bluuebunny/crossref_metadata_2025 huggingface dataset:
DELAYED RESPONSE IN TRACER EXPERIMENTS AND FRAGMENT-CARRIER APPROACH TO TRANSIT TIME DISTRIBUTIONS IN NONLINEAR CHEMICAL KINETICS
Authors: VLAD MARCEL O. , ROSS JOHN , MORAN FEDERICO , RODRIGUEZ YOEL
Published: December 2002

A delayed response tracer experiment is suggested, based on the following constraints: (1) The kinetics of the process can be expressed by local evolution equations without delays, for example by the mass action law. (2) The kinetic isotope effect can be neglected, that is, the rate coefficients for labeled and unlabeled chemicals are the same. (3) The total fluxes of the various chemicals are generally time dependent, but are not modified by the presence of the labeled compounds. (4) The experiment consists in the measurement of the time dependence of the fractions βu, u = 1, 2,… of labeled chemicals in the output fluxes as functionals of the time dependence of the fractions αu, u = 1, 2,… of labeled chemicals in the input fluxes, which are controlled by the researcher. We show that the output fluxes are related to the input fluxes by a linear delayed superposition theorem: βu(t) = ∑u′ ∫ χuu′(t,t′)αu′(t′)dt′, where χuu′(t,t′), is a delayed susceptibility function, which is related to the probability density of the transit time, that is, the time necessary for a molecular fragment to cross the system. This linear superposition law is not the result of a linearization procedure and holds even if the underlying kinetic equations are highly nonlinear. We establish a relationship between the transit time probability densities and the lifetime distributions of the various species in the system. The law permits extracting information about the mechanism and kinetics of chemical processes from response experiments.
EXACT FORMULA FOR THE MEAN LENGTH OF A RANDOM WALK ON THE SIERPINSKI TOWER
Authors: KOZAK JOHN J. , BALAKRISHNAN V.
Published: December 2002

We consider an unbiased random walk on a finite, nth generation Sierpinski gasket (or "tower") in d = 3 Euclidean dimensions, in the presence of a trap at one vertex. The mean walk length (or mean number of time steps to absorption) is given by the exact formula [Formula: see text]

The generalization of this formula to the case of a tower embedded in an arbitrary number d of Euclidean dimensions is also found, and is given by [Formula: see text]

This also establishes the leading large-n behavior [Formula: see text] that may be expected on general grounds, where Nn is the number of sites on the nth generation tower and [Formula: see text] is the spectral dimension of the fractal.
LOCALIZED PATTERNS AND FRONTS IN NONEQUILIBRIUM SYSTEMS
Authors: COULLET P.
Published: December 2002

The aim of this paper is to review some of the mechanisms which leads to stable localized patterns in nonequilibrium systems.
MODELING WITH INCREASED EFFICIENCY AND VERSATILITY FOR FLEXURAL-TORSIONAL BUCKLING OF UNSYMMETRICAL THIN-WALLED STRUCTURES
Authors: MARZOUK S. S. , GENDY A. S. , MIKHAIEL S. N. , SALEEB A. F.
Published: December 2002

Aiming at the performance-enhancement in coarse mesh modeling, we utilize a number of closed form solutions of a class of torsionally loaded thin-walled bars to formulate a two-noded element for spatial buckling analysis. The key in this relates to the use of the "exact" solution for the displacement fields (as oppose to the more conventional finite element approach where polynomial/Lagrangian-type interpolation is employed). That is, in addition to the well known "exact" solution for the coupled flexure/transverse-shear problem, we utilize a new "exact" solution for the more difficult case of coupled system of differential equations governing a torsionally loaded thin-walled beam using the higher-order theories of non-uniform twist/bi-moment with coupled warping-shear deformations. For the linear analysis, convergence and accuracy study indicated that the proposed model to be rapidly convergent, stable and computationally efficient; i.e. one element is sufficient to exactly represent an end loaded part of the beam. Such model has been extended to account for nonlinear analysis, in particular, the flexural torsional buckling of thin-walled structures. To this end, the effect of finite rotations in space is accounted for as per the modern theories of spatial buckling, resulting in second-order accurate geometric stiffness matrices. Compared with the classical theory of thin-walled structures, the present approach is more general in that all significant modes of stretching, bending, shear (due to both flexure and torsional/warping), torsion, and warping are accounted for. The inclusion of non-uniform torsion is accomplished through adoption of the principle sectorial area. This requires incorporation of a warping degree of freedom in addition to the conventional six degrees of freedom at each node. The element is derived for general cross sections including the Wagner-effect contributions. The model's properties and performance, particularly with regard to the resulting (significant) improvements in mesh accuracy, are assessed in a fairly complete set of numerical simulations.
BUCKLING OF COLUMNS WITH INTERNAL SLIDE RELEASE
Authors: EISENBERGER M. , AMBARSUMIAN H.
Published: December 2002

The exact buckling loads of columns with internal slide release are found using the exact stiffness matrix of the column including the effect of the axial forces. Two types of columns are considered: clamped–clamped and clamped-simply supported with internal slide release at variable locations along the member. It is found that for both the clamped–clamped and the clamped-simply supported columns the buckling load is constant and does not depend on the location of the slide discontinuity.
ASEISMIC CAPACITY ASSESSMENT FOR HIGH-RISE STEEL FRAMES CONSIDERING INELASTIC STABILITY EFFECTS WITH SIDESWAY
Authors: LEE WEN-HAE , CHERN CHING-CHURN
Published: December 2002

