bluuebunny/crossref_metadata_2025 huggingface dataset:
A short note on the general boundary element method for viscous flows with high Reynolds number
Authors: Zhao X. Y. , Liao S. J.
Published: May 2003

In this paper, the general boundary element method and the parallel computation are employed to solve laminar viscous flows in a driven square cavity, governed by the exact Navier–Stokes equations. Using the solution at Re=0 as the initial approximation, the convergent numerical results for high Reynolds number at Re=7500 are obtained, for the first time, by the boundary element method. This verifies the validity and great potential of the general boundary element method for highly non‐linear problems, which may greatly enlarge application regions of the boundary element method in science and engineering. Copyright © 2003 John Wiley & Sons, Ltd.
Numerical investigation from rarefied flow to continuum by solving the Boltzmann model equation
Authors: Li Zhi‐Hui , Zhang Han‐Xin
Published: May 2003

Based on the Bhatnagar–Gross–Krook (BGK) Boltzmann model equation, the unified simplified velocity distribution function equation adapted to various flow regimes can be presented. The reduced velocity distribution functions and the discrete velocity ordinate method are developed and applied to remove the velocity space dependency of the distribution function, and then the distribution function equations will be cast into hyperbolic conservation laws form with non‐linear source terms. Based on the unsteady time‐splitting technique and the non‐oscillatory, containing no free parameters, and dissipative (NND) finite‐difference method, the gas kinetic finite‐difference second‐order scheme is constructed for the computation of the discrete velocity distribution functions. The discrete velocity numerical quadrature methods are developed to evaluate the macroscopic flow parameters at each point in the physical space. As a result, a unified simplified gas kinetic algorithm for the gas dynamical problems from various flow regimes is developed. To test the reliability of the present numerical method, the one‐dimensional shock‐tube problems and the flows past two‐dimensional circular cylinder with various Knudsen numbers are simulated. The computations of the related flows indicate that both high resolution of the flow fields and good qualitative agreement with the theoretical, DSMC and experimental results can be obtained. Copyright © 2003 John Wiley & Sons, Ltd.
The effects of alternative reports of human resource development results on managerial support
Authors: Mattson Brent W.
Published: May 2003

Managerial responses to human resource development (HRD) results evaluation reports were
experimentally investigated as a function of (1) how evaluation information was presented and
(2) reported HRD program impact levels. Managers (n = 233) read a business scenario in
which they were asked to make a decision about whether to implement a development program. They were then exposed
to one of nine experimental treatment conditions (evaluation report type × reported program impact
level). The report types included utility analysis, critical outcome technique, and anecdotal evaluation
reports. Results were varied at three impact levels (low, average, and high). Findings of the study
showed that managers perceived utility analysis and critical outcome technique reports as almost equally useful
in decision making; however, the anecdotal evaluation report was found to be significantly less useful than
either of the other two report types. There was no effect of the reported program impact level on the perceived
usefulness of the evaluation reports for decision making. Furthermore, there was no interaction between report
type and impact level on the perceived usefulness of the reports for decision making. These findings show that
managers prefer information about the financial results of HRD interventions to anecdotal information, regardless
of the reported level of impact.
Invited reaction: The effects of alternative reports of human resource development results on managerial support
Authors: Cascio Wayne F.
Published: May 2003

Mattson's article is an important contribution to the literature in HRD and program evaluation for a
variety of reasons. It addresses an area that sorely needs rigorous research, it uses a theory‐based model
that is relevant to managers' evaluations of HRD programs, it provides valuable insights on how best to
present HRD evaluation results to managers, and it demonstrates that HRD program evaluations that are expressed in
terms of results do influence the decisions of operating managers. The ongoing challenge will be to articulate
linkages between HRD programs, employees' behavior, and outcomes that are important to managers. Doing so
will lead to even greater impact on managers' decisions about the future uses of HRD interventions.
The impact on career development of learning opportunities and learning behavior at work
Authors: Van der Sluis Lidewey E. C. , Poell Rob F.
Published: May 2003

This study focuses on the individual career development process of M.B.A.s on the job, in an era emphasizing
personal responsibility for learning and development. The impact of learning opportunities and individual learning
behavior was analyzed through repeated measures. Hierarchical regressions and difference‐of‐means
tests were performed based on survey data collected from early‐career M.B.A.s. Several relationships
between the research variables were found to be consistent with current literature. The results provide leads for
further research into effects of both context and personal characteristics on the individual's career
development process on the job.
Translating training science into practice: A study of managers' reactions to posttraining transfer interventions
Authors: Huint Philip , Saks Alan M.
Published: May 2003

The purpose of this study was to investigate managers' reactions to two posttraining transfer interventions
(relapse prevention and supervisor support training) and two types of information about their
effectiveness (utility analysis and research information). One hundred seventy‐four managers and
students received one of four scenarios and were then asked if they would adopt the intervention as part of a
training program to increase the productivity of clerical‐administrative staff. The results indicated no
significant differences between the posttraining transfer interventions or information conditions, although there
was a trend in favor of the supervisor support intervention; also, the utility analysis information was not as
well received as the research information. In general, managers did not indicate a high acceptance of either the
relapse prevention or the supervisor support intervention. The results are discussed in terms of the willingness of
managers to adopt training research innovations and the implications for HRD
research‐to‐practice.
Conceptualization and exploration of composite career anchors: An analysis of information systems personnel
Authors: Ramakrishna Hindupur V. , Potosky Denise
Published: May 2003

