bluuebunny/crossref_metadata_2025 huggingface dataset:
Deterministic approximation of a stochastic metapopulation model
Authors: Arrigoni Francesca
Published: August 2003

We analyse the limit behaviour of a stochastic structured metapopulation model as the number of its patches goes to infinity. The sequence of probability measures associated with the random process, whose components are the proportions of patches with different number of individuals, is tight. The limit of every convergent subsequence satisfies an infinite system of ordinary differential equations. The existence and the uniqueness of the solution are shown by semigroup methods, so that the whole random process converges weakly to the solution of the system.
Almost sure relative stability of the maximum of a stationary sequence
Authors: Naveau Philippe
Published: August 2003

The almost sure convergence of the maximum of a strictly stationary sequence is studied. We show that, if a particular mixing condition, related to the asymptotic independence of maxima defined by O'Brien, is satisfied, then the maximum behaves asymptotically like the quantile F←(1-1/n) whenever the marginal tail distribution decreases quickly enough. A necessary condition for the almost sure convergence of the maximum is derived. Applications are also discussed.
Random coefficient autoregression, regime switching and long memory
Authors: Leipus Remigijus , Surgailis Donatas
Published: August 2003

We discuss long-memory properties and the partial sums process of the AR(1) process {Xt, t ∈ 𝕫} with random coefficient {at, t ∈ 𝕫} taking independent values Aj ∈ [0,1] on consecutive intervals of a stationary renewal process with a power-law interrenewal distribution. In the case when the distribution of generic Aj has either an atom at the point a=1 or a beta-type probability density in a neighborhood of a=1, we show that the covariance function of {Xt} decays hyperbolically with exponent between 0 and 1, and that a suitably normalized partial sums process of {Xt} weakly converges to a stable Lévy process.
On the collapsibility of lifetime regression models
Authors: Duchesne Thierry , Rosenthal Jeffrey S.
Published: August 2003

In this paper we derive conditions on the internal wear process under which the resulting time to failure model will be of the simple collapsible form when the usage accumulation history is available. We suppose that failure occurs when internal wear crosses a certain threshold or a traumatic event causes the item to fail. We model the infinitesimal increment in internal wear as a function of time, accumulated internal wear, and usage history, and we derive conditions on this function to get a collapsible model for the distribution of time to failure given the usage history. We reach the conclusion that collapsible models form the subset of accelerated failure time models with time-varying covariates for which the time transformation function satisfies certain simple properties.
Idle period approximations and bounds for the GI/G/1 queue
Authors: Wolff Ronald W. , Wang Chia-Li
Published: August 2003

The average delay for the GI/G/1 queue is often approximated as a function of the first two moments of interarrival and service times. For highly irregular arrivals, however, it varies widely among queues with the same first two moments, even in moderately heavy traffic. Empirically, it decreases as the interarrival time third moment increases. For GI/M/1 queues, a heavy-traffic expression for the average delay with this property has been previously obtained. The method, however, sheds little light on why the third moment arises. We analyze the equilibrium idle-period distribution in heavy traffic using real-variable methods. For GI/M/1 queues, we derive the above heavy-traffic result and also obtain conditions under which it is either an upper or lower bound. Our approach provides an intuitive explanation for the result and also strongly suggests that similar results should hold for general service. This is supported by empirical evidence. For any given service distribution, it has been conjectured that the expected delay under pure-batch
arrivals, where interarrival times are scaled Bernoulli random variables, is an upper bound on the average delay over all interarrival distributions with the same first two moments. We investigate this conjecture and show, among other things, that pure-batch arrivals have the smallest third moment. We obtain conditions under which this conjecture is true and present a counterexample where it fails. Arrivals that arise as overflows from other queues can be highly irregular. We show that interoverflow distributions in a certain class have decreasing failure rate.
A reduced-peak equivalence for queues with a mixture of light-tailed and heavy-tailed input flows
Authors: Borst Sem , Zwart Bert
Published: August 2003

We determine the exact large-buffer asymptotics for a mixture of light-tailed and heavy-tailed input flows. Earlier studies have found a ‘reduced-load equivalence’ in situations where the peak rate of the heavy-tailed flows plus the mean rate of the light-tailed flows is larger than the service rate. In that case, the workload is asymptotically equivalent to that in a reduced system, which consists of a certain ‘dominant’ subset of the heavy-tailed flows, with the service rate reduced by the mean rate of all other flows. In the present paper, we focus on the opposite case where the peak rate of the heavy-tailed flows plus the mean rate of the light-tailed flows is smaller than the service rate. Under mild assumptions, we prove that the workload distribution is asymptotically equivalent to that in a somewhat ‘dual’ reduced system, multiplied by a certain prefactor. The reduced system now consists of only the light-tailed flows, with the service rate reduced by the peak rate of the heavy-tailed flows. The prefactor represents the probability that the heavy-tailed flows have sent at their peak rate for more than a certain amount of time, which may be interpreted as the ‘time to overflow’ for the light-tailed flows in the reduced system. The results provide crucial insight into the typical overflow scenario.
Generalized processor sharing queues with heterogeneous traffic classes
Authors: Borst Sem , Mandjes Michel , van Uitert Miranda
Published: August 2003

