bluuebunny/crossref_metadata_2025 huggingface dataset:
Growth defect in Grg5 null mice is associated with reduced Ihh signaling in growth plates
Authors: Wang Wen‐Fang , Wang You‐Gan , Reginato Anthony M. , Plotkina Sofiya , Gridley Thomas , Olsen Bjorn R.
Published: August 2002

Gene‐targeted disruption of Grg5, a mouse homologue of Drosophila groucho (gro), results in postnatal growth retardation in mice. The growth defect, most striking in approximately half of the Grg5 null mice, occurs during the first 4–5 weeks of age, but most mice recover retarded growth later. We used the nonlinear mixed‐effects model to fit the growth data of wild‐type, heterozygous, and Grg5 null mice. On the basis of preliminary evidence suggesting an interaction between Grg5 and the transcription factor Cbfa1/Runx2, critical for skeletal development, we further investigated the skeleton in the mice. A long bone growth plate defect was identified, which included shorter zones of proliferative and hypertrophic chondrocytes and decreased trabecular bone formation. This decreased trabecular bone formation is likely caused by a reduced recruitment of osteoblasts into the growth plate region of Grg5 null mice. Like the growth defect, the growth plate and trabecular bone abnormality improved as the mice grew older. The growth plate defect was associated with reduced Indian hedgehog expression and signaling. We suggest that Grg5, a transcriptional coregulator, modulates the activities of transcription factors, such as Cbfa1/Runx2 in vivo to affect Ihh expression and the function of long bone growth plates. © 2002 Wiley‐Liss, Inc.
Spatially dynamic expression of Sry in mouse genital ridges
Authors: Bullejos Monica , Koopman Peter
Published: August 2002

We have studied the spatial dynamics of Sry transcription in the genital ridges of mouse embryos. We find that Sry is expressed in a dynamic wave that emanates from the central and/or anterior regions, extends subsequently to both poles, and ends in the caudal pole. This dynamism may explain the relative positioning of ovarian and testicular tissue seen in ovotestes in mice. Since direct regulatory targets of SRY ought to be expressed in a corresponding or complimentary wave, our observations pave the way for identification of target genes. Sry is expressed in internal cells but not in coelomic surface epithelial cells, indicating that its effect on proliferation of surface cells is achieved non‐cell‐autonomously. The cellular dynamism of Sry expression revealed in this study thus provides important insights into both the cellular and molecular mode of action of SRY, and how perturbations in Sry expression can lead to anomalies of sexual development. © 2001 Wiley‐Liss, Inc.
Dynamic expression of chicken cMeso2 in segmental plate and somites
Authors: Buchberger Astrid , Bonneick Sonja , Klein Christian , Arnold Hans‐Henning
Published: August 2002

Abstract

Somitogenesis in vertebrates involves prepatterning of paraxial mesoderm into somitomeres, establishing of anteroposterior polarity within somite primordia, and boundary formation between individual somites. cMeso2 is a newly identified chicken gene encoding a bHLH transcription factor, which is expressed in a transient stripe pattern in anterior presomitic mesoderm before segmentation of somites. The expression pattern overlaps with that of cMeso1 and correlates in time with the formation cycle of somites, suggesting that it may have a role in this process. Unlike its homologues in other organisms cMeso2 transcripts in chicken locate to the posterior aspects of somitomeres and constitute a marker for the caudal half of somites. Initiation of cMeso2 expression in presomitic mesoderm as well as its maintenance appears to be independent from influences by surrounding tissues, suggesting that it is part of the intrinsic program underlying segmentation. Although cMeso1 contains a C‐terminal activator domain that can be transferred onto an independent DNA‐binding domain, no evidence for such a transactivator domain can be found in cMeso2. In contrast, cMeso2 exerts transcriptional inhibition when coexpressed with the cMeso1 transactivator and seems to contain a repressor domain. Thus, cMeso1 and cMeso2 may function in an antagonistic manner during somitogenesis. © 2001 Wiley‐Liss, Inc.
The role of acculturative stress and body dissatisfaction in predicting bulimic symptomatology across ethnic groups
Authors: Perez Marisol , Voelz Zachary R. , Pettit Jeremy W. , Joiner Thomas E.
Published: August 2002

Objective

This study examines the interactive effects of acculturative stress and body dissatisfaction in prediction of bulimic symptoms, particularly in non‐White females.

Method

We administered questionnaires to White, Black, and Hispanic females on acculturative stress, body dissatisfaction, and bulimic symptoms.

Results

Our results show that among minority women who report low levels of acculturative stress, body dissatisfaction and bulimia were not correlated. However, among minority women who reported high levels of acculturative stress, body dissatisfaction and bulimia were highly and significantly correlated.

Discussion

The combination of acculturative stress and body dissatisfaction may render minority women more vulnerable to bulimic symptoms; the absence of acculturative stress among minority women may buffer them against bulimic symptoms, even in the presence of body dissatisfaction. © 2002 by Wiley Periodicals, Inc. Int J Eat Disord 31: 442–454, 2002.
Central pontine myelinolysis in a patient with anorexia nervosa
Authors: Amann Benedikt , Schäfer Martin , Sterr Andrea , Arnold Stephan , Grunze Heinz
Published: August 2002

Myelinolysis may occur as a severe complication of eating disorders, especially anorexia nervosa (AN). One of the most important reasons can be a rapid correction of hyponatremia caused by tubulopathy, water intoxication (WI), or abuse of diuretics in individuals with AN.

