bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of the neural RNA‐binding protein Musashi1 in human gliomas
Authors: Toda Masahiro , Iizuka Yukihiko , Yu Wangjie , Imai Takao , Ikeda Eiji , Yoshida Kazunari , Kawase Takeshi , Kawakami Yutaka , Okano Hideyuki , Uyemura Keiichi
Published: August 2002

Tumor cells arising from a particular tissue may exhibit the same gene expression patterns as their precursor cells. To test this proposition, we have analyzed the expression of a neural RNA‐binding protein, Musashi1, in primary human central nervous system (CNS) tumors. In rodents, Musashi1 is expressed predominantly in proliferating multipotent neural precursor cells, but not in newly generated postmitotic neurons. The expression of Musashi1 is downregulated with the successive progression of neurogenesis. In normal adult human tissues, we detected low levels of Musashi1 expression in brain and testis by RT‐PCR analysis. In an RNA panel of 32 cancer tissues and cell lines, elevated expression of Musashi1 was seen in all five malignant gliomas studied, in contrast to the slight expression seen in other tumor cells, including those in several melanomas and a prostate cancer. Western blot analysis showed strong Musashi1 expression in malignant gliomas compared with nonneoplastic brain tissue. Glioblastomas, the most malignant form of glioma, showed higher Musashi1 expression than less malignant gliomas by immunohistochemical analysis. Tumors with strong Musashi1 expression tended to have high proliferative activity. Thus, the expression of Musashi1 correlated with the grade of the malignancy and proliferative activity in gliomas. These results suggest that primary CNS tumors may share gene expression patterns with primitive, undifferentiated CNS cells and that Musashi1 may be a useful marker for the diagnosis of CNS tumors. GLIA 34:1–7, 2001. © 2001 Wiley‐Liss, Inc.
Pigment epithelium‐derived factor supports normal Müller cell development and glutamine synthetase expression after removal of the retinal pigment epithelium
Authors: Jablonski Monica M. , Tombran‐Tink Joyce , Mrazek David A. , Iannaccone Alessandro
Published: August 2002

In conditions in which the retinal pigment epithelium (RPE) is dystrophic, carries a genetic mutation, or is removed physically, Müller cells undergo degenerative changes that contribute to the retinal pathology. We previously demonstrated that pigment epithelium‐derived factor (PEDF), a glycoprotein secreted by the RPE cells with neuroprotective and differentiation properties, protects against photoreceptor degeneration induced by RPE removal. The purpose of the present study was to analyze the putative gliosupportive activity of PEDF on Müller cells of RPE‐deprived retinas and assess whether protection of Müller cells was correlated with improved photoreceptor outer segment assembly. Eyes were dissected from Xenopus laevis tadpoles, and the RPE was removed before culturing in medium containing purified PEDF, PEDF plus anti‐PEDF, or medium alone. Control eyes matured with an adherent RPE or in medium containing PEDF plus nonimmune serum. Müller cell ultrastructure was examined. Glial fibrillary acidic protein (GFAP) and glutamine synthetase were localized immunocytochemically, and the corresponding protein levels were quantified. In control retinas, Müller cells were structurally intact and formed adherens junctions with neighboring photoreceptors. In addition, they did not express GFAP, whereas glutamine synthetase expression was high. RPE removal dramatically altered the ultrastructure and biosynthetic activity of Müller cells; Müller cells failed to form adherens junctions with photoreceptors and glutamine synthetase expression was suppressed. PEDF prevented the degenerative glial response; Müller cells were ultrastructurally normal and formed junctional complexes with photoreceptors. PEDF also preserved the expression of glutamine synthetase at near‐normal levels. The morphogenetic effects of PEDF were blocked by the anti‐PEDF antibody. Our study documents the glioprotective effects of PEDF and suggests that maintenance of the proper Müller cell ultrastructure and expression of glutamine synthetase may be necessary to support the proper assembly of photoreceptor outer segments. GLIA 35:14–25, 2001. © 2001 Wiley‐Liss, Inc.
A role for oligodendrocyte‐derived IGF‐1 in trophic support of cortical neurons
Authors: Wilkins Alastair , Chandran Siddharthan , Compston Alastair
Published: August 2002

Neurons and glia interact in the development of mammalian central nervous systems and in the maintenance of stable myelinated axons. Recent evidence suggests a role for oligodendrocytes in providing trophic support for neurons during development and in the mature nervous system. This work prompted us to study oligodendrocyte influences on neuronal survival and death in vitro. Rat embryonic cortical neurons were co‐cultured with purified oligodendrocytes at different developmental stages and separately with oligodendrocyte‐conditioned medium. Neuronal survival was measured by immunocytochemistry and3H‐GABA uptake. Neurons show a marked increase in survival when co‐cultured directly with oligodendrocyte precursors (OPCs) and differentiated oligodendrocytes. Neurons cultured in the presence of OPCs separated by a permeable membrane and those cultured in medium conditioned by oligodendrocytes also show a significant increase in survival. Medium conditioned by differentiated oligodendrocytes provides a greater survival effect than medium conditioned by OPCs. Neutralising antibodies to IGF‐1, but not to other candidate trophic factors, block the soluble survival effect of oligodendrocytes. Cells of the oligodendrocyte lineage produce IGF‐1 and recombinant IGF‐1 promotes neuronal survival under identical conditions. This study provides evidence that OPCs and differentiated oligodendrocytes support neuronal survival by both contact‐mediated and soluble mechanisms and that IGF‐1 significantly contributes to this effect. GLIA 36:48–57, 2001. © 2001 Wiley‐Liss, Inc.
Malignant glioma cells use MHC class II transactivator (CIITA) promoters III and IV to direct IFN‐γ‐inducible CIITA expression and can function as nonprofessional antigen presenting cells in endocytic processing and CD4+ T‐cell activation
Authors: Soos Jeanne M. , Krieger Jeffrey I. , Stüve Olaf , King Chelsea L. , Patarroyo Juan Carlos , Aldape Ken , Wosik Karolina , Slavin Anthony J. , Nelson Patricia A. , Antel Jack P. , Zamvil Scott S.
Published: August 2002