We consider a queue fed by a mixture of light-tailed and heavy-tailed traffic. The two traffic flows are served in accordance with the generalized processor sharing (GPS) discipline. GPS-based scheduling algorithms, such as weighted fair queueing (WFQ), have emerged as an important mechanism for achieving service differentiation in integrated networks. We derive the asymptotic workload behaviour of the light-tailed traffic flow under the assumption that its GPS weight is larger than its traffic intensity. The GPS mechanism ensures that the workload is bounded above by that in an isolated system with the light-tailed flow served in isolation at a constant rate equal to its GPS weight. We show that the workload distribution is, in fact, asymptotically equivalent to that in the isolated system, multiplied by a certain prefactor, which accounts for the interaction with the heavy-tailed flow. Specifically, the prefactor represents the probability that the heavy-tailed flow is backlogged long enough for the light-tailed flow to reach overflow. The results provide crucial qualitative insight in the typical overflow scenario.
Efficient Diastereodifferentiating E-Z Photoisomerization of Cyclooctene Tethered to Intramolecular Sensitizer through Optically Active Pentane-2,4-diyl Unit
Authors: Sugimura Takashi , Shimizu Hitoshi , Umemoto Shin’ichi , Tsuneishi Hiroshi , Hakushi Tadao , Inoue Yoshihisa , Tai Akira
Published: September 2003

Photolysis of a tethered cyclooctene (E)-4, in which the sensitizer benzoate is connected to the olefin moiety through a chiral 2,4-pentanediol tether, afforded the Z/E ratios up to 0.8 and the diastereomeric excess of 33% at −65 °C, while the terephthalate analogue (E)-5 gave higher de of 44% at the same temperature.
Allenylmethylsilane Derivative as a Synthetic Equivalent of 1,2,3-Butatriene: Synthesis and Reactions of Di-exo-methylenecyclobutanes and -cyclobutenes
Authors: Hojo Makoto , Murakami Chikara , Nakamura Shinya , Hosomi Akira
Published: September 2003

2-Methoxyallenylmethylsilane reacts with alkenes and alkynes in a [2+2] cycloaddition mode to give cyclobutanes and cyclobutenes, respectively. Cycloadducts are converted to di-exo-methylene compounds through 1,2-elimination of the methoxy and silyl groups. These di-exo-methylenecyclobutanes and -cyclobutenes react with alkenes and 1,3-dienes to afford fused bi- and tricyclic compounds.
Synthesis of Hyperbranched Aromatic Polyamide by Direct Polycondensation Method
Authors: Haba Osamu , Tajima Hiroyuki , Ueda Mitsuru , Nagahata Ritsuko
Published: September 2003

A hyperbranched aromatic polyamide was prepared from 5-aminoisophthalic acid by the direct polycondensation method using diphenyl (2,3-dihydro-2-thioxo-3-benzoxazolyl)phosphonate (DBOP) as a condensing agent. The resulting polymer was further reacted with p-anisidine to give methoxy-end-capped polymer (3). IR spectrum of 3 indicates the end-capping was achieved completely. MALDI-TOF MS spectrum of 3 indicates presence of no side-reaction. Number average molecular weight of 3 could be determined by its 1H NMR spectrum and was 1800.
Substituent Effect on the cis-trans Photoisomerization of trans,trans,trans-1,6-Diphenyl-1,3,5-hexatrienes
Authors: Sonoda Yoriko , Morii Hisayuki , Sakuragi Masako , Suzuki Yasuzo
Published: September 2003

Quantum yield of trans,trans,trans→cis,trans,trans photoisomerization of p,p′-disubstituted 1,6-diphenyl-1,3,5-hexatriene increased as the polarity of substituents increased, regardless of their electron-withdrawing or donating nature. On the contrary, quantum yield of trans,trans,trans→trans,cis,trans isomerization increased with increasing the electron-donating nature of substituents.
Effects of Cl Ions upon Combustion of Particulate on TiO2-supported CuO Catalysts
Authors: Imada Yasunori , Kakuta Noriyoshi , Ueno Akifumi , Yoshida Kiyohide
Published: September 2003

Combustion of diesel particulate on titania-supported copper oxide was enhanced when it was prepared from copper chloride. This was ascribed to chlorine ions still remaining in the catalyst, since the catalyst prepared from copper nitrate showed a poor activity for combustion. It was also found that the high activity was elongated by an addition of KCl into the catalyst prepared from copper chloride.
Monitoring of a second‐order reaction by electronic absorption spectroscopy using combined chemometric and kinetic models
Authors: Thurston Tom J. , Brereton Richard G. , Foord Dan J. , Escott Richard E. A.
Published: August 2003

This paper reports the application of 11 methods for obtaining kinetic constants from a second‐order reaction, that between phenylhydrazine and benzophenone. In this type of reaction the number of absorbing species is lower than the number of steps in the reaction minus one, resulting in a rank‐deficient response matrix. The methods used include traditional univariate curve fitting, classical least squares using previously recorded pure spectra, alternating least squares methods with both kinetic and non‐negativity constraints, and target‐testing methods using principal component scores. An additional recently proposed method based on difference spectra is also examined, suitable for any single‐step closed reaction. The methods that performed best were difference spectra, kinetically constrained alternating least squares, and target‐testing approaches. Limitations of the traditional methods are described. Copyright © 2003 John Wiley & Sons, Ltd.
A framework for sequential multiblock component methods
Authors: Smilde Age K. , Westerhuis Johan A. , de Jong Sijmen
Published: August 2003

