bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations between polymorphisms within the thymidylate synthase gene and spina bifida
Authors: Volcik Kelly A. , Shaw Gary M. , Zhu Huiping , Lammer Edward J. , Laurent Cecile , Finnell Richard H.
Published: November 2003

BACKGROUND

Polymorphisms within the thymidylate synthase (TS) gene that influence enzyme activity may affect plasma folate levels and, indirectly, plasma homocysteine concentrations. We investigated whether TS polymorphisms contribute to spina bifida (SB) risk, given that a reduction in the risk of SB has been linked to folate metabolism.

METHODS

Genomic DNA was extracted from newborn‐screening blood spots obtained from case infants with SB, and randomly selected, nonmalformed control infants. Genotype frequencies of two polymorphisms in the TS gene—a 28‐bp tandem repeat in the promoter enhancer region (TSER) and a 6‐bp deletion in the 3′UTR—were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. Additionally, all seven exons of the TS gene were sequenced to identify variations within the coding region of the gene.

RESULTS

We found that the TSER 2/2 homozygous genotype was associated with a slightly increased risk for SB infants (odds ratio [OR] = 1.4 [0.8–2.4], p = 0.1). When the cohort was divided into separate ethnic groups, this risk increased by 4‐fold with the TSER 2/2 homozygous genotype (OR = 4.0 [1.8–8.8], p = 0.001), and by 3‐fold with the 3′UTR +/+ homozygous genotype (OR = 3.6 [1.3–10.1], p = 0.02) in non‐Hispanic white cases. The combined TSER,3′UTR (2/2,+/+) genotype showed a more than 4‐fold increased risk for SB within this specific ethnic group (OR = 4.7 [1.1–19.8], p = 0.04).

CONCLUSIONS

This study is the first to evaluate how TS polymorphisms contribute to the risk of SB. The current findings indicate that polymorphisms in the untranslated regions of the TS gene are associated with 4‐fold or more increased risks of SB in non‐Hispanic whites, but not in Hispanic whites, African‐Americans, or Asian‐Americans. Birth Defects Research (Part A), 2003. © 2003 Wiley‐Liss, Inc.
Timetable for intestinal rotation in staged human embryos and fetuses
Authors: Kim Won Kyu , Kim Hyun , Ahn Dae Ho , Kim Myoung Hee , Park Hyoung Woo
Published: November 2003

BACKGROUND

The existing data on intestinal rotation during human development are contradictory regarding the timing of major events, and as such an exact timetable for rotation of the intestine in humans is not yet available.

METHODS

We studied the initial formation and rotation of the intestine by microdissection and histological observations in 72 human embryos and fetuses at two to 12 weeks postfertilization. The embryos were classified according to the Carnegie staging system.

RESULTS

The primordium of the primitive gut was first observed as a yolk sac at stage 5. With the formation of the embryonic foldings, three divisions of the primitive gut (the foregut, midgut, and hindgut) were observed at stage 10. At stage 12, the primitive gut was located on the midline. At stage 15, a 90° counterclockwise rotation of the intestine began. At stage 16, herniation of the intestine into the umbilical cord was not evident in observations of the external form or a transversely sectioned embryo, but was evident in a sagittally sectioned embryo. There was another 90° counterclockwise rotation at stage 20. Reduction of the intestine was a rapid process, since it was still in the cord in fetuses of <40 mm crown–rump length (CRL), and was reduced above 40 mm in general during nine weeks of development. When the intestine returned to the abdominal cavity, the cecum was located in the right lower quadrant (the adult position).

CONCLUSIONS

We have developed a standard timetable to describe the rotation of the intestine. The current results will be helpful in studies describing the pathogenesis of some developmental abnormalities in the intestine due to abnormal rotation. Birth Defects Research (Part A), 2003. © 2003 Wiley‐Liss, Inc.
Fetal bilateral renal agenesis, phocomelia, and single umbilical artery associated with cocaine abuse in early pregnancy
Authors: Kashiwagi Maki , Chaoui Rabih , Stallmach Thomas , Hürlimann Sandra , Lauper Urs , Hebisch Gundula
Published: November 2003

BACKGROUND

Maternal cocaine abuse in pregnancy is associated with complications such as intrauterine growth retardation, abruptio placentae, and preterm delivery.

CASE

We report what is, to our knowledge, the first published observation of fetal bilateral renal agenesis associated with a vascular disruption syndrome comprising upper limb reduction defect and a single umbilical artery following maternal cocaine abuse in early pregnancy.

CONCLUSIONS

This constellation in a fetus aborted at 18 weeks extends the spectrum of complications possibly associated with cocaine abuse in pregnancy. Birth Defects Research (Part A), 2003. © 2003 Wiley‐Liss, Inc.
Maternal febrile illnesses, medication use, and the risk of congenital renal anomalies
Authors: Abe Karon , Honein Margaret A. , Moore Cynthia A.
Published: November 2003

BACKGROUND

Renal anomalies occur in about three infants per 1000 live births and have been associated with several environmental risk factors. Researchers have yet to assess the effect of maternal febrile illnesses on renal anomalies, even though febrile illnesses have been associated with other birth defects. Our objective was to determine whether maternal illness, fever, or medication use during the first trimester of pregnancy is associated with the occurrence of renal anomalies.

METHODS

In this population‐based case‐control study, we evaluated 192 infants with renal anomalies (renal agenesis [n = 44], obstructive defects [n = 134], and renal duplication defects [n = 14]) and 3029 infant without birth defects, all of whom were born in metropolitan Atlanta, Georgia, from 1968 through 1980. Maternal illness was defined as reported flu‐like illness and/or episodic illness during the first trimester.