Some researchers have emphasized the importance of identifying individuals' dominant career anchors and
perhaps matching these anchors with HR planning initiatives. However, there has been little empirical research
addressing the existence and impact of clusters of dominant career anchors. This study addresses this gap in the
literature and examines the career anchors of 163 information systems (IS) professionals. Consistent
with
the findings of earlier studies, nine career anchors (managerial competence, identity, variety, service,
geographic security, autonomy, organizational stability, technical competence, and creativity) were evident
in
this sample. Results provide evidence of multiple dominant anchors for many individuals, and that individuals
with
multiple dominant anchors do not report significantly different career‐related outcomes than those with
single dominant anchors. The results suggest that clusters of career anchors, rather than a single dominant
anchor,
should be considered in HR planning efforts for IS personnel, and potentially for personnel in other career
fields.
Results from organizational development interventions in a technology call center
Authors: Workman Michael
Published: May 2003

Technology support call centers are becoming an increasingly important part of the American economy.
However, there are many scholarly reports of problems associated among these endeavors. Research into
mitigating these problems has tended to focus on structural alignment, or forms of team participation, leading
to conflicting outcomes. HRD researchers are left with an unclear picture of the outcomes, and HRD
practitioners have been left with the question of which of these interventions to implement. This study
concurrently investigated the effects on job satisfaction from structural‐alignment,
high‐involvement, autonomous‐team interventions compared to a control group. The analysis
indicated job satisfaction improvements in the alignment and high‐involvement groups, with the
high‐involvement groups suggesting the most significant improvements. As a result, recommendations are
made for HRD practitioners and future HRD research.
Efficacy of nefazodone in the treatment of neuroleptic induced extrapyramidal side effects: a double‐blind randomised parallel group placebo‐controlled trial
Authors: Wynchank Dora , Berk Michael
Published: May 2003

Many atypical antipsychotics show antagonism at both serotonergic and dopaminergic neurones and show fewer extrapyramidal side effects (EPS). Nefazodone blocks postsynaptic 5HT2A receptors and weakly inhibits serotonin reuptake. This study aimed to elucidate the role of nefazodone in the treatment of antipsychotic‐induced EPS. The trial was a double‐blind, randomised, placebo‐controlled trial of patients requiring antipsychotic treatment with haloperidol 10 mg daily; from which a subgroup of patients who developed EPS were selected for the study. Patients were randomised to add‐on therapy with either placebo (n = 24) or nefazodone (n = 25) 100 mg bd. EPS were measured on days 0, 3 and 7 using the Simpson Angus, Barnes akathisia, abnormal involuntary movement and Chouinard scales. Nefazodone significantly reduced EPS as measured by both the Simpson Angus scale and CGI (p = 0.007 and 0.0247, respectively). Akathisia and tardive dyskinesia did not differ between the two groups (p = 0.601; p = 0.507, respectively). These results suggest the role of 5HT2 antagonism in the mechanism of action of atypical antipsychotics with respect to lowering rates of drug‐induced EPS. In addition, a therapeutic role for nefazodone is suggested in the treatment of antipsychotic‐induced EPS. Copyright © 2003 John Wiley & Sons, Ltd.
Repetitive transcranial magnetic stimulation is effective following repeated courses in the treatment of major depressive disorder—a case report
Authors: Dannon Pinhas N. , Grunhaus Leon
Published: May 2003

Repetitive transcranial magnetic stimulation (rTMS) is a relatively new treatment modality for psychiatric patients. rTMS was demonstrated to be effective in the treatment of depression. However, longitudinal outcome studies have not yet been published. Relapse rates are higher in depressed patients and most of them do not respond to the same treatment with similar success. In this report we present a patient, who experienced relapse with the various conventional drug treatments, but responded well to rTMS at three different points in time. Copyright © 2003 John Wiley & Sons, Ltd.
Switching to tianeptine in patients with antidepressant‐induced sexual dysfunction
Authors: Atmaca Murad , Kuloglu Murat , Tezcan Ertan , Buyukbayram Ayten
Published: May 2003

Sexual side effects are frequent and are recently being considered as effects of antidepressant treatment. One method to improve the sexual dysfunction associated with the use of antidepressants is to change to another antidepressant. In the present work, the consequences of switching to tianeptine in patients with antidepressant‐induced sexual dysfunction were studied. The study group comprised 23 patients with major depressive disorder who experienced antidepressant‐induced sexual dysfunction. These antidepressants were stopped and switched to tianeptine (12.5 mg × 3/day). All patients were screened by using the clinical global impression‐improvement scale (CGI‐I), the Hamilton depression rating scale (HAM‐D) and the Arizona sexual experience scale (ASEX) at the beginning of the study, and at weeks 4 and 8. No patient failed to tolerate 37.5 mg of tianeptine or to complete the study except for one patient becoming pregnant. Paired t‐tests revealed a significant difference between baseline and week 4 or week 8 in scores on both the HAM‐D and ASEX. At 8 weeks, six patients were rated as very much improved (CGI‐I = 1) and ten patients were rated as much improved (CGI‐I = 2). Thus, with a CGI‐I score of 2 or less used to indicate a positive response, 72.7% of the patients were responders. The results suggest that switching to tianeptine appears to be useful for alleviating sexual dysfunction caused by other antidepressants. Copyright © 2003 John Wiley & Sons, Ltd.
Relationship of plasma amphetamine levels to physiological, subjective, cognitive and biochemical measures in healthy volunteers
Authors: Asghar Sheila J. , Tanay Veronique A. M. I. , Baker Glen B. , Greenshaw Andy , Silverstone Peter H.
Published: May 2003