Multiblock or multiset methods are starting to be used in chemistry and biology to study complex data sets. In chemometrics, sequential multiblock methods are popular; that is, methods that calculate one component at a time and use deflation for finding the next component. In this paper a framework is provided for sequential multiblock methods, including hierarchical PCA (HPCA; two versions), consensus PCA (CPCA; two versions) and generalized PCA (GPCA). Properties of the methods are derived and characteristics of the methods are discussed. All this is illustrated with a real five‐block example from chromatography. The only methods with clear optimization criteria are GPCA and one version of CPCA. Of these, GPCA is shown to give inferior results compared with CPCA. Copyright © 2003 John Wiley & Sons, Ltd.
A new family of genetic algorithms for wavelength interval selection in multivariate analytical spectroscopy
Authors: Goicoechea Héctor C. , Olivieri Alejandro C.
Published: August 2003

A new procedure is presented for wavelength interval selection with a genetic algorithm in order to improve the predictive ability of partial least squares multivariate calibration. It involves separately labelling each of the selected sensor ranges with an appropriate inclusion ranking. The new approach intends to alleviate overfitting without the need of preparing an independent monitoring sample set. A theoretical example is worked out in order to compare the performance of the new approach with previous implementations of genetic algorithms. Two experimental data sets are also studied: target parameters are the concentration of glucuronic acid in complex mixtures studied by Fourier transform mid‐infrared spectroscopy and the octane number in gasolines monitored by near‐infrared spectroscopy. Copyright © 2003 John Wiley & Sons, Ltd.
Dynamic determination of the dimension of PCA calibration models using F‐statistics
Authors: Vogt F. , Mizaikoff B.
Published: August 2003

Owing to experimental measurement errors, determination of the proper dimension of calibration models is difficult. Cross‐validation is a common approach for this purpose; however, if data evaluation is based on PCA only without consideration of sample concentrations, this computationally expensive method cannot be applied. In this study a statistical method for determining the proper dimension of PCA calibration models is presented from the viewpoint of multivariate regression analysis considering only measured data. For this iterative algorithm, individual principal components are included stepwise in a reduced model, which is subsequently tested against the full model including all principal components. This algorithm can be individually applied for optimized data evaluation to every measured data vector such as an optical spectrum of chemical analyte. This comparison is performed by an F‐test comparing estimates of residual variance of a measurement spectrum determined from the reduced and the full model. This approach determines a lack of fit due to insufficient principal components. If no lack of fit is evident for a certain reduced model, it is considered that a sufficiently large model has been found and inclusion of additional principal components is stopped. Hence the resulting reduced calibration model includes only statistically significant principal components (PCs) and determines the minimum number of required PCs for a given measurement spectrum. The proposed algorithm is initially investigated using simulated data and subsequently applied to three different experimental sets of spectra. It is shown that for synthetic data at reasonable noise levels the correct number of principal components can be determined in most cases. The experimental examples demonstrate that the number of principal components determined by the proposed algorithm is slightly larger than a user would select manually by subjective visual inspection. As one result, the algorithm is able to detect small but significant spectroscopic features of experimental data which would otherwise be neglected. Copyright © 2003 John Wiley & Sons, Ltd.
The influence of prenatal tactile and vestibular stimulation on auditory and visual responsiveness in bobwhite quail: A matter of timing
Authors: Honeycutt Hunter , Lickliter Robert
Published: August 2003

The fact that the sensory systems do not become functional at the same time during prenatal development raises the question of how experience in a given modality can influence functioning in other sensory modalities. The present study exposed groups of bobwhite quail embryos to augmented tactile and vestibular stimulation at times that either coincided with or followed the period of onset of function in the later‐developing auditory and visual modalities. Differences in the timing of augmented prenatal stimulation led to different patterns of subsequent auditory and visual responsiveness following hatching. No effect on normal visual responsiveness to species‐typical maternal cues was found when exposure to tactile and vestibular stimulation coincided with the emergence of visual function (Days 14–19), but when exposure took place after the onset of visual functioning (Days 17–22), chicks displayed enhanced responsiveness to the same maternal visual cues. When augmented tactile and vestibular stimulation coincided with the onset of auditory function (Days 9–14), embryos subsequently failed to learn a species‐typical maternal call prior to hatching. However, when given exposure to the same type and amount of augmented stimulation following the onset of auditory function (Days 14–19), embryos did learn the maternal call. These findings demonstrate that augmented stimulation to earlier‐emerging sensory modalities can either facilitate or interfere with perceptual responsiveness in later‐developing modalities, depending on when that stimulation takes place. © 2003 Wiley Periodicals, Inc. Dev Psychobiol 43: 71–81, 2003.
Ultrasonic call characteristics of rat pups are altered following prenatal malnutrition
Authors: Tonkiss John , Bonnie Kristin E. , Hudson Jamie L. , Shultz Penny L. , Duran Pilar , Galler Janina R.
Published: August 2003

