bluuebunny/crossref_metadata_2025 huggingface dataset:
Forest ecosystem processes at the watershed scale: hydrological and ecological controls of nitrogen export
Authors: Band L. E. , Tague C. L. , Groffman P. , Belt K.
Published: August 2002

We present a hierarchically distributed model of catchment forest hydrology and biogeochemistry. The goal of the model is to evaluate and predict the distribution of water, carbon and nitrogen cycling within a forested watershed, as well as the export of nitrate. We use a spatial hierarchy of land elements arranged through the stream network, and successively containing catchments, subcatchments, hillslopes, then patches (within each hillslope) to distribute key processes. Time scales of active processes range from those forced by daily meteorology to canopy growth and soil development occurring over decades. This allows us to follow the hydrological and biogeochemical dynamics of the landscape over a range of spatial and temporal scales. A key assumption of the model is that a substantial amount of the water movement through the unsaturated zone occurs as preferential flow. Nitrate is then transported downslope by rising saturated zones during storms. We test the predictions of the model with preliminary data generated as part of the Baltimore Long‐Term Ecological Research site. The hydrological modules of the model are calibrated with rainfall/runoff data from the 1980s, while the nitrogen cycling modules are uncalibrated. The model generated good correspondence to the seasonal dynamics of stream water nitrate concentration over the 1998–1999 water year. Copyright © 2001 John Wiley & Sons, Ltd.
A classification of drainage and macropore flow in an agricultural catchment
Authors: Heppell C. M. , Worrall F. , Burt T. P. , Williams R. J.
Published: August 2002

This paper uses a variety of multivariate statistical techniques in order to improve current understanding of the antecedent and rainfall controls on drainage characteristics for an agricultural underdrained clay site. Using the dataset obtained from a two‐year hillslope study at Wytham (Oxfordshire, UK) a number of patterns in the nature and style of drainage events were explored. First, using principal components analysis, a distinction was drawn between drainflow controlled by antecedent conditions and drainflow controlled by rainfall characteristics. Dimensional analysis then distinguished between two further types of drainflow event: antecedent limited events (ALE) and non‐antecedent limited events (NALE). These were drainflow events requiring a minimum antecedent hydraulic head to occur (ALE) and events that occurred in response to rainfall irrespective of the antecedent conditions, because the rainfall was either of high enough intensity or duration to prompt a response in drainflow (NALE). 2. The dataset also made possible a preliminary investigation into the controls on and types of macropore flow at the site. Principal components analysis identified that rainfall characteristics were more important than antecedent conditions in generating high proportions of macropore flow in drainflow. Of the rainfall characteristics studied, rainfall amount and intensity were the dominant controls on the amount of macropore flow, with duration as a secondary control. Two styles of macropore flow were identified: intensity‐driven and duration‐driven. Intensity‐driven events are characterized by rainfall of high intensity and short duration. During such events the amount of macropore flow is proportional to the rainfall intensity and the interaction between macropore and matrix flow is kinetically limited. The second style of macropore flow is characterized by long‐duration events. For these events the amount of macropore flow approaches a maximum value whatever the rainfall duration. This suggests that these events are characterized by an equilibrium interaction between macropores and matrix flow. Copyright © 2002 John Wiley & Sons, Ltd.
Practical applications of spectral analysis to hydrologic time series
Authors: Fleming Sean W. , Marsh Lavenue A. , Aly Alaa H. , Adams Alison
Published: August 2002

An Erratum has been published for this article in Hydrological Processes 17(4) 2003, 883.

Fourier‐transform‐based spectral analysis and filtering techniques, although potentially very useful, have seen little practical application in hydrology. We provide an overview of the Fourier transform and spectral analysis and present examples of how these methods may be applied to practical hydrologic problems: determination of the frequency content of a time series; inference of the physical mechanisms responsible for this frequency content; and evaluation of the performance of a process‐based simulation model used for water resource management. In all cases, the methods performed well and were reasonably straightforward to implement, highlighting their general utility. Copyright © 2002 John Wiley & Sons, Ltd.
Significance of processes in the near‐stream zone on stream water acidity in a small acidified forested catchment
Authors: Fölster Jens
Published: August 2002

The near‐stream zone has received increasing attention owing to its influence on stream water chemistry in general and acidity in particular. Possible processes in this zone include cation exchange, leaching of organic matter and redox reactions of sulphur compounds. In this study the influences of processes in the near‐stream zone on the acidity in runoff from a small, acidified catchment in central southern Sweden were investigated. The study included sampling of groundwater, soil water and stream water along with hydrological measurements. An input–output budget for the catchment was established based on data from the International Co‐operative Programme on Integrated Monitoring at this site.