Acute administration of the stimulant dextro‐amphetamine produces multiple physiological, subjective cognitive and biochemical changes. These effects are similar to those seen in mania, and may be a useful model for mania. The aim of the present study was more fully to determine the multiple effects of dextro‐amphetamine and to relate these to changes in plasma levels of the drug. In a double‐blind, placebo‐controlled crossover study in 25 healthy volunteers (ages 18–45), the effects of 25 mg of oral dextro‐amphetamine were examined. Physiological, subjective, cognitive changes, concentrations of amino acids and metabolites of biogenic amines period were related to changes in plasma amphetamine concentrations over 500 min. Peak concentrations of dextro‐amphetamine occurred at 2.5–3.5 h post‐administration and levels decreased to 75% of peak value after 500 min. The results from the present study indicate that the subjective psychological, cognitive and blood pressure changes frequently did not mirror the time course of plasma levels of the drug. Thus, there was no clear‐cut relationship between plasma levels and effects. In addition, dextro‐amphetamine caused no significant changes in amino acids or amino metabolite concentrations. In conclusion, while dextro‐amphetamine administration definitely causes several changes which are seen in mania, there remain some physiological and metabolic differences between these two conditions. Copyright © 2003 John Wiley & Sons, Ltd.
Specific memory deficits in ecstasy users? The results of a meta‐analysis
Authors: Verbaten Marinus N.
Published: May 2003

A meta‐analysis was carried out on the possible functional neurotoxic effects of ecstasy use in humans on verbal short‐term memory (STM), verbal long‐term memory (LTM), processing speed (RT) and % errors (attention). To that end studies were found on the effect of ecstasy that fulfilled the criteria for a meta‐analysis (number of subjects, means and standard deviations of the dependent variables). Ten studies were included on STM, ten on LTM, eight on RT and eight on % errors (attention). In addition meta‐regression analyses were carried out on the effect sizes with total lifetime ecstasy consumption (TLEC) as predictor. It was found that in all four meta‐analyses the mean effect size (ES) was significant: ecstasy users had lower verbal STM and LTM scores, reacted slower and made more errors. The meta‐regression coefficients were not significant, indicating no support for a linear relationship between the mean ES values and TLEC, leaving open the possibility for a stepwise relationship. Additional meta‐analyses on ecstasy groups that did not differ in lifetime cannabis consumption showed that only the ES for LTM became insignificant. This suggests that ecstasy use does not decrease LTM, but the number of studies on which this conclusion is based was very low. Copyright © 2003 John Wiley & Sons, Ltd.
Olanzapine induced neuroleptic malignant syndrome—a case review
Authors: Kogoj Aleš , Velikonja Ingrid
Published: May 2003

Neuroleptic malignant syndrome is the rarest and the most serious of the neuroleptic induced movement disorders. Although potent neuroleptics are more frequently associated with NMS, atypical antipsychotic drugs may also be a cause of NMS. Three databases were searched using the terms ‘olanzapine’ and ‘neuroleptic’ ‘malignant syndrome’. Case reports were selected and reviewed from among all articles that fulfilled the search criteria. Twenty six cases were reviewed. Twenty cases fulfilled the criteria published by Sachdev et al. Olanzapine was the most probable cause of NMS in 16 cases. The absence of rigidity was described in only two of 16 highly probable olanzapine induced NMS cases, which is not as often as it is reported in clozapine associated NMS (36%). It was found that prior NMS is an important risk factor in NMS. Copyright © 2003 John Wiley & Sons, Ltd.
Milnacipran plasma levels and antidepressant response in Japanese major depressive patients
Authors: Higuchi Hisashi , Yoshida Keizo , Takahashi Hitoshi , Naito Shingo , Kamata Mitsuhiro , Ito Kenichi , Sato Kazuhiro , Tsukamoto Kei , Shimizu Tetsuo , Nakanishi Mamoru , Hishikawa Yasuo
Published: May 2003

The relationship between antidepressant effects and plasma levels of milnacipran was studied in 49 cases of major depression without psychotic features during 6 weeks of milnacipran treatment. The daily dose of milnacipran was 50 mg/day for the first week, and up to 100 mg/day thereafter. Depressive symptoms were evaluated by the Montgomery and Åsberg depression rating scale (MADRS) before treatment and at 1, 2, 4 and 6 weeks after the beginning of this study. Thirty‐four patients (69.4%) were responders (defined as a 50% or greater decrease in the baseline MADRS score). Significant differences of MADRS scores were seen from 1 week after the beginning of this study (p = 0.004, unpaired t‐test) between responders and nonresponders. The mean plasma milnacipran level of responders, 82.0 ± 29.4 ng/ml, was similar to that of non‐responders, 78.6 ± 23.1 ng/ml; there was no significant difference between responders and nonresponders. Neither a significant linear nor a curvilinear relationship was obtained between the final MADRS score and the plasma levels of milnacipran. Although there was no significant relationship between the plasma levels of milnacipran and the antidepressant response, milnacipran should be considered an efficacious agent in the treatment of major depressive patients. Copyright © 2003 John Wiley & Sons, Ltd.
A placebo controlled investigation into the effects of paroxetine and mirtazapine on measures related to car driving performance
Authors: Ridout F. , Meadows R. , Johnsen S. , Hindmarch I.
Published: May 2003

Objective

To assess the effects of paroxetine and mirtazapine on psychometric performance related to car driving, including an on‐the‐road test of BRT.