The male offspring of rats provided with a protein deficient diet (6% casein) for 5 weeks prior to mating and throughout pregnancy were subjected to a brief period of isolation and cooling at postnatal Days (P)7, 9, and 11, and their ultrasonic vocalizations were compared with those of well‐nourished pups. Calls were categorized into 12 different types based upon their sonographic patterns. Although call rates were equal, the call characteristics of the prenatally malnourished pups differed significantly from those of well‐nourished controls. At P7, their mean peak sound frequency (irrespective of call type) was significantly higher, and constant frequency calls were of both higher frequency and longer duration. Over the age range studied, prenatally malnourished pups emitted a smaller variety of calls, with significantly fewer ascending frequency vocalizations while producing either significantly fewer (P9) or greater (P11) descending frequency calls. Altered crying patterns have been related to brain damage in human babies, with more abnormal cries being associated with more severe neurological impairment. Therefore, the present results most likely reflect altered central nervous system development and function. Ultrasonic vocalization characteristics in rat pups may provide a useful early marker of the severity of disturbance to the development of the central nervous system following an insult, and offer the potential for predicting the degree of functional and behavioral deficits later in life. © 2003 Wiley Periodicals, Inc. Dev Psychobiol 43: 90–101, 2003.
Testosterone, puberty, and the pattern of male aggression in Syrian hamsters
Authors: Romeo Russell D. , Schulz Kalynn M. , Nelson Aaron L. , Menard Tami A. , Sisk Cheryl L.
Published: August 2003

The interaction between testosterone and pubertal development on aggression in the male Syrian hamster (Mesocricetus auratus) was examined in two experiments. First, gonad‐intact prepubertal and adult male hamsters were tested for aggression using the resident–intruder paradigm with an age‐ and weight‐matched intruder. Prepubertal males engaged in a greater number of attacks and had longer attack durations than adults. In the second experiment, prepubertal and adult males were castrated and treated with either a 0‐, 2.5‐, or 5‐mg pellet of testosterone, and their aggression was assessed using the resident–intruder paradigm. Prepubertal males again showed shorter attack latencies and greater attack durations compared to adult males across all levels of testosterone. Testosterone treatment did not significantly affect these behaviors before or after pubertal development. We conclude that (a) pubertal development is associated with a decline in aggression in the male Syrian hamster, and (b) a developmental shift in behavioral sensitivity or responsiveness to testosterone does not underlie the pubertal decrease in aggression. © 2003 Wiley Periodicals, Inc. Dev Psychobiol 43: 102–108, 2003.
Direct and indirect effects of breast milk on the neurobehavioral and cognitive development of premature infants
Authors: Feldman Ruth , Eidelman Arthur I.
Published: August 2003

Eighty‐six premature infants were tested to examine the effects of maternal breast milk on infant development. Infants were classified by breast‐milk consumption during the hospitalization period (M = 57.4 days) into three groups: those receiving minimal (<25% of nutrition), intermediate (25–75%), and substantial (>75%) amounts of breast milk. Infants in the three groups were matched for birth weight, gestational age (GA), medical risk, and family demographics. At 37 weeks GA, mother–infant interaction was videotaped, maternal depression self‐reported, and neurobehavioral maturation assessed by the Neonatal Behavior Assessment Seale (Brazelton, 1973). At 6 months corrected age, infants were tested with the Bayley II (Bayley, 1993). Infants receiving substantial amounts of breast milk showed better neurobehavioral profiles—in particular, motor maturity and range of state. These infants also were more alert during social interactions, and their mothers provided more affectionate touch. Higher maternal depression scores were associated with lower quantities of breast milk, longer latencies to the first breast‐milk feeding, reduced maternal affectionate touch, and lower infant cognitive skills. Maternal affectionate touch moderated the relations between breast milk and cognitive development, with infants receiving a substantial amount of breast milk and frequent touch scoring the highest. In addition to its nutritional value, breast milk may be related to improved maternal mood and interactive behaviors, thereby indirectly contributing to development in premature infants. © 2003 Wiley Periodicals, Inc. Dev Psychobiol 43: 109–119, 2003.
Development of neural processes mediating rhyme judgments: Phonological and orthographic interactions
Authors: Weber‐Fox Christine , Spencer Rebecca , Cuadrado Elizabeth , Smith Anne
Published: August 2003

Development of neural processes underlying integration of phonological and orthographic information were assessed by measuring event‐related brain potentials (ERPs), judgment accuracies and reaction times (RTs) in 20 children (9–10 years) and 20 adults performing visual rhyme judgments. Half the trials were phonologically and orthographically congruent across the prime‐target pairs (e.g., thrown–own, cake–own), and half were incongruent (e.g., gown–own, cone–own). For both children and adults, behavioral performance was most affected when different phonological representations had to be encoded from similar orthographic representations (e.g., gown–own), and the amplitudes of the N350 reflected effects of both rhyme and phonological/orthographic congruency. Latencies of the N350 were shorter over the left hemisphere only in adults, and phonological/orthographic incongruence produced greater delays in children's processing. Therefore, it appears that neural systems mediating rhyming judgments develop early; however, adults exhibit increased efficiency for left‐hemisphere processing and are less affected by interference from incongruent phonological and orthographic codes. © 2003 Wiley Periodicals, Inc. Dev Psychobiol 43: 128–145, 2003.
The N400 in beginning readers
Authors: Coch Donna , Holcomb Phillip J.
Published: August 2003

In an event‐related potentials study of brain–behavior relations during learning‐to‐read, girls in first grade viewed known words, unknown words, difficult words, and nonwords presented in list form. Participants were divided into low‐ability and high‐ability reading groups based on standardized test scores. During the 300‐ to 600‐ms epoch, low‐ability readers lacked a substantial N400 while high‐ability readers evidenced a large, widely distributed negativity to all word types. During the 600‐ to 1,000‐ms epoch, high‐ability readers showed effects of repetition while low‐ability readers did not. The findings indicate a less selective neurocognitive word‐processing system in children as compared to adults and suggest that the N400 may serve as an oblique index of the automaticity of lower level processing. © 2003 Wiley Periodicals, Inc. Dev Psychobiol 43: 146–166, 2003.
BBVA‐ARIES: a forecasting and simulation model for EMU
Authors: Ballabriga Fernando C. , Castillo Sonsoles
Published: August 2003

