bluuebunny/crossref_metadata_2025 huggingface dataset:
Environment and archeology in Beringia
Authors: Hoffecker John F. , Elias Scott A.
Published: February 2003

The occupation of Beringia remains one of the most complex problems in human paleoecology. This is because of the wide array of variables that are likely to have affected the timing and character of settlement in the now partially submerged land that lies between the Lena and Mackenzie Rivers. At a minimum, these variables include changing sea levels and coastlines, advancing and retreating glaciers, changing fauna and flora (including trees), and evolving human adaptations to high‐latitude environments. Humans occupied Beringia during the interval between the end of the Last Glacial Maximum cold peak (ca. 20,000 cal BP) and the beginning of the Holocene (11,600 cal BP), when all of these variables were in an almost constant state of flux.
Development of highly accurate interpolation methodfor mesh‐free flow simulations III. Analysis of accuracy and stability
Authors: Tanaka Nobuatsu
Published: February 2003

A highly accurate interpolation method, CIVA, improves the accuracy of mesh‐free and grid‐less methods by taking into consideration first‐order spatial derivatives as variables; an approach based on the same idea as that on which CIP is based. In this study, the accuracy and stability of CIVA is evaluated by analytically and numerically. First, the general formulation of CIVA for the n‐dimensional case is described. Since CIVA contains the bubble function, we consider the determination methods: constant curvature condition and utilization of another computing point. Then, the relation between the bubble function in the CIVA method and the accuracy and stability is made clear by the analysis based on the Taylor expansion. Some computations of two‐dimensional passive scalar advection and advection–diffusion problems are performed for the verification of accuracy and stability. Copyright © 2003 John Wiley & Sons, Ltd.
Relaxation schemes for the shallow water equations
Authors: Delis A. I. , Katsaounis Th.
Published: February 2003

We present a class of first and second order in space and time relaxation schemes for the shallow water (SW) equations. A new approach of incorporating the geometrical source term in the relaxation model is also presented. The schemes are based on classical relaxation models combined with Runge–Kutta time stepping mechanisms. Numerical results are presented for several benchmark test problems with or without the source term present. Copyright © 2003 John Wiley & Sons, Ltd.
Der neue Weg ins All
Authors: Hüsken Dieter
Published: February 2003

Raumtransporter der nächsten Generation: die neue DFG‐Ausstellung wirft einen Blick in die Zukunft der Weltraumfahrt
Wie hoch kann ein Gebirge werden?
Authors: Ring Uwe
Published: February 2003

An der Erdoberfläche finden sich Gesteine aus großer Tiefe. Sie geben Auskunft über die Dicke von Kontinenten und erlauben Rückschlüsse auf gebirgsbildende Prozesse
Kommentar: Ein Erfolg wird weiter entwickelt
Authors: Schwarz Helmut
Published: February 2003

Graduiertenkollegs sind die „Keimzellen”︁ einer strukturierten Doktorandenförderung — Promotionskultur wurde verbessert
Ein frühes Abbild des Krebses
Authors: Bremer Christoph
Published: February 2003

Neue optische Verfahren ermöglichen die Darstellung von Enzymen, die für die Ausbreitung von Krebszellen verantwortlich sind
Über das Leben mit Kamelen
Authors: Köhler‐Rollefson Ilse
Published: February 2003

Traditionelle Hirtenkulturen betrachten eine enge soziale Bindung zu ihren Tieren als zentralen Bestandteil ihrer Kultur
High‐molecular‐weight tropomyosins localize to the contractile rings of dividing CNS cells but are absent from malignant pediatric and adult CNS tumors
Authors: Hughes Julie A.I. , Cooke‐Yarborough Claire M. , Chadwick Nigel C. , Schevzov Galina , Arbuckle Susan M. , Gunning Peter , Weinberger Ron P.
Published: February 2003

Tropomyosin has been implicated in the control of actin filament dynamics during cell migration, morphogenesis, and cytokinesis. In order to gain insight into the role of tropomyosins in cell division, we examined their expression in developing and neoplastic brain tissue. We found that the high‐molecular‐weight tropomyosins are downregulated at birth, which correlates with glial cell differentiation and withdrawal of most cells from the cell cycle. Expression of these isoforms was restricted to proliferative areas in the embryonic brain and was absent from the adult, where the majority of cells are quiescent. However, they were induced under conditions where glial cells became proliferative in response to injury. During cytokinesis, these tropomyosin isoforms were associated with the contractile ring. We also investigated tropomyosin expression in neoplastic CNS tissues. Low‐grade astrocytic tumors expressed high‐molecular‐weight tropomyosins, while highly malignant CNS tumors of diverse origin did not (P ≤ 0.001). Furthermore, high‐molecular‐weight tropomyosins were absent from the contractile ring in highly malignant astrocytoma cells. Our findings suggest a role for high‐molecular‐weight tropomyosins in astrocyte cytokinesis, although highly malignant CNS tumors are still able to undergo cell division in their absence. Additionally, the correlation between high‐molecular‐weight tropomyosin expression and tumor grade suggests that tropomyosins are potentially useful as indicators of CNS tumor grade. GLIA 42:25–35, 2003. © 2003 Wiley‐Liss, Inc.
Molecular mechanisms underlying dexamethasone inhibition of iNOS expression and activity in C6 glioma cells
Authors: Shinoda Jun , McLaughlin Katherine E. , Bell Helen S. , Swaroop Gopal R. , Yamaguchi Shin‐Ichi , Holmes Megan C. , Whittle Ian R.
Published: February 2003