Malignant gliomas (MGs), lethal human central nervous system (CNS) neoplasms, contain tumor infiltrating lymphocytes (TIL). Although MHC class II molecules are frequently detected on MG cells, suggesting that they may be capable of antigen (Ag) presentation to CD4+ T cells, deficiencies in CD4+ T‐cell activation are associated with these nonimmunogenic tumors. We evaluated regulation of the MHC class II transactivator (CIITA), the key intermediate that controls class II expression, in MG cells and tested whether MG cells could process native Ag. After interferon‐γ (IFN‐γ) stimulation, MG cells upregulated CIITA and class II molecules. IFN‐γ‐inducible CIITA expression in MG cells, as well as primary human astrocytes, was directed by two CIITA promoters, pIV, the promoter for IFN‐γ‐inducible CIITA expression in nonprofessional antigen‐presenting cells (APC), and pIII, the promoter that directs constitutive CIITA expression in B cells. Both pIII and pIV directed CIITA transcription in vivo in MGs and ex vivo in IFN‐γ‐activated primary MG cultures. We also demonstrate for the first time that MG cells can process native Ag for presentation to CD4+ MHC class II‐restricted Th1 cells, indicating that MG cells can serve as nonprofessional APC. CIITA may be a key target to modulate MHC class II expression, which could augment immunogenicity, Ag presentation, and CD4+ T‐cell activation in MG therapy. GLIA 36:391–405, 2001. © 2001 Wiley‐Liss, Inc.
Assessment of dementia in nursing home residents by nurses and assistants: criteria validity and determinants
Authors: Sørensen Lisbeth , Foldspang Anders , Gulmann Nils Christian , Munk‐Jørgensen Povl
Published: August 2002

Objectives

To describe the criterion validity of nursing home staff's assessment of organic disorder compared with ICD‐10 criteria, and to identify determinants of staff assessment of organic disorder.

Method

Two hundred and eighty‐eight residents were diagnosed using the GMS‐AGECAT. Nursing staff members were interviewed about the residents' activities of Daily Living, behavioural problems, orientation in surroundings and communication skills, and asked if the resident had an organic disorder. Multiple logistic regression was used to select the items that most strongly determined staff assessment of organic disorder.

Results

Sixty‐two per cent of the residents were diagnosed by GMS‐AGECAT as having organic disorder, 78% of these were correctly identified by the staff. Whether analysed among residents with or without organic disorder, or in the total group of residents, the staff assessment of the presence of organic disorder depended on a limited set of behavioural characteristics of the resident, namely ‘going to the toilet in inappropriate places’, ‘saying things that do not make sense’ and impairment in orientation.

Conclusions

Staff comprehension of organic disorder resulted in over‐ as well as under‐labelling of residents, a tendency that will affect communication with medical personnel and may lead to inadequate or wrong medical treatment and to negative performance as well as negative role expectations in everyday life in nursing homes. Copyright © 2001 John Wiley & Sons, Ltd.
Psychotropic drug use in elderly people with and without dementia
Authors: Giron Maria Stella T. , Forsell Yvonne , Bernsten Cecilia , Thorslund Mats , Winblad Bengt , Fastbom Johan
Published: August 2002

Objective

To determine the prevalence of psychotropic drug use in very old persons with and without dementia in two time periods, and describe the patterns of psychotropic drug use between institutions and non‐institutions.

Methods

Descriptive analysis on a sample of subjects aged 81+ from a population‐based study in Stockholm, Sweden. Psychotropic drug use data were collected from the 1987–1989 and 1994–1996 periods of the study. The diagnosis of dementia was based on the DSM III‐R.

Results

About 41% of the subjects used at least one psychotropic drug in both periods. Women and subjects in institutions more commonly used psychotropic drugs. The most commonly reported were, in rank order, hypnotics‐sedatives, anxiolytics, antipsychotics and antidepressants. Hypnotics‐sedatives and anxiolytics were the most commonly used in both institutions and non‐institutions. More persons with dementia used psychotropic drugs in both periods. The use of newer drugs, for example, SSRI, was evident. Multivariate analyses showed increased risk for psychotropic drug use among subjects in institutions.

Conclusions

This study confirms the high rate of psychotropic drug use in the very old, particularly in persons with dementia. Psychotropic drug use was high among subjects living in institutions. Copyright © 2001 John Wiley & Sons, Ltd.
Depression and anxiety disorders among Jews from the former Soviet Union five years after their immigration to Israel
Authors: Zilber Nelly , Lerner Yaakov , Eidelman Raphael , Kertes Jenny
Published: August 2002

Background

Epidemiological studies have shown that the prevalence rates of major depression and anxiety are lower in the elderly than in younger adults. In a recent survey, we found, among immigrants, that the association of age with psychological distress was the reverse.

Objective

The objective of the present study was to examine, among immigrants, whether the relationship of age with clinically diagnosed depression and anxiety disorders is also reversed. This was done by assessing the age‐specific incidence and prevalence of depression and anxiety among immigrants from the former Soviet Union to Israel five years after their immigration.

