions and the payoff is a sum of discounted semi-instantaneous payoffs. The purpose of this paper is to present some simple properties and applications of these games. The main result is an equivalence between dynamic equilibria and families of static equilibria in the corresponding static perfect-foresight games, as well as between dynamic and static best response sets. The existence of a dynamic equilibrium is also proven. These results are counterintuitive since they differ from results that can be obtained in games with a finite number of players.

The theoretical results are illustrated with examples describing large financial markets: markets for futures and stock exchanges.
SEMIVALUES AND VOTING POWER
Authors: LARUELLE ANNICK , VALENCIANO FEDERICO
Published: April 2003

In this paper we revise the axiomatic foundations and meaning of semivalues as measures of power on the domain of simple games, when these are interpreted as models of voting procedures. In this context we characterize the family of preferences on roles in voting procedures they represent, and each of them in particular. To this end we first characterize the family of semivalues and each of them in particular up to the choice of a zero and a unit of scale. As a result a reinterpretation of semivalues as a class of power indices is proposed and critically discussed.
1/f NOISE AS A DIAGNOSTIC TOOL TO INVESTIGATE THE QUALITY OF ANISOTROPIC CONDUCTIVE ADHESIVE (ACA) BONDS FOR BALL GRID ARRAYS (BGA'S)
Authors: JONGEN R. J. J. M. , VANDAMME L. K. J. , BONNÉ H. H. , DE VRIES J. W. C.
Published: April 2003

Reliability assessment of conductive adhesive bonds by humidity and temperature tests is time consuming and does not provide enough information about the details of the onset of degradation. There is a need for measurements that can give an early warning about the contact quality with more quantitative details about its degradation. Here 1/f noise of such contact arrays is investigated before and after temperature and humidity stress tests with different durations. 1/f Noise stems from conductance fluctuations.

We investigated the constriction resistance 1/f noise SR of the contact constriction resistance RC before accelerated aging and during aging at temperatures of 85°C and 110°C with an 85% relative humidity. Noise analysis on non-degraded samples is also a fast diagnostic tool for reliability characterization. From the analysis based on a noise model for a multispot contact, the onset of constriction resistance increase goes hand in hand with a strong increase in resistance noise. This is understood and can be characterized by a reduction in the electrical contact area Ae . The degree of contact degradation is expressed in a reduction of the real electrical contact area Ae of a multispot contact and is quantitatively given by the D-factor.
Continuous homomorphisms of Arens‐Michael algebras
Authors: Chigogidze Alex
Published: April 2003

It is shown that every continuous homomorphism of Arens‐Michael
algebras can be obtained as the limit of a morphism of certain
projective systems consisting of Fréchet algebras. Based on
this, we prove that a complemented subalgebra of an uncountable
product of Fréchet algebras is topologically isomorphic to
the product of Fréchet algebras.
A min‐max theorem and its applications to nonconservative systems
Authors: Weiguo Li , Hongjie Li
Published: April 2003

A nonvariational generation of a min‐max principle by A. Lazer is
made. And it is used to prove a new existence results for a
nonconservative systems of ordinary differential equations with
resonance.
Statistically strongly regular matrices and some core theorems
Authors: Mursaleen M. , Edely Osama H. H.
Published: April 2003

We define the statistically strongly regular matrices analogous to
the strongly regular matrices, and further we use these matrices to establish necessary and sufficient conditions to prove some core theorems.
Randers manifolds of positive constant curvature
Authors: Bejancu Aurel , Farran Hani Reda
Published: April 2003

We prove that any simply connected and complete Riemannian
manifold, on which a Randers metric of positive constant flag curvature exists, must be diffeomorphic to an odd‐dimensional sphere, provided a certain 1‐form vanishes on it.
Riesz bases and positive operators on Hilbert space
Authors: Holub James R.
Published: April 2003

It is shown that a normalized Riesz basis for a Hilbert space H (i.e., the isomorphic image of an orthonormal basis in H) induces in a natural way a new, but equivalent, inner product on
H in which it is an orthonormal basis, thereby extending the
sense in which Riesz bases and orthonormal bases are thought of
as being the same. A consequence of the
method of proof of this result yields a series representation for
all positive isomorphisms on a Hilbert space.
On the structure of multipliers of ℤ2
Authors: Martínez-Moro Edgar , Canogar-Mckenzie Roberto
Published: April 2003