The catchment was heavily acidified by deposition of anthropogenic sulphur, with pH in stream water between 4·4 and 4·6. There was also no relationship between stream flow and pH, which is indicative of chronic acidification. Indications of microbial reduction of sulphate were found in some places near the stream, but the near‐stream zone did not have a general impact on the sulphate concentration in discharging groundwater. The near‐stream zone was a source of dissolved organic carbon (DOC) in the stream, which had a median DOC of 6·8 mg L1. The influence on stream acidity from organic anions was overshadowed by the effect of sulphate, however, except during a spring flow episode, when additional organic matter was flushed out and the sulphate‐rich ground water was mixed with more diluted event water. Ion exchange was not an important process in the near‐stream zone of the Kindla catchment. Different functions of the near‐stream zone relating to discharge acidity are reported in the literature. In this study there was even a variation within the site. There is therefore a need for more case studies to provide a more detailed understanding of the net effects that the near‐stream zone can have on stream chemistry under different circumstances. Copyright © 2001 John Wiley & Sons, Ltd.
Prevalence of the BRCA2 6174 del T mutation in Israeli uveal melanoma patients
Authors: Iscovich Jose , Abdulrazik Mohammed , Cour Carol , Fischbein Alf , Pe'er Jacob , Goldgar David E.
Published: August 2002

Substantial differences exist in the incidence rates of uveal melanoma (UM) among Israeli Jewish subpopulations: high in immigrants from North America and Europe (Ashkenazic) and low in immigrants from Africa and Asia (Sepharadic). This trend persists in Israeli‐born individuals when stratified by their ancestral place of birth. There have been several anecdotal reports of uveal melanoma occurring in breast cancer families with mutations in the BRCA2 gene as well as one systematic study reporting BRCA2 mutations in UM. A single BRCA2 mutation, 6174 del T, occurs in about 1% of the Ashkenazic population and rarely in non‐Ashkenazic. To assess the contribution of this germline mutation to uveal melanoma in Jewish Israeli patients, we tested this relationship through analysis of blood samples from a series of UM patients. A total of 153 cases (84 female, 69 male) were available for study, which represents 30% of all cases of UM diagnosed in Israel during the period 1984–1999 (82% for the period 1992–1999). Of the 143 UM patients for which a result could be obtained (4 due to refusals, 6 due to damage to the blood sample), 4 (2.8%, 95% confidence interval [CI] 0–5.6) carried the 6174 del T mutation. Assuming a population frequency of the mutation of 1% as estimated among Ashkenazic Jews in the United States, the probability of observing 4 or more carriers with the 6174 del T mutation, assuming no relationship between uveal melanoma and BRCA2, is 0.057. Although our study confirms the relationship between uveal melanoma and BRCA2, it is clear that the 6174 del T mutation accounts for only a small fraction of all Israeli UM cases. Therefore, BRCA2 mutations are likely to account for an even smaller proportion in populations with low frequencies of BRCA2 alterations. © 2001 Wiley‐Liss, Inc.
Inhibition of cell proliferation, invasion, tumor growth and metastasis by an oral non‐antimicrobial tetracycline analog (COL‐3) in a metastatic prostate cancer model
Authors: Lokeshwar Bal L. , Selzer Marie G. , Zhu Bao‐Qian , Block Norman L. , Golub Lorne M.
Published: August 2002