This paper describes the BBVA‐ARIES, a Bayesian vector autoregression (BVAR) for the European Economic and Monetary Union (EMU). In addition to providing EMU‐wide growth and inflation forecasts, the model provides an assessment of the interactions between key EMU macroeconomic variables and external ones, such as world GDP or commodity prices. A comparison of the forecasts generated by the model and those of private analysts and public institutions reveals a very positive balance in favour of the model. For their part, the simulations allow us to assess the potential macroeconomic effects of macroeconomic developments in the EMU. Copyright © 2003 John Wiley & Sons, Ltd.
On seasonal error correction when the processes include different numbers of unit roots
Authors: Lyhagen Johan , Löf Mårten
Published: August 2003

We propose a seasonal cointegration model (SECM) for quarterly data which includes variables with different numbers of unit roots and thus needs to be transformed in different ways in order to yield stationarity. A Monte Carlo simulation is carried out to investigate the consequences of specifying a SECM with all variables in annual diffrerences in this situation. The SECM in annual differences is compared to the correctly specified model. Pre‐testing for unit roots using two different approaches, and where the models are specified according to the unit root test results, is also considered. The forecast mean squared error criterion and certain parameter estimation results indicate that, in practice, a cointegration model where all variables are transformed with the annual difference filter is more robust than one obtained by pre‐testing for a smaller number of unit roots. The second‐best choice when the true model is not known and when the aim is to forecast, is an ordinary VAR model also in annual differences. Copyright © 2003 John Wiley & Sons, Ltd.
Forecasting new product trial in a controlled test market environment
Authors: Fader Peter S. , Hardie Bruce G. S. , Zeithammer Robert
Published: August 2003

A number of researchers have developed models that use test market data to generate forecasts of a new product's performance. However, most of these models have ignored the effects of marketing covariates. In this paper we examine what impact these covariates have on a model's forecasting performance and explore whether their presence enables us to reduce the length of the model calibration period (i.e. shorten the duration of the test market). We develop from first principles a set of models that enable us to systematically explore the impact of various model ‘components’ on forecasting performance. Furthermore, we also explore the impact of the length of the test market on forecasting performance. We find that it is critically important to capture consumer heterogeneity, and that the inclusion of covariate effects can improve forecast accuracy, especially for models calibrated on fewer than 20 weeks of data. Copyright © 2003 John Wiley & Sons, Ltd.
Antigen‐specific immunotherapy and cancer vaccines
Authors: Jäger Elke , Jäger Dirk , Knuth Alexander
Published: August 2003

The specific activation of the immune system to control cancer growth in vivo has been a long‐standing goal in cancer immunology and medical oncology. The identification of tumor‐associated antigens has provided the basis for new concepts in antigen‐specific immunotherapy. The first clinical trials on cancer vaccines were designed to evaluate the toxicity and objectively measurable immunologic effects in relation to clinical developments mostly in patients with metastatic disease. MHC class I‐ and II‐restricted peptide epitopes, antigenic proteins, viral constructs, mini‐genes and whole tumor cells have been used either alone or combined with different cytokines (i.e., IL‐2, IL‐12, GM‐CSF), adjuvants (incomplete Freund's adjuvant, montanide, QS21) or with dendritic cells to induce specific immune responses in vivo. Standardized assay systems to evaluate the immunologic effects of cancer vaccines have been established. Clinical developments during and after vaccination were followed in relation to vaccine‐induced immune responses. Prognostic tumor features, i.e., homogeneity of tumor antigen and MHC class I/II expression and intratumoral cellular infiltrates, have been identified that may help to select patients who are more likely to benefit from antigen‐specific cancer vaccines in the future. © 2003 Wiley‐Liss, Inc.
Experimental radioimmunotherapy of small peritoneal metastases of colorectal origin
Authors: Koppe Manuel J. , Soede Annemieke C. , Pels Wikke , Oyen Wim J.G. , Goldenberg David M. , Bleichrodt Robert P. , Boerman Otto C.
Published: August 2003

Radioimmunotherapy using radiolabeled monoclonal antibodies (MoAbs) directed against tumor‐associated antigens might be an effective treatment modality for small volume disease. Our aim was to optimize an experimental model of radioimmunotherapy for small peritoneal metastases of colorectal origin using the anti‐CEA MoAb MN‐14. In nude mice with intraperitoneal (i.p.) LS174T tumors, a protein dose‐escalation study was carried out to determine the maximal dose of radioiodinated MN‐14 to be used in radioimmunotherapy. The biodistribution of radioiodinated MN‐14 was determined after intravenous (i.v.) and i.p. administration. Finally, the therapeutic efficacy of escalating activity doses of 131I‐labeled MN‐14 (62.5–500 μCi) was assessed and compared to that of unlabeled MN‐14 or 500 μCi of 131I‐labeled irrelevant control antibody. At protein doses higher than 25 μg, uptake in tumor was reduced, presumably due to saturation of tumor antigen. During the first 24 hours i.p. administration led to higher tumor uptake and higher tumor:blood ratios than i.v. administration. Median survival of the control groups was 38 days (unlabeled MN‐14) and 52 days (131I‐labeled nonspecific antibody). Median survival of the groups treated with increasing activity doses of 131I‐labeled MN‐14 was 42 days (62.5 μCi), 49 days (125 μCi), 63 days (250 μCi) and 101 days (500 μCi), respectively (p < 0.0001 compared to unlabeled MN‐14). The present study shows that the anti‐CEA‐antibody MN‐14 preferentially accumulates in i.p. LS174T tumor xenografts after both i.p. and i.v. administration. Intraperitoneal radioimmunotherapy using 131I‐labeled MN‐14 delays significantly the outgrowth of peritoneal LS174T metastases, even at relatively low activity doses. © 2003 Wiley‐Liss, Inc.
Frequent allelic changes at chromosome 7q34 but lack of mutation of the BRAF in papillary renal cell tumors
Authors: Nagy Anett , Balint Ildiko , Kovacs Gyula
Published: August 2003