We show the combinatorial structure of ℤ2 modulo sublattices similar to ℤ2. The tool we use for dealing with this purpose is the notion of association scheme. We classify when the scheme defined by the lattice is imprimitive and characterize its decomposition in terms of the decomposition
of the Gaussian integer defining the lattice. This arises in the classification of different forms of tiling ℤ2 by lattices of this type. The main application of these structures is
that they are closely related to two‐dimensional signal constellations with a Mannheim metric in the coding theory.
On a thin set of integers involving the largest prime factor function
Authors: De Koninck Jean-Marie , Doyon Nicolas
Published: April 2003

For each integer n ≥ 2, let P(n) denote its largest prime factor. Let S : = {n ≥ 2 : n does not divide P(n)!} and S(x) : = #{n ≤ x : n ∈ S}. Erdős (1991) conjectured that S is a set of zero density. This was proved by Kastanas (1994) who established that S(x) = O(x/logx). Recently, Akbik (1999) proved that . In this paper, we show that . We also investigate small and large gaps among the elements of S and state some conjectures.
Some submersions of CR‐hypersurfaces of Kaehler‐Einstein manifold
Authors: Mangione Vittorio
Published: April 2003

The Riemannian submersions of a CR‐hypersurface M of a Kaehler‐Einstein manifold are studied. If M is an extrinsic CR‐hypersurface of , then it is shown that the base space of the submersion is also a Kaehler‐Einstein
manifold.
Asymptotic expansions for ratios of products of gamma functions
Authors: Bühring Wolfgang
Published: April 2003

An asymptotic expansion for a ratio of products of gamma
functions is derived.
Ky Fan inequality and bounds for differences of means
Authors: Gao Peng
Published: April 2003

We prove an equivalent relation between Ky Fan‐type inequalities
and certain bounds for the differences of means. We also generalize a result of Alzer et al. (2001).
Gene Therapy Applications to Cancer Treatment
Authors: Scholl Susy M. , Michaelis Silke , McDermott Ray
Published: April 2003

Over the past ten years significant advances have been made in
the fields of gene therapy and tumour immunology, such that there
now exists a considerable body of evidence validating the proof
in the principle of gene therapy based cancer vaccines. While
clinical benefit has so far been marginal, data from preclinical
and early clinical trials of gene therapy combined with standard
therapies are strongly suggestive of additional benefit. Many
reasons have been proposed to explain the paucity of clinical
responses to single agent vaccination strategies including the
poor antigenicity of tumour cells and the development of
tolerance through down‐regulation of MHC, costimulatory, signal
transduction, and other molecules essential for the generation of
strong immune responses. In addition, there is now evidence from
animal models that the growing tumour may actively inhibit the
host immune response. Removal of the primary tumour prior to T
cell transfer from the spleen of cancer bearing animals, led to
effective tumour cell line specific immunity in the recipient
mouse suggesting that there is an ongoing tumour‐host
interaction. This model also illustrates the potential
difficulties of clinical vaccine trials in patients with advanced
stage disease.
Prodrugs for Gene‐Directed Enzyme‐Prodrug Therapy (Suicide Gene Therapy)
Authors: Denny William A.
Published: April 2003

This review focuses on the prodrugs used in suicide gene therapy.
These prodrugs need to satisfy a number of criteria. They must be
efficient and selective substrates for the activating enzyme, and
be metabolized to potent cytotoxins preferably able to kill cells
at all stages of the cell cycle. Both prodrugs and their
activated species should have good distributive properties, so
that the resulting bystander effects can maximize the
effectiveness of the therapy, since gene transduction
efficiencies are generally low. A total of 42 prodrugs explored
for use in suicide gene therapy with 12 different enzymes are
discussed, particularly in terms of their physiocochemical
properties. An important parameter in determining bystander
effects generated by passive diffusion is the lipophilicity of
the activated form, a property conveniently compared by diffusion
coefficients (log P for nonionizable compounds
and log D7 for compounds containing an
ionizable centre). Many of the early antimetabolite‐based
prodrugs provide very polar activated forms
that have limited abilities to diffuse across cell membranes, and
rely on gap junctions between cells for their bystander effects.
Several later studies have shown that more lipophilic, neutral
compounds have superior diffusion‐based bystander effects.
Prodrugs of DNA alkylating agents, that are less cell cycle‐specific than antimetabolites and more effective against noncycling tumor cells, appear in general to be more active
prodrugs, requiring less prolonged dosing schedules to be
effective. It is expected that continued studies to optimize the
bystander effects and other properties of prodrugs and the
activated species they generate will contribute to improvements
in the effectiveness of suicide gene therapy.
Sequestration of p27Kip1 protein by cyclin D1 in typical and blastic variants of mantle cell lymphoma (MCL): implications for pathogenesis
Authors: Quintanilla-Martinez Leticia , Davies-Hill Theresa , Fend Falko , Calzada-Wack Julia , Sorbara Lynn , Campo Elias , Jaffe Elaine S. , Raffeld Mark
Published: April 2003