Methods

A stratified subsample was chosen from a larger random sample of immigrants from the Former Soviet Union who arrived in Israel in 1990. We selected the subsample to include an over‐representation of those with a high level of distress in order to increase the probability of finding people suffering from psychopathology. The subjects were interviewed with a diagnostic instrument, the CIDI‐S, an abbreviated version of the CIDI. Prevalence and incidence rates of depression and anxiety were calculated separately for two age groups (those below age 65 and those aged 65 and above).

Results

Before immigration, incidence rates were lower among the elderly than among younger adults, a finding consistent with the literature. However, after immigration, the reverse was found, with higher prevalence and incidence rates among elderly immigrants.

Conclusion

The data suggest that immigration contributes to an increase of psychopathology which is particularly pronounced among the elderly. Copyright © 2001 John Wiley & Sons, Ltd.
Differences in auditory processing of words and pseudowords: An fMRI study
Authors: Newman Sharlene D. , Twieg Donald
Published: August 2002

Although there has been great interest in the neuroanatomical basis of reading, little attention has been focused on auditory language processing. The purpose of this study was to examine the differential neuroanatomical response to the auditory processing of real words and pseudowords. Eight healthy right‐handed participants performed two phoneme monitoring tasks (one with real word stimuli and one with pseudowords) during a functional magnetic resonance imaging (fMRI) scan with a 4.1 T system. Both tasks activated the inferior frontal gyrus (IFG), the posterior superior temporal gyrus (pSTG) and the inferior parietal lobe (IPL). Pseudoword processing elicited significantly more activation within the posterior cortical regions compared with real word processing. Previous reading studies have suggested that this increase is due to an increased demand on the lexical access system. The left inferior frontal gyrus, on the other hand, did not reveal a significant difference in the amount of activation as a function of stimulus type. The lack of a differential response in IFG for auditory processing supports its hypothesized involvement in grapheme to phoneme conversion processes. These results are consistent with those from previous neuroimaging reading studies and emphasize the utility of examining both input modalities (e.g., visual or auditory) to compose a more complete picture of the language network. Hum. Brain Mapping 14:39–47, 2001. © 2001 Wiley‐Liss, Inc.
C‐phosphorylation of 1,2,4‐triazoles with phosphorus(III) halides. Synthesis of 4,5‐dihydrobenzo[e][1,2,4]triazolo[5,1‐c][1,4,2]diazaphosphinine derivatives
Authors: Zarudnitskii Evgenij V. , Ivanov Vladimir V. , Yurchenko Alexandr A. , Pinchuk Alexandr M. , Tolmachev Andrej A.
Published: August 2002

Phosphorylation of 4‐ and 1‐substituted 1,2,4‐triazoles with PCl3, PhPCl2, Ph2PCl, and (Et2N)2 PCl was carried out. A novel phosphorus‐containing condensed heterocyclic system (18, 23) was constructed by the reactions of 2‐(1H‐1,2,4‐triazol‐1‐yl)‐1‐(4‐chlorophenylcarboxamido)‐5‐trifluoromethylbenzene with PBr3 and PhPBr2. Treatment of the bromophosphonite 18 with an excess of morpholine in the presence of sulfur resulted in a diazaphosphinine ring opening and provided functionalized 1H‐1,2,4‐triazol‐5‐ylphosphonic acid derivatives 21 and 22. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:146–152, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10010
Synthesis and metal transport ability of a new series of thiamacrocycles containing thiol and disulfide groups inside the ring
Authors: Nabeshima Tatsuya , Aoki Taizo , Haruyama Tsutomu , Shinnai Toshinobu , Ohshiro Hideaki , Saiki Toshiyuki , Yano Yumihiko
Published: August 2002

Synthetic methods for thiamacrocycles containing two thiol groups or a disulfide linkage and their abilities to effect single heavy‐metal‐ion transport across a liquid membrane were examined. High Ag+ selectivity was accomplished by the thiol or disulfide hosts, although all the corresponding crown ether analogs bearing a disulfide group showed no Ag+ selectivity. The difference of the transport preferences among the thiacrown ethers prepared here is considered to be reflected by the position and the number of the sulfur atoms ligating to Ag+ and the cavity size of the hosts. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:276–281, 2001
Reaction of 2‐amino‐3‐cyano‐4,5,6,7‐tetrahydrobenzo‐[b]thiophene with ethyl acetoacetate: Novel syntheses of pyridines, pyrazoles, and their fused derivatives
Authors: Mohareb Rafat M. , Mohamed Mona H.
Published: August 2002

The reaction of 2‐amino‐3‐cyano‐4,5,6,7‐tetrahydrobenzo[b]thiophene 1 with ethyl acetoacetate 2 gave compound 3. The reactivity of the latter product toward a variety of chemical reagents was studied to give fused thiophene derivatives of potential pharmaceutical interest. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:518–527, 2001
Reversible C ⇆ N migration of the ethoxycarbonyl group in the reactions of pyridinium and isoquinolinium ylides derived from malonic ester with isocyanates
Authors: Gololobov Yuri G. , Dovgan Olga V. , Golding Igor R. , Petrovskii Pavel V. , Garbuzova Irina A.
Published: August 2002

Pyridinium and isoquinolinium ylides (7 and 12) derived from malonic ester react in an unusual manner with isocyanates giving the new pyridinium ylide (9) and the new isoquinolinium ylide (14). C → N Migration of the COOEt group takes place at room temperature, but, at an elevated temperature, reverse N → C migration of the COOEt group proceeds and ylides 9 and 14 are reconverted into the starting ylides 7 and 12, respectively. © 2002 John Wiley & Sons, Inc. Heteroatom Chem 13:36–45, 2002; DOI 10.1002/hc.1104
Radiotherapy for carcinoma in situ of the true vocal cords
Authors: Garcia‐Serra Allie , Hinerman Russell W. , Amdur Robert J. , Morris Christopher G. , Mendenhall William M.
Published: August 2002

Purpose

To report long‐term rates of tumor control after radiotherapy (RT) for carcinoma in situ (CIS) of the true vocal cords (TVC). A comprehensive literature review was performed, and outcomes with other modalities of treatment for CIS of the TVC were compared.