RESULTS

Our adjusted multivariate analyses showed that among the 192 case‐infants, 38 had mothers with an illness (adjusted odds ratio [AOR], 1.71; 95% confidence interval [CI], 1.15–2.52), 20 had mothers who reported a fever (AOR, 1.80; 95% CI, 1.07–3.02) and 26 had mothers who reported taking medication (AOR, 1.69; 95% CI, 1.07–2.68). Fifteen mothers reported a fever and medication use (AOR, 1.90; 95% CI, 1.05–3.45). Nonprescription aspirin‐containing medication use showed the strongest association (AOR, 3.45; 95% CI, 1.36–8.75) with renal anomalies.

CONCLUSIONS

Our data suggest that maternal exposure to illness, fever, and medication (particularly aspirin) may increase the risk of congenital renal anomalies. Birth Defects Research (Part A), 2003. © 2003 Wiley‐Liss, Inc.
Induction of decision trees using fuzzy partitions
Authors: Myles A. J. , Brown S. D.
Published: November 2003

A new method for the induction of fuzzy decision trees is introduced. The fuzzy decision tree classifier improves prediction accuracy using smaller models by locating more robust splitting regions. The proposed method also provides a measure of confidence for sample classification by propagating partition memberships into all leaf nodes, thereby relaxing local subspace restrictions. The fuzzy decision tree algorithm is presented and compared against standard and bagged decision tree classifiers. Copyright © 2003 John Wiley & Sons, Ltd.
Hierarchical multivariate analysis of cockle phenomena
Authors: Stefanov Zdravko I. , Hoo Karlene A.
Published: November 2003

The phenomena called cockle are small wrinkles on the paper surface that appear during paper production. This condition poses significant economic and operability problems in the production of magazine paper, as it deteriorates the printabilty of the paper. There are many and varied sources that can lead to cockle, and their detection is often very complicated. In this work a multivariate hierarchical approach is proposed to analyze the cause of cockle. The hierarchy has two levels, the first of which is a three‐way decomposition and analysis of the data collected from sections of a paper machine. The second level is a two‐way decomposition and analysis between the combined loadings from the three‐way decomposition and the measured cockle data. The results show that this approach is capable of identifying the important process sections and process variables, in spite of the large dimensionality of the problem. Data analyzed from two real industrial paper machines, involving several grades of paper, are used to demonstrate the proposed hierarchical approach. Copyright © 2003 John Wiley & Sons, Ltd.
AlGaN/GaN heterojunction FETs for high‐power applications
Authors: Kuzuhara Masaaki , Ando Yuji , Inoue Takashi , Okamoto Yasuhiro , Kasahara Kensuke , Nakayama Tatsuo , Miyamoto Hironobu
Published: November 2003

GaN and its heterojunction structures are attracting considerable attention as materials for high‐voltage, high‐frequency power device applications. This paper gives an overview of the basic device structure, process technology, and recent device performance achieved with AlGaN/GaN heterojunction FET structures. The emphasis is on the performance of power amplifiers developed for use in cellular base station transmitters and pseudo‐millimeter‐wave wireless access systems. Future research topics and prospects of nitride‐based transistors are also discussed. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 86(12): 52–60, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.10161
Numerical analysis for three‐dimensional optical waveguides with periodic structure using Fourier series expansion method
Authors: Miyamoto Tokuo , Momoda Michiko , Yasumoto Kiyotoshi
Published: November 2003

Three‐dimensional optical waveguides with an arbitrary cross section and a periodic configuration have been important as optical IC elements. However, it is not always easy to obtain highly accurate solutions for them without respect to the number of periods. In this paper, the Fourier series expansion method, improved for accurate numerical analysis independently of the number of periods introducing Floquet's theorem, is applied to a fiber grating and various thin‐film optical waveguides with index‐modulation‐type periodic structures and rectangular cross sections. The wavelength characteristics of the transmitted and reflected powers of the guided mode and the radiation field are derived at each period (40 to 1000). As a result, the wavelength characteristics of the power are made clear for periodic optical waveguides of embedded type and raised type with a glass or semiconductor substrate, including inhomogeneous cases. The algorithm thus proves to be useful for detailed analysis of various three‐dimensional periodic optical waveguides. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 86(12): 22–31, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.10171
Examinations of linearity characteristics of resistive digitizer with parallel electrodes
Authors: Kanagawa Makoto , Suzuki Ikuo
Published: November 2003

The linearity characteristics of a resistive film pressure‐sensitive digitizer with parallel electrodes are theoretically studied. Three typical methods for sensing the two‐dimensional coordinates by a digitizer with a bar‐shaped electrode are analyzed. The linearity between the detected voltage or detected current and the pressure point coordinates is studied theoretically. Further, the characteristics are studied for an approximate realization of the bar electrode with a series of point electrodes. In both the methods of coordinate sensing by the potential slope and by current division, the characteristics of the entire digitizer surface are shown to be expressed by a periodic extension of the characteristics of the two‐point electrode model. Finally, based on the two‐point electrode model, the relationship between the aspect ratio of the resistive film and the distortion in the linearity characteristics is found. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 86(12): 10–21, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.10176
Adiabatic switching by quasistatic operation of single‐electron‐tunneling devices
Authors: Akazawa Masamichi
Published: November 2003