The synthetic glucocorticoid dexamethasone is routinely used to stabilize patients with malignant gliomas. One putative target for glucocorticoid action is inducible nitric oxide synthase (iNOS), which is produced by the tumor cells as well as the host immune cells. In this study, we characterize the stimulatory effects of lipopolysaccharide (LPS) and the cytokine, tumor necrosis factor‐α (TNFα), as well as the inhibitory effect of glucocorticoids, on iNOS gene expression and activity in C6 glioma cells cultured in vitro. LPS significantly increased iNOS mRNA expression, peaking at 6 h, while nitrite formation increased with time up to 72 h. Although TNFα alone induced neither iNOS mRNA expression nor nitrite formation, it significantly potentiated the effect of LPS on both. iNOS activity induced by LPS with or without TNFα was dose‐dependently inhibited by dexamethasone, reaching a maximum of approximately 83% inhibition. This was completely reversed by the addition of RU38486, an antagonist of glucocorticoid receptors (GR). Dexamethasone inhibited iNOS mRNA expression; however, the maximum inhibition obtained was only 10%. These results suggest that as for induction of iNOS activity in C6 cells in vitro, the stimulatory effect of LPS is mainly due to an action at the transcriptional level. TNFα does not have intrinsic inducing activity, but has potentiating effects at the transcriptional and possibly at the posttranscriptional levels in the presence of LPS. The inhibitory effect of dexamethasone is GR‐mediated and is mainly due to action at the posttranscriptional level. GLIA 42:68–76, 2003. © 2003 Wiley‐Liss, Inc.
Diffusion parameters of the extracellular space in human gliomas
Authors: Vargová Lýdia , Homola Aleš , Zámečník Josef , Tichý Michal , Beneš Vladimír , Syková Eva
Published: February 2003

Tumor cell migration through the extracellular space (ECS) might be affected by its pore size and extracellular matrix molecule content. ECS volume fraction α (α = ECS volume/total tissue volume), tortuosity λ (λ2= free/apparent diffusion coefficient) and nonspecific uptake k′ were studied by the real‐time tetramethylammonium method in acute slices of human tissue. The diffusion parameters in temporal cortical tissue resected during surgical treatment of temporal lobe epilepsy (control) were compared with those in brain tumors. Subsequently, tumor slices were histopathologically classified according to the grading system of the World Health Organization (WHO), and proliferative activity was assessed. The average values of α, λ, and k′ in control cortex were 0.24, 1.55, and 3.66 × 10−3s−1, respectively. Values of α, λ, and k′ in oligodendrogliomas did not significantly differ from controls. In pilocytic astrogliomas (WHO grade I) as well as in ependymomas (WHO grade II), α was significantly higher, while λ and k′ were unchanged. Higher values of α as well as λ were found in low‐grade diffuse astrocytomas (WHO grade II). In cellular regions of high‐grade astrocytomas (WHO grade III and IV), α and λ were further increased, and k′ was significantly larger than in controls. Classic medulloblastomas (WHO grade IV) had an increased α, but not λ or k′, while in the desmoplastic type α and k′ remained unchanged, but λ was greatly increased. Tumor malignancy grade strongly corresponds to an increase in ECS volume, which is accompanied by a change in ECS structure manifested by an increase in diffusion barriers for small molecules. GLIA 42:77–88, 2003. © 2003 Wiley‐Liss, Inc.
Evaluating AHRD research using a feminist research framework
Authors: Bierema Laura L. , Cseh Maria
Published: February 2003

Over 600 AHRD Proceedings papers from 1996 to 2000 were analyzed according to a feminist
research framework. Although knowledge in HRD is being produced through both traditional and nontraditional
methodologies, few studies recognize gender and race/ethnicity as a category of analysis. Nearly absent from
the literature are studies concerned with women/diverse people's experience; asymmetrical power
arrangements; problems of racism and sexism; and advocacy of social justice and change. Implications
for research are discussed.
The effects of home‐based teleworking on work‐family conflict
Authors: Madsen Susan R.
Published: February 2003

A key issue in HRD is to identify and determine factors that influence the performance of employees and
organizations. Two possible factors are the initiation of teleworking and the reduction of work‐family
conflict. The purpose of this survey questionnaire study was to investigate the differences in work‐family
conflict between full‐time worksite employees and full‐time teleworking employees (individuals
who worked from home at least two days per week). Two hundred and twenty‐one usable surveys were
returned from full‐time teleworkers and nonteleworkers in seven corporate organizations. The findings
indicate that teleworkers had lower levels of various dimensions of work‐family conflict. Relationships
were also found between work‐family conflict and gender, health, number of hours worked, and number of
children.
Stress audits as a precursor to stress management workshops: An evaluation of the process
Authors: Ormond Wayne E. , Keown‐Gerrard Janine L. , Kline Theresa
Published: February 2003

This study describes the stress audit process and how it can be effectively linked with stress management
workshop development and delivery. Specifically, four stress audits and four workshops based on them were
conducted within an organization. Reactions indicated that the stress audit is a valuable tool for trainers.
Low doses of alcohol have a selective effect on the recognition of happy facial expressions
Authors: Kano Michiko , Gyoba Jiro , Kamachi Miyuki , Mochizuki Hideki , Hongo Michio , Yanai Kazuhiko
Published: February 2003