During a severe earthquake, plastic hinges can occur at the ends of beams or columns of a high-rise steel frame. Because of this, the critical load of a steel column of the frame cannot be evaluated directly from the conventional alignment charts. In this study, the inelastic stability characteristic equations for five types of substructures that cover a total of twenty-two stability modes for steel columns are derived, from which the critical load Pcrand effective length factor K of a column of the frame in the inelastic stage are solved. The results show that the inelastic effective length factors K computed for the steel columns are larger than those for the elastic case for some modes, meaning that the inelastic critical load is less than the elastic critical load for the same steel column. Thus, the seismic lateral resistant capacity of a steel frame is overestimated if the columns of the frame are designed solely based on the elastic stability analysis.
QUANTUM PARRONDO GAMES: BIASED AND UNBIASED
Authors: MEYER DAVID A. , BLUMER HEATHER
Published: December 2002

Although the dissipative character of thermal diffusion, which is modelled by Parrondo games, might seem necessary to achieve the "paradoxical" behaviour corresponding to ratcheting, quantum Parrondo games with similar properties can be constructed. There are subtle differences, however, which manifest themselves in distinct asymptotic behaviours for biased and unbiased games.
A CHARACTERIZATION OF NONSINGULAR PAIRS OF QUADRATIC FORMS
Authors: LEEP DAVID B. , SCHUELLER LAURA MANN
Published: December 2002

Let F, G be a pair of quadratic forms defined over an arbitrary field k. We give a characterization for when every nontrivial zero of F = G = 0 defined over the algebraic closure of k is nonsingular. When chark ≠ 2, this result is well known. When chark = 2, the problem divides into two cases. If n is odd, we use the half-determinant, and if n is even, we use the Arf invariant for this characterization. The characterization depends only on the coefficients of the quadratic forms and operations taking place in the field k.
ALMOST PERFECT LOCAL DOMAINS AND THEIR DOMINATING ARCHIMEDEAN VALUATION DOMAINS
Authors: ZANARDO PAOLO
Published: December 2002

A commutative ring R is said to be almost perfect if R/I is perfect for every nonzero ideal I of R. We prove that an almost perfect local domain R is dominated by a unique archimedean valuation domain V of its field of quotients Q if and only if the integral closure of R contains an ideal of V. We show how to construct almost perfect local domains dominated by finitely many archimedean valuation domains. We provide several examples illustrating various possible situations. In particular, we construct an almost perfect local domain whose maximal ideal is not almost nilpotent.
FINITE-FINITARY GROUPS OF AUTOMORPHISMS
Authors: WEHRFRITZ B. A. F.
Published: December 2002

In this paper we attempt to describe the structure of groups G of automorphisms of an abelian group M with the property that M(g - 1) is finite for every element g of G. These groups are closely related to the finitary linear groups over finite fields. The abelian case is critical for our work and the core result of this paper is the following. An abelian group A is isomorphic to a group G as above with M torsion if and only if A is torsion and has a residually-finite subgroup B with A/B a direct sum of cyclic groups.
DIRECTED GROWTH OF SINGLE-WALLED CARBON NANOTUBES
Authors: DELZEIT LANCE , STEVENS RAMSEY , NGUYEN CATTIEN , MEYYAPPAN M.
Published: December 2002

Single-walled carbon nanotubes (SWNTs) are grown by thermal chemical vapor deposition at 900°C using methane. Application of an electric field (0.4 V/μm) in situ during the growth process results in directed growth of SWNTs on a horizontal plane bridging a distance as long as 25 μm. This approach is useful in the fabrication of nanotube based transistors.
ENGINEERING CARBON NANOTUBES VIA TEMPLATE GROWTH
Authors: PAPADOPOULOS C. , CHANG B. H. , YIN A. J. , XU J. M.
Published: December 2002

Controlled growth and precise placement of carbon nanotubes (CNTs) are two vital capabilities for the practical implementation of CNT device designs. This article presents an overview of our research activities aimed at using CVD template growth to both structure and precisely align CNTs into functional system building blocks. Fabrication results on highly-ordered CNT arrays and Y-junction CNTs are described along with an outline of their novel physical properties that could lead to unique device applications.
COMPUTING NARROW NANOTUBES AND THEIR DERIVATIVES
Authors: SLANINA ZDENĚK , UHLÍK FILIP , STOBINSKI LESZEK , LIN HONG-MING , ADAMOWICZ LUDWIK
Published: December 2002

Very recently, narrow nanotubes have been observed with diameters of 5 or even 4 Å. In this report we survey calculations that have so far been performed on narrow model nanotubes, namely capped by fragments of D2d and D6h C 36 fullerene cages or by fragments of C 32 and C 16quasi-fullerene cages with two four-membered rings, or finally by a fragment of dodecahedral C 20. The computations can reproduce the observed diameters of the narrow nanotubes. The results also indicate that fragments of C 32, used as caps instead of C 36, can lead to quite competitive energetics. Thus, a novel possibility that some of the narrow nanotubes can contain four-membered rings at their tips seems plausible. The present paper also surveys computational study of oxygen additions to the narrow nanotubes, i.e., a problem frequently studied with fullerenes. Both thermodynamic enthalpy changes and kinetic activation barriers for oxygen addition to selected bonds are computed and analyzed. The lowest isomer (thermodynamically the most stable) is never of the 6/6 type, i.e., the thermodynamically most convenient structures are produced by oxygen additions to the nanotube tips. The computations show that narrow nanotubes should be relatively prone to additions of oxygen.
TRANSPORT PROPERTIES OF TEMPLATE-SYNTHESIZED GOLD AND CARBON NANOTUBE MEMBRANES
Authors: WIRTZ MARC , MILLER SCOTT A. , MARTIN CHARLES R.
Published: December 2002