Materials and Methods

Thirty patients with CIS of the TVC were treated between July 1967 and May 1998 with curative intent using megavoltage RT. Most patients (28 of 30) were treated with cobalt‐60 through small (usually 5 × 5 cm) fields. Median RT dose was 56.25 Gy (range, 56.25–75 Gy; mean dose, 59.15 Gy) at 2.25 Gy per fraction. One patient was treated for a synchronous head and neck primary malignancy with large fields to a total dose of 75 Gy at 1.8 Gy per fraction. Approximately two thirds of the patients (19 of 30) were referred for RT because of recurrence after at least one stripping procedure.

Results

With a mean follow‐up of 7.1 years (range, 2–17 years), the 5‐year rates of local control, local control with larynx preservation, and ultimate local control (including salvage surgery) were the following: 88%, 88%, and 100%, respectively. Invasive squamous cell carcinoma developed in three (10%) of the patients. Time to failure was 14 months, 34 months, and 48 months, respectively. All three patients were surgically salvaged with a total laryngectomy. Cause‐specific survival at 5 years was 100%. There were no late complications.

Conclusions

RT to approximately 60 Gy at 2.25 Gy per fraction using small (5 × 5 cm) fields produces excellent results with CIS of the TVC. © 2002 Wiley Periodicals, Inc. Head Neck 24: 390–394, 2002; DOI 10.1002/hed.10071
Prognostic significance of Bcl‐2 and p53 expression in advanced laryngeal squamous cell carcinoma
Authors: Friedman Michael , Lim Jessica W. , Manders Ernie , Schaffner Adam D. , Kirshenbaum Gary L. , Tanyeri Hasan M. , Caldarelli David D. , Coon John S.
Published: August 2002

Background

Proteins regulating the cell cycle and cell death are frequently abnormally expressed in cancer. Several of these, particularly p53 and Bcl‐2, have been widely suggested as possible prognostic markers in diverse human malignancies. Their role in predicting outcome in squamous cell carcinomas of the head and neck is unclear and may depend on the location, stage, and treatment of the tumor.

Methods

To assess this question specifically for advanced squamous cell carcinoma of the larynx, we studied 69 patients with stage III or IV tumors, all but 6 of whom were treated with surgery plus postoperative irradiation by a single physician. We studied the patients retrospectively to test the association between expression of Bcl‐2 and p53, as assessed by immunohistochemistry, with treatment outcome and survival.

Results

Twenty of the 69 patients died from their tumor (poor outcome); the rest were alive and tumor free at the last follow‐up or died of unrelated causes without clinical tumor recurrence (good outcome). Fourteen tumors had detectable Bcl‐2 expression, including 8 scored as overexpressors. Thirty‐nine tumors overexpressed p53. Expression of neither Bcl‐2 nor p53 was associated with outcome, overall survival, or disease‐free survival. Only tumor stage was significantly associated with outcome and disease‐free survival.

Conclusion

These data indicate that assessing expression of p53 or Bcl‐2 is unlikely to be prognostically useful for surgically treated advanced laryngeal carcinoma. © 2001 John Wiley & Sons, Inc. Head Neck 23: 280–285, 2001.
The buccal fat pad flap in oral reconstruction
Authors: Dean Alicia , Alamillos Francisco , García‐López Alicia , Sánchez Juan , Peñalba Manuel
Published: August 2002

Background

The aim of this study is to describe the surgical technique, indications, advantages, and possible complications of the buccal fat pad flap and to report our clinical experience with this flap for intraoral reconstruction after tumor removal.

Methods

The flap has been used to reconstruct oral defects after tumor resection in 32 patients, who have been retrospectively analyzed.

Results

Adequate closure of the defect was achieved during surgery in all cases. In one case, there was partial loss of the flap; this was treated conservatively. In five cases there was some retraction in the reconstructed area.

Conclusions

Buccal fat pad as a flap offers an adequate reconstructive option to be born in mind when reconstructing small to medium defects in the oral cavity. It is a simple and quick surgical technique with a low incidence of complications. © 2001 John Wiley & Sons, Inc. Head Neck 23: 383–388, 2001.
Is mossy fiber sprouting present at the time of the first spontaneous seizures in rat experimental temporal lobe epilepsy?
Authors: Nissinen Jari , Lukasiuk Katarzyna , Pitkänen Asla
Published: August 2002