Alcohol is one of the most widely used recreational drugs, yet it is associated with undesirable social behaviour. It is used primarily for its psychoactive properties, increasing sociability and talkativeness. We hypothesize that low doses of alcohol can improve the performance related to positive emotional cognition. In this experiment, we examined the effect of low doses of alcohol on the processing of emotional facial expressions. Fifteen young male volunteers drank alcohol at volumes of 30, 60, 120 ml (0.14, 0.28, 0.56 g/kg) and performed discrimination tasks on morphed facial emotion expressions of anger, happiness, sadness and surprise‐neutral. One‐way ANOVA co‐varying pretreatment performances revealed significant differences between alcohol levels in happy face discrimination ( p<0.01). Bonferroni correction demonstrated that low doses of alcohol caused a significantly better discrimination of happy faces, and that the performances were worse with higher doses ( p<0.001). No significance was observed with the other three emotional faces. These results indicate that low doses of alcohol affect positive emotional cognition of happy facial expressions. Copyright © 2002 John Wiley & Sons, Ltd.
Mirtazapine in combination with amitriptyline: a drug–drug interaction study in healthy subjects
Authors: Sennef C. , Timmer C. J. , Sitsen J. M. A.
Published: February 2003

Objective

To assess the steady‐state pharmacokinetics of mirtazapine (30 mg/day orally) and amitriptyline (75 mg/day orally) during combined administration compared with that of either drug administered alone. To evaluate the tolerability and effects on psychometric tests of acute and subchronic administration of both drugs combined and alone.

Methods

In a single‐blind, three‐way cross‐over study, 24 (12 male and 12 female) healthy subjects were randomly assigned to six different sequences of three 9‐day treatments, i.e. racemic mirtazapine (30 mg/day), amitriptyline (75 mg/day) or the combination of these drugs. To control for acute pharmacodynamic assessments, during the first treatment period, a placebo group (n = 8; 4 females and 4 males) was added. Serial blood samples were drawn for plasma level measurements that were subsequently subjected to pharmacokinetic analysis. Psychometric tests assessed attentional performance, and a computer‐assisted telephone questionnaire assessed self‐ratings of drowsiness/alertness and sleep quality.

Results

Amitriptyline increased the Cmax of mirtazapine (+ 36%, p < 0.05) in male subjects only. Mirtazapine altered the Cmax of amitriptyline in both male (+ 23%, p < 0.05) and female (− 23%, p < 0.05) subjects. No changes were observed for other pharmacokinetic parameters. Metabolite parameters were not affected. Changes in parent compound levels mainly resulted from effects on absorption. The psychometric test results did not reveal significant changes between combined and single drug treatments. The telephone registrations of VAMRS and LSEQ did not show clinically relevant differences between the active treatments.

Conclusion

Combined administration of mirtazapine (30 mg/day) and amitriptyline (75 mg/day) alters the pharmacokinetics of either compound to a minor extent. Adding one drug to the other and substituting one drug by the other had no major effects on tolerability. Nevertheless, caution is warranted when combining amitriptyline and mirtazapine. Copyright © 2003 John Wiley & Sons, Ltd.
A preliminary study of baclofen‐induced growth hormone release in generalised social phobia
Authors: Condren Rita M. , Lucey Jim V. , Thakore Jogin H.
Published: February 2003

Objective

The authors sought to examine central GABAB receptor responses in patients with generalised social phobia using the growth hormone (GH) response to baclofen.

Method

Baclofen 20 mg was administered to 15 patients and 15 healthy matched controls and plasma growth hormone was monitored over a 3 h period.

Results

The GH response in patients was significantly reduced in comparison to that of controls when calculated as both area under the curve (AUC) and delta (Δ) response.

Conclusions

The results suggest an abnormality of central GABAB receptor function in this disorder. Copyright © 2002 John Wiley & Sons, Ltd.
Effect of citalopram on ouabain‐induced arrhythmia in isolated guinea‐pig atria
Authors: Pousti Abbas , Malihi Golrokh , Naghibi Bijan
Published: February 2003

The effect of citalopram (CTP) a selective serotonin reuptake inhibitor agent was studied on ouabain‐induced arrhythmia in spontaneously beating isolated guinea‐pig atria. CTP (2–32 μg/ml) produced a dose‐dependent decrease in the force of contractions (7–62%), and in the rate of contractions (11–72%). Pre‐administration of the atria with CTP inhibited the ouabain‐induced arrhythmia in isolated atria. Ouabain alone (1.2 μg/ml) produced arrhythmia at 4.5 min, and asystole at 20.7 min. Pretreatment with CTP (8 μg/ml) significantly increased the time of onset of arrhythmia to 9.5 min. In addition CTP prolonged the beating of atria (survival time) to more than 56 min, and inhibited the occurrence of asystole. These findings indicate that CTP produces direct cardiac action, probably due to the inhibition of cardiac Na+ and Ca2+ channels. Moreover our results suggest that CTP may reduce the membrane conductance through inhibition of ionic channels which decrease ouabain‐induced arrhythmia. Copyright © 2002 John Wiley & Sons, Ltd.
Young children's spontaneous utterances of mental terms and the accuracy of their memory behaviors: a different methodological approach
Authors: Cherney Isabelle D.
Published: February 2003

The purpose of this study was to determine whether young children's spontaneous utterances of mental terms would be congruent with the accuracy of their memory behaviours, and whether the use of an incidental memory task would yield similar developmental patterns as other methodologies. It was hypothesized that if children realize that internal mental activities influence behavioural actions, then the children's behavioural actions (recall) would be congruent with their utterances. A total of 27 three‐ and five‐year‐old children spontaneously used cognitive verbs such as knowing, forgetting, remembering, thinking, guessing and betting during a recall task. The results revealed that 39% of the 3‐year‐old children's behavioural responses and 67% of the 5‐year‐old children were congruent with their spontaneous utterances. These and other findings were consistent with studies that utilized different methodologies. Copyright © 2002 John Wiley & Sons, Ltd.
The effects of early relational antecedents and other factors on the parental sensitivity of mothers and fathers
Authors: Pelchat Diane , Bisson Jocelyn , Bois Caroline , Saucier Jean‐François
Published: February 2003