We discuss the fabrication of gold and carbon nanotubes prepared by the template method. The gold nanotubes are prepared via electroless deposition of Au onto the pore walls of a nanoporous polycarbonate filtration membrane. Carbon nanotube membranes (CNMs) are prepared by doing chemical vapor deposition of carbon within the pores of a microporous alumina template. The pores in these filtration membranes act as templates for the nanotubes. We have shown that by controlling the Au deposition time, Au nanotubes that have effective inside diameters of molecular dimensions (<1 nm) can be prepared. These membranes are a new class of molecular sieves and can be used to separate molecules based on size. Furthermore, we describe fundamental investigations of electro osmotic flow (EOF) in carbon nanotube membranes. In addition, an electrochemical derivatization method was used to attach carboxylate groups to the nanotube walls; this enhances the anionic surface charge density, resulting in a corresponding increase in the EOF rate in the CNM.
SYMMETRY AND ELECTRO-OPTICAL PROPERTIES OF NANOTUBES
Authors: DAMNJANOVIĆ M. , MILOŠEVIĆ I. , VUKOVIĆ T. , NIKOLIĆ B. , DOBARDŽIĆ E.
Published: December 2002

The symmetry of single-wall carbon and inorganic tubes is reviewed. For the carbon nanotubes it is used to get the full set of quantum numbers, in the efficient precision (combined density functional and tight-binding methods) calculation of electronic bands and their complete assignation, to obtain the selection rules for optical transitions and the momenta matrix elements for the Bloch eigen-states. The optical characteristics are thoroughly found, and discussed.
STUDIES OF HYDROGEN MOLECULAR FLUX ENCAGING INTO CARBON NANOTUBE USING COMPUTER SIMULATION
Authors: ELTEKOV V. A.
Published: December 2002

The encaging of H 2 or D 2 molecules flux by carbon closed nanotube is considered. The investigation is based on the computer simulation of the process. Several equations of particle motion were solved numerically by the use of high-speed computer. The nanotube was represented by carbon closed tube consisting of 1572 atoms. The interatomic forces were supposed to be defined from combined potential. The interaction of all participating atoms with each others was taken into account. The energy of incident molecules varied from 25 to 175 eV/atom. The direction of molecular beam was chosen to be orthogonal to the tube axis. The statistical validity was provided by 1000 modeled trajectories of incident molecules for each value of initial energy. The variety of final situations were considered. The encaging events were registered at the low energies. They consisted about 15% at energy values up to 80 eV for H and up to 60 eV for D. At higher energies the encaging probability diminished monotonically. The adsorption probability falls from 80% at the 25-to-90-eV energy interval to 10% at 150 eV for H and at 120 eV for D and then monotonically to zero. The penetration of H atoms through two walls of carbon nanotube grows from zero to 10% at 80 eV, then reaches 50% at 110 eV. At 140 eV it is close to 90%. The corresponding values of energy for D atoms are less by factor 1.2 or so. The molecule dissociation probability was not more than 10% for the total energy interval under investigation. The investigation allows to conclude that the carbon closed nanotube is able to serve as the light atom trap at the incident molecule energies up to about 100 eV/atom.
ROLE OF DEFECTS IN CARBON NANOTUBE CIRCUITS
Authors: JOHNSON A. T. , FREITAG M. , RADOSAVLJEVIC M. , KALININ S. V. , BONNELL D. A.
Published: December 2002

We summarize recent results on the impact of defects on the electronic properties of single-wall carbon nanotubes. We probe the influence of defects on electron transport in CNFETs by combined scanning gate microscopy (SGM) and scanning impedance microscopy (SIM). Depletion surface potential of individual defects is quantified from the SGM-imaged defect radius as a function of tip bias voltage. This provides a measure of the Fermi level at the defect with zero tip voltage. In the "off" state, transport is first dominated by barriers at depleted defects. It becomes diffusive as the CNFET is turned on, and finally is quasi-ballistic in the regime of "degenerate electrostatic doping". Metallic nanotubes with good contacts show a metal-to-insulator crossover as the gate voltage is varied. In the metallic state we see quantitative agreement with the "twiston" scattering picture.
FORMATION OF CARBON NANOTUBES ON CARBON PAPER AND STAINLESS STEEL SCREEN BY OHMICALLY HEATING CATALYTIC SITES
Authors: SUN X. , LI R. , LEBRUN G. , STANSFIELD B. , DODELET J. P. , DÉSILETS S.
Published: December 2002

A newly designed gas phase thermal decomposition reactor, ohmically heating the catalytic sites, has been used to synthesize multiwall carbon nanotubes (MWCNTs) on carbon paper and stainless steel screen. Co-Ni catalyst particles were dispersed by a silane intermediate layer adsorbed onto the carbon fibers or the stainless steel threads of the supports. MWCNTs were obtained on both substrates by a tip grown mechanism. They are about 20 μm in length and 15–50 nm in diameter. A methanol pretreatment of the carbon fibers significantly increased the density of the tubes on the carbon paper, but the same treatment had a negative effect on stainless steel. The MWCNTs, which adhere firmly to the carbon paper and the stainless steel screen, may find applications as electrodes in fuel cells, sensors and in photonics.
SOLUBILIZATION OF CARBON NANOTUBES VIA POLYMER ATTACHMENT
Authors: HILL DARRON E. , LIN YI , ALLARD LAWRENCE F. , SUN YA-PING
Published: December 2002