Method

In a 4‐way, double blind randomised crossover study, 12 healthy volunteers received paroxetine 20 mg mane, mirtazapine 15 mg/30 mg nocte (comparator), mirtazapine 15 mg mane/15 mg b.i.d.(verum) and placebo over a 5 day period with a washout period of 7 days between treatments. Psychometric assessments included ‘on‐the‐road’ BRT (BRT), CFF (CFF), CRT (CRT) and subjective measures of sedation and sleep parameters.

Results

Paroxetine had no significant effect on BRT compared with placebo. Although subjective ratings of sleep quality and sedation were impaired, there were significant improvements in both CFF and the recognition reaction component of CRT with paroxetine. Mirtazapine 15 mg/30 mg nocte impaired laboratory performance and some subjective tests. Mirtazapine 15 mg mane/15 mg b.i.d. improved sleep, but significantly impaired all other measures.

Conclusion

Paroxetine 20 mg/day has no psychomotor or behavioural toxicity and has no negative impact on BRT. Further research into the chronic and sub‐chronic effects of mirtazapine is needed to establish the clinical significance of these results. Copyright © 2003 John Wiley & Sons, Ltd.
Animal models of depression: are there any?
Authors: O'Neil Michael F. , Moore Nicholas A.
Published: May 2003

Simple tests for antidepressant‐like activity, such as 5‐HTP‐induced syndrome or reserpine‐induced hypomotility, are often mechanism‐based tests, pharmacologically specific for certain known classes of therapeutically successful antidepressant agents. Many of these behavioural assays have been superseded by neurochemical techniques such as in vivo microdialysis. In contrast to these mechanistic‐based models, investigators have also endeavoured to reproduce in the laboratory, factors that are believed to precipitate depression in people. It is a strong assumption in this approach that depression is a response to stress. This strategy profiles the consequences of chronic stress particularly psychosocial stress or early life events, in order to reproduce in animals the behavioural signs and pathologies associated with depression. The advances in the social psychological, clinical pathological and new areas such as neuroimaging research offer the possibility of establishing more sophisticated models for depression in animals with a broader range of biomarkers from the immunological and endocrinological to neurochemical and behavioural. Combining these novel insights with more traditional tests of depression may not only increase our understanding of the neurobiology of depression but also afford more precise and predictive preclinical models of depression. The responsiveness of different strains or genetically modified animals to stress is likely to be a key area of study. Furthermore we must look to individual differences in subjects, even within the same strain, to more fully understand why some individuals show pathological responses to stress whereas others appear unaffected. Conversely in validating our models using currently available treatments we must include the concept of non‐responders so as not to disregard models that may extend therapeutic possibilities in these patients. Copyright © 2003 John Wiley & Sons, Ltd.
Mitogenic and antiapoptotic role of constitutive NF‐κB/Rel activity in pancreatic cancer
Authors: Liptay Susanne , Weber Christoph K. , Ludwig Leopold , Wagner Martin , Adler Guido , Schmid Roland M.
Published: May 2003

The transcription factor NF‐κB/Rel was found to be constitutively activated in human pancreatic cancer. RelA is present in the nucleus in primary human pancreatic cancer samples as well as in pancreatic cancer cell lines. NF‐κB/Rel–binding activity consists of NF‐κB1(p50) and RelA(p65). Constitutive NF‐κB/Rel activity correlates with IκB kinase (IKK) activity and can be blocked by dominant negative mutants of IKKβ and to a lesser extent by IKKα. Constitutive NF‐κB/Rel activity and the transactivation potential of RelA(p65) can be inhibited by dominant negative mutant Ras, the PI3 kinase inhibitor LY294002, or dominant negative mutant Akt kinase. Transfection of a dominant negative mutant epidermal growth factor receptor (EGF‐R), EGF‐R kinase inhibitor Tyrphostin and LY 294002 blocked IKK activity and NF‐κB–dependent transcription. Inhibition of constitutive IKK or NF‐κB/Rel activity increased the number of apoptotic cells. Stably expressing a nondegradable form of IκBα inhibited anchorage‐dependent and ‐independent proliferation in MiaPaCa2 and Panc1 cells. Our data demonstrate that an EGF‐R/Ras/PI3 kinase/Akt/IKK‐dependent pathway contributes to constitutive NF‐κB/Rel activity in pancreatic cancer. Inhibition of NF‐κB/Rel activity reveals a mitogenic and antiapoptotic role for NF‐κB/Rel in pancreatic cancer. © 2003 Wiley‐Liss, Inc.
A national case‐control study of Ewing's sarcoma family of tumours in Australia
Authors: Valery Patricia Casarolli , McWhirter William , Sleigh Adrian , Williams Gail , Bain Chris
Published: May 2003

Limited population‐based epidemiologic information is available on Ewing's sarcoma family of tumours (ESFT), a rare group of neoplasms. Several associations have been noted on a few studies but results were not consistent, except for exposure to farming among cases and their parents. Here we present the non‐farm findings of a nationwide case‐control study of ESFT in children and young adults in Australia. The analysis included 106 persons with confirmed ESFT and 344 population‐based controls selected randomly via telephone. Information was collected by interview (84% face to face). We found a strong and significant association of ESFT with hernias, in particular hernia repaired in hospital (OR = 5.6, 95% CI 1.3–6.4). Among other factors, there was a near doubling of risk for males, and male cases had their pubertal signs earlier (started shaving earlier) than male controls. There was also an increased risk of ESFT at higher levels of self‐assessed exercise, but no other factor really stood out. For pregnancy‐related factors, there was a tripling of risk for glandular fever, a doubling of risk for urinary tract infection and a near doubling of risk for X‐rays during or just before pregnancy, but these estimates were not significant. In addition, there was a large number of inverse associations with medical conditions (specifically bone disorders), case exposure to medications, vaccinations and X‐rays, with ultrasound during the pregnancy having the most certain effects. We conclude that, although the aetiology of ESFT remains obscure, overall there is strong evidence of an association with inguinal hernia; this can now be added to the farm‐associated risk reported by others and us. The other associations reported here await replication and refinement in future studies. © 2003 Wiley‐Liss, Inc.
HER 2/neu expression and gene amplification in colon cancer
Authors: Nathanson Daniel R. , Culliford Alfred T. , Shia Jinru , Chen Beiyun , D'Alessio Matthew , Zeng Zhao‐Shi , Nash Garrett M. , Gerald William , Barany Francis , Paty Philip B.
Published: May 2003