The contribution of mossy fiber sprouting to the generation of spontaneous seizures in the epileptic brain is under dispute. The present study addressed this question by examining whether sprouting of mossy fibers is present at the time of appearance of the first spontaneous seizures in rats, and whether all animals with increased sprouting have spontaneous seizures. Epileptogenesis was induced in 16 rats by electrically stimulating the lateral nucleus of the amygdala for 20–30 min until the rats developed self‐sustained status epilepticus (SSSE). During and after SSSE, rats were monitored in long‐term by continuous video‐electroencephalography until they developed a second spontaneous seizure (8–54 days). Thereafter, monitoring was continued for 11 days to follow seizure frequency. The density of mossy fiber sprouting was analyzed from Timm‐stained preparations. The density of hilar neurons was assessed from thionin‐stained sections. Of 16 rats, 14 developed epilepsy. In epileptic rats, the density of mossy fiber sprouting did not correlate with the severity or duration (115–620 min) of SSSE, delay from SSSE to occurrence of first (8–51 days) or second (8–54 days) spontaneous seizure, or time from SSSE to perfusion (20–63 days). In the temporal end of the hippocampus, the sprouting correlated with the severity of neuronal damage (ipsilateral: r = −0.852, P < 0.01 contralateral: r = −0.748, P < 0.01). The two animals without spontaneous seizures also had sprouting. Increased density of sprouting in animals without seizures, and its association with the severity of neuronal loss was confirmed in another series of 30 stimulated rats that were followed‐up with video‐EEG monitoring for 60 d. Our data indicate that although mossy fiber sprouting is present in all animals with spontaneous seizures, its presence is not necessarily associated with the occurrence of spontaneous seizures. Hippocampus 2001;11:299–310. © 2001 Wiley‐Liss, Inc.
Crafting a Human Resource Strategy to Foster Organizational Agility: A Case Study
Authors: Shafer Richard A. , Dyer Lee , Kilty Janine , Amos Jeff , Ericksen Jeff
Published: August 2002

A decade ago, the Chief Executive Officer of Albert Einstein Healthcare Network (AEHN), anticipating
a tumultuous and largely unpredictable period in its industry, undertook to convert this organization from one
that was basically stable and complacent to one that was agile, “nimble, and change‐hardy”.
This case study, while briefly addressing AEHN's approaches to business strategy and organization design,
focuses primarily on the human resource strategy that emerged over time to foster the successful attainment of
organizational agility. Although exploratory, the study suggests a number of lessons for those who are—or
will be—studying or trying to create and sustain this promising new organizational paradigm. © 2001
John Wiley & Sons, Inc.
A simple model of hillslope response for overland flow generation
Authors: Agnese Carmelo , Baiamonte Giorgio , Corrao Cecilia
Published: August 2002

This paper deals with the derivation of the hydrological response of a hillslope on the assumption of quick runoff by surface runoff generation. By using the simple non‐linear storage based model, first proposed by Horton, an analytical solution of the overland flow equations over a plane hillslope was derived. This solution establishes a generalization for different flow regimes of Horton's original solution, which is valid for the transitional flow regime only. The solution proposed was compared successfully with that of Horton and, for the turbulent flow regime, to the one derived from kinematic wave theory. This solution can be applied easily to both stationary and non‐stationary rainfall excess events. An analytical solution for the instantaneous response function (IRF) was also derived. Finally, simple expressions to compute peak and time to peak of IRF are proposed. Copyright © 2001 John Wiley & Sons, Ltd.
Effects of climate and land‐use change on storm runoff generation: present knowledge and modelling capabilities
Authors: Bronstert Axel , Niehoff Daniel , Bürger Gerd
Published: August 2002

There are several indications that changes in land cover have influenced the hydrological regime of various river basins. In addition, the effects of climate change on the hydrological cycle and on the runoff behaviour of river catchments have been discussed extensively in recent years. However, it is at present rather uncertain how, how much and at which spatial scale these environmental changes are likely to affect the generation of storm runoff, and consequently the flood discharges of rivers. Firstly, this paper gives an overview of the possible effects of climatic and land‐use change on storm runoff generation. Secondly, it discusses models dealing with the hydrological response to climate and land‐use variations, including both the downscaling of climate information from global circulation models and the way flood forecasting models represent land‐use conditions. Finally, two modelling studies of meso‐scale catchments in Germany are presented: the first shows the possible impacts of climate change on storm runoff production, and the second the impacts of land‐use changes. Copyright © 2002 John Wiley & Sons, Ltd.
Three‐month‐old infants learn arbitrary auditory–visual pairings between voices and faces
Authors: Brookes Helen , Slater Alan , Quinn Paul C. , Lewkowicz David J. , Hayes Rachel , Brown Elizabeth
Published: August 2002

The ability of 3‐month‐old infants to learn arbitrary auditory–visual associations between voices and faces was investigated by familiarizing each infant to two alternating stimuli presented on a VCR monitor. Each stimulus was a voice–face combination, where the voices and faces were male and/or female. On the post‐familiarization test trials each infant was presented alternately with a familiar and a novel voice–face combination, where the novel combination consisted of a voice and a face they had heard and seen previously (but not together), and on these test trials attention was significantly higher to the novel combination. These findings are a clear demonstration that 3‐month‐olds can learn arbitrary voice–face associations, and they are discussed in terms of early intermodal perception and face perception. Copyright © 2001 John Wiley & Sons, Ltd.
Melanoma in adolescents: A case‐control study of risk factors in Queensland, Australia
Authors: Youl Philippa , Aitken Joanne , Hayward Nicholas , Hogg David , Liu Ling , Lassam Norman , Martin Nicholas , Green Adèle
Published: August 2002