This study examines the effect of early relational antecedents (ERA, i.e. the quality of parenting parents recalled receiving as children), parenting stress, marital stress, socio‐economic factors and children's characteristics (gender and disability condition) on the parental sensitivity of mothers and fathers. The sample consisted of 116 mothers and 84 fathers of 117 eighteen month old children drawn from a larger longitudinal study on the adaptation of parents to a child with a disability. Thirty‐four children were diagnosed with Down syndrome (DS), 51 with a cleft lip and/or palate (CLP), and 32 were non‐disabled children. Multiple regression analyses reveal that mothers' sensitivity is best predicted by her level of education and family income, whereas fathers' sensitivity is best predicted by their ERA, marital stress, family income and the child's disability condition. Mothers with more education and a greater family income displayed a greater sensitivity to their children, as did fathers who perceive less marital stress, those with a greater family income and those who perceived their parents as less controlling. Also, fathers of children with DS displayed less sensitivity for their children than fathers of children with CLP or fathers of non‐disabled children. These results concord with many studies about the importance of socio‐economic factors, ERA, marital stress, parent's gender and children's factors in the understanding of parental sensitivity. Copyright © 2003 John Wiley & Sons, Ltd.
Sociodemographic determinants of incidence of primary fallopian tube carcinoma, Finland 1953–97
Authors: Riska Annika , Leminen Arto , Pukkala Eero
Published: February 2003

Primary fallopian tube carcinoma is very rare. In Western countries, it accounts for about 1% of all female genital malignant tumors. Its etiology remains poorly known, but high parity is considered to be protective. We studied determinants of incidence of primary fallopian tube carcinoma in Finland. Incidence rates for primary fallopian tube carcinoma, according to the population based Finnish Cancer Registry, from 1953– 97 were assessed by age, year of diagnosis, and type of residential area. Standardized incidence ratios (SIRs) for the years 1971– 95 were calculated by occupation and social class variables taken from the 1970 Population Census. There were 485 cases of primary fallopian tube carcinoma registered during 45 years. The age‐adjusted incidence rate increased from 1.2/1,000,000 in 1953–57 to 5.4/1,000,000 in 1993–97. This 4.5‐fold increase in incidence rate corresponds to a 7‐fold increase in the number of new cases. The increase is attributable to the age group beyond 55 years, the peak incidence occurring between 60–64 years. Although the relative increase in incidence rate has been larger in rural areas than in cities, the rate in the latter remains 2‐fold. Women in the 2 highest social classes had a 1.8‐fold incidence (95% CI = 1.2–2.6) as compared to the lowest social class. Women in agriculture and those not working outside the home had only half the cancer incidence of those in academic or clerical occupations. The incidence of primary fallopian tube carcinoma increases in Finland. Evidently, the incidence has increased simultaneously with the affluence of urban life. Part of the variation in incidence correlates with variation in parity. © 2003 Wiley‐Liss, Inc.
Prinomastat, a hydroxamate inhibitor of matrix metalloproteinases, has a complex effect on migration of breast carcinoma cells
Authors: Deryugina Elena I. , Ratnikov Boris I. , Strongin Alex Y.
Published: February 2003

Membrane type‐1 matrix metalloproteinase (MT1‐MMP) and αvβ3 integrin have been directly implicated in tumor cell dissemination and metastasis. We have demonstrated that in the case of breast carcinoma MCF7 cells co‐expressing MT1‐MMP and αvβ3 integrin, the proteinase processes the pro‐αv integrin subunit, thus facilitating αvβ3 integrin maturation and cell migration on vitronectin. Our findings show that cell surface MT1‐MMP is a short‐lived protein with a life span in the range of several hours. In contrast, turnover of αvβ3 integrin is much slower. The half‐life of αvβ3 heterodimer is about 24 hr. This large difference in life span allowed us to distinguish between the effects of MT1‐MMP on cell migration brought by matrix proteolysis from those imposed through αvβ3 integrin maturation. We then modulated the enzyme's activity by a potent hydroxamate MMP inhibitor, Prinomastat (AG3340), to analyze the divergent effects of MT1‐MMP on cell migration. Although Prinomastat immediately blocked MT1‐MMP‐mediated matrix degradation, the pool of MT1‐MMP‐modified αvβ3 integrin molecules was still capable of mediating cell‐matrix interactions. To our considerable surprise, inhibition of MT1‐MMP‐dependent vitronectin proteolysis by Prinomastat allowed a several‐fold increase in migration of MCF7 cells co‐expressing MT1‐MMP and αvβ3 integrin. In contrast, long‐term Prinomastat inhibition of MT1‐MMP‐dependent pro‐αv cleavage and thus αvβ3 integrin maturation strongly inhibited cell motility. Our studies suggest that MT1‐MMP could actually promote cell migration via modification of the cell surface receptors, including αvβ3 integrin, rather than facilitate cell migration through direct cleavage of the matrix proteins. © 2003 Wiley‐Liss, Inc.
A pivotal role for ERK in the oncogenic behaviour of malignant melanoma?
Authors: Smalley Keiran S.M.
Published: February 2003