This paper presents the possibility of an adiabatic switching operation that is lossless, with zero power consumption, in the limit of a quasistatic operation of a single‐electron device. Usually, in a switching device represented by a transistor, there exists a threshold. Since an abrupt energy dissipation accompanies crossing of the threshold, there is a limitation in the reduction of power consumption by quasistatic operation. However, in an appropriately designed single‐electron device, switching without an abrupt energy dissipation is possible by a quasistatic voltage change. In this paper, in regard to the quasistatic operation of a single‐electron device, the power consumption characteristics are estimated numerically. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 86(12): 1–9, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.10177
Automated annotation of significant scenes based on structure of broadcast sports video
Authors: Nitta Naoko , Babaguchi Noboru , Kitahashi Tadahiro
Published: November 2003

For broadcast sports video, the authors attempted automatic generation of semantic annotations for parts that seem important from the viewpoint of story, in accordance with the composition of the video and the game. First, the parts of a sports video which seem significant in the progress of the game are extracted from the closed caption text stream by keyword sequence search. The information concerning the play and the player in each part is extracted and the annotation is generated. Then, in order to determine the position in the video to which the annotation should be attached, the video is partitioned by similarly extracting the game‐progress part by matching to the image stream. Finally, by establishing the time synchronization of the two streams, the generated annotation is attached to the video. An experiment was performed in which the method was applied to videos of American football games, as an example of sports videos. Automatic annotation was achieved accurately for the game‐progress part with a reproduction rate of 75% and a match rate of 90%. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 86(12): 69–78, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.10206
'Everything is relative': Comparison processes in social judgment The 2002 Jaspars Lecture
Authors: Mussweiler Thomas
Published: November 2003

Any judgment involves a comparison of the evaluated target to a pertinent norm or standard, so that comparison processes lie at the core of human judgment. Despite this prominent role, however, little is known about the psychological mechanisms that underlie comparisons and produce their variable consequences. To understand these consequences, one has to examine what target knowledge is sought and activated during the comparison process. Two alternative comparison mechanisms are distinguished. Similarity testing involves a selective search for evidence indicating that the target is similar to the standard and leads to assimilation. Dissimilarity testing involves a selective search for evidence indicating that the target is dissimilar from the standard and leads to contrast. Distinguishing between these alternative mechanisms provides an integrative perspective on comparison consequences in the realm of social comparison and beyond. Copyright © 2003 John Wiley & Sons, Ltd.
Emotional prejudice, essentialism, and nationalism The 2002 Tajfel lecture
Authors: Leyens Jacques‐Philippe , Cortes Brezo , Demoulin Stéphanie , Dovidio John F. , Fiske Susan T. , Gaunt Ruth , Paladino Maria‐Paola , Rodriguez‐Perez Armando , Rodriguez‐Torres Ramon , Vaes Jeroen
Published: November 2003

In explaining differences between groups, people ascribe the human essence to their ingroup and consider outgroups as less human. This phenomenon, called infra‐humanization, occurs outside people's awareness. Because secondary emotions (e.g. love, hope, contempt, resentment) are considered uniquely human emotions, people not only attribute more secondary emotions to their ingroup than to outgroups, but are reluctant to associate these emotions with outgroups. Moreover, people behave less cooperatively (in terms of altruism, imitation, and approach) with an outgroup member who expresses himself through secondary emotions. Infra‐humanization occurs for high and low status groups, even in the absence of conflict between groups. It does not occur when the outgroup target is adequately individualized, by a complete name or through perspective taking, for instance. The differential familiarity with the ingroup and the outgroup cannot explain infra‐humanization. Yet, preliminary results show that subjective essentialism and ingroup identification may mediate the effects of infra‐humanization. A connection is made between nationalism and infra‐humanization. Copyright © 2003 John Wiley & Sons, Ltd.
Explaining credit default swap premia
Authors: Benkert Christoph
Published: November 2003

This article proposes a simple approach for explaining credit default swap premia. Specifically, it
investigates the effects of historical and option‐implied equity volatility on credit default swap premia,
thus extending an idea proposed by Campbell and Taksler (in press) in the
context of corporate bond yields. Using panel data of credit default swaps on 120 international firms from 1999 to
mid‐2002, it becomes evident that option‐implied volatility is a more important factor in explaining
variation in credit default swap premia than historical volatility. © 2004 Wiley Periodicals, Inc. Jrl Fut
Mark 24:71–92, 2004
Language impairment in dementia: impact on symptoms and care needs in residential homes
Authors: Potkins Dawn , Myint Pat , Bannister Carol , Tadros George , Chithramohan Ramilgan , Swann Alan , O'Brien John , Fossey Jane , George Eugenie , Ballard Clive , Margallo‐Lana Marisa
Published: November 2003

Background

Impairment of language skills affects the level of functioning of an individual, interferes with effective communication and can result in development of disruptive behaviour. Social skills and capacity for self care may be compromised. Few studies have evaluated the impact of language problems on symptoms and socialization in people with dementia in care environments.

Method

315 elderly residents with dementia (29% living in nursing homes, 71% in social care facilities) were assessed using standardized psychiatric schedules including the Sheffield Screening Test for Acquired Language Disorders and Neuropsychiatric Inventory. Dementia Care Mapping was undertaken at random in at least 50% of residents in each facility.