HER 2/neu is an important oncogene in breast cancer, but the prevalence and significance of HER 2/neu gene amplification in colon cancer have been poorly documented. We have evaluated HER 2/neu gene amplification and protein overexpression in a series of colon cancers to assess the frequency, concordance and clinical significance of these events. HER 2/neu gene copy number was measured in 154 primary colon tumors, 15 liver metastases and matched normal tissues using a quantitative PCR/ligase detection reaction (LDR) technique developed and validated in our laboratory. HER 2/neu copy number was confirmed by fluorescent in situ hybridization (FISH) in all tumors found to have gene amplification. In an independent and blinded fashion, HER 2/neu expression was assessed in paraffin sections from 139 of the tumor specimens using the HercepTest kit. HER 2/neu gene amplification was observed in 4 (2.4%) of the 169 tumor specimens and in none of the normal tissues. There was no apparent association with stage of disease, tumor grade or patient survival. Among 139 cases evaluated by immunohistochemistry (IHC), HER 2/neu overexpression was seen in 5 cases (3.6%). There was extremely high concordance (kappa = 0.852) between gene amplification and protein overexpression. The low prevalence of HER 2/neu gene amplification and protein overexpression suggests that this oncogene plays an infrequent role in the development and progression of colon cancer. These data indicate that the primary mechanism of dysregulated HER 2/neu expression in colon cancer, as in breast cancer, is gene amplification. © 2003 Wiley‐Liss, Inc.
Biodistribution and pharmacokinetics of 125I‐labeled monoclonal antibody M75 specific for carbonic anhydrase IX, an intrinsic marker of hypoxia, in nude mice xenografted with human colorectal carcinoma
Authors: Chrastina Adrián , Závada Jan , Parkkila Seppo , Kaluz Štefan , Kaluzová Milota , Rajčáni Július , Pastorek Jaromír , Pastoreková Silvia
Published: May 2003

Carbonic anhydrase IX (CA IX) is frequently expressed in human carcinomas and absent from the corresponding normal tissues. Strong induction by tumor hypoxia predisposes CA IX to serve as a target for cancer diagnostics and therapy. Here we evaluated targeting properties and pharmacokinetics of CA IX‐specific monoclonal antibody (MAb) M75. Binding parameters of 125I‐labeled M75, including equilibrium dissociation constant, hypoxia‐related binding to various cell lines and internalization, were analyzed in vitro. Biodistribution of 125I‐M75 in nude mice bearing HT‐29 human colorectal carcinoma xenografts with hypoxic pattern of CA IX expression was studied by measurements of radioactivity in dissected tissues and macroautoradiography of tissue sections. Pharmacokinetics of intravenously administered 125I‐M75 was described using a 2‐compartment model. Blood clearance showed a distribution phase t1/2(α) = 3.4 hr and an elimination phase t1/2(β) = 55.3 hr postinjection. Despite predominant CA IX localization in less accessible perinecrotic regions, 125I‐M75 exhibited specific accumulation in xenograft, with a mean uptake of 15.3 ± 3.6% of injected dose per gram of tumor tissue at 48 hr postadministration. Specificity of M75 localization was confirmed by low tumor uptake of control antibody. Altogether, our data demonstrate that M75 MAb is a promising tool for selective immunotargeting of hypoxic human tumors that express CA IX. © 2003 Wiley‐Liss, Inc.
Overexpression of RbAp46 facilitates stress‐induced apoptosis and suppresses tumorigenicity of neoplastigenic breast epithelial cells
Authors: Li Guan‐Cheng , Guan Li‐Shuang , Wang Zhao‐Yi
Published: May 2003

We have found previously that the retinoblastoma (Rb) suppressor associated protein 46 (RbAp46) is a gene upregulated by the Wilms' tumor suppressor, WT1, and functions as a potent growth inhibitor. To investigate the effect of RbAp46 overexpression on early development of breast cancer, we established stable cell lines from neoplastigenic breast epithelial cells, MCF10AT3B, a cell line derived from a model of human proliferative disease, to constitutively express exogenous RbAp46. We have found that expression of RbAp46 suppressed colony formation of MCF10AT3B cells in soft‐agar, and inhibited tumor formation of these cells in nude mice. Expression of RbAp46 sensitized MCF10AT3B cells to apoptosis induced by serum deprivation and hydrocortisone withdrawal. Furthermore, we have found that the c‐Jun NH2‐terminal kinase (JNK) pathway and GADD45, a growth arrest‐ and DNA damage‐inducible gene, are constitutively activated in RbAp46‐expressing cells. Our data suggested that high levels of RbAp46 expression inhibit the tumorigenicity of neoplastigenic breast epithelial cells by facilitating JNK‐dependent apoptotic cell death. Our data also suggested that dysregulation of RbAp46 gene may be involved in the early development of breast cancer. © 2003 Wiley‐Liss, Inc.
Recombinant E. coli efficiently delivers antigen and maturation signals to human dendritic cells: Presentation of MART1 to CD8+ T cells
Authors: Radford Kristen J. , Jackson Andrew M. , Wang Jui‐Ho , Vassaux Georges , Lemoine Nicholas R.
Published: May 2003