Carbon nanotubes were functionalized by polystyrene copolymers, poly(styrene-co-hydroxymethylstyrene) and poly(styrene-co-aminomethylstyrene), under esterification and amidation reaction conditions, respectively. The polymer-attached carbon nanotubes are soluble in common organic solvents, forming colored homogeneous solutions. Results from the characterization of the functionalized carbon nanotubes are presented and discussed.
MAGNETO-OPTIC PROPERTIES OF CARBON NANOPARTICLES IN SUSPENSION
Authors: POLUSHIN SERGEY , RJUMTSEV EVGENY , NIKITIN VLADIMIR , PONOMAREV ANDREY , LETENKO DMITRY
Published: December 2002

The magnetic birefringence of the water suspension of materials containing up to 5% of multi-walled carbon nanotubes (MWNTs) was investigated in this work. The observed magneto-optic effect may be considered as a superposition of competitive effects. The negative one is due to the presence of graphite nanoclusters in the suspension, and the positive effect is due to the stick-like nanostructures such as MWNTs and their aggregates. It was found that the speed of sedimentation for nanotubes is less than it for graphite-like particles. As a result, the enrichment process takes place.
Measurement of strain‐dependent toxicity in the indene bioconversion using multiparameter flow cytometry
Authors: Amanullah A. , Hewitt C. J. , Nienow A. W. , Lee C. , Chartrain M. , Buckland B. C. , Drew S. W. , Woodley J. M.
Published: December 2002

The bionconversion of indene to cis‐(1S,2R)‐indandiol, a potential key intermediate in the synthesis of Merck's HIV protease inhibitor, CRIXIVAN™, can be achieved using Rhodococcus, Pseudomonas putida, and Escherichia coli strains. This study reports on the application of multiparameter flow cytometry for the measurement of cytoplasmic membrane integrity and membrane depolarization as indicators of toxic effects of the substrate, product, and by‐products using each of these strains. Measurements of oxygen uptake rate (OUR) and optical density (OD) as indicators of metabolic activity and biomass growth, respectively, were also made. Measurements of the cytoplasmic membrane potential, cell viability, and respiratory activity provided a sensitive set of parameters to assess toxicity in the indene bioconversion and provided the basis for process improvements and strain selection. The toxic concentrations of the substrate, product, and by‐products for each strain have been determined. The results show that it is possible to accumulate cis‐(1S,2R)‐indandiol and cis‐1‐amino‐2‐indanol up to 20 g/L without significant negative effects on cell physiology using any of the strains tested. The Gram‐negative P. putida (421‐5 and GM 730) and E. coli strains were more resistant to indene and the isolated chemicals of the biotransformation than the Gram‐positive Rhodoccoccus I24 strain, possibly due to the presence of the outer membrane and efflux pump mechanisms. P. putida GM 730 and the E. coli TDO 123 strains responded similarly to toxic effects, and the E. coli TDO 123 strain was more resistant than the P. putida 421‐5 strain. In addition to the recommendations for strain selection, the identified targets for bioprocess improvement include a combination of genetic as well as process engineering approaches. © 2003 Wiley Periodicals, Inc. Biotechnol Bioeng 81: 405–420, 2003.
Determination of in vivo oxygen uptake and carbon dioxide evolution rates from off‐gas measurements under highly dynamic conditions
Authors: Wu L. , Lange H. C. , van Gulik W. M. , Heijnen J. J.
Published: December 2002

In vivo kinetics of Saccharomyces cerevisiae are studied, in a time window of 150 s, by analyzing the response of O2 and CO2 in the fermentor off‐gas after perturbation of chemostat cultures by metabolite pulses. Here, a new mathematical method is presented for the estimation of the in vivo oxygen uptake rate (OUR) and carbon dioxide evolution rate (CER) directly from the off‐gas data in such perturbation experiments. The mathematical construction allows effective elimination of delay and distortion in the off‐gas measurement signal under highly dynamic conditions. A black box model for the fermentor off‐gas system is first obtained by system identification, followed by the construction of an optimal linear filter, based on the identified off‐gas model. The method is applied to glucose and ethanol pulses performed on chemostat cultures of S. cerevisiae. The estimated OUR is shown to be consistent with the independent dissolved oxygen measurement. The estimated in vivo OUR and CER provide valuable insights into the complex dynamic behavior of yeast and are essential for the establishment and validation of in vivo kinetic models of primary metabolism. © 2003 Wiley Periodicals, Inc. Biotechnol Bioeng 81: 448–458, 2003.
Geminivirus vectors for high‐level expression of foreign proteins in plant cells
Authors: Mor Tsafrir S. , Moon Yong‐Sun , Palmer Kenneth E. , Mason Hugh S.
Published: December 2002