The incidence of melanoma increases markedly in the second decade of life but almost nothing is known of the causes of melanoma in this age group. We report on the first population‐based case‐control study of risk factors for melanoma in adolescents (15–19 years). Data were collected through personal interviews with cases, controls and parents. A single examiner conducted full‐body nevus counts and blood samples were collected from cases for analysis of the CDKN2A melanoma predisposition gene. A total of 201 (80%) of the 250 adolescents with melanoma diagnosed between 1987 and 1994 and registered with the Queensland Cancer Registry and 205 (79%) of 258 age‐, gender‐ and location‐matched controls who were contacted agreed to participate. The strongest risk factor associated with melanoma in adolescents in a multivariate model was the presence of more than 100 nevi 2 mm or more in diameter (odds ratio [OR] = 46.5, 95% confidence interval [CI] = 11.4–190.8). Other risk factors were red hair (OR = 5.4, 95%CI = 1.0–28.4); blue eyes (OR = 4.5, 95%CI = 1.5‐13.6); inability to tan after prolonged sun exposure (OR = 4.7, 95%CI = 0.9–24.6); heavy facial freckling (OR = 3.2, 95% CI = 0.9–12.3); and family history of melanoma (OR = 4.0, 95%CI = 0.8–18.9). Only 2 of 147 cases tested had germline variants or mutations in CDKN2A. There was no association with sunscreen use overall, however, never/rare use of sunscreen at home under the age of 5 years was associated with increased risk (OR = 2.2, 95%CI = 0.7–7.1). There was no difference between cases and controls in cumulative sun exposure in this high‐exposure environment. Factors indicating genetic susceptibility to melanoma, in particular, the propensity to develop nevi and freckles, red hair, blue eyes, inability to tan and a family history of the disease are the primary determinants of melanoma among adolescents in this high solar radiation environment. Lack of association with reported sun exposure is consistent with the high genetic susceptibility in this group. © 2001 Wiley‐Liss, Inc.
Collagen type I expression in experimental anaplastic thyroid carcinoma: Regulation and relevance for tumorigenicity
Authors: Dahlman Thèrése , Lammerts Ellen , Bergström Daniel , Franzén Åsa , Westermark Kerstin , Heldin Nils‐Erik , Rubin Kristofer
Published: August 2002

Fibrosis in solid malignancies plays a significant role in tumor pathophysiology. Potential mechanisms for collagen type I deposition in anaplastic thyroid carcinoma (ATC) were investigated using 6 characterized ATC cell lines. Three of these cell lines, which produced collagen type I, had, as a group, a poor tumorigenicity when inoculated in athymic mice. This group of cells generated tumors in 4 of 24 injected animals (17%). Pro‐α1(I) collagen mRNA‐expressing carcinoma and stromal cells were interdispersed in the tumors generated by these ATC cells. By contrast, the 3 noncollagen‐producing ATC cell lines were all tumorigenic with a tumor take of 60% in the whole group. In the latter tumors, pro‐α1(I) collagen mRNA‐expressing cells were confined to the stromal compartment, well delineated from carcinoma cell islets. To study the influence of ATC cells on collagen type I synthesis by fibroblasts, we used AG 1518 diploid human fibroblasts cultured on poly‐(2‐hydroxyethyl methacrylate) (poly[HEMA])‐coated plates. This culture condition allows the study of the effect of collagen mRNA translation in the regulation of collagen type I synthesis. Conditioned media from the 6 ATC cell lines did not influence collagen synthesis. The ATC cell line KAT‐4 stimulated fibroblast synthesis of collagen type I when the two cell types were cocultured on poly[HEMA]‐coated substrates. Specific inhibitors of PDGF and TGF‐β reduced the KAT 4 carcinoma cell‐induced stimulation of collagen type I synthesis. Our data suggest that collagen type I production by carcinoma cells correlates negatively with tumorigenicity and that the formation of a well‐defined stroma is of importance for tumor growth. Furthermore, our data suggest that tumor cells are able to stimulate collagen mRNA translation in stromal fibroblasts in direct cell‐cell contact by, at least in part, transferring PDGF or TGF‐β. © 2001 Wiley‐Liss, Inc.
Tumor apoptosis in cervical cancer: Its role as a prognostic factor in 42 radiotherapy patients
Authors: Kim Joo‐Young , Cho Hyun‐Yee , Lee Kyu‐Chan , Hwang You‐Jin , Lee Myung‐Hak , Roberts Stephen A. , Kim Chul Hwan
Published: August 2002

To investigate tumor apoptosis as a prognostic factor for outcome following radiation therapy, comparisons were made of apoptotic index (AI) as a predictor of short‐ vs. long‐term response and pretreatment vs. radiation‐induced apoptosis. Forty‐two patients with proven squamous cell carcinoma of the uterine cervix were treated by radiation alone. Apoptosis was measured by light microscopic observation of hematoxylin and eosin‐stained sections from biopsies taken before treatment and 4 and 24 hr after 2 Gy. Patients were evaluated at the end of the external radiation for determination of short‐term response and for long‐term outcome as well (median follow‐up of 27 months). Patients with high spontaneous AI showed poor short‐term response, local control, and survival. The significance of AI as a predictor of short‐term response was lost after allowing for differences in tumor size. The positive predictive value of AI for local control and survival was independent of tumor size and stage. High AI was associated with poor local control and long‐term prognosis in advanced squamous cell carcinoma of the cervix. The in vivo radiation‐induced AI after 4 or 24 hr did not predict radiation therapy outcome. © 2001 Wiley‐Liss, Inc.
Tumor targeting properties of monoclonal antibodies with different affinity for target antigen CD44V6 in nude mice bearing head‐and‐neck cancer xenografts
Authors: Verel Iris , Heider Karl‐Heinz , Siegmund Miranda , Ostermann Elínborg , Patzelt Erik , Sproll Marlies , Snow Gordon B. , Adolf Günther R. , van Dongen Guus A.M.S.
Published: August 2002