We have analyzed the BRAF locus on chromosome 7q34 with microsatellites for allelic changes and exons 11 and 15 of the BRAF with sequencing for mutations in 50 kidney cancers including 20 papillary, 15 conventional and 15 chromophobe renal cell carcinomas (RCC). Allelic changes at the BRAF locus were seen in 16 of the 20 papillary, 3 of the 15 conventional RCCs and 2 of the 15 chromophobe RCCs. Sequencing failed to disclose mutations in exons 11 and 15 of the BRAF gene in any of the tumors. Our data indicate that BRAF mutation does not play a role in the development of renal cell tumors. © 2003 Wiley‐Liss, Inc.
Oral contraceptive use and risk of breast cancer by histologic type
Authors: Newcomer Laura M. , Newcomb Polly A. , Trentham‐Dietz Amy , Longnecker Matthew P. , Greenberg E. Robert
Published: August 2003

We examined the association between oral contraceptive use and risk of specific breast cancer histopathologies in a large, multi‐center, population‐based, case‐control study. Women younger than age 75 with a new diagnosis of invasive breast cancer were identified from 4 statewide tumor registries. We compared women with lobular (n = 493) and ductal carcinoma (n = 5,510) to randomly selected controls (n = 9,311). Odds ratios (OR) and 95% confidence intervals (CI) for each histologic type were estimated using polytomous logistic regression, adjusted for other breast cancer risk factors. Current oral contraceptive use was associated with increased risk of lobular carcinoma (OR = 2.6, 95%CI = 1.0–7.1) and there was a significant trend (p = 0.017) of increased risk with more recent use. Oral contraceptive use was not clearly associated with ductal carcinoma (OR = 1.2, 95%CI = 0.8–1.9). These results suggest that the association between oral contraceptive use and risk of breast cancer may vary by histologic type. © 2003 Wiley‐Liss, Inc.
Involvement of p53 in specific anti‐neuroectodermal tumor activity of aloe‐emodin
Authors: Pecere Teresa , Sarinella Federica , Salata Cristiano , Gatto Barbara , Bet Alessandra , Dalla Vecchia Francesca , Diaspro Alberto , Carli Modesto , Palumbo Manlio , Palù Giorgio
Published: August 2003

Previously, we have identified aloe‐emodin (AE) as a new type of anticancer agent, with activity that is based on apoptotic cell death promoted by a neuroectodermal tumor‐specific drug uptake. We attempt to clarify the intracellular target of AE and the apoptosis‐signaling pathway activated by AE in neuroblastoma cell lines. Two‐photon excitation microscopy and spectroscopic titrations documented that AE is highly concentrated in susceptible cells and binds to DNA. One of the most important mediators of apoptotic response to genotoxic stimuli, such as anticancer agents, is the p53 tumor suppressor gene. To evaluate the role played by p53 in AE‐induced apoptosis a p53 mutant cell line, which lacks transcriptional activity of p53 targeted genes, was tested. AE displayed a reduced growth inhibitory and pro‐apoptotic activity in p53 mutant cells (SK‐N‐BE(2c)) with respect to the p53 wild‐type line (SJ‐N‐KP). This effect was not caused by a reduced drug uptake in the mutant neuroblastoma cell line but was related to a different apoptotic cell phenotype. Whereas SJ‐N‐KP cells were susceptible to a p53 transcription‐dependent pathway of apoptosis, SK‐N‐BE(2c) cells underwent apoptosis with up‐regulation of p53 expression but not of p53‐target genes. After AE treatment p53 translocates to the mitochondria inter‐membrane space in both neuroblastoma cell lines. Due to its high accumulation in neuroectodermal tumor cells AE could also kill tumor cells harboring p53 mutant genes. This property would further contribute to AE specific anti‐tumor activity and might be exploitable in the clinic. © 2003 Wiley‐Liss, Inc.
Vascular endothelial growth factor expression correlates with matrix metalloproteinases MT1‐MMP, MMP‐2 and MMP‐9 in human glioblastomas
Authors: Munaut Carine , Noël Agnès , Hougrand Olivier , Foidart Jean‐Michel , Boniver Jacques , Deprez Manuel
Published: August 2003