Method and Results

We report on a 24‐year‐old female patient with an 8‐year history of AN. A rapid correction of severe hyponatremia and hypokalemia induced by WI led to central pontine myelinolysis, which was confirmed by magnetic resonance imaging (MRI) examination. Besides affective lability, incoherence, and an acute confusional state, surprisingly, no severe neurological symptoms emerged.

Conclusion

Thus, physicians should be aware of the risk of pontine myelinolysis with new psychiatric symptoms emerging in the absence of obvious neurological deficits. © 2001 by John Wiley & Sons, Inc. Int J Eat Disord 30: 462–466, 2001.
Tracking a three‐dimensional moving target with distributed passive sensors using extended Kalman filter
Authors: Ito Masayoshi , Tsujimichi Shingo , Kosuge Yoshio
Published: August 2002

A method is proposed for combining the acquired information of several passive sensors in order to obtain two‐dimensional information on the elevation and azimuth angles of the target and to estimate the location and velocity of the moving target in a three‐dimensional space. In the case of a moving target, several sensors are required to observe the target at the same time if the so‐called triangulation measurement is used. Hence, if each sensor carries out measurement asynchronously, the target position cannot be accurately computed. In the proposed system, angular tracking is carried out first at each sensor level of two sensors. After a certain time, the time alignment is carried out for the results of angular tracking. Then, the initial value of the three‐dimensional trajectory is computed by combining the angular tracking results. Further, once the initial value is computed, a three‐dimensional tracking maintenance process by an extended Kalman filter is initiated at the central level. Every time a new observed value from one of N sensors is obtained, this is used for updating the three‐dimensional trajectory. In the present system, a moving target can be tracked even if several sensors carry out observation asynchronously. The effectiveness of the present method is verified by simulation. © 2001 Scripta Technica, Electron Comm Jpn Pt 1, 84(7): 74–85, 2001
Problems of the application of N2/SF6 mixtures to gas‐insulated bus
Authors: Inami Kiyoshi , Maeda Yasuhiro , Habuchi Yoshitaka , Yoshimura Manabu , Hamano Suenobu , Hama Hiroyuki
Published: August 2002

In designing a gas‐insulated bus (GIB) using N2/SF6 mixtures, there are many application problems, such as the mixture pressure needed in order to maintain the required dielectric and heat transfer performance. Problems of recycling SF6 are also essential in applying N2/SF6 mixtures. This paper presents the minimum breakdown field strength at lightning impulse and the temperature rise of the conductor and enclosure as measured for N2/SF6 mixtures. Considering the dielectric and heat transfer properties, we clarify the problems of application of mixtures to a GIB and discuss the appropriate mixture ratio of SF6 in designing a GIB comparable to the present dimensions. In addition, the lowest limit of SF6 content in a liquefied recovering method is theoretically estimated for reference in practical SF6 recovery from mixtures. It is important for design to consider both breakdown phenomena, including the area effect of electrode, and the heat transfer properties of mixtures. © 2001 Scripta Technica, Electr Eng Jpn, 137(4): 25–31, 2001
Further characterization and validation of gpt delta transgenic mice for quantifying somatic mutations in vivo
Authors: Swiger Roy R. , Cosentino Lidia , Masumura Ken‐Ichi , Nohmi Takehiko , Heddle John A.
Published: August 2002

The utility of any mutation assay depends on its characteristics, which are best discovered using model mutagens. To this end, we report further on the characteristics of the lambda‐based gpt delta transgenic assay first described by Nohmi et al. ([1996]: Environ Mol Mutagen 28:465–470). Our studies show that the gpt transgene responds similarly to other transgenic loci, specifically lacZ and cII, after treatment with acute doses of N‐ethyl‐N‐nitrosourea (ENU). Because genetic neutrality is an important factor in the design of treatment protocols for mutagenicity testing, as well as for valid comparisons between different tissues and treatments, a time‐course study was conducted. The results indicate that the gpt transgene, like cII and lacZ, is genetically neutral in vivo. The sensitivities of the loci are also equivalent, as evidenced by spontaneous mutant frequency data and dose– response curves after acute treatment with 50, 150, or 250 mg/kg ENU. The results are interesting in light of transgenic target size and location and of host genetic background differences. Based on these studies, protocols developed for other transgenic assays should be suitable for the gpt delta. Additionally, a comparison of the gpt and an endogenous locus, Dlb‐1, within the small intestine of chronically treated animals (94 μg/mL ENU in drinking water daily) shows differential accumulation of mutations at the loci during chronic exposure. The results further support the existence of preferential repair at endogenous, expressed genes relative to transgenes. Environ. Mol. Mutagen. 37:297–303, 2001 © 2001 Wiley‐Liss, Inc.
Use of a shared tuned mass damper (STMD) to reduce vibration and pounding in adjacent structures
Authors: Abdullah Makola M. , Hanif Jameel H. , Richardson Andy , Sobanjo John
Published: August 2002

The dynamic response of tall civil structures due to earthquakes is very important to civil engineers. Structures exposed to earthquakes experience vibrations that are detrimental to their structural components. Structural pounding is an additional problem that occurs when buildings experience earthquake excitation. This phenomena occurs when adjacent structures collide from their out‐of‐phase vibrations. Many energy dissipation devices are presently being used to reduce the system response. Tuned mass dampers (TMD) are commonly used to improve the response of structures. The stiffness and damping properties of the TMD are designed to be a function of the natural frequency of the building to which it is connected. This research involves attaching adjacent structures with a shared tuned mass damper (STMD) to reduce both the structures vibration and probability of pounding. Because the STMD is connected to both buildings, the problem of tuning the STMD stiffness and damping parameters becomes an issue. A design procedure utilizing a performance function is used to obtain the STMD parameters to result in the best overall system response. Copyright © 2001 John Wiley & Sons, Ltd.
Understanding and predicting effects of supplemental viscous damping on seismic response of asymmetric one‐storey systems
Authors: Lin Wen‐Hsiung , Chopra Anil K.
Published: August 2002