Bean yellow dwarf virus (BeYDV) is a monopartite geminivirus that can infect dicotyledonous plants. We have developed a high‐level expression system that utilizes elements of the replication machinery of this single‐stranded DNA virus. The replication initiator protein (Rep) mediates release and replication of a replicon from a DNA construct (“LSL vector”) that contains an expression cassette for a gene of interest flanked by cis‐acting elements of the virus. We used tobacco NT1 cells and biolistic delivery of plasmid DNA for evaluation of replication and expression of reporter genes contained within an LSL vector. By codelivery of a GUS reporter‐LSL vector and a Rep‐supplying vector, we obtained up to 40‐fold increase in expression levels compared to delivery of the reporter‐LSL vectors alone. High‐copy replication of the LSL vector was correlated with enhanced expression of GUS. Rep expression using a whole BeYDV clone, a cauliflower mosaic virus 35S promoter driving either genomic rep or an intron‐deleted rep gene, or 35S‐rep contained in the LSL vector all achieved efficient replication and enhancement of GUS expression. We anticipate that this system can be adapted for use in transgenic plants or plant cell cultures with appropriately regulated expression of Rep, with the potential to greatly increase yield of recombinant proteins. © 2003 Wiley Periodicals, Inc. Biotechnol Bioeng 81: 430–437, 2003.
Bioimmobilization of keratinase using Bacillus subtilis and Escherichia coli systems
Authors: Wang Jeng‐Jie , Swaisgood Harold E. , Shih Jason C. H.
Published: December 2002

Immobilized keratinase can improve stability while retaining its proteolytic and keratinolytic properties. Conventional purification followed by chemical immobilization is a laborious and costly process. A new genetic construct was developed to produce the keratinase–streptavidin fusion protein. Consequently, the purification and immobilization of the fusion protein onto a biotinylated matrix can be accomplished in a single step. The method was tested in both the Bacillus subtilis and Escherichia coli systems. In B. subtilis, the fusion protein was produced extracellularly and readily immobilized from the medium. In E. coli, the fusion protein was produced intracellularly in inclusion bodies; additional separation and renaturation processes were required prior to immobilization from the cell extract. The overall efficiencies were approximately the same, 24–28%, using both systems. © 2003 Wiley Periodicals, Inc. Biotechnol Bioeng 81: 421–429, 2003.
Transfection of NS0 myeloma fusion partner cells with HSP70 gene results in higher hybridoma yield by improving cellular resistance to apoptosis
Authors: Lasunskaia Elena B. , Fridlianskaia Irina I. , Darieva Zoulfia A. , Da Silva Mariele S.R. , Kanashiro Milton M. , Margulis Boris A.
Published: December 2002

Mouse myeloma NS0 cells widely used in hybridoma technology lack the expression of a major stress protein Hsp70 which is the principal component of the basic cellular defense mechanism. These cells rapidly undergo apoptosis at the late‐stationary phase of batch culture following nutrient exhaustion. Since Hsp70 was recently demonstrated to protect cells against numerous apoptotic stimuli, the aim of the present study was to examine the protective potential of the protein expression in engineered myeloma NS0 cells and in resulting hybridomas. Myeloma cells were transfected with the hsp70 gene under beta‐actin gene promoter. To imitate harmful conditions that hybridoma or myeloma cells often experience when cultivated in large scale for an antibody production, NS0wt and NS0hsp70 cell cultures were maintained without changing the medium for a few days, and the expression of apoptotic markers has been studied. It was found that long‐term cultivation induced apoptosis in original cells manifested by typical nuclei fragmentation, DNA ladders and activation of caspase‐3. In contrast, in transfected cells under the same conditions the outcome of apoptosis was postponed for 24 hours. Most relevant was that the fusion of transfected myeloma cells with immune splenocytes resulted in twofold hybridomas output compared with wild‐type fusion partner. Almost half of the hybridomas continued to be hsp70‐positive and maintained higher robustness in culture. The level of monoclonal antibodies production by hybridoma cells obtained with the use of NS0wt and NS0hsp70 was similar, however, the secreted product was better preserved in culture supernatants of Hsp70‐positive cells. It is concluded that transfection of mouse myeloma cells with the hsp70 gene can be a novel means to increase hybridoma yield and reduce the sensitivity of myeloma and hybridoma cells to culture conditions insults accompanying monoclonal antibody production. © 2003 Wiley Periodicals, Inc. Biotechnol Bioeng 81: 496–504, 2003.
Adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5‐fluorouracil, vincristine, and prednisone compared with single‐agent L‐phenylalanine mustard for patients with operable breast carcinoma and positive axillary lymph nodes
Authors: Rivkin Saul E. , Green Stephanie J. , Lew Danika , Costanzi John J. , Athens John W. , Osborne C. Kent , Vaughn Clarence B. , Martino Silvana
Published: December 2002

BACKGROUND

Adjuvant combination chemotherapy with cyclophosphamide, methotrexate, and 5‐fluorouracil plus vincristine and prednisone (CMFVP) was compared with single‐agent L‐phenylalanine mustard (L‐PAM) for the treatment of patients with axillary lymph node positive primary breast carcinoma over 20‐years of follow‐up.

METHODS

Four hundred forty‐one women with axillary lymph node positive breast carcinoma were randomized to receive either combination chemotherapy with cyclophosphamide (60 mg/m2orally every day for 1 year), fluorouracil (300 mg/m2intravenously [IV] weekly for 1 year), methotrexate (15 mg/m2IV weekly for 1 year), vincristine (0.625 mg/m2IV for 10 weeks), prednisone (30 mg/m2orally on Days 1–14, 20 mg/m2on Days 15–28, and 10 mg/m2on Days 29–42), or single‐agent chemotherapy with L‐PAM (5 mg/m2orally every day for 5 days every 6 weeks for 2 years) after undergoing surgery. Patients were stratified according to menopausal status and number of positive lymph nodes (1–3 positive lymph nodes or > 3 positive lymph nodes). Seventy‐seven patients were ineligible.