Antibiotic forms of tetracycline exhibit antitumor activity in some tumor models. However, their low in vivo efficacy and associated morbidity limit their long‐term application in cancer therapy. This report appraises the efficacy of doxycycline (DC) and non‐antimicrobial, chemically modified tetracyclines (CMTs) against prostate cancer. Both DC and several CMTs inhibited prostate tumor cell proliferation in vitro. Some of the CMTs were significantly more potent than DC. One of the CMTs, 6‐deoxy, 6‐demethyl, 4‐de‐dimethylamino tetracycline (CMT‐3, COL‐3), was the most potent inhibitor (50% inhibition dose [GI50] ≤ 5.0 μg/ml). Exposure of tumor cells to CMT‐3 induced both apoptosis and necrosis. Mitochondrial depolarization and increased levels of reactive hydroxyl radicals were also observed in cells treated with CMT‐3. Cell cycle arrest at the G0/G1 compartment was observed in CMT‐3‐ and DC‐treated cells. DC and CMTs also inhibited the invasive potential of the tumor cells in vitro, from 10% (CMT‐6) to >90% (CMT‐3). CMT‐3 and DC decreased matrix metalloproteinase (MMP)‐2, tissue inhibitor of MMP (TIMP)‐1 and TIMP‐2 secretion in treated cultures and inhibited activity of secreted MMPs, CMT‐3 was a stronger inhibitor. Daily oral gavage of DC and CMT‐3 inhibited tumor growth and metastasis in the Dunning MAT LyLu rat prostate tumor. Decreases in tumor growth (27–35%) and lung metastases were observed (28.9 ± 15.4 sites/animal [CMT‐3‐treated] versus 43.6 ± 18.8 sites/animal [DC‐treated] versus 59.5 ± 13.9 [control]; p < 0.01]. A delay in tumor growth (27 ± 9.3%, p < 0.05), reduction in metastases (58 ± 8%) and decrease in tumor incidences (55 ± 9%, CMT‐3‐treated) were also observed, when rats were predosed for 7 days. No significant drug‐induced morbidity was observed in any of the animals. These results, along with a recently concluded clinical trial, suggest a potential use of CMT‐3 as an oral, nontoxic drug to treat metastatic prostate and other cancers. © 2001 Wiley‐Liss, Inc.
Immunotherapy with recombinant SFV‐replicons expressing the P815A tumor antigen or IL‐12 induces tumor regression
Authors: Colmenero Paula , Chen Margaret , Castaños‐Velez Esmeralda , Liljeström Peter , Jondal Mikael
Published: August 2002

Replicons based on alphaviruses are emerging as candidate vectors for vaccination and gene therapy purposes. We have reported previously that mice vaccinated with a recombinant Semliki Forest virus (a member of the alphavirus genus) carrying the gene encoding the P815A tumor antigen (rSFV/E‐P1A) were protected against a lethal challenge with the P815 tumor. In this study we investigated the anti‐tumor therapeutic efficacy of rSFV/E‐P1A or rSFV expressing the cytokine interleukin 12 (rSFV/IL12) on Day 5‐established tumors. The results show that both antigen‐specific and cytokine‐mediated rSFV treatments exhibited a significant effect on P815 tumor growth, by delaying tumor progression and even inducing complete tumor regressions in several mice. The therapeutic potency of these vectors was dependent on the size of the treated tumor, as treatment of mice bearing larger tumors showed lower efficacy. In addition, rSFV treatment resulted in long‐term immunity as observed by the lack of tumor recurrence in the majority of tumor‐regressing mice after rechallenge with the tumor. Furthermore, the anti‐tumor therapeutic effect was only achieved by local intratumoral injection of rSFV, as treatment by injection in the contralateral site resulted in tumor progression comparable to control‐untreated mice. Accordingly, expression of a rSFV‐RNA was localized to the tumor and draining lymph node. These results further demonstrate the potential of rSFV replicons as tumor therapeutic agents. © 2002 Wiley‐Liss, Inc.
Novel monoclonal antibody specific for the de2‐7 epidermal growth factor receptor (EGFR) that also recognizes the EGFR expressed in cells containing amplification of the EGFR gene
Authors: Johns Terrance G. , Stockert Elisabeth , Ritter Gerd , Jungbluth Achim A. , Huang H‐J. Su , Cavenee Webster K. , Smyth Fiona E. , Hall Cathrine M. , Watson Nadine , Nice Edouard C. , Gullick William J. , Old Lloyd J. , Burgess Antony W. , Scott Andrew M.
Published: August 2002