Supplemental damping could mitigate the earthquake‐induced damage in buildings with asymmetric plan, known to be more vulnerable to damage than comparable symmetric‐plan buildings. This investigation aims to improve the understanding of how and why planwise distribution of fluid viscous dampers (FVDs) influences the response of linearly elastic, one‐storey, asymmetric‐plan systems. Starting with vibration mode shapes, we predict this influence on the modal damping ratios, and in turn on the individual modal responses and the total response. These predictions are confirmed by the computed responses, which demonstrated that the reduction in earthquake response of the system achieved by supplemental damping is strongly influenced by its planwise distribution, which is characterized by four parameters. Identified are asymmetric distributions of supplemental damping that are more effective in reducing the response compared to symmetric distribution. The percentage reduction achieved by a judiciously selected asymmetric distribution can be twice or even larger compared to symmetric distribution. Copyright © 2001 John Wiley & Sons, Ltd.
Numerical study of flows with multiple free surfaces
Authors: Mohapatra P. K. , Murty Bhallamudi S. , Eswaran V.
Published: August 2002

This paper demonstrates that a numerical method based on the generalized simplified marker and cell (GENSMAC) flow solver and Youngs' volume of fluid (Y‐VOF) surface‐tracking technique is an effective tool for studying the basic mechanics of hydraulic engineering problems with multiple free surfaces and non‐hydrostatic pressure distributions. Two‐dimensional flow equations in a vertical plane are solved numerically for this purpose. The numerical results are compared with experimental data and earlier numerical results based on a higher‐order depth‐averaged flow model available in the literature. Two classical problems, (i) flow in a free overfall and (ii) flow past a floor slot, are considered. The numerical results correspond very well with the experimental data for both sub‐critical and supercritical flows. Copyright © 2001 John Wiley & Sons, Ltd.
High‐order Cartesian grid method for calculation of incompressible turbulent flows
Authors: Gullbrand J. , Bai X. S. , Fuchs L.
Published: August 2002

A high‐order wall treatment is proposed and implemented into a Cartesian grid method and the wall treatment is evaluated for incompressible turbulent flows. The Cartesian grid method employs a sequence of locally refined, uniformly spaced, Cartesian grids. In order to achieve a high‐order accuracy, a wall treatment procedure has been developed for arbitrarily shaped geometries. The procedure consists of high‐order Lagrangian polynomial interpolations and extrapolations for determining the dependent variables around the wall boundaries. The wall treatment procedure and the Cartesian grid method are used together with a highly efficient multi‐grid acceleration method and a local grid refinement strategy for optimal distribution of the grid points. The high‐order Cartesian grid method is evaluated using test functions as well as for laminar and turbulent flows. The proposed approach maintains the high‐order discretization and yields high‐order accuracy of the numerical results. Large eddy simulation of a turbulent swirling flow indicates that the high‐order wall treatment leads to significantly different results from those calculated using a low‐order piecewise constant wall description. The differences in the results are smaller at a low level of turbulence near the inlet region, but become significant in the region far away from the inlet where the turbulence is more intense. In the latter situation the effect of the wall treatment is as important as the choice of the subgrid scale stress model. Copyright © 2001 John Wiley & Sons, Ltd.
Efficient construction of high‐resolution TVD conservative schemes for equations with source terms: application to shallow water flows
Authors: Burguete J. , García‐Navarro P.
Published: August 2002

High‐resolution total variation diminishing (TVD) schemes are widely used for the numerical approximation of hyperbolic conservation laws. Their extension to equations with source terms involving spatial derivatives is not obvious. In this work, efficient ways of constructing conservative schemes from the conservative, non‐conservative or characteristic form of the equations are described in detail. An upwind, as opposed to a pointwise, treatment of the source terms is adopted here, and a new technique is proposed in which source terms are included in the flux limiter functions to get a complete second‐order compact scheme. A new correction to fix the entropy problem is also presented and a robust treatment of the boundary conditions according to the discretization used is stated. Copyright © 2001 John Wiley & Sons, Ltd.
Suppression of vortex shedding for flow around a circular cylinder using optimal control
Authors: Homescu C. , Navon I. M. , Li Z.
Published: August 2002

Adjoint formulation is employed for the optimal control of flow around a rotating cylinder, governed by the unsteady Navier–Stokes equations. The main objective consists of suppressing Karman vortex shedding in the wake of the cylinder by controlling the angular velocity of the rotating body, which can be constant in time or time‐dependent. Since the numerical control problem is ill‐posed, regularization is employed. An empirical logarithmic law relating the regularization coefficient to the Reynolds number was derived for 60⩽Re⩽140. Optimal values of the angular velocity of the cylinder are obtained for Reynolds numbers ranging from Re=60 to Re=1000. The results obtained by the computational optimal control method agree with previously obtained experimental and numerical observations. A significant reduction of the amplitude of the variation of the drag coefficient is obtained for the optimized values of the rotation rate. Copyright © 2002 John Wiley & Sons, Ltd.
Information Role of U.S. Futures Trading in a Global Financial Market
Authors: Fung Hung‐Gay , Leung Wai K. , Xu Xiaoqing Eleanor
Published: August 2002