During the process of oncogenic transformation, melanoma cells escape from normal growth‐control mechanisms and acquire the ability to invade surrounding tissues and organs. The Ras/Raf/MEK/ERK pathway is a major pathway involved in the control of growth signals, cell survival and invasion. Melanomas are known to harbour activating mutations of both Ras and BRAF, suggesting that the downstream effector ERK may be playing a major role in the oncogenic behaviour of these tumours. The past few years have seen a growth in the understanding of the role of ERK and the MAP kinase pathway in melanoma. The aim of the current review is to assess the role of ERK in melanoma behaviour and to determine whether modulation of these kinases could offer new therapeutic opportunities. © 2003 Wiley‐Liss, Inc.
Hodgkin lymphoma and Epstein‐Barr virus (EBV): No evidence to support hit‐and‐run mechanism in cases classified as non‐EBV‐associated
Authors: Gallagher Alice , Perry Jacqueline , Freeland June , Alexander Freda E. , Carman William F. , Shield Lesley , Cartwright Ray , Jarrett Ruth F.
Published: February 2003

The Epstein‐Barr virus (EBV) is associated with a proportion of Hodgkin lymphoma (HL) cases, and this association is believed to be causal. The aetiology of cases lacking EBV in the tumour cells (EBV HRS‐ve), which make up the majority of cases in western countries, is obscure. It has been suggested that EBV may also cause these tumours by using a hit‐and‐run mechanism. Support for this idea comes from the finding that most young adult patients, who are likely to have a good immune response to EBV, have EBV HRS‐ve HL. We investigated this possibility using a combined serologic and molecular approach. Analysis of EBV seroprevalence rates in an epidemiologic study of young adult HL revealed that cases with EBV HRS‐ve HL were more likely to be EBV‐seronegative than controls. Furthermore, additional studies clearly showed that some HL patients have never been infected by EBV. Quantitative PCR was used to look for the presence of deleted EBV genomes in a series of adult cases with both EBV HRS+ve and HRS‐ve HL. Subgenomic fragments were detected in equimolar proportions. This study, therefore, found no evidence to support the idea that a hit‐and‐run mechanism involving EBV plays a role in the pathogenesis of HL. © 2003 Wiley‐Liss, Inc.
Expression of peroxisome proliferator‐activated receptors (PPARs) in human urinary bladder carcinoma and growth inhibition by its agonists
Authors: Yoshimura Rikio , Matsuyama Masahide , Segawa Yoshihiro , Hase Taro , Mitsuhashi Makoto , Tsuchida Kennji , Wada Seiji , Kawahito Yutaka , Sano Hajime , Nakatani Tatsuya
Published: February 2003

Recent studies have demonstrated that peroxisome proliferator activator‐receptors(PPAR)‐γ is expressed in various cancer tissues and its ligand induces growth arrest of these cancer cells through apoptosis. In our study, we investigated the expression of PPAR‐α, β and γ in human bladder tumor (BT) and normal bladder (NB) tissues as well as the effects of PPAR‐γ ligands. Specimens were obtained from 170 patients with BT and 20 with NB. The expressions were investigated using RT‐PCR and immunohistochemical methods. We also investigated the inhibitory effect of PPAR‐γ ligands on BT‐derived cell line. Immunoreactive PPAR‐α and ‐β were significantly apparent in both BT and NB tissues. Although no marked expression of PPAR‐γ was observed in NB tissue, significant expression was found in BT tissue. The extent and intensity of immunoreactive PPAR‐γ polypeptides in BT cells were statistically much greater than those of NB cells. Correlation between PPAR‐γ expression and tissue type or progression of bladder cancer was observed; PPAR‐γ expression was higher in G3 of bladder cancer than in G1 and was higher in advanced than in early cancer. PPAR‐γ agonists, troglitazone and 15‐deoxy‐Δ12, 14‐prostaglandin J2 inhibited the growth of the BT cells. PPAR‐γ is expressed in bladder tumor, and results suggest that PPAR‐γ ligands may mediate potent antiproliferative effects against BT cells. Thus, PPAR‐γ has the ability to become a new target in treatment of bladder tumor. © 2003 Wiley‐Liss, Inc.
Resveratrol acts as an estrogen receptor (ER) agonist in breast cancer cells stably transfected with ER α
Authors: Levenson Anait S. , Gehm Barry D. , Pearce Sandra Timm , Horiguchi Jun , Simons Laura A. , Ward James E. , Jameson J. Larry , Jordan V. Craig
Published: February 2003