p27 is a cyclin-dependent kinase inhibitor that plays a critical role in regulating G1/S progression, and whose activity is, in part, regulated through interactions with D-type cyclins. Mantle cell lymphoma (MCL) is characterized by the t(11;14) translocation resulting in deregulated cyclin D1. We previously showed that p27 expression in MCL, as assessed by immunohistochemistry (IHC), does not show the usual inverse relationship to proliferate seen in most other lymphomas that do not overexpress cyclin D1. This suggested that the normal expression or control of p27 activity on cell growth might be altered through potential interactions with cyclin D1. Using Western blot and coimmunoprecipitation studies, we assessed the interrelationship between cyclin D1 and p27 in several cyclin D1+ cell lines and primary MCL cases. Similar to our previous results by IHC, typical MCLs showed lower expression of p27 when compared to the more highly proliferative blastic cases or cell lines (mean arbitrary units: 58 versus 236 versus 120). Cyclin D1 was expressed at variable levels in both typical and blastic MCLs. p27 protein could be consistently coimmunoprecipitated with cyclin D1 from both cell lines and cases. Using techniques of exhaustive immunoprecipitation, we could demonstrate that most p27 protein was sequestered into complexes containing cyclin D1. We hypothesize that mantle cell lymphomagenesis results not only from direct consequences of inappropriate cyclin D1 expression, but also from the ability of overexpressed cyclin D1 to buffer physiologic changes in p27 levels, thereby rendering p27 ineffective as an inhibitor of cellular growth.
Roles of neutrophil β2 integrins in kinetics of bacteremia, extravasation, and tick acquisition of Anaplasma phagocytophila in mice
Authors: Borjesson Dori L. , Simon Scott I. , Hodzic Emir , DeCock Hilde E. V. , Ballantyne Christie M. , Barthold Stephen W.
Published: April 2003

Tick saliva contains anti-inflammatory and immunosuppressive substances that facilitate blood feeding and enhance tick-vectored pathogen transmission, including Anaplasma phagocytophila,an etiologic agent of granulocytic ehrlichiosis. As such, inflammation at a tick-feeding site is strikingly different than that typically observed at other sites of inflammation. Up-regulation of CD11b/CD18 occurs in host granulocytes following interaction or infection withA phagocytophila, and the absence of CD11b/CD18 results in early increases in bacteremia. We hypothesized that β2 integrin–dependent infection kinetics and leukocyte extravasation are important determinants of neutrophil trafficking to, and pathogen acquisition at, tick-feeding sites.A phagocytophila infection kinetics were evaluated in CD11a/CD18, CD11b/CD18, and CD18 knock-out mice using quantitative polymerase chain reaction (PCR) of blood, ticks, and skin biopsies in conjunction with histopathology. A marked increase in the rate ofA phagocytophila infection of neutrophils and pathogen burden in blood followed tick feeding. Infection kinetics were modified by β2 integrin expression and systemic neutrophil counts. Significant neutrophil-pathogen trafficking was observed to both suture and tick sites. Despite the prominent role for β2 integrins in neutrophil arrest in flowing blood, successful pathogen acquisition by ticks occurred in the absence of β2 integrins. Establishment of feeding pools that rely less on leukocyte trafficking and more on small hemorrhages may explain the ready amplification of A phagocytophila DNA from ticks infested on CD11/CD18-deficient mouse strains.
Signal transducer and activator of transcription proteins in leukemias
Authors: Benekli Mustafa , Baer Maria R. , Baumann Heinz , Wetzler Meir
Published: April 2003