Results

Expressive language impairment was associated with the presence of delusions even when severity of dementia was controlled for (p=0.02) and showed a tendency of association with depression (p=0.06). Receptive language difficulties were strongly associated with presence of Aberrant Motor Behaviour, even controlling for severity of dementia (p=0.04). Decreased participation in social activities was correlated with both expressive (p=0.048) and receptive aspects of language (p<0.01) but social withdrawal was only correlated with receptive language difficulties (p=0.01).

Conclusion

Language disorders are associated with both behavioural and psychological symptoms of dementia even when severity of dementia is controlled for. Patients' needs in communication skills should be addressed earlier to help them maintain social interactions and reduce the impact on behavioural problems and patients' quality of life. Copyright © 2003 John Wiley & Sons, Ltd.
Family carers' responses to behavioural and psychological symptoms of dementia
Authors: Ward Sandy , Opie Janet , O'Connor Daniel W.
Published: November 2003

Objectives

To describe the responses of family carers to the behavioural and psychological symptoms associated with dementia.

Methods

Thirty family carers of people with dementia were identified in a survey of mental disorder in general practice. Another 20 were referred by local aged mental health services. Carers were interviewed using the Manchester and Oxford University Scale for the Psychopathological Assessment of Dementia (MOUSEPAD) which rates behavioural and psychological disturbances. Carers' customary responses to current symptoms were recorded verbatim and categorised using a structured typology.

Results

Symptom frequency increased in line with dementia severity. Disturbances were generally well tolerated. Most were ignored where possible, except for wandering from home. Other common responses included avoiding triggers, providing reassurance, reality orientation, diversion, and collusion with false beliefs. Restrictive or punitive responses were uncommon.

Conclusions

Few carers articulated clear strategies to deal with behavioural and psychological symptoms. For most, tolerance proved more effective and less distressing than arguments and reprimands. Carers' responses are likely to be influenced by social and cultural factors and may differ in other settings. Copyright © 2003 John Wiley & Sons, Ltd.
Rey verbal learning test is a useful tool for differential diagnosis in the preclinical phase of Alzheimer's disease: comparison with mild cognitive impairment and normal aging
Authors: Estévez‐González Armando , Kulisevsky Jaime , Boltes Anunciación , Otermín Pilar , García‐Sánchez Carmen
Published: November 2003

Objective

To confirm that performance in verbal learning and memory test (Rey's Auditory Verbal Learning Test‐RAVLT) is a helpful early neuropsychological marker of dementia of Alzheimer's type (DAT).

Methods

RAVLT was administered as part of a more extensive neuropsychological battery at baseline evaluation in 116 unselected patients referred by subjective memory complaints (SMC). Patients were followed longitudinally for 2 years (average interval of 27.7±4 months). Seventy patients were included in the study: 27 developed probable DAT; 17 were diagnosed as cognitively normal persons and 26 were diagnosed with Mild Cognitive Impairment (MCI). Remaining patients abandoned or they did not meet the criteria for DAT, MCI or control. Performance on RAVLT at the baseline evaluation was compared between groups.

Results

Patients diagnosed two years later with probable DAT showed lower results, more frequently performed a score of zero at the delayed recall test (Trial 6) and had a percentage of forgetting (difference between Trials 5 and 6) higher than 75%. Score at delayed recall test and percentage of forgetting correlated with functional scales such as MMSE, Geriatric Depression Screening, Informant Questionnaire and Blessed's Dementia Rating.

Conclusions

RAVLT could help to identify those patients with SMC who would progress to DAT over a few years, and also to differentiate between the preclinical phase of Alzheimer's disease, mild cognitive impairment and normal aging. A score of zero at the delayed recall test or a percentage of forgetting ≥75% in patients with SMC is suggestive of probable DAT in the future. Copyright © 2003 John Wiley & Sons, Ltd.
Knowledge about symptoms of Alzheimer's disease: correlates and relationship to help‐seeking behavior
Authors: Werner Perla
Published: November 2003

Objective

The aim of this study was to assess relationships between knowledge about symptoms of Alzheimer's disease (AD) and help seeking intention among the lay public.

Design, setting and participants

A convenience sample of 150 community‐dwelling persons aged over 45, who did not have a close relative diagnosed with AD, participated in the study.

Measures

Knowledge about 11 warning signs of AD as described in the information provided by the Alzheimer's Association, and four non‐AD symptoms was assessed, together with intentions to seek help from professional and non‐professional sources. Background characteristics included socio‐demographic characteristics, personal experience with AD, and perceived threat.

Results

Although participants' knowledge about AD symptoms overall was fair, only a slight percentage reported memory problems to be symptoms of the disease. Participants differentiated between AD warning and non‐warning signs. Older participants reported consistently more AD and non‐AD symptoms, while higher concerns about developing the disease was associated with reporting more non‐AD symptoms. Higher knowledge about AD symptoms was associated with increased intentions to seek help from professional sources.

Conclusions

Efforts to increase knowledge about AD symptoms should be expanded, with special attention to risk groups. Improved recognition of AD symptoms will promote adequate help‐seeking behaviors and will increase early identification and treatment of AD. Copyright © 2003 John Wiley & Sons, Ltd.
Basal ganglia calcification and psychotic symptoms in the very old
Authors: Östling Svante , Andreasson Lars Arne , Skoog Ingmar
Published: November 2003

Background

Basal ganglia calcification (BGC) is associated with psychotic symptoms in young and middle‐aged patient samples.