Resveratrol (Res) is a phytoestrogen found in grapes and present in red wine. Res has been shown to function as an estrogen receptor (ER) agonist, but it remains unclear whether it may also exert antagonist activity. Our aim was to study the effects of Res at both the molecular (TGFα gene activation) and the cellular (cell growth) levels in breast cancer cells stably transfected with wild‐type (wt) ER(D351) and mutant (mut) ER (D351Y). TGFα mRNA induction was used as a specific marker of estradiol (E2) responsiveness. Res caused a concentration‐dependent (10−8–10−4 M) stimulation of TGFα mRNA, indicating that it acts as an estrogen agonist in these cell lines. The pure antiestrogen ICI 182,780 (ICI) blocked Res‐induced activation of TGFα, consistent with action through an ER‐mediated pathway. Further studies that combined treatments with E2 and Res showed that Res does not act as an antagonist in the presence of various (10−11−10−8 M) concentrations of E2. To determine whether Res can be classified as a type I or type II estrogen (Jordan et al., Cancer Res 2001;61:6619–23,), we examined Res with the D351G ER in the TGFα assay and found that Res belongs to the type I estrogens. Both Res and E2 had concentration‐dependent growth inhibitory effects in cells expressing wtER and D351Y ER. Although the pure antiestrogen ICI blocked the growth inhibitory effects of E2, it did not block the inhibitory effects of Res, suggesting that the antiproliferative effects of Res also involve ER‐independent pathways. Interestingly, Res differentially affected the levels of ER protein in these 2 cell lines: Res down‐regulated wtER levels while significantly up‐regulating the amount of mutD351Y ER. Co‐treatment with ICI resulted in strongly reduced ER levels in both cell lines. Gene array studies revealed Res‐induced up‐regulation of more than 80 genes, among them a profound activation of p21CIP1/WAF1, a gene associated with growth arrest. The p21CIP1/WAF1 protein levels measured by Western blotting confirmed Res‐induced significant up‐regulation of this protein in both cell lines. In summary, Res acts as an ER agonist at low doses but also activates ER‐independent pathways, some of which inhibit cell growth. © 2003 Wiley‐Liss, Inc.
Helicobacter pylori and carcinogenesis of gastric B‐cell lymphomas
Authors: Seydel Johannes , Ullrich Andreas , Bender Ralf , Fischbach Wolfgang , Blettner Maria
Published: February 2003

Primary non‐Hodgkin's lymphomas of the stomach are associated with Helicobacter pylori infection. We analyzed gastric lymphoma onset data with respect to prior H. pylori infections based on the multistage theory of carcinogenesis. This theory provides a link between epidemiological data and biological processes. The study involved 133 patients, aged 29–75 years, diagnosed with marginal zone B‐cell lymphoma (MZBL) and diffuse large cell B‐cell lymphoma (DLBL). A 2‐parametric Weibull model was applied to MZBL and DLBL onset data. Median age of diagnosis of MZBL (DLBL) was 59 years (55 years) in males and 65.5 years (64 years) in females. Infection with H. pylori was found in 81.3% (59.5%) of the patients diagnosed with MZBL (DLBL). Lymphoma latency data were fitted to Weibull distributions with a shape parameter of 5.7 for MZBL cases and 4.2 for DLBL. The shape parameter that indicates the number of steps in carcinogenesis was approximately independent of the status of infection with H. pylori in DLBL in contrast to MZBL. It was shown that gastric lymphoma onset data can be described by Weibull distribution functions. The findings support the hypothesis that MZBL and DLBL have different lines of development. There is indication of stronger antigen dependency in the carcinogenesis of MZBL in comparison to DLBL. © 2003 Wiley‐Liss, Inc.
CYP1A1 T3801 C polymorphism and lung cancer: A pooled analysis of 2,451 cases and 3,358 controls
Authors: Vineis Paolo , Veglia Fabrizio , Benhamou Simone , Butkiewicz Dorota , Cascorbi Ingolf , Clapper Margie L. , Dolzan Vita , Haugen Aage , Hirvonen Ari , Ingelman‐Sundberg Magnus , Kihara Masahiro , Kiyohara Chikako , Kremers Pierre , Le Marchand Loic , Ohshima Susumu , Pastorelli Roberta , Rannug Agneta , Romkes Marjorie , Schoket Bernadette , Shields Peter , Strange Richard C. , Stucker Isabelle , Sugimura Haruhiko , Garte Seymour , Gaspari Laura , Taioli Emanuela
Published: February 2003

CYP1A1 is involved in the metabolism of benzopyrene, a suspected lung carcinogen; it is therefore conceivable that genetically determined variations in its activity modify individual susceptibility to lung cancer. The role of the CYP1A1 MspI polymorphism in lung cancer has been widely studied but has not been fully clarified. We have included 2,451 cases and 3,358 controls in a pooled analysis of 22 case‐control studies on CYP1A1 and lung cancer risk. We found a clear association between the CYP1A1 homozygous MspI restriction fragment length polymorphism (RFLP) and lung cancer risk in Caucasians (age‐ and gender‐adjusted odds ratio = 2.36; 95% confidence interval 1.16–4.81); other associations were weaker or not statistically significant. The association with the homozygous variant was equally strong for squamous cell carcinomas and adenocarcinomas among Caucasians. We analyzed the risk by duration of smoking: for Caucasian subjects with the MspI RFLP combined variants (homozygotes plus heterozygotes), the increase in the risk of lung cancer was steeper than among the individuals with the homozygous reference allele. Our analysis suggests that Caucasians with homozygous variant CYP1A1 polymorphism have a higher risk of lung cancer. The data were more consistent among Caucasians, with a strong association between the homozygous variant in both squamous cell carcinomas and adenocarcinomas, and a stronger association in men than in women. The analyses were more inconsistent and failed to reach statistical significance in Asians. This observation might be due to design specificities or unknown effect modifiers in the Asian studies. © 2003 Wiley‐Liss, Inc.
Malignant mesothelioma growth inhibition by agents that target the VEGF and VEGF‐C autocrine loops
Authors: Masood Rizwan , Kundra Ajay , Zhu SuTao , Xia Guangbin , Scalia Pierluigi , Smith D. Lynne , Gill Parkash S.
Published: February 2003