Signal transducer and activator of transcription (STAT) proteins are a 7-member family of cytoplasmic transcription factors that contribute to signal transduction by cytokines, hormones, and growth factors. STAT proteins control fundamental cellular processes, including survival, proliferation, and differentiation. Given the critical roles of STAT proteins, it was hypothesized that inappropriate or aberrant activation of STATs might contribute to cellular transformation and, in particular, leukemogenesis. Constitutive activation of mutated STAT3 has in fact been demonstrated to result in transformation. STAT activation has been extensively studied in leukemias, and mechanisms of STAT activation and the potential role of STAT signaling in leukemogenesis are the focus of this review. A better understanding of mechanisms of dysregulation of STAT signaling pathways may serve as a basis for designing novel therapeutic strategies that target these pathways in leukemia cells.
Fetal liver stroma consists of cells in epithelial-to-mesenchymal transition
Authors: Chagraoui Jalila , Lepage-Noll Adeline , Anjo Aurora , Uzan Georges , Charbord Pierre
Published: April 2003

Liver becomes the predominant site of hematopoiesis by 11.5 dpc (days after coitus) in the mouse and 15 gestational weeks in humans and stays so until the end of gestation. The reason the liver is the major hematopoietic site during fetal life is not clear. In this work, we tried to define which of the fetal liver microenvironmental cell populations would be associated with the development of hematopoiesis and found that a population of cells with mixed endodermal and mesodermal features corresponded to hematopoietic-supportive fetal liver stroma. Stromal cells generated from primary cultures or stromal lines from mouse or human fetal liver in the hematopoietic florid phase expressed both mesenchymal markers (vimentin, osteopontin, collagen I, α smooth muscle actin, thrombospondin-1, EDa fibronectin, calponin, Stro-1 antigens, myocyte-enhancer factor 2C) and epithelial (α-fetoprotein, cytokeratins 8 and 18, albumin, E-cadherin, hepatocyte nuclear factor 3 α) markers. Such a cell population fits with the description of cells in epithelial-to-mesenchymal transition (EMT), often observed during development, including that of the liver. The hematopoietic supportive capacity of EMT cells was lost after hepatocytic maturation, induced by oncostatin M in the cell line AFT024. EMT cells were observed in the fetal liver microenvironment during the hematopoietic phase but not in nonhematopoietic liver by the end of gestation and in the adult. EMT cells represent a novel stromal cell type that may be generated from hepatic endodermal or mesenchymal stem cells or even from circulating hematopoietic stem cells (HSCs) seeding the liver rudiment.
Central venous catheters and upper-extremity deep-vein thrombosis complicating immune heparin-induced thrombocytopenia
Authors: Hong Aaron P. , Cook Deborah J. , Sigouin Christopher S. , Warkentin Theodore E.
Published: April 2003

Heparin-induced thrombocytopenia (HIT) is a transient antibody-mediated hypercoagulability state strongly associated with lower-limb deep-vein thrombosis (DVT). Whether HIT is additionally associated with upper-limb DVT—either with or without central venous catheter (CVC) use—is unknown. We therefore studied 260 patients with antibody-positive HIT to determine the influence of CVC use on frequency and localization of upper-extremity DVT in comparison with 2 non-HIT control populations (postoperative orthopedic surgery and intensive-care unit patients). Compared with the control populations, both upper- and lower-extremity DVTs were found to be associated with HIT. Upper-extremity DVTs occurred more frequently in HIT patients with a CVC (14 of 145 [9.7%]) versus none of 115 (0%) patients without a CVC (P = .000 35). All upper-extremity DVTs occurred at the CVC site (right, 12; left, 2; kappa = 1.0; P = .011). We conclude that a localizing vascular injury (CVC use) and a systemic hypercoagulability disorder (HIT) interact to explain upper-extremity DVT complicating HIT.
Sustained complete hematologic remission after administration of the tyrosine kinase inhibitor imatinib mesylate in a patient with refractory, secondary AML
Authors: Kindler Thomas , Breitenbuecher Frank , Marx Andreas , Hess Georg , Gschaidmeier Harald , Gamm Heinold , Kirkpatrick Charles J. , Huber Christoph , Fischer Thomas
Published: April 2003

Imatinib mesylate, a tyrosine kinase inhibitor targeting bcr-abl, platelet-derived growth factor receptor (PDGF-R), and c-Kit, effectively induces hematologic and cytogenetic remissions in bcr-abl+ chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) with only mild to moderate side effects. Here, we describe the successful treatment of a 64-year-old man with c-Kit+ secondary acute myeloid leukemia (AML) refractory to standard chemotherapy. Upon 2 weeks of imatinib mesylate administration, the patient achieved a complete hematologic remission in peripheral blood. In addition, complete clearance of leukemic blasts in bone marrow and a significant cytogenetic response lasting for more than 5 months was observed. Sequence analysis of exons 2, 8, 10, 11, and 17 of the c-Kit receptor did not reveal structural alterations as previously described in a subset of AML cases. This is the first report of complete remission achieved upon administration of imatinib mesylate in a patient with highly refractory, secondary AML.
Mitochondrial DNA mutations in patients with myelodysplastic syndromes
Authors: Shin Myung Geun , Kajigaya Sachiko , Levin Barbara C. , Young Neal S.
Published: April 2003