Vascular endothelial growth factor (VEGF) is the major endothelial mitogen in central nervous system neoplasms and it is expressed in 64–95% of glioblastomas (GBMs). Tumour cells are the main source of VEGF in GBMs whereas VEGF receptors (VEGFR‐1, its soluble form sVEGFR‐1, VEGFR‐2 and neuropilin‐1) are expressed predominantly by endothelial cells. Infiltrating tumour cells and newly‐formed capillaries progress through the extracellular matrix by local proteolysis involving matrix metalloproteinases (MMPs). Recent studies have shown that VEGF expression and bioavailability can be modulated by MMPs. We reported previously that the expression of MT1‐MMP in human breast cancer cells was associated with an enhanced VEGF expression. We used quantitative RT‐PCR, Western blot, gelatin zymography and immunohistochemistry to study the expression of VEGF, VEGFR‐1, VEGFR‐2, sVEGFR‐1, neuropilin‐1, MT1‐MMP, MMP‐2, MMP‐9 and TIMP‐2 in 20 human GBMs and 5 normal brains. The expression of these MMPs was markedly increased in most GBMs with excellent correlation between mRNA and protein levels; activated forms of MMP‐2 and MMP‐9 were present in 8/18 and 7/18 of GBMs. A majority of GBMs (17/20) also expressed high levels of VEGF, as previously reported, with strong correlation between VEGF and MT1‐MMP gene expression levels, and double immunostaining showed that VEGF and MT1‐MMP peptides co‐localize in tumour and endothelial cells. Our results suggest that the interplay between metalloproteinases and VEGF previously described in experimental tumours may also be operative in human GBMs. Because of its dual ability to activate MMP‐2 and to up‐regulate VEGF, MT1‐MMP might be of central importance in the growth of GBMs and represent an interesting target for anti‐cancer treatments. © 2003 Wiley‐Liss, Inc.
Role of thymidine phosphorylase on invasiveness and metastasis in lung adenocarcinoma
Authors: Sato Jun , Sata Makoto , Nakamura Hidenori , Inoue Sumito , Wada Toshihiro , Takabatake Noriaki , Otake Kazuhisa , Tomoike Hitonobu , Kubota Isao
Published: August 2003

Thymidine phosphorylase (TP) is expressed at higher levels in a variety of human cancers than in adjacent normal tissue. It is reported that the higher expression is associated with an increase of intratumoral microvessel density and a poor prognosis. We investigated the role of TP in human non small cell lung cancers (NSCLCs). The concentrations of TP in the tumors and the adjacent normal tissue from surgically resected specimens of 54 cases of NSCLCs were measured by using an enzyme‐linked immunosorbent assay. Tumor specimens were also examined immunohistochemically. TP concentrations in the tumors were 169 ± 18 units/mg protein (mean ± SD), whereas those in normal tissue were 43 ± 4 units/mg protein (mean ± SD), consistent with TP staining patterns. There was no correlation between TP expression and microvessel density. Among clinicopathologic factors examined, the concentrations of TP but not TP immunoreactivity correlated with tumor differentiation in lung adenocarcinoma. Although a specific TP inhibitor (TPI) and overexpression of TP did not affect the growth of A549 lung adenocarcinoma cells, Matrigel invasion assay showed that A549 transfected with TP had higher invasive potential than mock transfectant, and such enhanced invasive activity was markedly diminished by treatment with TPI. Furthermore, administration of TPI suppressed lung metastasis of TP‐overexpressing A549 cells in nude mice. These results demonstrate that TP may play an important role in tumor differentiation, invasiveness and metastasis in lung adenocarcinoma, and suggest that TP could be a novel target for treatment of TP‐overexpressing lung adenocarcinoma. © 2003 Wiley‐Liss, Inc.
Epigallocatechin‐3‐gallate is a potent natural inhibitor of fatty acid synthase in intact cells and selectively induces apoptosis in prostate cancer cells
Authors: Brusselmans Koen , De Schrijver Ellen , Heyns Walter , Verhoeven Guido , Swinnen Johannes V.
Published: August 2003

Chemical inhibitors of fatty acid synthase (FAS) inhibit growth and induce apoptosis in several cancer cell lines in vitro and in tumor xenografts in vivo. Recently the green tea component epigallocatechin‐3‐gallate (EGCG) was shown to act as a natural inhibitor of FAS in chicken liver extracts. Here we investigated whether EGCG inhibits FAS activity in cultured prostate cancer cells and how this inhibition affects endogenous lipid synthesis, cell proliferation and cell viability. The high levels of FAS activity in LNCaP cells were dose‐dependently inhibited by EGCG and this inhibition was paralleled by decreased endogenous lipid synthesis, inhibition of cell growth and induction of apoptosis. In contrast, epicatechin (EC), another closely related green tea polyphenolic compound, which does not inhibit FAS, had no effect on LNCaP cell growth or viability. Treatment of nonmalignant cells with low levels of FAS activity (fibroblasts) with EGCG led to a decrease in growth rate but not to induction of apoptosis. These data indicate that EGCG inhibits FAS activity as efficiently as presently known synthetic inhibitors and selectively causes apoptosis in LNCaP cells but not in nontumoral fibroblasts. These findings establish EGCG as a potent natural inhibitor of FAS in intact cells and strengthen the molecular basis for the use of EGCG as a chemopreventive and therapeutic antineoplastic agent. © 2003 Wiley‐Liss, Inc.
Malignant transformation of human bronchial epithelial cells with the tobacco‐specific nitrosamine, 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone
Authors: Zhou Hongning , Calaf Gloria M. , Hei Tom K.
Published: August 2003