Malignant mesothelioma (MM) is a locally aggressive tumor that originates from the mesothelial cells of the pleural and sometimes peritoneal surface. Conventional treatments for MM, consisting of chemotherapy or surgery give little survival benefit to patients, who generally die within 1 year of diagnosis. Hence, there is an urgent need for the development of alternative therapies. Vascular endothelial growth factor (VEGF) is an autocrine growth factor for MM. The closely related molecule, VEGF‐C, is also implicated in malignant mesothelioma growth. VEGF‐C and its cognate receptor VEGFR‐3 are co‐expressed in mesothelioma cell lines. A functional VEGF‐C autocrine growth loop was demonstrated in mesothelioma cells by targeting VEGF‐C expression and binding to VEGFR‐3. The ability of novel agents that reduce the levels of VEGF and VEGF‐C to inhibit mesothelioma cell growth in vitro was assessed. Antisense oligonucleotide (ODN) complementary to VEGF that inhibited VEGF and VEGF‐C expression simultaneously specifically inhibited mesothelioma cell growth. Similarly, antibodies to VEGF receptor (VEGFR‐2) and VEGF‐C receptor (VEGFR‐3) were synergistic in inhibiting mesothelioma cell growth. In addition, a diphtheria toxin‐VEGF fusion protein (DT‐VEGF), which is toxic to cells that express VEGF receptors was very effective in inhibiting mesothelioma cell growth in vitro. These results indicate that targeting VEGF and VEGF‐C simultaneously may be an effective therapeutic approach for malignant mesothelioma. © 2003 Wiley‐Liss, Inc.
Comparison of electron density properties in frozen and relaxed electronic distributions
Authors: Alkorta Ibon , Elguero Jose , Espinosa Enrique , Mata Ignasi , Molins Elies
Published: February 2003

Two kinds of electron densities for several small molecules (H2, FH, CH3CH3, CH3NH2, CH3OH, and CH3F) have been generated for a wide range of bond distances. The first one, as the sum of the electron density of the isolated fragments, and the second one by optimizing the electron density at each given geometrical disposition. A number of properties of this two electronic distributions have been compared (position of the bond critical points, electron density, Laplacian, curvatures, and local energies). The differences, associated to the bond formation, are found to be very important for most of the cases. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 416–421, 2003
Ab initioquality one‐electron properties of large molecules: Development and testing of molecular tailoring approach
Authors: Babu K. , Gadre Shridhar R.
Published: February 2003

The development of a linear‐scaling method, viz. “molecular tailoring approach” with an emphasis on accurate computation of one‐electron properties of large molecules is reported. This method is based on fragmenting the reference macromolecule into a number of small, overlapping molecules of similar size. The density matrix (DM) of the parent molecule is synthesized from the individual fragment DMs, computed separately at the Hartree–Fock (HF) level, and is used for property evaluation. In effect, this method reduces the O(N3) scaling order within HF theory to ann·O(N′3) one, wherenis the number of fragments andN′, the average number of basis functions in the fragment molecules. An algorithm and a program in FORTRAN 90 have been developed for an automated fragmentation of large molecular systems. One‐electron properties such as the molecular electrostatic potential, molecular electron density along with their topography, as well as the dipole moment are computed using this approach for medium and large test chemical systems of varying nature (tocopherol, a model polypeptide and a silicious zeolite). The results are compared qualitatively and quantitatively with the correspondingactualones for some cases. This method is also extended to obtain MP2 level DMs and electronic properties of large systems and found to be equally successful. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 484–495, 2003
Rational determination of charge distributions for free energy calculations
Authors: Chipot Christophe
Published: February 2003

Point charges derived from RHF/6‐31G* electrostatic potentials are attractive because they tend to exaggerate the polarity of solvated molecules, thereby compensating in an average fashion missing induction effects. In the context of free energy calculations, wherein the molecule is transferred from a polar environment to a nonpolar one, we propose a more rational approach based on a self‐consistent reaction field computation at a higher level of theory, supplemented by an estimation of the corresponding distortion energy to account for the change of polarity of the surroundings. Application of this method to the test cases acetamide, acetic acid, methyl acetate and phenol, using multinanosecond molecular dynamics/“umbrella sampling” simulations, yields consistent hydration free energies in reasonably good agreement with experiment. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 409–415, 2003
Application of the quantum theory of atoms in molecules to selected physico‐chemical and biophysical problems: Focus on correlation with experiment
Authors: Matta Chérif F.
Published: February 2003

This article reviews how the quantum theory of atoms in molecules (QTAIM) can be used to predict experimental physico‐chemical properties of molecules of biologic interest: the amino acids, the polycyclic aromatic hydrocarbons (PAH), and the opiates, for example, morphine and PEO. The predicted experimental properties are as diverse as the partial molar volumes, the free energies of hydration, the second code‐letter in the genetic code, the resonance energies, and the proton spin–spin coupling constants. Recent examples of the utilization of QTAIM to construct excellent statistical models (with squared correlation coefficients (r2) > 0.9) correlating properties of the electron density and of the pair density to experiment are reviewed. Some new results on the solvent effects on electron delocalization are also presented. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 453–462, 2003
Wave functions derived from experiment. V. Investigation of electron densities, electrostatic potentials, and electron localization functions for noncentrosymmetric crystals
Authors: Grimwood Daniel J. , Bytheway Ian , Jayatilaka Dylan
Published: February 2003