Methods

We studied the cross‐sectional relationship between psychotic symptoms and BGC in a population sample of non‐demented 85‐year‐olds, of whom 86 were mentally healthy, 11 had hallucinations or delusions, 21 had mood disorders and 20 had anxiety disorders. BGC was measured using computerized tomography (CT). Mental disorders were diagnosed using DSM‐III‐R criteria and psychotic symptoms were evaluated using information from psychiatric examinations, key‐informant interviews and review medical records.

Results

BGC on CT was observed in 19% of mentally healthy and 64% of non‐demented individuals with hallucinations or delusions [Odds Ratio (OR) 7.7, 95% Confidence Intervals (CI) 2.9–29.7, p=0.003]. There were no associations between BGC and mood or anxiety disorders.

Conclusions

BGC is strongly associated with psychotic symptoms in very old age, possibly due to a disturbance in the basal ganglia dopaminergic system. Copyright © 2003 John Wiley & Sons, Ltd.
Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: A longitudinal, nested case‐control study in the Nordic countries
Authors: Tuohimaa Pentti , Tenkanen Leena , Ahonen Merja , Lumme Sonja , Jellum Egil , Hallmans Göran , Stattin Pär , Harvei Sverre , Hakulinen Timo , Luostarinen Tapio , Dillner Joakim , Lehtinen Matti , Hakama Matti
Published: November 2003

Vitamin D inhibits the development and growth of prostate cancer cells. Epidemiologic results on serum vitamin D levels and prostate cancer risk have, however, been inconsistent. We conducted a longitudinal nested case‐control study on Nordic men (Norway, Finland and Sweden) using serum banks of 200,000 samples. We studied serum 25(OH)‐vitamin D levels of 622 prostate cancer cases and 1,451 matched controls and found that both low (≤19 nmol/l) and high (≥80 nmol/l) 25(OH)‐vitamin D serum concentrations are associated with higher prostate cancer risk. The normal average serum concentration of 25(OH)‐vitamin D (40–60 nmol/l) comprises the lowest risk of prostate cancer. The U‐shaped risk of prostate cancer might be due to similar 1,25‐dihydroxyvitamin D3 availability within the prostate: low vitamin D serum concentration apparently leads to a low tissue concentration and to weakened mitotic control of target cells, whereas a high vitamin D level might lead to vitamin D resistance through increased inactivation by enhanced expression of 24‐hydroxylase. It is recommended that vitamin D deficiency be supplemented, but too high vitamin D serum level might also enhance cancer development. © 2003 Wiley‐Liss, Inc.
Constitutive activation of the androgen receptor by a point mutation in the hinge region: A new mechanism for androgen‐independent growth in prostate cancer
Authors: Céraline Jocelyn , Cruchant Marion D. , Erdmann Eva , Erbs Philippe , Kurtz Jean‐Emmanuel , Duclos Brigitte , Jacqmin Didier , Chopin Dominique , Bergerat Jean‐Pierre
Published: November 2003

Androgen receptor (AR) mutations that modify both the ligand binding and the transactivation capacities of the AR represent one of the mechanisms involved in the transition of prostate cancer (PCa) from androgen‐dependent to androgen‐independent growth. We use a yeast‐based functional assay to detect and analyze mutant ARs in PCa. We report the detection of 2 different mutant ARs within the same metastatic tumour sample harvested in a patient with advanced PCa who had escaped androgen deprivation. Concomitantly to the widely described T877A mutant AR, we identified an additional double mutant AR harboring the nonsense mutation Q640Stop just downstream the DNA binding domain together with the T877A point mutation. This type of mutation, which leads to a c‐terminal truncated AR, has not been described yet in PCa. Using luciferase reporter assays we demonstrated that this truncated AR exhibited constitutive transactivation properties. In conclusion, our data suggest that mutation‐induced constitutive activation of the AR could be a mechanism used by PCa cells to escape androgen deprivation. © 2004 Wiley‐Liss, Inc.
Geographic variation in Epstein‐Barr virus–associated Burkitt's lymphoma in children from Brazil
Authors: Klumb Claudete Esteves , Hassan Rocio , De Oliveira Deilson Elgui , De Resende Lídia Maria Magalhães , Carriço Maria Kadma , De Almeida Dobbin Jane , Pombo‐De‐Oliveira Maria S. , Bacchi Carlos E. , Maia Raquel Ciuvalschi
Published: November 2003

In developing countries, BL has a strong association with EBV infection during childhood. In South America, the data have shown an EBV association intermediate between that reported in the United States (30%) and that in equatorial Africa (95%). Early age at EBV infection and lower socioeconomic status have been related to increased EBV‐associated BL in developing countries. In Brazil, there are not enough data on childhood BL related to EBV infection. Our aim was to evaluate the clinicopathologic features and EBV association of 44 children with NHL from the state of Rio de Janeiro, situated in the southeast of Brazil. EBV was detected using RNA in situ hybridization in 36 biopsy specimens. DNA from fresh tumor samples and from paraffin‐embedded tissues of patients were analyzed by PCR, in which the first reaction included primers for an EBNA‐2 common region while the nested reaction amplified the region discriminating between EBV types 1 and 2 in separate reactions. EBV was detected in 21 of 29 BLs (72%), and type 1 virus infected the majority of EBV‐positive BLs (18/21). There was a trend for younger age in children with EBV‐positive BL compared to EBV‐negative BL (median age 4 compared to 6 years, respectively; p = 0.056). Our study confirmed that in the southeast of Brazil BL had an intermediate association with EBV. A higher rate of EBV‐associated BL was described in the northeast of Brazil. These differences are probably related to regional socioeconomic status. In conclusion, our study suggests that early infection with EBV in the background of a low socioeconomic condition associated with other environmental factors could contribute to BL in Brazil. © 2003 Wiley‐Liss, Inc.
Familial risk of cancer: Data for clinical counseling and cancer genetics
Authors: Hemminki Kari , Li Xinjun , Czene Kamila
Published: November 2003