The generation of tumour‐specific cytotoxic T‐lymphocyte (CTL) responses is the primary focus in the design of immunotherapeutic cancer vaccines. We have recently demonstrated generation of ovalbumin (OVA)‐specific CTLs and tumour‐protection in a murine tumour model using vaccination with dendritic cells (DCs) pulsed with E. coli expressing listeriolysin O (LLO) and OVA as a model antigen. In this system paraformaldehyde fixation of E. coli/LLO provided an additional safety feature without compromising vaccine efficacy. We therefore reasoned that paraformaldehyde‐fixed recombinant E. coli expressing LLO would be an efficient vehicle for the delivery of human tumour antigens to human DCs. In the present study, we demonstrate that fixed E. coli expressing LLO are taken up efficiently by human monocyte‐derived DCs (MoDCs) with minimal toxicity. As a consequence of the interaction with bacteria, human DCs undergo marked phenotypic and functional maturation. Furthermore, we show that fixed E. coli/LLO expressing the well‐characterised human melanoma antigen, MART1, efficiently deliver the HLA‐A2‐restricted MART127–35 epitope for processing and presentation on human MoDCs, suggesting the potential of this system as a novel strategy for human tumour immunotherapy. © 2003 Wiley‐Liss, Inc.
Downregulation of Cap43 gene by von Hippel‐Lindau tumor suppressor protein in human renal cancer cells
Authors: Masuda Katsuaki , Ono Mayumi , Okamoto Masahiro , Morikawa Wataru , Otsubo Michihiro , Migita Toshiro , Tsuneyoshi Masazumi , Okuda Heiwa , Shuin Taro , Naito Seiji , Kuwano Michihiko
Published: May 2003

We previously identified 9 genes (i.e., thymosin β4, secreted protein acidic and rich in cysteine, Cap43, ceruloplasmin, serum amyloid A, heat shock protein 90, LOT1, osteopontin and casein kinase Iγ) that are more highly expressed in cancerous regions than in noncancerous regions in human renal cancers. In our study, we considered the possibility that the von Hippel‐Lindau (VHL) tumor suppressor gene might be able to affect the expression of these 9 genes in renal cancer cells. We first established 2 VHL‐positive cell lines, 786/VHL‐1 and 786/VHL‐2, after the introduction of wild‐type VHL into VHL‐negative renal cancer 786‐O cells. Of these 9 genes, expression of the Cap43 gene was specifically downregulated by VHL. Expression of Cap43 was also much lower in 4 other VHL‐positive renal cancer cell lines than in VHL‐negative 786‐O cells. Cap43 promoter assays with several deletion or mutation constructs demonstrated that the Sp1 site in the element from –286 base pairs (bp) to –62 bp was partly responsible for VHL‐induced suppression of the Cap43 gene. Immunostaining analysis with human specimens of renal cancers demonstrated that the Cap43 protein was expressed in most cancer cells and macrophages. We also observed a marked and specific increase of Cap43 mRNA levels in response to hypoxia or nickel in all VHL‐positive cell lines. Cellular expression of Cap43 mRNA in response to hypoxia or nickel thus is closely associated with VHL gene expression in renal cancer cells. Although the function of the Cap43 protein remains unclear, the expression of Cap43 protein could be a molecular marker closely associated with VHL in renal cancer. © 2003 Wiley‐Liss, Inc.
Growth inhibitory retinoid effects after recruitment of retinoid X receptor β to the retinoic acid receptor β promoter
Authors: Cheung Belamy , Yan Joanne , Smith Stewart A. , Nguyen Tue , Lee Michelle , Kavallaris Maria , Norris Murray D. , Haber Michelle , Marshall Glenn M.
Published: May 2003

Nuclear retinoid receptors mediate retinoid effects through tissue‐specific, ligand–receptor interactions and subsequent transcriptional regulation of secondary target genes. Retinoic acid receptor beta (RARβ) is itself a retinoid target gene with a retinoic acid response element (βRARE) in the 5′ untranslated region of the RARβ2 gene. Altered transcriptional regulation of RARβ may play a role in human carcinogenesis and the retinoid‐responsiveness of malignant cells. Here we used retinoid X receptor‐specific antibodies in electrophoretic mobility shift assays to show that the retinoid X receptor β (RXRβ) protein was recruited to the βRARE, after retinoid treatment of retinoid‐sensitive neuroblastoma (NB), lung and breast cancer cell lines, but not retinoid‐resistant lung and breast cancer cell lines. RXRβ selectively enhanced retinoid‐induced transcriptional activation of the βRARE. Stable overexpression of RXRα and RXRβ in NB cells resulted in marked growth inhibition and cell death, which increased after retinoid treatment. However, only proteins from the RXRβ transfectants exhibited specific RXRβ binding to the βRARE in vitro and in vivo, enhanced histone acetylation and increased endogenous RARβ expression. These data indicate that recruitment of RXRβ to the βRARE, and consequent induction of endogenous RARβ expression, is an important component in the retinoid anticancer signal. RXRα may also participate in the retinoid signal, but through mechanisms that do not involve RARβ. © 2003 Wiley‐Liss, Inc.
Transforming growth factor β‐1 and amphiregulin act in synergy to increase the production of urokinase‐type plasminogen activator in transformed breast epithelial cells
Authors: Giusti Corinne , Desruisseau Sylvie , Ma Lin , Calvo Fabien , Martin Pierre‐Marie , Berthois Yolande
Published: May 2003