RESULTS

The maximum follow‐up is 24 years, with a median follow‐up of 21.5 years. Disease free survival and overall survival were superior with CMFVP (two‐sided log‐rank test;P= 0.0008 andP= 0.007, respectively). For all patients, the estimated 20‐year survival rate of patients who received CMFVP was 40% compared with 27% for patients who received L‐PAM. There was a substantial survival benefit for CMFVP compared with L‐PAM in the subsets of premenopausal patients and patients with four or more positive lymph nodes. The estimated 20‐year survival rate for premenopausal women who received CMFVP was 49% compared with 33% for premenopausal women who received L‐PAM. Among women with ≥ 4 positive lymph nodes, the estimated survival rate for patients who received CMFVP was 31% compared with 15% for patients who received L‐PAM. Both regimens were tolerated well. Toxicity was more severe and frequent among patients who received CMFVP.

CONCLUSIONS

The authors conclude that, after 20 years of follow‐up, adjuvant chemotherapy with CMFVP remains superior to L‐PAM for the treatment of patients with lymph node positive breast carcinoma. Cancer 2003;97:21–9. © 2003 American Cancer Society.

DOI 10.1002/cncr.10982
Phase I trial of weekly docetaxel and gemcitabine in patients with refractory malignancies
Authors: Mekhail Tarek , Hutson Thomas E. , Elson Paul , Budd G. Thomas , Srkalovic Gordon , Olencki Thomas , Peereboom David , Pelley Robert , Bukowski Ronald M.
Published: December 2002

BACKGROUND

A Phase I study using weekly docetaxel and gemcitabine was conducted to investigate toxicity; to determine the maximum tolerated dose (MTD) of each agent; and, in a preliminary fashion, to determine the antitumor activity of the combination.

METHODS

Docetaxel and gemcitabine were administered intravenously on Days 1, 8, and 15 every 28 days. The dose levels of docetaxel and gemcitabine were as follows: Level I, docetaxel 20 mg/m2and gemcitabine 400 mg/m2; Level II, docetaxel 30 mg/m2and gemcitabine 400 mg/m2; Level III, docetaxel 30 mg/m2and gemcitabine 600 mg/m2; Level IV, docetaxel 36 mg/m2and gemcitabine 600 mg/m2; and Level V, docetaxel 36 mg/m2and gemcitabine 800 mg/m2.

RESULTS

Thirty‐three eligible patients were entered. The diagnoses were as follows: Eleven patients had nonsmall cell lung carcinoma, 3 patients had carcinoma of the bladder, 3 patients had renal carcinoma, 2 patients had adrenal carcinoma, 5 patients had unknown primary tumors, and 9 patients had miscellaneous malignancies. Fifty‐nine percent of patients had received prior chemotherapy. The median age was 62 years (range, 27–77 years), and the median Eastern Cooperative Oncology Group performance status was 1 (range, 0–1). Five patients were treated at Dose Levels I and II, 6 patients were treated at Dose Levels III and V, and 11 patients were treated at Dose Level IV. Grade 3–4 toxicities during Cycle I included neutropenia, thrombocytopenia, mucositis, and diarrhea. Dose‐limiting toxicity, consisting of neutropenia and thrombocytopenia, occurred in three of six patients at Dose Level V. The combination of docetaxel 36 mg/m2 and gemcitabine 600 mg/m2 (Dose Level IV) was determined as the MTD and was the recommended Phase II dose. Two patients had a partial response: one patient with bladder carcinoma (Dose Level II) and one patient with nonsmall cell lung carcinoma (Dose Level III).

CONCLUSIONS

Overall, weekly docetaxel and gemcitabine were well tolerated. Further studies using this combination are planned, including a Phase II trial in patients with advanced nonsmall cell lung carcinoma. Cancer 2003;97:170–8. © 2003 American Cancer Society.

DOI 10.1002/cncr.10991
Phase II study of cladribine and cyclophosphamide in patients with chronic lymphocytic leukemia and prolymphocytic leukemia
Authors: Montillo Marco , Tedeschi Alessandra , O'Brien Susan , Raimondo Francesco Di , Lerner Susan , Ferrajoli Alessandra , Morra Enrica , Keating Michael J.
Published: December 2002

BACKGROUND

One of the mechanisms of action of cladribine is the inhibition of DNA repair of damage caused by radiation, alkylating agents, or other drugs. To determine its antitumor activity in combination with cyclophosphamide, we initiated a Phase II trial of the two agents in patients with advanced chronic lymphocytic leukemia (CLL) or prolymphocytic leukemia (PLL).

METHODS

Twenty‐nine patients with refractory or recurrent CLL or PLL received cladribine 4 mg/m2/day and cyclophosphamide 350 mg/m2/day (both administered intravenously) for 3 days every 4 weeks.

RESULTS

Eleven patients (38%), nine with CLL and two with PLL, had a response. The median duration of response was 12 months. Severe extrahematologic toxicity (National Cancer Institute Grade 3–4) occurred in two patients, consisting of skin rash in one patient and progressive multifocal leukoencephalopathy in the other. The most common form of hematologic toxicity was severe neutropenia, which developed after 25% of the 84 courses was administered. Severe thrombocytopenia and anemia developed after 12% and 7% of the courses, respectively, and five episodes of anemia were immunomediated. In addition, three major infections resulted in the death of one patient.

CONCLUSIONS

Although inferior to the combination fludarabine plus cyclophosphamide, this regimen showed interesting activity in patients with advanced CLL or PLL. Myelosuppression was the major dose‐limiting toxic effect. Cancer 2003;97:114–20. © 2003 American Cancer Society.