Using a bivariate, asymmetric generalized autoregressive conditional heteroskedasticity model, we examine the
patterns of information flows for three financial futures contracts that are dual‐listed on U.S. and
Asian markets (i.e., Nikkei 225 Index, Eurodollar, and dollar–yen currency futures). The results
indicate that the U.S. market plays a leading role in terms of pricing‐information transmission across
markets. In terms of volatility spillover across markets, however, foreign markets seem to play a similar role
(e.g., Nikkei Index futures) or even a more significant role than the United States (e.g.,
Eurodollar futures in Singapore and dollar–yen currency futures in Japan). © 2001 John Wiley
& Sons, Inc. Jrl Fut Mark 21:1071–1090, 2001
Cyclin D1 gene contains a cryptic promoter that is functional in human cancer cells
Authors: Terrinoni Alessandro , Dell'Arciprete Roberta , Fornaro Mara , Stella Manuela , Alberti Saverio
Published: August 2002

A novel cyclin D1 (CCND1)–TROP2 fusion oncogene has been isolated from human cancer cells. Unexpectedly, the chimeric cDNA was found to express TROP2 in the absence of exogenous promoters. Mutagenesis of the TROP2 and CCND1 sequences and in vitro transcription/translation show that a cryptic promoter is present in the 3′ coding region of CCND1. The CCND1 cryptic promoter is functional in luciferase assays, where it augments the basal expression levels by eightfold and efficiently cooperates with an SV‐40 enhancer. The transcription start sites of the cryptic promoter map at bases 797 and 935 of CCND1, as determined by RNase protection assays. The cryptic promoter possesses canonical binding sites for ubiquitous transcription factors and W/S, X1, and CAAT/Y boxes that are characteristic of major histocompatibility complex class II gene promoters. Remarkably, the cryptic CCND1 promoter is active in human cancer cells and generates a truncated transcript that contains CCND1 instability sequences. Thus, this novel CCND1 transcription unit may play a role in the regulation of the expression of cyclin D1 and in tumor cell growth. © 2001 Wiley‐Liss, Inc.
Shape‐selective stereo processing in human object‐related visual areas
Authors: Gilaie‐Dotan Sharon , Ullman Shimon , Kushnir Tammar , Malach Rafael
Published: August 2002

Object related areas in the human ventral stream were previously shown to be activated, in a shape‐selective manner, by luminance, motion, and texture cues. We report on the preferential activation of these areas by stereo cues defining shape. To assess the relationship of this activation to object recognition, we employed a perceptual stereo effect, which profoundly affects object recognition. The stimuli consisted of stereo‐defined line drawings of objects that either protruded in front of a flat background (“front”), or were sunk into the background (“back”). Despite the similarity in the local feature structure of the two conditions, object recognition was superior in the “front” compared to the “back” configuration. We measured both recognition rates and fMRI signal from the human visual cortex while subjects viewed these stimuli. The results reveal shape selective activation from images of objects defined purely by stereoscopic cues in the human ventral stream. Furthermore, they show a significant correlation between recognition and fMRI signal in the object‐related occipito‐temporal cortex (lateral occipital complex). Hum. Brain Mapping 15:67–79, 2001. © 2001 Wiley‐Liss, Inc.
Characterizing instantaneous phase relationships in whole‐brain fMRI activation data
Authors: Laird Angela R. , Rogers Baxter P. , Carew John D. , Arfanakis Konstantinos , Moritz Chad H. , Meyerand M. Elizabeth
Published: August 2002

Typically, fMRI data is processed in the time domain with linear methods such as regression and correlation analysis. We propose that the theory of phase synchronization may be used to more completely understand the dynamics of interacting systems, and can be applied to fMRI data as a novel method of detecting activation. Generalized synchronization is a phenomenon that occurs when there is a nonlinear functional relationship present between two or more coupled, oscillatory systems, whereas phase synchronization is defined as the locking of the phases while the amplitudes may vary. In this study, we developed an application of phase synchronization analysis that is appropriate for fMRI data, in which the phase locking condition is investigated between a voxel time series and the reference function of the task performed. A synchronization index is calculated to quantify the level of phase locking, and a nonparametric permutation test is used to determine the statistical significance of the results. We performed the phase synchronization analysis on the data from five volunteers for an event‐related finger‐tapping task. Functional maps were created that provide information on the interrelations between the instantaneous phases of the reference function and the voxel time series in a whole‐brain fMRI activation data set. We conclude that this method of analysis is useful for revealing additional information on the complex nature of the fMRI time series. Hum. Brain Mapping 16:71–80, 2002. © 2002 Wiley‐Liss, Inc.
Changes in cerebellar activation pattern during two successive sequences of saccades
Authors: Stephan Thomas , Mascolo Andrea , Yousry Tarek A. , Bense Sandra , Brandt Thomas , Dieterich Marianne
Published: August 2002

The changes in the cerebellar activation pattern of two successive fMRI scanning runs were determined for visually guided to‐and‐fro saccades in 12 healthy volunteers familiar with the study paradigm. Group and single subject‐analyses revealed a constant activation of the paramedian cerebellar vermis (uvula, tonsils, tuber, folium/declive), which reflects constant ocular motor activity in both runs. A significant decrease in activation of the cerebellar hemispheres found in the second run is best explained by either a decrease in attention or the effects of motor optimization and learning. The significant, systematic changes of the cerebellar activation pattern in two successive runs were not expected, because the ocular motor task was simple, familiar, and highly automated. These findings indicate that similar effects may bias other cerebellar activation studies, in which sensorimotor tasks are repeated in a single session. Hum. Brain Mapping 16:63–70, 2002. © 2002 Wiley‐Liss, Inc.
Reaction with hydrazonoyl halides. Part 32 [1]: Reaction of C‐acyl‐N‐(3‐phenyl‐5‐pyrazolyl)hydrazonoyl chlorides with potassium thiocyanate and synthesis of some new 2,3‐dihydro‐1,3,4‐thiadiazoles and slenadiazoles
Authors: Abdelhamid Abdou O. , Sallam M. M. M. , Amer S. A.
Published: August 2002