Familial risks for cancer are important for clinical counseling and understanding cancer etiology. Medically verified data on familial risks have not been available for all types of cancer. The nationwide Swedish Family‐Cancer Database includes all Swedes born in 1932 and later (0–to 68‐year‐old offspring) with their parents, totaling over 10.2 million individuals. Cancer cases were retrieved from the Swedish Cancer Registry up to year 2000. Standardized incidence ratios (SIR) and 95% confidence limits (CI) were calculated for age‐specific familial risk in offspring by an exact proband status. The familial risks for offspring cancer were increased at 24/25 sites from concordant cancer in only the parent, at 20/21 sites from a sibling proband and at 12/12 sites from a parent and sibling proband. The highest SIRs by parent were for Hodgkin's disease (4.88) and testicular (4.26), non‐medullary thyroid (3.26), ovarian (3.15) and esophageal (3.14) cancer and for multiple myeloma (3.33). When a sibling was affected, even prostate, renal, squamous cell skin, endocrine, gastric and lung cancer and leukemia showed SIRs in excess of 3.00. The highest cumulative risks were found for familial breast (5.5%) and prostate (4.2%) cancers. We identified reliable familial risks for 24 common neoplasms, most of which lack guidelines for clinical counseling or action level. If, for example, a familial SIR of 2.2 would be use as an action level, counseling would be needed for most cancers at some diagnostic age groups. The present data provide the basis for clinical counseling. © 2003 Wiley‐Liss, Inc.
Inhibition of prostate cancer metastatic colonization by ∼4.2 Mb of human chromosome 12
Authors: Jaeger Erich B. , Chekmareva Marina A. , Tennant Thelma R. , Luu Hue H. , Hickson Jonathan A. , Chen Stephen L. , Samant Rajeev S. , Sokoloff Mitchell H. , Rinker‐Schaeffer Carrie W.
Published: November 2003

Our previous studies demonstrate that introduction of a ∼70 cM region (now estimated at 63.75 Mb by the Human Genome Project) of human chromosome 12 into the highly metastatic Dunning rat prostate cancer cell line AT6.1 results in >30‐fold (≥90%) reduction in the number of overt metastases in spontaneous metastasis assays. We report the further localization and biological characterization of the metastasis‐suppressor activity encoded by a reduced region of chromosome 12. To localize this metastasis‐suppressor activity, a panel of AT6.1 microcell hybrids that retain varying portions of human chromosome 12 was constructed and subjected to sequence‐tagged site (STS)‐based PCR analysis and assessment of in vivo metastatic ability. Data from these complementary approaches localized the metastasis‐suppressor activity to a ∼4.2 Mb portion of human chromosome 12q24.3 comprised of 3 separate regions. Reverse transcriptase‐polymerase chain reaction (RT‐PCR) and immunoblotting were used for differential expression analyses to identify which characterized genes, predicted gene sequences and expressed sequence tags (ESTs) within this region could be responsible for the observed metastasis suppression. Comprehensive in vivo studies showed that suppressed AT6.1‐12 hybrids that retain the metastasis‐suppressor region on 12q24.3 are capable of arriving at the secondary site, but are not able to persist there. Thus, unlike other metastasis‐suppressor genes characterized to date, the metastasis‐suppressor gene encoded by this region appears to utilize a different biologic mechanism to suppress the growth of overt metastases at the secondary site. © 2003 Wiley‐Liss, Inc.
Clusterin (SGP‐2, ApoJ) expression is downregulated in low‐ and high‐grade human prostate cancer
Authors: Scaltriti Maurizio , Brausi Maurizio , Amorosi Andrea , Caporali Andrea , D'Arca Domenico , Astancolle Serenella , Corti Arnaldo , Bettuzzi Saverio
Published: November 2003

Clusterin is overexpressed during tissue and cell involution and downregulated in proliferating cells. Its role in cell survival, cell death and neoplastic transformation remains debated. We studied the expression and distribution of clusterin mRNA and protein in human prostate carcinoma (CaP) specimens of different degrees of malignancy. Fresh CaP specimens were obtained from 25 patients subjected to long‐term androgen ablation before surgery. Clusterin expression was studied by Northern and Western analysis, in situ hybridization and immunohistochemistry, in comparison with Gas1 and histone H3 mRNA (markers of cell quiescence and S phase of the cell cycle, respectively). Clusterin is downregulated in CaP in comparison with matched benign controls. In low‐grade CaP, clusterin colocalized with Gas1 to the stromal compartment, and in some glands, the basal lamina was heavily stained. In high‐grade CaP clusterin stained the remnants of stromal matrix while histone H3 localized to cancer cells, which were very rarely clusterin positive. High clusterin expression was found in the branches of a nerve infiltrated by tumor. The periglandular clusterin expression found in low‐grade CaP could result from induction of quiescence and/or apoptosis of prostatic fibroblasts lining those glands in which tumor invasion is at an initial stage, involving basal lamina. In advanced CaP, the staining of the remnants of the extracellular matrix suggests a role for clusterin in the process of dismantling the stromal organization caused by cancer progression. © 2003 Wiley‐Liss, Inc.
Small interfering RNA (siRNA) inhibits the expression of the Her2/neu gene, upregulates HLA class I and induces apoptosis of Her2/neu positive tumor cell lines
Authors: Choudhury Aniruddha , Charo Jehad , Parapuram Sunil K. , Hunt Richard C. , Hunt D. Margaret , Seliger Barbara , Kiessling Rolf
Published: November 2003