We undertook to systematically analyze the entire mitochondrial genome by gene amplification and direct sequencing in 10 patients with myelodysplasia; results were compared with concomitantly studied 8 healthy volunteers as well as mtDNA sequences in a standard database. Nucleotide changes that were present in our healthy controls as well as those in published databases were counted as polymorphisms. Overall, there was no increase in the number of mtDNA genes harboring polymorphisms or “new” mutations between our patients and healthy controls, although there were a few more mtDNA changes resulting in amino acid changes in myelodysplasia (9 in 8 controls versus 16 in 10 patients). Thirty new mutations, all nucleotide substitutions, were found among the 10 patients, distributed throughout the mitochondrial genome; 5 mutations resulted in amino acid changes. None of the mutations in controls produced amino acid changes. We were not able to confirm previously described mutations in sideroblastic anemia or “hot spots” in the cytochrome c oxidase I and II genes. Our data do not support a major role for mitochondrial genomic instability in myelodysplasia, and they fail to reproduce previous reports of significant or widespread mitochondrial mutations in this disease. Modest changes in mutation numbers and mitochondrial microsatellites may be evidence of increased mutagenesis in mtDNA, or, more likely, a reflection of limited clonality among hematopoietic stem cells in this bone marrow failure syndrome.
Selective serotonin reuptake inhibitors directly signal for apoptosis in biopsy-like Burkitt lymphoma cells
Authors: Serafeim Adamantios , Holder Michelle J. , Grafton Gillian , Chamba Anita , Drayson Mark T. , Luong Quang T. , Bunce Christopher M. , Gregory Christopher D. , Barnes Nicholas M. , Gordon John
Published: April 2003

Selective serotonin reuptake inhibitors (SSRIs) are the treatment of choice for clinical depression and a range of anxiety-related disorders. They are well tolerated over extended periods with more than 50 million people worldwide benefiting from their use. Here we show that 3 structurally distinct SSRIs—fluoxetine, paroxetine, and citalopram—act directly on Burkitt lymphoma (BL) cells to trigger rapid and extensive programmed cell death. SSRIs unexpectedly stimulated calcium flux, tyrosine phosphorylation, and down-regulation of the c-myc and nm23 genes in Burkitt lymphoma cells remaining faithful to the biopsy phenotype. Resultant SSRI-induced apoptosis was preceded by caspase activation, poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, DNA fragmentation, a loss of mitochondrial membrane potential, and the externalization of phosphatidylserine, and reversed by the overexpression of bcl-2. Normal peripheral blood mononuclear cells and tonsil B cells, whether resting or stimulated into cycle, were largely resistant to SSRI-induced death as were 5 non-BL lymphoid cell lines tested. We discuss these findings within the context of whether the SSRI class of antidepressants could find future application as potential therapeutics for the highly aggressive and—because of its association with AIDS—increasingly more common Burkitt lymphoma.
Active suppression of allogeneic proliferative responses by dendritic cells after induction of long-term allograft survival by CTLA4Ig
Authors: Guillot Cécile , Ménoret Séverine , Guillonneau Carole , Braudeau Cécile , Castro Maria G. , Lowenstein Pedro , Anegon Ignacio
Published: April 2003