C‐acyl‐N‐(3‐phenyl‐5‐pyrazolyl)hydrazonoyl chlorides 1a,b react with potassium thiocyanate and potassium selenocyanate to give 5‐acyl‐2,3‐dihydro‐2‐imino‐3‐(3′‐phenyl)pyrazol‐5′‐yl)‐1,3,4‐thiadiazoles 2a,b and 5‐acetyl‐2,3‐dihydro;‐2‐imino‐3‐(3′‐phenyl)pyrazol‐5′‐yl)‐1,3,4‐selenadiazole 10a,b. Also, 2‐[mercapto‐(methylthio)methylene]indan‐1,3‐dione 16 reacts with hydrazonoyl halides 15 and 22–25 to afford 2,3‐dihydro‐1,3,4‐thiadiazoles 19 and 26–29, respectively. Structures of the newly synthesized compounds are elucidated on the basis of spectral data, chemical transformations, and alternative synthesis methods. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:468–474, 2001
Syntheses of optically active 2‐(2‐benzothiazolylimino)‐heterazolidines
Authors: Cruz Alejandro , Gayosso Martha , Contreras Rosalinda
Published: August 2002

The syntheses of compounds 4R, 5R‐2‐[2‐benzothiazolylimino]‐3‐hydro‐4‐methyl‐5‐phenylthiazolidine (5a), 4S,5S‐2‐[2‐benzothiazolylimino]‐3,4‐dimethyl‐5‐phenylthiazolidine (5b), 4R,5S‐[2‐benzothiazolylimino]‐3‐hydro‐4‐methyl‐5‐phenyloxazolidine (5c), 4R,5S‐2‐[2‐benzothiazolyl‐imino]‐3,4‐dimethyl‐5‐phenyloxazolidine (5d), and 4R,5S‐2‐[2‐benzothiazolylimino]‐1,3,4‐trimethyl‐5‐phenylimidazolidine (5e) are reported. The stereochemistry of the reaction products and the X‐ray diffraction analyses of compounds 5a–d are discussed. Compounds 5a–d present planar structures. We have found short distances between the thiazolidine S1 atom and the benzothiazole N9 atom for 5a and 5b (2.782 and 2.824 Å, respectively) and the distance between the oxazolidine O1 and the benzothiazole S7 for 5d (2.721 Å). These distances are shorter than the sum of the van der Waals radii. These distances, together with the coplanarity of the heterocycles, seem to indicate the existence of a weak coordination bonding from sp2 oxygen or nitrogen atoms towards the sulfur atom. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:586–593, 2001
Wait‐and‐see policy for the N0 neck in early‐stage oral and oropharyngeal squamous cell carcinoma using ultrasonography‐guided cytology: Is there a role for identification of the sentinel node?
Authors: Nieuwenhuis Eline J. C. , Castelijns Jonas A. , Pijpers Rik , van den Brekel Michiel W. M. , Brakenhoff Ruud H. , van der Waal Isaac , Snow Gordon B. , Leemans Charles R.
Published: August 2002

Background

Management of the N0 neck in patients with head and neck squamous cell carcinoma (SCC) remains controversial. We describe the outcome of patients who underwent transoral tumor excision and a wait‐and‐see policy for the neck staged N0 by ultrasonography‐guided cytology (USgFNAC). Because selection of lymph nodes for USgFNAC is currently based on size criteria, we investigated the additional value of sentinel node (SN) identification.

Methods

The outcome of 161 patients with T1–T2 oral/oropharyngeal SCC was determined. In a subgroup of 39 patients the SN was identified and aspirated in addition.

Results

SN identification and aspiration was possible in 38 of 39 patients but without decreasing the false‐negative rate of USgFNAC. During follow‐up (12–99 months) 34 of 161 (21%) patients developed lymph node metastases. After therapeutic neck dissection and postoperative radiotherapy, 27 of 34 (79%) could be salvaged (88% regional control).

Conclusions

Wait‐and‐see seems justified in case of negative USgFNAC. Strict follow‐up with USgFNAC is required. SN identification and aspiration is feasible but did not improve lymph node selection. © 2002 Wiley Periodicals, Inc. Head Neck 24: 282–289, 2002; DOI 10.1002/hed.10018
Omental free flap reconstruction in complex head and neck deformities
Authors: Losken Albert , Carlson Grant W. , Culbertson John H. , Scott Hultman C. , Kumar Ajay V. , Jones Glyn E. , Bostwick John , Jurkiewicz Maurice J.
Published: August 2002

Background

Microvascular free flaps continue to revolutionize coverage options in head and neck reconstruction. This article reviews our 25‐year experience with omental free tissue transfers.

Methods

All patients who underwent free omental transfer to the head and neck region were reviewed.

Results

Fifty‐five patients were included with omental transfers to the scalp (25%), craniofacial (62%), and neck (13%) region. Indications were tumor resections, burn wound, hemifacial atrophy, trauma, and moyamoya disease. Average follow‐up was 3.1 years (range, 2 months–13 years). Donor site morbidities included abdominal wound infection, gastric outlet obstruction, and postoperative bleeding. Recipient site morbidities included partial flap loss in four patients (7%) total flap loss in two patients (3.6%), and three hematomas.