The CD44 protein family consists of isoforms with tissue‐specific expression, which are encoded by standard exons and up to 9 alternatively spliced variant exons (v2–v10) of the same gene. The murine MAbs U36 and BIWA‐1, directed against overlapping epitopes within the v6 region of CD44, have previously been shown to efficiently target HNSCC. We herein report on the construction of 1 chimeric (BIWA‐2) and 2 humanized (BIWA‐4 and BIWA‐8) derivatives of BIWA‐1. Together with U36 and BIWA‐1, these new antibodies were evaluated for affinity to the antigen in vitro as well as for biodistribution and efficacy in RIT using nude mice bearing the HNSCC xenograft line HNX‐OE. As determined by surface plasmon resonance, the MAbs bound to CD44v6 with an up to 46‐fold difference in affinity (Kd ranging from 1.1 × 10−8 to 2.4 × 10−10 M) with the following ranking: mMAb U36 < hMAb BIWA‐4 < hMAb BIWA‐8 < mMAb BIWA‐1 ∼ cMAb BIWA‐2. To evaluate their in vivo tumor‐targeting properties, 2 MAbs with identical murine or human isotype were labeled with either 131I or 125I and administered simultaneously (50 μg/10 μCi each) as pairs showing a stepwise decrease in the difference in affinity: U36 vs. BIWA‐1 (35.0‐fold difference), BIWA‐4 vs. BIWA‐2 (14.0‐fold) and BIWA‐4 vs. BIWA‐8 (4.0‐fold). Biodistribution was assessed at 1, 2, 3 or 4 and 7 days after injection. Remarkably, for all 3 MAb pairs tested, the lower‐affinity MAb showed a higher degree and specificity of tumor localization. The difference in tumor localization was more pronounced when the difference in affinity was larger. For example, 3 days after injection, the lower‐affinity mMAb U36 showed a 50% higher tumor uptake than the higher‐affinity mMAb BIWA‐1, while blood levels and uptake in organs were similar. After labeling with 186Re (300 or 400 μCi), the same MAb pairs showed RIT efficacy consistent with the biodistribution data: 186Re‐U36 was more effective than 186Re‐BIWA‐1, 186Re‐BIWA‐4 was slightly more effective than 186Re‐BIWA‐2 and 186Re‐BIWA‐4 and 186Re‐BIWA‐8 demonstrated similar efficacy. Based on these data, we conclude that antibodies with markedly lower affinity to a given target antigen (e.g., U36, BIWA‐4) may show superior tumor targeting in comparison with higher‐affinity versions of these antibodies. © 2002 Wiley‐Liss, Inc.
Body mass index in relation to ovarian cancer: A multi‐centre nested case‐control study
Authors: Lukanova Annekatrin , Toniolo Paolo , Lundin Eva , Micheli Andrea , Akhmedkhanov Arslan , Muti Paola , Zeleniuch‐Jacquotte Anne , Biessy Carine , Lenner Per , Krogh Vittorio , Berrino Franco , Hallmans Goran , Riboli Elio , Kaaks Rudolf
Published: August 2002

The incidence of ovarian cancer is up to 10 times higher in Western countries than in rural Asia and Africa. One common consequence of a Western lifestyle is the development of excessive body weight and obesity. A multi‐centre prospective study was conducted to investigate the association between body mass index (BMI) and ovarian cancer risk. A case‐control study was nested within 3 prospective cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). Information on anthropometry, demographic characteristics, medical history and lifestyle was obtained at the time of subjects' recruitment in each cohort. Women diagnosed with primary, invasive epithelial ovarian cancer from the 3 cohorts (n = 122) diagnosed 12 months or later after recruitment into the respective cohort served as case subjects. For each case subject, 2 control subjects that matched the case subject on cohort, menopausal status, age and date of recruitment were randomly identified. Data were analyzed by conditional logistic regression. There was an inverse association between BMI and ovarian cancer risk. For increasing quartiles of BMI above the lowest, the ORs were 0.62 (0.32–1.21), 0.59 (0.30–1.17) and 0.46 (0.23–0.92), p = 0.03. Analyses limited to women diagnosed 3 or more years after recruitment into the cohorts did not alter these findings. When obese women (BMI > 30) were compared to lean women (BMI ≤ 23), the inverse association became stronger, with an OR of 0.38 (0.17–0.85), p < 0.02. There was some evidence of direct association of ovarian cancer with height, which was limited to cancers diagnosed before age 55. Our data suggest that increasing body weight may confer a protection against ovarian cancer. © 2002 Wiley‐Liss, Inc.
A HLA‐A2 restricted human CTL line recognizes a novel tumor cell expressed p53 epitope
Authors: Würtzen Peter A. , Claesson Mogens H.
Published: August 2002

A p53 peptide‐specific CTL line was generated through stimulation with autologous monocyte‐derived dendritic cells (DC) pulsed with wild‐type HLA‐A2 binding p53 derived peptides. A p53 peptide‐specific CD8+ CTL line was established from a healthy HLA‐A2 positive donor. The CTL line was characterized with respect to specificity, affinity and killing of cell lines derived from p53 mutated spontaneous tumors. The CTL line demonstrated lysis of p53139–147 pulsed target cells and cold target inhibition experiments as well as antibody blocking confirmed that the killing was epitope‐specific, HLA‐A2 restricted and dependent on CD8‐binding. Interestingly, the affinity of the CTL line was only in the micromole per liter range and target cells pulsed with less than 0.01 μM peptide were not recognized. Furthermore, 3 HLA‐A2+ p53 mutated tumor cell lines were efficiently lysed by the CTL line, indicating that this novel p53 peptide epitope is endogenously processed and presented by the HLA‐A2 molecules of the tumor cells. In conclusion, CTL reactivity towards a wild‐type p53 peptide was revealed through induction with DC pulsed with a pool of HLA‐A2 binding p53 peptides. In addition, the CTL line, which expressed relatively low affinity for the HLA‐A2/peptide complex, was able to kill 3 different HLA‐A2+ p53 mutated tumor cell lines. The present and our previous observations expand the number of p53‐derived peptides suitable for vaccination protocols for cancer patients with p53 positive tumors. © 2002 Wiley‐Liss, Inc.
Molecular genetic characterization of the EWS/ATF1 fusion gene in clear cell sarcoma of tendons and aponeuroses
Authors: Panagopoulos Ioannis , Mertens Fredrik , Dêbiec‐Rychter Maria , Isaksson Margareth , Limon Janusz , Kardas Iwona , Domanski Henryk A. , Sciot Raf , Perek Danuta , Crnalic Sead , Larsson Olle , Mandahl Nils
Published: August 2002