Silencing of a specific mRNA using double stranded RNA oligonucleotides represents one of the newest technologies for suppressing a specific gene product. Small interfering RNA (siRNA) are 21 nucleotides long, double stranded RNA fragments that are identical in sequence to the target mRNA. We designed 3 such siRNA against the Her2/neu (HER2) gene. The HER2 gene is known to play an important role in the oncogenesis of several types of cancers, such as breast, ovarian, colon and gastric cancers. Introduction of the siRNA into HER2 positive tumor lines in vitro greatly reduced the cell surface expression of the HER2 protein. Concurrently, a range of effects on cell physiology, such as growth inhibition or apoptosis, was observed. The expression of HLA class I was observed to be upregulated when HER2 was silenced with siRNA. Treatment of SKBr3 and MCF7/HER2 tumor cell lines with the HER2 siRNA resulted in growth arrest of cells in the late G1/S‐phase. Our results suggest that siRNA may be an effective method of abrogating the effect of HER2 in tumorigenesis. © 2003 Wiley‐Liss, Inc.
Tenascin‐C regulates angiogenesis in tumor through the regulation of vascular endothelial growth factor expression
Authors: Tanaka Keiichiro , Hiraiwa Noriko , Hashimoto Hisashi , Yamazaki Yoji , Kusakabe Moriaki
Published: November 2003

In order to verify whether tenascin‐C (TN‐C) is involved in angiogenesis as an extracellular signal molecule during tumorigenesis, cancerous cell transplantation experiments and coculture experiments were carried out, focusing on the regulation of vascular endothelial growth factor (VEGF). The A375 human melanoma cells introduced the GFP gene (A375‐GFP), implanted subcutaneously into BALB/cA nude (WT) and TN‐C knockout BALB/cA nude (TNKO) congenic mice. Furthermore, coculture experiments between A375‐GFP and embryonic mesenchyme, which was prepared from both genotypes, were carried out to investigate the molecular mechanism in the cell‐cell interactions. Both the content of TN‐C and that of VEGF in the tumor and the conditioned medium were analyzed by the sandwich ELISA method. Seven days after transplantation of the A375‐GFP, capillary nets became far more abundant in the tumors grown in WT mice than those in TNKO mice. Interestingly, VEGF and TN‐C expressions showed antithetical expression patterns between the tumors in WT mice and those in TNKO mice. This peculiar phenomenon seems to be caused by a time lag prior to the onset of the mesenchymal regulation for the TN‐C expression of A375‐GFP. The coculture experiments revealed that WT mesenchyme had a much stronger effect than TNKO mesenchyme on both TN‐C and VEGF expression. However, the defects of TNKO mesenchyme were restored in all cases by additional TN‐C. These results clearly indicated that the expressions of both TN‐C and VEGF depend on the surrounding mesenchyme, and that the function of mesenchyme is regulated by its own mesenchymal TN‐C. In conclusion, the present data suggest that the matrix microenvironment organized by the host mesenchyme is very important for angiogenesis in tumor development. © 2003 Wiley‐Liss, Inc.
Detecting lung cancer in plasma with the use of multiple genetic markers
Authors: Andriani Francesca , Conte Davide , Mastrangelo Tiziana , Leon MariaElena , Ratcliffe Cathy , Roz Luca , Pelosi Giuseppe , Goldstraw Peter , Sozzi Gabriella , Pastorino Ugo
Published: November 2003

Recent studies have demonstrated the possibility to detect genetic changes in plasma DNA of cancer patients. The goal of this study was to validate a panel of molecular markers for lung cancer detection in plasma DNA. Three markers, p53, FHIT and microsatellite alterations at loci on chromosome 3, were used to detect mutations in tumor and plasma DNA of 64 stage I–III non small cell lung cancer patients. p53 mutations were studied by direct sequencing of exons 5 through 8 in tumor DNA and by plaque hybridization assay and sequencing in plasma DNA. Allelic losses were evaluated by fluorescent PCR in tumor and plasma DNA. p53 genomic mutations were detected in 26 (40.6%) of 64 tumor DNA samples and the identical mutation was identified in plasma of 19 (73.1%) of them. Microsatellite alterations at FHIT and 3p loci were observed in 40 (62.5%) tumors and in 23 (35.9%) plasma samples. Of the 40 patients showing microsatellite alterations in tumors, 19 (47.5%) displayed the same change in plasma DNA. At least 1 of the 3 genetic markers (p53, FHIT and 3p) was altered in plasma of 51.6% of all patients and 60.7% of stage I patients. Moreover, genetic markers in plasma identified 29 of 45 (64.4%) of all stages and 15 of 22 (68.2%) of stage I patients whose tumors had an alteration. These results provide the proof of principle that plasma DNA alterations are tumor‐specific in most cases and support blood testing as a noninvasive strategy for early detection. © 2003 Wiley‐Liss, Inc.
Reversal of breast cancer resistance protein (BCRP/ABCG2)‐mediated drug resistance by novobiocin, a coumermycin antibiotic
Authors: Shiozawa Ken , Oka Mikio , Soda Hiroshi , Yoshikawa Megumi , Ikegami Yoji , Tsurutani Junji , Nakatomi Katsumi , Nakamura Yoichi , Doi Seiji , Kitazaki Takeshi , Mizuta Yohei , Murase Kunihiko , Yoshida Hisahiro , Ross Douglas D. , Kohno Shigeru
Published: November 2003