Amphireguline (AR) is an epidermal growth factor (EGF)‐related peptide that seems to play an important role in breast cancer progression. We have demonstrated recently that suppression of AR expression in transformed breast epithelial cells considerably reduced both size and neovascularization of tumors developed in nude mice. We show that the reduction of AR expression allowed to an important decrease of the levels of urokinase‐type plasminogen activator (uPA) and transforming growth factor‐beta1 (TGFβ1). According to these data, exogenous AR (10−10 M–10−8 M) stimulated the production of uPA and TGFβ1 in AR antisense‐transfected A2‐15 and A2‐P17F25 cells. The addition of 2 × 10−10 M TGFβ1 into culture medium increased the level of uPA produced by AR‐expressing parental cells but not by A2‐15 and A2‐P17F25 cell clones. Whereas AR alone stimulated uPA production to 200% of control, combined AR and TGFβ1 treatment increased protease level in A2‐15 and A2‐P17F25 cells to 500–600% of control, demonstrating a synergism between TGFβ1 and AR. This was accompanied by an important augmentation of the number of tumoral cells that invaded matrigel in vitro. The synergistic induction of uPA protein resulted of an early and transient augmentation of steady state mRNA level and was blocked in the presence of the MAP kinase kinase inhibitor PD098059, strongly suggesting that synergistic effect of AR and TGFβ1 on uPA expression required MAPK pathway. This data demonstrates concerted action between AR and TGFβ1 that may have profound effect on protease production and consequently on breast cancer progression. © 2003 Wiley‐Liss, Inc.
Physical inactivity, energy intake, obesity and the risk of rectal cancer in Canada
Authors: Mao Yang , Pan Saiyi , Wen Shi Wu , Johnson Kenneth C. ,   The Canadian Cancer Registries Epidemiology Research Group
Published: May 2003

We conducted a population‐based case‐control study of 1,447 incident rectal cancer cases and 3,106 population controls aged 20–76 years to assess the effect of recreational physical activity, energy intake and obesity on rectal cancer risk in 7 of 10 Canadian provinces in 1994–97. After adjustment for the effect of various potential confounding factors, total recreational physical activity in the highest quartile was associated with an odds ratio (OR) for rectal cancer risk of 0.88 (95% confidence interval [CI] = 0.64–1.20) in women and 1.15 (95% CI = 0.88–1.49) in men. Women and men in the highest quartile of caloric intake (> = 56,741 and > = 63,143 kJ/week) had ORs of 1.50 (95% CI = 1.00–2.25) and 1.61 (95% CI = 1.13–2.28), respectively. Total dietary fat intake was not associated with a risk of rectal cancer after adjustment for caloric intake. Obesity (BMI > = 30 kg/m2) was associated with an OR of 1.44 (95% CI = 1.06–1.95) for women and 1.78 (95% CI = 1.36–2.34) for men. Men and women with lifetime maximum body mass index (BMI) > = 30 kg/m2 had respective ORs of 1.70 (95% CI = 1.30–2.23) and 1.26 (95% CI = 0.96–1.66). The greatest increase in rectal cancer risk was observed in men and women with simultaneous high energy intake, high BMI and low physical activity. Our study provides evidence that physical inactivity, high energy intake and obesity are associated with the risk of rectal cancer, and there is a probable synergic effect among the 3 risk factors. © 2003 Wiley‐Liss, Inc.
Induction of systemic immunity by expression of interleukin‐23 in murine colon carcinoma cells
Authors: Wang Yan‐Qing , Ugai Shin‐ichi , Shimozato Osamu , Yu Ling , Kawamura Kiyoko , Yamamoto Hiroshi , Yamaguchi Taketo , Saisho Hiromitsu , Tagawa Masatoshi
Published: May 2003

Interleukin‐23 (IL‐23), a novel cytokine composed of a newly identified p19 molecule and the p40 subunit of IL‐12, can stimulate the proliferation in vitro of memory T cells. We examined whether Colon 26 murine colon carcinoma cells that were retrovirally transduced with the p19‐linked p40 gene (Colon 26/IL‐23) could produce antitumor effects in inoculated mice. The growth of Colon 26/IL‐23 tumors developed in immunocompetent mice was significantly retarded and the tumors disappeared thereafter. Spleen cells from the mice that received Colon 26/IL‐23 cells produced significant amounts of interferon‐γ, when they were cultured with irradiated Colon 26 but not irrelevant cells. Depletion of CD8+ T cells suppressed the production of interferon‐γ. The mice that had rejected Colon 26/IL‐23 tumors were resistant to subsequent challenge of parent but not irrelevant tumor cells. Colon 26/IL‐23 tumors were not rejected in nude mice but the growth was retarded compared to parent tumors. Treatment of nude mice with anti‐asialo GM1 antibody did not influence the growth of Colon 26/IL‐23 tumors. These data suggest that expression of IL‐23 in tumors produces T cell‐dependent antitumor effects and induces systemic immunity. © 2003 Wiley‐Liss, Inc.
Expression of ADAM‐9 mRNA and protein in human breast cancer
Authors: O'Shea Caroline , McKie Norman , Buggy Yvonne , Duggan Catherine , Hill Arnold D.K , McDermott Enda , O'Higgins Niall , Duffy Michael J.
Published: May 2003