DOI 10.1002/cncr.11000
Treatment of large cell lymphoma in elderly patients with a mitoxantrone, cyclophosphamide, etoposide, and prednisone regimen
Authors: Rigacci Luigi , Carpaneto Andrea , Alterini Renato , Carrai Valentina , Bernardi Franco , Bellesi Giampiero , Longo Giovanni , Bosi Alberto , Rossi Ferrini Pierluigi
Published: December 2002

BACKGROUND

Patients with aggressive non‐Hodgkin lymphoma (NHL) require intensive and extensive therapy, which seems impracticable in elderly patients due to hematologic and extrahematologic toxicity. Consequent dose reduction and therapy attenuation can reduce treatment‐related toxicity but also decreases therapeutic efficacy. Thus, age represents a fundamental prognostic factor that has a profound influence on both therapeutic decisions and patient outcome.

METHODS

Between January, 1990 and June, 1997, 145 patients age > 64 years (median age, 72.3 years) with a diagnosis of aggressive NHL were treated on a chemotherapy regimen that consisted of mitoxantrone, cyclophosphamide, etoposide, and prednisone.

RESULTS

Ninety‐one patients (63%) achieved complete remission, and 48 patients (33%) achieved partial remission, for an overall response rate of 96%. Six patients (4%) were resistant to therapy. The overall survival rate, with a median follow‐up of 66 months, was 44%, and the failure free survival rate was 42%. The disease free survival rate was 63.5%, with a median follow‐up of 60 months. Multivariate survival analysis showed that the achievement of complete remission was the single most important prognostic factor, which was associated significantly with longer survival (P < 0.0001). Toxicity was moderate, with 5 deaths (3%) due to complications related to therapy.

CONCLUSIONS

The current results confirm that a protocol devised specifically for elderly patients may reduce toxicity and allow longer overall survival in this particular subset of patients. Cancer 2003;97:97–104. © 2003 American Cancer Society.

DOI 10.1002/cncr.11032
A Phase I study of 9‐nitrocamptothecin given concurrently with capecitabine in patients with refractory, metastatic solid tumors
Authors: Michaelson M. Dror , Ryan David P. , Fuchs Charles S. , Supko Jeffrey G. , Garcia‐Carbonero Rocio , Paul Eder J. , Clark Jeffrey W.
Published: December 2002

BACKGROUND

9‐Nitrocamptothecin (9‐NC) is an orally available camptothecin analog with antineoplastic activity that results from the inhibition of DNA topoisomerase I. Previous studies have suggested that it has significant clinical efficacy. The primary toxicities of 9‐NC include gastrointestinal upset, cystitis, and myelosuppression at the maximum tolerated dose (MTD) of 1.5 mg/m2 per day. Capecitabine is a prodrug of 5‐fluorouracil that is approved for use in patients with metastatic breast carcinoma and colorectal carcinoma, and it offers the convenience of oral administration. This trial examined the combination of these two oral agents in patients with metastatic solid tumors.

METHODS

Capecitabine was administered twice daily at a total daily dose of 1300 mg/m2 per day for 14 days followed by a 1‐week break. 9‐NC was taken daily 5 days per week for 2 weeks in a dose‐escalation scheme. The starting dose was 0.5 mg/m2 per day, and cohorts of 3 patients were enrolled until the dose level reached 1.25 mg/m2 per day.

RESULTS

Twenty‐one patients were evaluable for toxicity and response, and nausea and emesis were the dose‐limiting toxicities. Despite antiemetic prophylaxis with 5‐hydroxytryptamine‐3 antagonists, 2 of 3 patients at the 1.0 mg/m2 per day dose level had Grade 2–3 nausea; while at the MTD of 0.75 mg/m2 per day, 3 of 14 patients had Grade ≥ 2 nausea. The incidence of hand‐foot syndrome, stomatitis, diarrhea, and myelosuppression did not exceed that expected with capecitabine alone, suggesting that 9‐NC does not exacerbate these side effects. No objective responses were seen. Stable disease was observed in 9 patients (43%) with a median duration of 11 weeks, including 3 patients with responses that lasted from 20 weeks to 40 weeks.

CONCLUSIONS

The combination of 9‐NC and capecitabine with the current schedule was limited in dose by nausea and had minimal clinical efficacy in a group of patients with refractory solid tumors. Cancer 2003;97:148–54. © 2003 American Cancer Society.

DOI 10.1002/cncr.11038
Cancer chronotherapy: Principles, applications, and perspectives
Authors: Mormont Marie‐Christine , Levi Francis
Published: December 2002

BACKGROUND

Cell physiology is regulated along the 24‐hour timescale by a circadian clock, which is comprised of interconnected molecular loops involving at least nine genes. The cellular clocks are coordinated by the suprachiasmatic nucleus, a hypothalamic pacemaker that also helps the organism adjust to environmental cycles. The rest‐activity rhythm is a reliable marker of the circadian system function in both rodents and humans. This circadian organization is responsible for predictable changes in the tolerability and efficacy of anticancer agents, and possibly also may be involved in tumor promotion or growth.

METHODS

Expected least toxic times of chemotherapy were extrapolated from experimental models to human subjects with reference to the rest‐activity cycle. The clinical relevance of the chronotherapy principle (i.e., treatment administration as a function of rhythms) has been investigated previously in randomized multicenter trials.

RESULTS

In the current study, chronotherapeutic schedules were used to safely document activity of the combination of oxaliplatin, 5‐fluorouracil, and leucovorin against metastatic colorectal carcinoma and to establish new medicosurgical management for this disease, and were reported to result in unprecedented long‐term survival.