In some respects, the EGFR appears to be an attractive target for tumor‐targeted antibody therapy: it is overexpressed in many types of epithelial tumor and inhibition of signaling often induces an anti‐tumor effect. The use of EGFR specific antibodies, however, may be limited by uptake in organs that have high endogenous levels of the wild type EGFR such as the liver. The de2‐7 EGFR (or EGFRvIII) is a naturally occurring extracellular truncation of the EGFR found in a number of tumor types including glioma, breast, lung and prostate. Antibodies directed to this tumor specific variant of the EGFR provide an alternative targeting strategy, although the lower proportion of tumors that express the de2‐7 EGFR restricts this approach. We describe a novel monoclonal antibody (MAb 806) that potentially overcomes the difficulties associated with targeting the EGFR expressed on the surface of tumor cells. MAb 806 bound to de2‐7 EGFR transfected U87MG glioma cells (U87MG.Δ2‐7) with high affinity (∼1 × 109 M−1), but did not bind parental cells that express the wild type EGFR. Consistent with this observation, MAb 806 was unable to bind a soluble version of the wild type EGFR containing the extracellular domain. In contrast, immobilization of this extracellular domain to ELISA plates induced saturating and dose response binding of MAb 806, suggesting that MAb 806 can bind the wild type EGFR under certain conditions. MAb 806 also bound to the surface of A431 cells, which due to an amplification of the EGFR gene express large amounts of the EGFR. Interestingly, MAb 806 only recognized 10% of the total EGFR molecules expressed by A431 cells and the binding affinity was lower than that determined for the de2‐7 EGFR. MAb 806 specifically targeted U87MG.Δ2‐7 and A431 xenografts grown in nude mice with peak levels in U87MG.Δ2‐7 xenografts detected 8 h after injection. No specific targeting of parental U87MG xenografts was observed. Following binding to U87MG.Δ2‐7 cells, MAb 806 was rapidly internalized by macropinocytosis and subsequently transported to lysosomes, a process that probably contributes to the early targeting peak observed in the xenografts. Thus, MAb 806 can be used to target tumor cells containing amplification of the EGFR gene or de2‐7 EGFR but does not bind to the wild type EGFR when expressed on the cell surface. © 2002 Wiley‐Liss, Inc.
Infiltration of Th1 and Th2 lymphocytes around Hodgkin and Reed‐Sternberg (H&RS) cells in Hodgkin disease: Relation with expression of CXC and CC chemokines on H&RS cells
Authors: Ohshima Koichi , Tutiya Takeshi , Yamaguchi Takahiro , Suzuki Keiko , Suzumiya Junji , Kawasaki Chika , Haraoka Seiji , Kikuchi Masahiro
Published: August 2002

Hodgkin disease (HD) is characterized by the presence of Hodgkin and Reed‐Sternberg cells (H&RS) and a prominent lymphocytic infiltration. Various CXC and CC chemokines [e.g., interferon‐γ‐inducible protein‐10 (IP10), monokine induced by interferon‐γ (MIG) and TARC] are expressed on H&RS cells. Our study was designed to investigate the expression of MIG, IP10 and TARC on H&RS cells and their relations on lymphocyte infiltration. Immunohistochemical staining was performed using antibodies for CXCR3 (a specific receptor for IP10 and MIG), which is characteristic of Th1 helper phenotype and CCR3, CCR4 and ST2, which are features of Th2 cells. We studied 15 cases of HD [lymphocyte predominance (LP) type, 2; mixed cellularity (MC) type, 6; and nodular sclerosis (NS) type, 7]. All 6 MC cases contained TARC‐, IP10‐ and MIG‐expressing H&RS cells, however only 2 of 5 NS cases contained TARC‐expressing H&RS cells, 3 of 7 NS contained MIG‐expressing H&RS cells and only 1 of 7 NS contained IP10‐expressing H&RS cells. Neither of the 2 LP cases contained HR&S cells that expressed these chemokines. The chemokines were more frequently expressed by MC than by NS and LP types. IP10‐, MIG‐ and TARC‐positive HD cases contained higher numbers of Th2 lymphocytes (ST2‐ CCR3‐ or CCR4‐positive lymphocytes), compared to IP10‐, MIG‐ and TARC‐negative HD cases (p < 0.05 or <0.5). The number of CXCR3 (MIG and IP10 receptor)‐positive lymphocytes (Th1 lymphocytes) was not different between MIG‐ and IP10‐positive and ‐negative HD. Lymphocytes surrounding MIG‐ and IP10‐positive H&RS cells were more frequently CXCR3‐positive, however, compared to MIG‐ and IP10‐negative cases. The CCR4 (TARC receptor)‐positive lymphocytes, surrounding H&RS cells, were minority and the surrounding lymphocytes were not different between TARC‐positive and negative cases. Our results indicate that MIG, IP10 and TARC chemokines influenced the response of Th2 cells in HD. It is possible, however, that IP10 and MIG may locally influence Th1 cells via cell migration. © 2002 Wiley‐Liss, Inc.
Increased expression of CHK2 in human gastric carcinomas harboring p53 mutations
Authors: Shigeishi Hideo , Yokozaki Hiroshi , Oue Naohide , Kuniyasu Hiroki , Kondo Tomohiro , Ishikawa Takenori , Yasui Wataru
Published: August 2002