The ADAMs (a disintegrin and metalloprotease) are membrane proteins containing both protease and adhesion domains and thus may be potentially important in cancer invasion and metastasis. The aim of our study was to investigate the distribution and potential clinical significance of ADAM‐9 in breast cancer. ADAM‐9 expression was measured using both reverse transcriptase‐polymerase chain reaction (RT‐PCR) and Western blotting. ADAM‐9 mRNA was expressed more frequently in both breast carcinomas (72/110, 66%) and fibroadenomas (21/38, 55%) compared to normal breast tissue (6/25, 24%) (p = 0.0004, p = 0.028, respectively). Multiple forms of ADAM‐9 protein were detected by Western blotting, i.e., at 124, 84 and 48 kDa under reducing conditions and at 115, 76, 55, 52 and 46 kDa under nonreducing conditions. The 84 and 55 kDa forms were detected more frequently in the primary cancers compared to normal breast tissue (p < 0.0001, p = 0.0002, respectively). In addition, relative levels of the 84 kDa mature form were significantly higher in the primary cancers than in the fibroadenomas (p = 0.003), while the reverse was found for the 124 kDa precursor form (p = 0.026). In the carcinomas, the 84 kDa form of ADAM‐9 protein was expressed at higher levels in node‐positive than node‐negative cancers (p = 0.05) and correlated positively with HER‐2/neu protein levels (r = 0.313, p = 0.016). This is the first report to describe expression of any ADAM in a large number of human carcinomas. © 2003 Wiley‐Liss, Inc.
Evaluation of hypermethylated tumor suppressor genes as tumor markers in mouth and throat rinsing fluid, nasopharyngeal swab and peripheral blood of nasopharygeal carcinoma patient
Authors: Chang Hsiao Wen , Chan Amy , Kwong Dora Lai Wan , Wei William Ignace , Sham Jonathan Shun Tong , Yuen Anthony Po Wing
Published: May 2003

The purpose of our study was to evaluate the frequency of hypermethylated tumor suppressor genes (TSGs) in peripheral blood, mouth and throat (M&T) rinsing fluid and nasopharyngeal (NP) swabs of nasopharyngeal carcinoma (NPC) patients. Six normal NP tissues, 43 M&T rinsing fluid, 37 NP swabs and 43 peripheral blood from healthy non‐smokers and non‐drinkers without a family history of NPC, and 30 NPC tumors and their matched body fluid were analyzed for the presence of hypermethylated p15, p16, Ras association domain family 1 (RASSF1A), E‐cadherin, and death‐associated protein kinase (DAPK) by methylation‐specific PCR. Sequencing analysis was carried out on selected NPC tumors and body fluid samples. Twenty‐nine (97%) tumors displayed methylation in at least 1 of the 5 genes. The methylation frequencies were 80% for p15, 77% for DAPK, 67% for RASSF1A, 53% for E‐cadherin and 33% for p16. The frequency range of aberrant methylated genes in the body fluids were NP swabs (17–63%) and M&T rinsing fluid (17–50%). Methylation was found in <20% of peripheral blood for each respective gene. Methylation was, however, detected in 1 M&T rinsing fluid in which the primary tumor showed methylation free for RASSF1A. Five healthy individuals exhibited methylation for DAPK, or RASSF1A, or p15 in their body fluid samples. All body fluid samples of healthy controls showed methylation free for E‐cadherin and p16. Epigenetic change is found frequently in NPC and the high detection rate in body fluids suggest its potential application in non‐invasive screening of NPC or detection of residual carcinoma after treatment. © 2003 Wiley‐Liss, Inc.
Increased toxicity and lack of efficacy of Rofecoxib in combination with chemotherapy for treatment of metastatic colorectal cancer: A phase II study
Authors: Becerra Carlos R. , Frenkel Eugene P. , Ashfaq Raheela , Gaynor Richard B.
Published: May 2003

Preclinical and clinical models have demonstrated that cyclooxygenase‐2 (COX‐2) is overexpressed in primary and metastatic colorectal tumors. In preclinical models, there appears to be additive or synergistic effects when combining 5‐Fluorouracil (5‐FU) with nonsteroidal anti‐inflammatory agents (NSAIDs) for the treatment of colorectal neoplasms. This data raised the question as to whether adding a COX‐2 inhibitor to 5‐FU‐based regimens would increase the response rates with an acceptable toxicity profile in patients with metastatic colon cancer. In the current study, patients with metastatic colorectal cancer, who were either untreated or previously treated (more than 1 year ago) with adjuvant 5‐FU and Leucovorin (LV) received 5‐FU and LV (Mayo regimen) in addition to Rofecoxib. Tumor samples from all patients exhibited evidence of moderate COX‐2 over‐expression. 4 patients entered on the study developed upper gastrointestinal bleeding (grade III). Other toxicities included grade II stomatitis (3 patients), grade II thrombocytopenia (1 patient), grade II diarrhea (2 patients) and grade I nausea (1 patient). There were no partial or complete responses in the first 10 patients entered on the study so the study was terminated (probability of success < 0.3 with type 1 error of 0.05 and power of 0.8). Thus, Rofecoxib did not appear to increase antitumor activity and resulted in increased gastrointestinal toxicity when combined with 5‐FU/LV. Future studies will need to consider the added gastrointestinal toxicity of Rofecoxib when combined with chemotherapy for the treatment of patients with colorectal cancer. © 2003 Wiley‐Liss, Inc.