CONCLUSIONS

Chronotherapy concepts appear to offer further potential to improve current cancer treatment options as well as to optimize the development of new anticancer or supportive agents. Cancer 2003;97:155–69. © 2003 American Cancer Society.

DOI 10.1002/cncr.11040
Slower molecular response to treatment predicts poor outcome in patients with TEL/AML1 positive acute lymphoblastic leukemia
Authors: Madžo Jozef , Zuna Jan , Mužíková Kateřina , Kalinová Markéta , Krejčí Ondřej , Hrušák Ondřej , Otová Berta , Starý Jan , Trka Jan
Published: December 2002

BACKGROUND

The translocation t(12;21)(p13;q22), which produces the TEL/AML1 fusion gene, is the most frequent chromosomal abnormality in patients with childhood acute lymphoblastic leukemia (ALL) and generally is associated with a favorable prognosis. Furthermore, real‐time quantitative‐polymerase chain reaction (RQ‐PCR)‐based detection of TEL/AML1 represents an accurate technique for the reproducible assessment of minimal residual disease (MRD).

METHODS

The authors employed RQ‐reverse transcriptase‐PCR (RQ‐RT‐PCR) technology to analyze MRD levels in 57 newly diagnosed patients with TEL/AML1 positive ALL in a prospective study.

RESULTS

On Day + 33, a particularly important time point in terms of outcome prediction based on MRD monitoring, 75% of patients reached negativity, 13% of patients were positive at very low levels (< 10−4; i.e., 1 or more leukemic cell per 104 normal cells), and another 13% of patients were positive at the level of 10−2 to 10−4 cells. No patient showed MRD levels ≥ 10−2 cells at this time. The data demonstrate that patients with TEL/AML1 positive ALL had a better response to induction chemotherapy on Day + 33 compared with a group of unselected patients with ALL (P = 0.0001). However, four patients with TEL/AML1 positive ALL developed relapse disease. Remarkably, these children were positive for MRD on Day + 33 at a level between 10−2 cells and 10−4 (n = 3 patients) and at < 10−4 (n = 1 patient). Kaplan–Meier analysis of disease free survival showed the statistical significance of this distribution (MRD positive vs. MRD negative; log‐rank P = 0.0016).

CONCLUSIONS

The authors conclude that, although the TEL/AML1 positive leukemias generally are associated with a favorable outcome, MRD positivity assessed by RQ‐RT‐PCR analysis at the end of induction therapy represents a significantly negative prognostic feature. Cancer 2003;97:105–13. © 2003 American Cancer Society.

DOI 10.1002/cncr.11043
Granulocyte‐macrophage–colony‐stimulating factor added to a multipeptide vaccine for resected Stage II melanoma
Authors: Weber Jeffrey , Sondak Vernon K. , Scotland Ronaldo , Phillip Ramila , Wang Flora , Rubio Valerie , Stuge Tor B. , Groshen Susan G. , Gee Conway , Jeffery Georgia G. , Sian Shirley , Lee Peter P.
Published: December 2002

BACKGROUND

Forty‐eight patients with resected Stages IIA and IIB melanoma were immunized with two tumor antigen epitope peptides derived from gp100209–217 (210M) (IMDQVPSFV) and tyrosinase368–376 (370D) (YMDGTMSQV) emulsified with incomplete Freund's adjuvant (IFA). Patients were assigned randomly to receive either peptides/IFA alone or with 250 μm of granulocyte‐macrophage–colony‐stimulating factor (GM‐CSF) subcutaneously daily for 5 days to evaluate the toxicities and immune responses in either arm. Time to recurrence and survival were secondary end points.

METHODS

Immunizations were administered every 2weeks × 4, then every 4 weeks × 3, and once 8 weeks later. A leukapheresis to obtain peripheral blood mononuclear cells for immune analyses and skin testing with peptides and recall reagents was performed before and after eight vaccinations.

RESULTS

Local pain and granuloma formation, fever, and lethargy of Grade 1 or 2 were observed. Transient vaccine‐related Grade III and no Grade IV toxicity was observed. Seventeen of the 40 patients for whom posttreatment skin tests were performed developed a positive skin test response to the gp100 peptide, but only 1 of the 40 patients developed a positive skin test response to tyrosinase. Immune responses were measured by release of interferon‐gamma (IFN‐γ) in an enzyme‐linked immunosorbent assay (ELISA) by effector cells in the presence of peptide‐pulsed antigen‐presenting cells, by cytokine release of IFN‐γ, GM‐CSF, and tumor necrosis factor‐alpha in a Luminex assay, or by an antigen‐specific tetramer flow cytometry assay. Thirty‐four of the 39 patients for whom the ELISA data were performed demonstrated an immune response after vaccination, as did 37 of 42 patients by tetramer assay. Enzyme‐linked immunosorbent assay, Luminex, and tetramer responses in the GM‐CSF/peptide/IFA group were higher than in the peptide/IFA group. Epitope spreading to the MART‐1/MelanA 27‐35 and 26‐35 (27L) epitopes was detected by tetramer assay in 10 patients. Seven of 48 patients experienced disease recurrence with a median of 24 months of follow‐up and 2 patients in this intermediate to high risk group have died.

CONCLUSION

These data suggest a significant number of patients with resected melanoma mount an antigen‐specific immune response against a peptide vaccine. There is a trend for GM‐CSF to modestly increase the immune response and support further development of GM‐CSF as a vaccine adjuvant. Cancer 2003;97:186–200. © 2003 American Cancer Society.

DOI 10.1002/cncr.11045