Human Chk1 and Chk2 are DNA damage–activated protein kinases that function as downstream mediators of ataxia‐telangiectasia mutated (ATM), which is involved in G2/M cell cycle arrest. To clarify the relation between the expression of Chk1/Chk2 and p53 gene status in human gastric carcinomas, we examined expression of Chk1, Chk2 and p53 proteins in 87 gastric carcinomas by Western blotting and immunohistochemistry. We found a significant correlation between the expression levels of Chk1 and p53 proteins in gastric carcinomas (p = 0.016). Significant statistical association was also observed between levels of Chk2 and p53 proteins (p = 0.00024). To clarify the genetic alterations of p53 in gastric carcinomas, we performed PCR‐SSCP analysis on 47 gastric carcinomas. Although we found that 5 of 7 (71%) gastric cancers expressed elevated levels of Chk1 had p53 mutation, there was not a statistically significant correlation between expression of Chk1 and genetic status of p53. We also found that 7 of 11 (78%) gastric carcinomas expressed elevated levels of Chk2 had p53 mutation, and this correlation was significant (p = 0.0157). We used a highly quantitative 5′ nuclease fluorogenic RT‐PCR method (TaqMan) to analyze the expression of Chk2 mRNA in 22 gastric carcinomas. Chk2 mRNA expression was higher in gastric carcinomas with p53 mutations compared to those harboring wild‐type p53. A significant association was recognized between the expression of Chk2 mRNA and p53 mutational status (p = 0.031). Our findings support the hypothesis that expression of Chk2 protein is increased in gastric carcinomas with mutant p53. Chk1 and Chk2 may play important roles in the checkpoint function in human gastric carcinomas harboring p53 mutation when their functions are preserved to prevent cell cycle progression. © 2002 Wiley‐Liss, Inc.
Loss of single HLA Class I allospecificities in melanoma cells due to selective genomic abbreviations
Authors: Geertsen Ralf , Böni Roland , Blasczyk Rainer , Romero Pedro , Betts David , Rimoldi Donata , Hong Xin , Laine Elisabeth , Willers Jörg , Dummer Reinhard
Published: August 2002