Conclusions

The omental free flap has acceptable abdominal morbidity and provides sufficient soft tissue coverage with a 96.4% survival. The thickness \and versatility of omentum provide sufficient contour molding for craniofacial reconstruction. It is an attractive alternative for reconstruction of large scalp defects and badly irradiated tissue. © 2002 Wiley Periodicals, Inc. Head Neck 24: 326–331, 2002; DOI 10.1002/hed.10082
Beyond health care cost containment: creating collaborative arrangements among the stakeholders
Authors: Young David W. , McCarthy Sheila M. , Barrett Diana , Kenagy John W. , Pinakiewicz Diane C.
Published: August 2002

The causes of escalating healthcare costs in the United States and many other industrial countries are well documented. Less evident are the structural factors that underlie the increases and their implications for the future. This paper discusses these structural factors, puts them in the context of the healthcare marketplace, and proposes a way to address them using a collaborative arrangement among all stakeholders in a healthcare system, called value‐based partnering. To be successful, the effort must include not only final purchasers (such as employers or Medicare in the USA) but all stakeholders in a healthcare system. Each stakeholder must develop a value equation in terms that are meaningful to the others, and must identify opportunities for value‐enhancing partnerships. The paper also identifies some of the impediments to value‐based partnering and discusses ways to overcome them, including the need for senior management intervention within some stakeholder groups, and the importance of collaborative discussions among all stakeholders. Copyright © 2001 John Wiley & Sons, Ltd.
A non‐conventional watershed partitioning method for semi‐distributed hydrological modelling: the package ALADHYN
Authors: Menduni Giovanni , Pagani Alessandro , Rulli Maria Cristina , Rosso Renzo
Published: August 2002

The extraction of the river network from a digital elevation model (DEM) plays a fundamental role in modelling spatially distributed hydrological processes. The present paper deals with a new two‐step procedure based on the preliminary identification of an ideal drainage network (IDN) from contour lines through a variable mesh size, and the further extraction of the actual drainage network (AND) from the IDN using land morphology. The steepest downslope direction search is used to identify individual channels, which are further merged into a network path draining to a given node of the IDN. The contributing area, peaks and saddles are determined by means of a steepest upslope direction search. The basin area is thus partitioned into physically based finite elements enclosed by irregular polygons. Different methods, i.e. the constant and variable threshold area methods, the contour line curvature method, and a topologic method descending from the Hortonian ordering scheme, are used to extract the ADN from the IDN. The contour line curvature method is shown to provide the most appropriate method from a comparison with field surveys. Using the ADN one can model the hydrological response of any sub‐basin using a semi‐distributed approach. The model presented here combines storm abstraction by the SCS‐CN method with surface runoff routing as a geomorphological dispersion process. This is modelled using the gamma instantaneous unit hydrograph as parameterized by river geomorphology. The results are implemented using a project‐oriented software facility for the Analysis of LAnd Digital HYdrological Networks (ALADHYN). Copyright © 2002 John Wiley & Sons, Ltd.
Impact of human bladder cancer cell architecture on autologous T‐lymphocyte activation
Authors: Dangles Virginie , Validire Pierre , Wertheimer Mireille , Richon Sophie , Bovin Christophe , Zeliszewski Dominique , Vallancien Guy , Bellet Dominique
Published: August 2002

To investigate the influence of tumor cell architecture on T‐cell activation, we used an autologous human model based on 2 bladder tumor cell lines as targets for cytotoxic tumor‐infiltrating lymphocytes (TILs). These tumor cell lines were grown in vitro as either standard 2‐dimensional (2D) monolayers or 3‐dimensional (3D) spheroids. T‐cell activation was determined by measuring the production of three major cytokines (tumor necrosis factor, granulocyte/macrophage colony‐stimulating factor and interferon‐γ), known to be secreted by most activated TILs. Changes in the architecture of target cells from 2D to 3D induced a dramatic decrease in their capacity for stimulating TILs. Interestingly, neither TIL infiltration nor MHC class I, B7.1 costimulatory or lymphocyte function‐associated factor‐3 adhesion molecule downregulation played a major role in this decrease. These findings demonstrate that tumor architecture has a major impact on T‐cell activation and might be implicated in the escape of tumor cells from the immune system. © 2001 Wiley‐Liss, Inc.
Bcl‐XL is a chemoresistance factor in human melanoma cells that can be inhibited by antisense therapy
Authors: Heere‐Ress Elisabeth , Thallinger Christiane , Lucas Trevor , Schlagbauer‐Wadl Hermine , Wacheck Volker , Monia Brett P. , Wolff Klaus , Pehamberger Hubert , Jansen Burkhard
Published: August 2002

Malignant melanoma is a tumor that responds poorly to a variety of apoptosis‐inducing treatment modalities, such as chemotherapy. The expression of genes that regulate apoptotic cell death plays an important role in determining the sensitivity of tumor cells to chemotherapeutic intervention. Bcl‐xL is an antiapoptotic member of the Bcl‐2 family and is universally expressed in human melanoma. To evaluate the Bcl‐xL protein as a potential therapeutic target in melanoma, the influence of Bcl‐xL expression levels on the chemoresistance of human melanoma cells was investigated. Overexpression of Bcl‐xL in stably transfected human melanoma Mel Juso cells significantly reduced sensitivity to cisplatin‐induced apoptosis (p ≤ 0.05). In a parallel approach, reduction of Bcl‐xL protein by specific AS oligonucleotide (ISIS 16009) treatment enhanced the chemosensitivity of Mel Juso cells by 62% compared to cells treated with MM control oligonucleotide (ISIS 16967) as well as chemotherapy‐induced apoptosis. These data suggest that Bcl‐xL is an important factor contributing to the chemoresistance of human melanoma. Reduction of Bcl‐xL expression by AS oligonucleotides provides a rational and promising approach that may help to overcome chemoresistance in this malignancy. © 2002 Wiley‐Liss, Inc.
Comparison of aluminium (III) phthalocyanine tetrasulfonate‐ and meta‐tetrahydroxyphenylchlorin‐monoclonal antibody conjugates for their efficacy in photodynamic therapy in vitro
Authors: Vrouenraets Maarten B. , Visser Gerard W.M. , Stigter Marÿke , Oppelaar Hugo , Snow Gordon B. , van Dongen Guus A.M.S.
Published: August 2002