Sufficient evidence has demonstrated that cigarette smoking is causally associated with various types of human cancers. In the United States, about 90% of deaths from lung cancer among men and 79% of those among women are associated with smoking. Tobacco‐specific nitrosamines are formed from nicotine and related tobacco alkaloids and are the most carcinogenic compounds of tobacco smoke. The most potent N‐nitrosamine contained in tobacco smoke is 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone, NNK. In the our study, the oncogenic transforming effects of graded doses of NNK were examined using papillomavirus‐immortalized human bronchial epithelial cells. Growth kinetics, saturation density, resistance to serum‐induced terminal differentiation, anchorage independent growth and tumorigenicity in nude mice were used to investigate the various stages of transformation in bronchial epithelial cells. We show here that immortalized human bronchial epithelial cells in culture can be malignantly transformed by treatment with NNK (100 μg/ml or 400 μg/ml) for 7 days. Transformed cells produced progressively growing subcutaneous tumors upon inoculation into nude mice. Immunofluorescence staining for keratin expression confirmed the epithelial nature of the tumor cells. Increased expression of p16, β‐catenin and PCNA in the established cell lines were detected by immunofluorescence staining and quantified by confocal microscopy. These data suggested that NNK can induce malignant transformation of human bronchial epithelial cells, and the tumor cell lines established are useful models in investigating the carcinogenic mechanism(s) of NNK. © 2003 Wiley‐Liss, Inc.
Renal cell carcinoma‐infiltrating natural killer cells express differential repertoires of activating and inhibitory receptors and are inhibited by specific HLA class I allotypes
Authors: Schleypen Julia S. , von Geldern Marion , Weiß Elisabeth H. , Kotzias Nicole , Rohrmann Karl , Schendel Dolores J. , Falk Christine S. , Pohla Heike
Published: August 2003

Among tumor‐infiltrating lymphocytes (TILs) directly isolated from renal cell carcinomas (RCCs), we found substantial numbers of natural killer (NK) cells in most tumor tissues. They could be identified reliably in situ with an antibody directed against the activating receptor (AR) NKp46 that is exclusively expressed by all NK cells. NK‐enriched TILs (NK‐TILs) showed cytotoxicity against major histocompatibility complex (MHC) class I‐negative cell lines. The ability to detect lysis of target cells was dependent on the percentage of NK cells within the TILs, and cytotoxicity was only observed after overnight activation with low‐dose interleukin‐2 (IL‐2). Infiltrating NK cells were found to express various inhibitory receptors (IRs); among these the CD94/NKG2A receptor complex was overrepresented compared to the autologous peripheral blood mononuclear cell (PBMC) population. Other IRs were underrepresented, indicating that NK subpopulations vary in their tumor‐infiltrating capacity. IRs expressed by NK‐TILs are functional since receptor engagement with MHC class I ligands presented by human leukocyte antigen (HLA)‐transfected target cell lines was able to inhibit NK‐mediated cytotoxicity. NK‐TILs were also able to lyse autologous or allogeneic tumor cell lines in vitro. This activity correlated with low HLA class I surface expression since lysis could be inhibited by interferon (IFN)‐γ‐expressing RCC transductants that displayed a higher surface density of HLA class I molecules. Therefore, NK cells infiltrating tumor tissues have an inherent ability to recognize transformed cells, but they require cytokine activation and are sensitive to inhibition by IR ligands. © 2003 Wiley‐Liss, Inc.
Aberrant p16 promoter methylation in smokers and former smokers with nonsmall cell lung cancer
Authors: Jarmalaite Sonata , Kannio Annamaria , Anttila Sisko , Lazutka Juozas R. , Husgafvel‐Pursiainen Kirsti
Published: August 2003

Hypermethylation of cytosines in CpG‐rich islands of the promoter regions of regulatory genes has been discovered as a common mechanism of gene silencing during carcinogenesis. We analysed 64 primary lung carcinomas for promoter methylation of the tumour suppressor genes (TSGs) p16 (p16INK4a/CDKN2A) and p14 (p14ARF) by methylation‐specific PCR, in order to evaluate aberrant methylation as a potential biomarker for epigenetic alterations in tobacco‐related lung cancer. Methylation of p16 was observed in 34% (22/64) of the lung tumours examined. In particular, p16 methylation occurred in nonsmall cell lung cancer (NSCLC) only, with 41 % (22/54) of the tumours being positive. The highest frequency was found in large cell carcinoma (5/7, 71%), followed by adenocarcinoma (9/25, 36%) and squamous cell carcinoma (7/21, 33%). Methylation of the p14 gene was less frequent in lung cancer (4/52, 8%). When association with tobacco smoking was analysed, 42% (21/50) of NSCLC from ever smokers exhibited p16 methylation. Interestingly, the analysis revealed a significantly higher risk of p16 methylation in former smokers as compared to current smokers [odds ratio (OR) 5.1; 95% confidence interval (CI) 1.3–22]. The difference was retained after adjustment for age (OR 3.7; 95% CI 0.9–17). The promoter methylation results were then combined with data on genetic alterations determined previously in the same set of tumours. This data similarly showed that p16 methylation in parallel with p53 gene mutation or p14 methylation occurred more frequently in former smokers than in current smokers (44% vs. 14%; P = 0.035). Taken together, our data suggest that analysis of promoter methylation in TSGs may provide a valuable biomarker for identification of groups with an elevated risk of cancer, such as smokers and ex‐smokers. © 2003 Wiley‐Liss, Inc.