Expression of human leucocyte antigen (HLA) Class I molecules is essential for the recognition of malignant melanoma (MM) cells by CD8+ T lymphocytes. A complete or partial loss of HLA Class I molecules is a potent strategy for MM cells to escape from immunosurveillance. In 2 out of 55 melanoma cell cultures we identified a complete phenotypic loss of HLA allospecificities. Both patients have been treated unsuccessfully with HLA‐A2 peptides. To identify the reasons underlying the loss of single HLA‐A allospecificities, we searched for genomic alterations at the locus for HLA Class I α‐chain on chromosome 6 in melanoma cell cultures established from 2 selected patients with MM in advanced stage. This deficiency was associated with alterations of HLA‐A2 gene sequences as determined by polymerase chain reaction‐sequence specific primers (PCR‐SSP). Karyotyping revealed a chromosomal loss in Patient 1, whereas melanoma cell cultures established from Patient 2 displayed 2 copies of chromosome 6. Loss of heterozygosity (LOH) using markers located around position 6p21 was detected in both cases. By applying group‐specific primer‐mixes spanning the 5′‐flanking region of the HLA‐A2 gene locus the relevant region was amplified by PCR and subsequent sequencing allowed alignment with the known HLA Class I reference sequences. Functional assays using HLA‐A2‐restricted cytotoxic T‐cell clones were performed in HLA‐A2 deficient MM cultures and revealed a drastically reduced susceptibility to CTL lysis in HLA‐A2 negative cells. We could document the occurrence of selective HLA‐A2 deficiencies in cultured advanced‐stage melanoma metastases and identify their molecular causes as genomic alterations within the HLA‐A gene locus. © 2002 Wiley‐Liss, Inc.
Genetic analysis of RET, GFRα1 and GDNF genes in Spanish families with multiple endocrine neoplasia type 2A
Authors: Gil Laura , Azañedo Marta , Pollán Marina , Cristobal Eva , Arribas Begoña , García‐Albert Luis , García‐Sáiz Alfredo , Maestro María Luisa , Torres Antonio , Menárguez Javier , Rojas José M.
Published: August 2002

Multiple endocrine neoplasia type 2A (MEN 2A) is associated with specific germline missense mutations in the RET proto‐oncogene. This locus encodes a receptor tyrosine kinase whose activation requires the formation of a multimeric receptor complex including GDNF as a ligand and GFRα1 as a coreceptor. In order to explore the role of RET, GFRα1 and GDNF genes in the variation of phenotypes observed in MEN2A families, we analysed germline mutations of these genes in 4 unrelated Spanish MEN2A families (23 cases studied). We found 2 novel variants corresponding to a single change in position + 47 (intron 12) of RET and position +22 (intron 7) of GFRα1. Furthermore, we observed strong co‐segregation between 2 polymorphisms of RET [G691S (exon 11) and S904S (TCC‐TCG, exon 15) (100%, Fisher's exact test, p< 0.001)]. More interestingly, we found that these polymorphisms occurred at a significantly high frequency in patients with age at onset < 20 years old (Kruskal‐Wallis's and Fisher's exact test, p = 0.007). These findings suggest that the G691S and S904S variants of RET may somehow play a role on the age of onset of MEN 2A. © 2002 Wiley‐Liss, Inc.
Human Ly‐6 antigen E48 (Ly‐6D) regulates important interaction parameters between endothelial cells and head‐and‐neck squamous carcinoma cells
Authors: Eshel Rinat , Zanin Alexandra , Kapon Dina , Sagi‐Assif Orit , Brakenhoff Ruud , van Dongen Guus , Witz Isaac P.
Published: August 2002

Selectin ligands are crucial components in the interaction between endothelial cells and extravasating cancer cells and, thus, play an important role in metastasis formation. Head‐and‐neck squamous cell carcinoma (HNSCC) variants expressing high levels of E48, a human Ly‐6 protein (E48hi), expressed higher levels of the fucose‐generating FX enzyme and of the fucosylated E‐selectin ligand sLea than cells expressing low levels of E48 (E48lo). Signaling through E48 upregulated expression levels of these molecules in HNSCC. In this work, we provide further evidence supporting the E48–FX–sLea link by showing that FX antisense oligonucleotides reduced sLea expression levels in HNSCC. We also show that E48 may be causally involved in regulating expression levels in HNSCC of 2 additional enzymes involved in the biosynthesis of sLea, namely, ST‐30 and FucTIII. Also, selectin‐mediated adhesion of E48hi variants to activated HUVECs was significantly higher than that of E48lo variants. Transfection experiments utilizing sense or antisense E48 cDNA indicated that E48 may be causally involved in this adhesion. Chemokines are involved in the extravasation process of tumor cells. The release of chemoattractants from HNSCC variants differing in E48 expression was therefore analyzed. HNSCC did not release any chemoattractants but induced the release of such factors from HUVECs. Supernatants from E48hi variants were significantly more efficient than E48lo cells at inducing the release of chemoattractants from HUVECs. Transfection experiments indicated that E48 may be causally involved in the induction of chemoattractant release from HUVECs. Angiogenesis is an important manifestation of cancer–endothelium interactions. We therefore assayed for the presence of angiogenic factors in culture supernatants of HNSCC. Supernatants from E48lo variants contained significantly higher amounts of PDGF than E48hi cells. Transfection experiments indicated that E48 may be causally involved. Taken together, our results suggest that E48 controls important interaction parameters between HNSCC and endothelial cells. © 2002 Wiley‐Liss, Inc.
Matrix metalloproteinases in cancer: Prognostic markers and therapeutic targets
Authors: Vihinen Pia , Kähäri Veli‐Matti
Published: August 2002