A challenge in photodynamic therapy (PDT) is to improve the tumour selectivity of the photosensitizers by using monoclonal antibodies (MAbs). With this aim, we developed MAb‐conjugates with the hydrophobic photosensitizer meta‐tetrahydroxyphenylchlorin (mTHPC) and with the hydrophilic sensitizer aluminium (III) phthalocyanine tetrasulfonate (AlPcS4). The capacity of these photoimmunoconjugates for selective targeting of squamous cell carcinoma (SCC) in vivo was demonstrated previously in SCC‐bearing nude mice. Preliminary in vitro PDT studies with the vulvar SCC cell line A431 showed promising phototoxicity with both sensitizers when coupled to the internalizing MAb 425. To rank the photosensitizers for their potential in photoimmunotherapy, we herein describe an extensive in vitro evaluation of mTHPC‐MAb and AlPcS4‐MAb conjugates. Both classes of conjugates were directly compared using 5 different SCC cell lines as target and 3 different MAbs (BIWA 4, E48 and 425) for tumour cell targeting. In contrast to free AlPcS4 (IC50 ≥ 700 nM), MAb‐conjugated AlPcS4 was found to be highly phototoxic in PDT in all 5 cell lines. AlPcS4‐BIWA 4 was most consistently effective with IC50 values ranging from 0.06–5.4 nM. mTHPC‐MAb conjugates were in general hardly effective. Phototoxicity (log IC50) of the AlPcS4‐MAb conjugates was found to be strongly correlated with their total cell binding capacity (internalized and surface bound) and to be less correlated with their internalization capacity. In conclusion, these data show a high potential of AlPcS4‐MAb conjugates in comparison to mTHPC‐MAb conjugates for use in PDT. © 2002 Wiley‐Liss, Inc.
Molecular classification of borderline ovarian tumors using hierarchical cluster analysis of protein expression profiles
Authors: Alaiya Ayodele A. , Franzén Bo , Hagman Anders , Dysvik Bjarte , Roblick Uwe J. , Becker Susanne , Moberger Birgitta , Auer Gert , Linder Stig
Published: August 2002

Ovarian tumors range from benign to aggressive malignant tumors, including an intermediate class referred to as borderline carcinoma. The prognosis of the disease is strongly dependent on tumor classification, where patients with borderline tumors have much better prognosis than patients with carcinomas. We here describe the use of hierarchical clustering analysis of quantitative protein expression data for classification of this type of tumor. An accurate classification was not achieved using an unselected set of 1,584 protein spots for clustering analysis. Different approaches were used to select spots that were differentially expressed between tumors of different malignant potential and to use these sets of spots for classification. When sets of proteins were selected that differentiated benign and malignant tumors, borderline tumors clustered in the benign group. This is consistent with the biologic properties of these tumors. Our results indicate that hierarchical clustering analysis is a useful approach for analysis of protein profiles and show that this approach can be used for differential diagnosis of ovarian carcinomas and borderline tumors. © 2002 Wiley‐Liss, Inc.
Nuclear PTEN expression and clinicopathologic features in a population‐based series of primary cutaneous melanoma
Authors: Whiteman David C. , Zhou Xiao‐Ping , Cummings Margaret C. , Pavey Sandra , Hayward Nicholas K. , Eng Charis
Published: August 2002

Germline mutations of the PTEN tumor‐suppressor gene, on 10q23, cause Cowden syndrome, an inherited hamartoma syndrome with a high risk of breast, thyroid and endometrial carcinomas and, some suggest, melanoma. To date, most studies which strongly implicate PTEN in the etiology of sporadic melanomas have depended on cell lines, short‐term tumor cultures and noncultured metastatic melanomas. The only study which reports PTEN protein expression in melanoma focuses on cytoplasmic expression, mainly in metastatic samples. To determine how PTEN contributes to the etiology or the progression of primary cutaneous melanoma, we examined cytoplasmic and nuclear PTEN expression against clinical and pathologic features in a population‐based sample of 150 individuals with incident primary cutaneous melanoma. Among 92 evaluable samples, 30 had no or decreased cytoplasmic PTEN protein expression and the remaining 62 had normal PTEN expression. In contrast, 84 tumors had no or decreased nuclear expression and 8 had normal nuclear PTEN expression. None of the clinical features studied, such as Clark's level and Breslow thickness or sun exposure, were associated with cytoplasmic PTEN expressional levels. An association with loss of nuclear PTEN expression was indicated for anatomical site (p = 0.06) and mitotic index (p = 0.02). There was also an association for melanomas to either not express nuclear PTEN or to express p53 alone, rather than both simultaneously (p = 0.02). In contrast with metastatic melanoma, where we have shown previously that almost two‐thirds of tumors have some PTEN inactivation, only one‐third of primary melanomas had PTEN silencing. This suggests that PTEN inactivation is a late event likely related to melanoma progression rather than initiation. Taken together with our previous observations in thyroid and islet cell tumors, our data suggest that nuclear–cytoplasmic partitioning of PTEN might also play a role in melanoma progression. © 2002 Wiley‐Liss, Inc.
Suberoylanilide hydroxamic acid (SAHA) overcomes multidrug resistance and induces cell death in P‐glycoprotein‐expressing cells
Authors: Ruefli Astrid A. , Bernhard David , Tainton Kellie M. , Kofler Reinhard , Smyth Mark J. , Johnstone Ricky W.
Published: August 2002