The constrained Hartree–Fock method using experimental X‐ray diffraction data is extended and applied to the case of noncentrosymmetric molecular crystals. A new way to estimate the errors in derived properties as a derivative with respect to added Gaussian noise is also described. Three molecular crystals are examined: ammonia [NH3], urea [CO(NH2)2], and alloxan [(CO)4(NH)2]. The energetic and electrical properties of these molecules in the crystalline state are presented. In all cases, an enhancement of the dipole moment is observed upon application of the experimental constraint. It is found that the phases of the structure factors are robustly determined by the constrained Hartree–Fock model, even in the presence of simulated noise. Plots of the electron density, electrostatic potential, and the electron localization function for the molecules in the crystal are displayed. In general, relative to the Hartree–Fock model, there is a depletion of charge around hydrogen atoms and lone pair regions, and a build‐up of charge within the molecular framework near nuclei, directed along the bonds. The electron localization function plots reveal an increase in the pair density between vicinal hydrogen atoms. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 470–483, 2003
Ab initio determination of the electric multipole moments and static (hyper)polarizability of HCCX, X = F, Cl, Br, and I
Authors: Maroulis George
Published: February 2003

We report electric multipole moments and (hyper)polarizabilities for the haloethynes HCCX, X = F, Cl, Br, and I. The molecular properties have been obtained from finite‐field self‐consistent field, Møller–Plesset perturbation theory and coupled cluster calculations with large, carefully optimized basis sets of gaussian‐type functions. The mean dipole (hyper)polarizability and the mean quadrupole polarizability near the Hartree–Fock limit are α/e2aE = 23.74 (HCCF), 37.26 (HCCCl), 43.97 (HCCBr), 56.44 (HCCI), β/e3aE = −73.9 (HCCF), −67.0 (HCCCl), −39.5 (HCCBr), 42.7 (HCCI), γ/e4aE = 4914 (HCCF), 6554 (HCCCl), 9328 (HCCBr), 14949 (HCCI), and C/e2aE = 160.3 (HCCF), 317.1 (HCCCl), 471.2 (HCCBr), 671.2 (HCCI). Electron correlation has a small effect on the dipole polarizability but affects strongly the hyperpolarizability. Agreement with the available experimental data is more or less fair for HCCF, HCCCl, and HCCBr but less satisfactory for HCCI. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 443–452, 2003
Transferable atom equivalent multicentered multipole expansion method
Authors: Whitehead C. E. , Breneman C. M. , Sukumar N. , Ryan M. D.
Published: February 2003

The transferability of atomic and functional group properties is an implicit concept in chemistry. The work presented here describes the use of Transferable Atom Equivalents (TAE) to represent molecular electrostatic potential fields through the use of integrated atomic multipole moments that are associated with each TAE atom type used in the reconstruction. TAE molecular surface distributions of electrostatic potentials are compared with analyticalab initioand empirical (Gasteiger) partial charge reference models for several conformations of test peptides. Surface electrostatic potential distributions computed using TAE multipole representations were found to converge at the octopole level, with incremental improvement observed when hexadecapoles were included. Molecular electrostatic potential fields that were produced using the TAE method were observed to be responsive to conformational changes and to compare well withab initioreference distributions. Generation of TAE atom types and their associated multipoles does not involve fitting to sample electrostatic potential fields, but rather utilizes integrated AIM atomic electron density distributions within representative chemical environments. The RECON program was used for TAE reconstruction. RECON is capable of processing 5000 drug‐sized molecules or 25 proteins per minute per 1.7 GHz P4 Linux processor. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 512–529, 2003
Hirshfeld partitioning of the electron density: Atomic dipoles and their relation with functional group properties
Authors: Proft F. De , Vivas–Reyes R. , Peeters A. , Van Alsenoy C. , Geerlings P.
Published: February 2003

Atomic dipole moments, derived within the Hirshfeld partitioning of the molecular electron density, have been studied for compounds of the type HX and ClX, for a series of functional groups X frequently encountered in organic molecules. In the case of the HX compounds, the component of the atomic dipole moment on H along the axis connecting H with the central atom in X is found to be linearly correlated with the electronegativity of X, the hardness of X playing no significant role. In the case of the ClX compounds, the situation is less clear. However, evidence seems to point to the conclusion that for these compounds, also the group hardness plays an important role. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 463–469, 2003
Electron probability distribution in AIM and ELF basins
Authors: Chamorro E. , Fuentealba P. , Savin A.
Published: February 2003

The probabilities of finding a certain number of electrons enclosed in a given volume is calculated and discussed for a series of molecules. Two different methodologies to do the partition of the molecular space in separate volumes are investigated: the Atoms in the Molecules, AIM, topologic analysis of the density, and the topologic analysis of the Electron Localization Function (ELF). The formulas to calculate the probability distribution are reviewed and the way to implement them shortly explained. For a series of molecules, we present how the probability distribution complement the chemical information about the localization of the electrons in certain regions of the space. The calculations show that the probability of findingZelectrons in the AIM atomic basin associated to an atom of atomic numberZis, in general, low, even when the average number of electrons is close toZ. The probability distribution on the ELF basins associated to bonds yields new insight about the nature of the respective bond. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 496–504, 2003
Well‐functioning double‐orifice mitral valve in a young adult
Authors: Karas Spilios , Barbetseas John , Lambrou Spyros , Parissis John , Metzikof Demetrios , Toutouzas Pavlos
Published: February 2003

We report the case of a rare congenital anomaly, a double‐orifice mitral valve, in a 23‐year‐old woman who was asymptomatic and had no history of heart disease. Transthoracic and multiplane transesophageal echocardiography revealed 2 functionally normal orifices of equal size, the least frequent anatomic presentation of this anomaly. We prescribed antibiotic prophylaxis because of the concomitant presence of a mildly stenotic bicuspid aortic valve and recommended annual follow‐up examinations to monitor both lesions for possible progression. © 2003 Wiley Periodicals, Inc. J Clin Ultrasound 31:170–173, 2003