Costimulatory blockade using cytotoxic T lymphocyte–associated antigen 4 immunoglobulin (CTLA4Ig) efficiently down-regulates immune responses in animal models and is currently used in autoimmune and transplantation clinical trials, but the precise cellular and molecular mechanisms involved remain unclear. Rats that received allogeneic heart transplants and were treated with adenoviruses coding for CTLA4Ig show long-term allograft survival. The immune mechanisms regulating induction of long-term allograft acceptance were analyzed in splenocytes using mixed leukocyte reactions (MLRs). MLRs of splenocytes but not purified T cells from CTLA4Ig-treated rats showed higher than 75% inhibition compared with controls. Splenocytes from CTLA4Ig-treated rats inhibited proliferation of naive and allogeneically primed splenocytes or T cells. MLR suppression was dependent on soluble secreted product(s). Production of soluble inhibitory product(s) was triggered by a donor antigen-specific stimulation and inhibited proliferation in an antigen-nonspecific manner. CTLA4Ig levels in the culture supernatant were undetectable and neither interleukin-10 (IL-10), transforming growth factor β1 (TGFβ1), IL-4, nor IL-13 were responsible for suppression of MLRs. Inhibition of nitrous oxide (NO) production or addition of IL-2 could not restore proliferation independently, but the combined treatment synergistically induced proliferation comparable with controls. Stimulation of APCs using tumor necrosis factor (TNF)–related activation-induced cytokine (TRANCE) or CD40L and addition of IL-2 normalized MLRs of CTLA4Ig-treated splenocytes. Finally, dendritic cells (DCs), but not T cells, from CTLA4Ig-treated rats inhibited naive MLRs. Altogether, these results provide evidence that after in vivo CTLA4Ig treatment, splenocytes, and in particular DCs, can inhibit alloantigen-induced proliferative responses through secretion of inhibitory products, thus promoting alloantigen-specific tolerance in vivo.
UbcH5A, a member of human E2 ubiquitin-conjugating enzymes, is closely related to SFT, a stimulator of iron transport, and is up-regulated in hereditary hemochromatosis
Authors: Gehrke Sven G. , Riedel Hans-Dieter , Herrmann Thomas , Hadaschik Boris , Bents Karin , Veltkamp Claudia , Stremmel Wolfgang
Published: April 2003

SFT, a stimulator of iron (Fe) transport, has been described as a transmembrane protein that facilitates the uptake of ferrous and ferric iron in mammalian cells. This study was initiated to investigate the 5′ regulatory region of SFT and its role in the etiology of hereditary hemochromatosis. Sequence analyses of the putative 5′ regulatory region revealed that the SFT cDNA sequence corresponds to intron 6/exon 7 of UbcH5A, a member of E2 ubiquitin-conjugating enzymes, which is involved in the iron-dependent ubiquitination of the hypoxia-inducible factor (HIF) by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. Further mRNA expression studies using a sequence-specific reverse transcriptase–polymerase chain reaction (RT-PCR) assay showed that UbcH5A is significantly up-regulated in the liver of iron-overloaded patients with hereditary hemochromatosis, as previously published for SFT. However, in vitro studies on HepG2 cells failed to demonstrate any significant UbcH5A regulation in response to iron loading or iron chelation. In conclusion, in vivo mRNA expression data previously obtained for SFT might be attributed to UbcH5A. The role of UbcH5A and the ubiquitination pathway in the etiology of hereditary hemochromatosis remains to be elucidated further.
Regulation of the cell-surface expression of an HTLV-I binding protein in human T cells during immune activation
Authors: Nath Manisha D. , Ruscetti Francis W. , Petrow-Sadowski Cari , Jones Kathryn S.
Published: April 2003

Little is known about the requirements for human T-cell leukemia virus type I (HTLV-I) entry, including the identity of the cellular receptor(s). Recently, we have generated an HTLV-I surface glycoprotein (SU) immunoadhesin, HTSU-IgG, which binds specifically to cell-surface protein(s) critical for HTLV-I–mediated entry in cell lines. Here, expression of the HTLV-I SU binding protein on primary cells of the immune system was examined. The immunoadhesin specifically bound to adult T cells, B cells, NK cells, and macrophages. Cell stimulation dramatically increased the amount of binding, with the highest levels of binding on CD4+ and CD8+ T cells. Naive (CD45RAhigh, CD62Lhigh) CD4+ T cells derived from cord blood cells, in contrast to other primary cells and all cell lines examined, bound no detectable HTLV-I SU. However, following stimulation, the level of HTSU-IgG binding was rapidly induced (fewer than 6 hours), reaching the level of binding seen on adult CD4+ T cells by 72 hours. In contrast to HTLV-I virions, the soluble HTSU-IgG did not effect T-cell activation or proliferation. When incubated with human peripheral blood mononuclear cells in a mixed leukocyte reaction, HTSU-IgG inhibited proliferation at less than 1 ng/mL. These results indicate that cell-surface expression of the HTLV SU binding protein is up-regulated during in vitro activation and suggest a role for the HTLV-I SU binding proteins in the immunobiology of CD4+ T cells.