Breast cancer resistance protein (BCRP/ABCG2) of an ATP‐binding cassette half‐transporter confers resistance against mitoxantrone and camptothecin derivatives of topotecan and irinotecan. Novobiocin, a coumermycin antibiotic, is known to enhance anticancer drug sensitivity of cancer cells in vitro and in vivo, the mechanism of which remains undetermined. Here we focused on drug efflux pump and examined whether novobiocin reversed drug resistance in multidrug‐resistant cells highly expressing BCRP. To explore the reversal mechanisms, intracellular drug accumulation was measured by flow cytometry, and a topotecan transport study using plasma membrane vesicles was performed. We used PC‐6/SN2‐5H2 small cell lung cancer and MCF‐7/MX breast cancer cells selected with SN‐38 of the active irinotecan metabolite and mitoxantrone, respectively, and the BCRP cDNA transfectant MCF‐7/clone 8 cells. These cells expressed high levels of BCRP mRNA but not other known transporters. Compared to the parental PC‐6 cells, PC‐6/SN2‐5H2 cells were 141‐, 173‐ and 57.2‐fold resistant to topotecan, SN‐38 and mitoxantrone, respectively. Novobiocin at 60 μM decreased the degree of the above resistance by approximately 26‐fold in PC‐6/SN2‐5H2 cells, and similarly reversed resistance in MCF‐7/MX, MCF‐7/clone 8 and un‐selected NCI‐H460 cells highly expressing BCRP. Furthermore, novobiocin increased the intracellular topotecan accumulation in these cells and inhibited the topotecan transport into the membrane vesicles of PC‐6/SN2‐5H2 cells. No effects of novobiocin in these assay were observed in the parental PC‐6 and MCF‐7 cells. The kinetic parameters in the transport study indicated that novobiocin was a inhibitor for BCRP, resulting in competitive inhibition of BCRP‐mediated topotecan transport. These findings suggest that novobiocin effectively overcomes BCRP‐mediated drug resistance at acceptable concentrations. © 2004 Wiley‐Liss, Inc.
Combined inhibition of estrogen‐dependent human breast carcinoma by soy and tea bioactive components in mice
Authors: Zhou Jin‐Rong , Yu Lunyin , Mai Zhiming , Blackburn George L.
Published: November 2003

Breast cancer is significantly less prevalent among Asian women, whose diets contain high intake of soy products and tea. The objective of our present study was to identify the combined effects of dietary soy phytochemicals and tea components on breast tumor progression in a clinically relevant in vivo model of MCF‐7 androgen‐dependent human breast tumor in female SCID mice. MCF‐7 tumor growth, tumor cell proliferation and apoptosis, microvessel density, and expressions of tumor estrogen receptors were compared in mice treated with genistin‐rich soy isoflavones (GSI), soy phytochemical concentrate (SPC), black tea (BT), green tea (GT), SPC/BT combination and SPC/GT combination. GSI and SPC led to dose‐dependent inhibition of MCF‐7 tumor growth via inhibition of cancer cell proliferation in vivo. GT showed more potent anti‐breast tumor activity than BT. GT infusion at 1.5 g tealeaf/100 mL water produced significant (p < 0.05) reductions of 56% in final tumor weight. GT plus SPC at 0.1% of the diet further reduced final tumor weight by 72% (p < 0.005). Analysis of serum and tumor biomarkers showed that the combined effects of SPC and GT inhibited tumor angiogenesis, and reduced estrogen receptor (ER)‐α and serum levels of insulin‐like growth factor (IGF)‐I. Our study suggests that dietary SPC plus GT may be used as a potential effective dietary regimen for inhibiting progression of estrogen‐dependent breast cancer. © 2003 Wiley‐Liss, Inc.
Alterations of ΔTA‐p 73 splice transcripts during melanoma development and progression
Authors: Tuve Sebastian , Wagner Stephan N. , Schittek Birgit , Pützer Brigitte M.
Published: November 2003

In the last 2 years, it has become apparent that the p53‐family members p53 and p73 play fundamentally different roles in human malignancies. In contrast to p53, many studies on cancer patients failed to detect mutational inactivation of p73 and reported overexpression of wild‐type p73 instead. A possible explanation was provided by the recent discovery of N‐terminal truncated isoforms of p73 (ΔTA‐p73) that act as dominant‐negative inhibitors of wild‐type p53 and TA‐p73 and result in tumor growth in nude mice. We investigated the role of ΔTA‐p73 in the development and progression of human melanomas, which lack p53 mutations. We analyzed 8 benign melanocytic nevi, 8 primary melanomas and 19 melanoma metastases for alterations of TA‐p73 and ΔTA‐p73 expression using isoform‐specific real‐time RT‐PCR. Based on our results, p73Δex2 and Δex2/3 spliced transcripts derived from the first promoter were significantly up‐regulated in melanoma metastases, whereas ΔN‐p73 generated from the second promoter was the predominant isoform in benign nevi. Moreover, increased expression of p73Δex2 and p73Δex2/3 correlated with high‐levels of both TA‐p73 and E2F1. Our data suggest a potential function of ΔTA‐p73 splice isoforms in melanoma progression. © 2003 Wiley‐Liss, Inc.