Clear cell sarcoma (CCS) is a rare malignant soft tissue tumor particularly associated with tendons and aponeuroses. The cytogenetic hallmark is the translocation t(12;22)(q13;q12) resulting in a chimeric EWS/ATF1 gene in which the 3′‐terminal part of EWS at 22q is replaced by the 3′‐terminal part of ATF1 at 12q. To date, only 13 cases of CCS have been analyzed for fusion genes at the transcription level, and there is no information about the breakpoints at the genomic level. In the present study, we describe the molecular genetic characteristics of CCS from 10 patients. Karyotypes were obtained from 10 cases, 7 of which showed the characteristic t(12;22). As an initial step in the characterization of the EWS/ATF1 and ATF1/EWS chimeras, we constructed an exon/intron map of the ATF1 gene. The entire ATF1 gene spanned >40 kb and was composed of 7 exons. Intron 3, in which most of the genomic breakpoints occurred, was to a large extent (83%) composed of repetitive elements. RT‐PCR amplified EWS/ATF1 cDNA fragments in all patients and ATF1/EWS cDNA fragments in 6 of 10 patients. Four types of EWS/ATF1 chimeric transcript, designated types 1–4, were identified. The most frequent chimeric transcript (type 1) was an in‐frame fusion of exon 8 of EWS with exon 4 of ATF1. This was the only chimeric transcript in 5 patients but found together with other variants in 3 tumors. The type 2 transcript of EWS/ATF1, an in‐frame fusion of exon 7 of EWS with exon 5 of ATF1, was detected in 4 patients, as the only transcript in 1 case and together with other variants in 3 cases. An in‐frame fusion of exon 10 of EWS with exon 5 of ATF1 (type 3) was found in 1 patient as the only transcript, and an out‐of‐frame fusion of EWS exon 7 with ATF1 exon 7 (type 4) was detected in 1 patient together with type 1 and type 2 transcripts. Sequencing of the amplified ATF1/EWS cDNA fragments showed in 5 patients that ATF1 exon 3 was fused with EWS exon 10, resulting in an out‐of‐frame chimeric transcript. In 1 case, nt 428 of ATF1 (exon 4) was fused with EWS exon 8; at the junction, there was an insertion of 4 nucleotides, also resulting in an out‐of‐frame transcript. Genomic extra long PCR and sequence analysis mapped the genomic breakpoints to introns 7, 8 and 9 of EWS and intron 3 and exon 4 of ATF1. While a simple end‐to‐end fusion was observed in 2 cases, additional nucleotides were found at the junctions in 2 other cases. In addition, topoisomerase I consensus sequences were found close to the junctions, suggesting that this enzyme may participate in the genesis of the EWS/ATF1 fusion. © 2002 Wiley‐Liss, Inc.
Large‐scale randomized prostate cancer screening trials: Program performances in the European randomized screening for prostate cancer trial and the prostate, lung, colorectal and ovary cancer trial
Authors: de Koning Harry J. , Auvinen Anssi , Berenguer Sanchez Antonio , Calais da Silva Fernando , Ciatto Stefano , Denis Louis , Gohagan John K. , Hakama Matti , Hugosson Jonas , Kranse Ries , Nelen Vera , Prorok Philip C. , Schröder Fritz H. ,   ERSPC and the PLCO Trials (the International Prostate Cancer Screening Trials Evaluation Group)
Published: August 2002

Two large‐scale randomized screening trials, the Prostate, Lung, Colorectal and Ovary (PLCO) cancer trial in the USA and the European Randomized Screening for Prostate Cancer (ERSPC) trial in Europe are currently under way, aimed at assessing whether screening reduces prostate cancer mortality. Up to the end of 1998, 102,691 men have been randomized to the intervention arm and 115,322 to the control arm (which represents 83% of the target sample size) from 7 European countries and 10 screening centers in the USA. The principal screening method at all centers is determination of serum prostate‐specific antigen (PSA). The PLCO trial and some European centers use also digital rectal examination (DRE) as an ancillary screening test. In the core age group (55–69 years), 3,362 of 32,486 men screened (10%) had a serum PSA concentration of 4 ng/ml or greater, which is 1 cut‐off for biopsy (performed in 84%). An additional 6% was referred for further assessment based on other criteria, with much less efficiency. Differences in PSA by country are largely attributable to the age structure of the study population. The mean age‐specific PSA levels are lower in the PLCO trial (1.64 ng/ml [in the age group 55–59 years], 1.80 [60–64 years] and 2.18 [65–69 years) than in the ERSPC trial (1.28–1.71 [55–59], 1.75–2.87 [60–64] and 2.48–3.06 [65–69 years]). Detection rates at the first screen in the ERSPC trial range from 11 to 42/1,000 men screened and reflect underlying differences in incidence rates and screening procedures. In centers with consent to randomization design, adherence in the screening arm is 91%, but less than half of the men in the target population are enrolled in the trial. In population‐based centers in which men were randomized prior to consent, all eligible subjects are enrolled, but only about two‐thirds of the men in the intervention arm undergo screening. Considerable progress has been made in both trials. Enrollment will be completed in 2001. A substantial number of early prostate cancers have been detected. The differences between countries seem to reflect both underlying prostate cancer incidence and screening policy. The trials have the power to show definitive results in 2005–2008. © 2002 Wiley‐Liss, Inc.