Multidrug resistance (MDR) mediated by the ATP‐dependent efflux protein P‐glycoprotein (P‐gp) is a major obstacle to the successful treatment of many cancers. In addition to effluxing toxins, P‐gp has been shown to protect tumor cells against caspase‐dependent apoptosis mediated by Fas and tumor necrosis factor receptor (TNFR) ligation, serum starvation and ultraviolet (UV) irradiation. However, P‐gp does not protect against caspase‐independent cell death mediated by granzyme B or pore‐forming proteins (perforin, pneumolysin and activated complement). We examined the effects of the chemotherapeutic hybrid polar compound suberoylanilide hydroxamic acid (SAHA) on P‐gp‐expressing MDR human tumor cell lines. In the CEM T‐cell line, SAHA, a histone deacetylase inhibitor, induced equivalent death in P‐gp‐positive cells compared with P‐gp‐negative cells. Cell death was marked by the caspase‐independent release of cytochrome c, reactive oxygen species (ROS) production and Bid cleavage that was not affected by P‐gp expression. However, consistent with our previous findings, SAHA‐induced caspase activation was inhibited in P‐gp‐expressing cells. These data provide evidence that P‐gp inhibits caspase activation after chemotherapeutic drug treatment and demonstrates that SAHA may be of value for the treatment of P‐gp‐expressing MDR cancers. © 2002 Wiley‐Liss, Inc.
Optimized intensity‐modulated arc therapy for prostate cancer treatment
Authors: Ma Lijun , Yu Cedric X. , Earl Matthew , Holmes Tim , Sarfaraz Mehrdad , Li X. Allen , Shepard David , Amin Pradip , DiBiase Steven , Suntharalingam Mohan , Mansfield Carl
Published: August 2002

We recently implemented intensity‐modulated arc therapy (IMAT) at our institution. In this study, we evaluate the dosimetric merits of the application of this technique to the treatment of prostate cancer. Each IMAT treatment plan incorporated bilateral overlapping arcs. The dose from each beam segment was computed using the three‐dimensional dose model of a clinical treatment planning system (Render Plan 3.5, Precision Therapy). The weights assigned to the individual arc segments were optimized using a gradient search method. For 12 patients, comparisons were made between the IMAT treatment plans and corresponding plans using fixed cone‐beam intensity‐modulated radiotherapy (IMRT) from a commercial inverse planning system (CORVUS, NOMOS Corp.). We found that the optimized IMAT treatments produced similar dose distributions to the IMRT deliveries. Compared with the IMRT treatments, the IMAT treatments produced slightly less target dose homogeneity with consistently greater sparing of the rectum in regions of lower dose. The trade‐off between target dose conformity and rectum sparing can be adjusted in both optimization procedures. Because the total beam‐on time for IMAT delivery is 1 to 2 minutes with approximately 5–6 minutes of patient setup time, the delivery efficiency of the IMAT treatment was significantly better than the multiple‐beam IMRT treatment. © 2001 Wiley‐Liss, Inc.
Melphalan availability in hypoxia‐inducible factor‐1α+/+ and factor‐1α–/– tumors is independent of tumor vessel density and correlates with melphalan erythrocyte transport
Authors: Wildiers Hans , Guetens Gunter , de Boeck Gert , Landuyt Willy , Verbeken Eric , Highley Martin , de Bruijn Ernst A. , van Oosterom Allan T.
Published: August 2002

Many tumors are impervious to anticancer agents. Resistance due to lack of cytotoxic penetration into the tumor is often overlooked but can play a significant role in undermining therapy. Insufficient and irregular vascularization of tumors is a possible barrier to drug delivery, but there are others, e.g., impaired vessel permeability and poor interstitial transport. We evaluated the importance of tumor vessel density in the availability of melphalan to tumors. A nude mouse tumor model with different vascularization due to a single‐gene deletion of hypoxia‐inducible factor 1α (HIF‐1α+/+ and HIF‐1α–/– embryonic stem cell–derived tumors) was used. The availability of melphalan to HIF‐1α+/+ (n = 20) and HIF‐1α–/– (n = 23) tumors was not significantly different (p = 0.12). Furthermore, in the various subgroup analyses accentuating the difference in vessel density, no significant correlation between vessel density and melphalan availability was found. In the second part of the study, melphalan, was demonstrated to be transported in blood in mice with a distribution of 24% in erythrocytes vs. 76% in plasma. A strong correlation (r = 0.93, p < 0.000001) between melphalan concentrations in plasma and erythrocytes was found, indicating an equilibrium between these 2 compartments. Plasma and erythrocyte concentrations of melphalan are correlated with the tumor availability of melphalan (r = 0.66 and 0.64, respectively, both p < 0.001). These data suggest that tumor vessel density is not an important predictor of the tumor availability of small cytotoxic drugs such as melphalan and indicate the importance of erythrocytes in the transport of melphalan. © 2002 Wiley‐Liss, Inc.