Degradation of extracellular matrix is crucial for malignant tumour growth, invasion, metastasis and angiogenesis. Matrix metalloproteinases (MMPs) are a family of zinc‐dependent neutral endopeptidases collectively capable of degrading essentially all matrix components. Elevated levels of distinct MMPs can be detected in tumour tissue or serum of patients with advanced cancer and their role as prognostic indicators in cancer is studied. In addition, therapeutic intervention of tumour growth and invasion based on inhibition of MMP activity is under intensive investigation and several MMP inhibitors are in clinical trials in cancer. In this review, we discuss the current view on the feasibility of MMPs as prognostic markers and as targets for therapeutic intervention in cancer. © 2002 Wiley‐Liss, Inc.
Heparin‐derived disaccharides modulate proliferation and Erb‐B2–mediated signal transduction in colon cancer cell lines
Authors: Fishman Sigal , Brill Shlomo , Papa Moshe , Halpern Zamir , Zvibel Isabel
Published: August 2002

Organ‐specific extracellular matrix (ECM) determines metastasis formation by regulating tumor cell proliferation. Hepatocyte‐derived ECM enhances proliferation of colon cancer cell lines by increasing expression of tyrosine kinase receptors of the erb‐B family. The active components in the ECM are the heparan sulfates, which are highly heterogenous in their chemistry and size. We determined the effect of heparan sulfate disaccharides, of defined chemistry and present in high amounts in the liver heparan sulfate chains, on the proliferation of colon cancer cell lines and investigated the mechanism involved. The low‐metastatic cell line KM12 was stimulated to proliferate by a highly sulfated disaccharide, found in the highest amounts in hepatocyte‐derived heparan sulfate. Growth of the highly metastatic cell line KM12SM was inhibited by the second most common disaccharide in hepatocyte‐derived heparan sulfate. The effect of both disaccharides was not accompanied by changes in the expression of erb‐B1, erb‐B2, erb‐B3 or heregulin‐α. We determined whether the disaccharides modified the signal‐transduction pathways mediated by the erb‐B receptors. The erb‐B2‐specific tyrosine kinase inhibitor AG825 abolished the enhancement of KM12 cell proliferation by the stimulatory disaccharide. This disaccharide increased tyrosine phosphorylation of erb‐B1 and erb‐B2 receptors, effects that were abolished by AG825. Moreover, the disaccharide caused increased expression of cyclin D1 and of activated MAP kinase, again reduced in the presence of the inhibitor AG825. The growth‐inhibitory disaccharide reduced phosphorylation of erb‐B1, but not of erb‐B2, receptors in KM12SM cells. In conclusion, not only hepatocyte‐derived heparan sulfate but also disaccharide molecules derived from heparan sulfate can affect colon cancer cell proliferation. Their effect is mediated by modulation of the erb‐B signal transduction. © 2002 Wiley‐Liss, Inc.
Laminin‐γ2 overexpression in head‐and‐neck squamous cell carcinoma
Authors: Patel Vyomesh , Aldridge Kay , Ensley John F. , Odell Edward , Boyd Andrea , Jones Judith , Gutkind J. Silvio , Yeudall W. Andrew
Published: August 2002

To identify molecular markers for the progression of head‐and‐neck squamous cell carcinoma (HNSCC), we used RNA arbitrarily primed (RAP) PCR to determine the qualitative and quantitative differences in gene expression between normal epithelial cells, those derived from dysplastic oral mucosa and invasive and metastatic HNSCC. Three differentially expressed DNA fragments (RAP20, RAP21, RAP26) that were upregulated in a tumor cell line (T45) were identified as being regions of the γ2 subunit of human laminin‐5. Northern blot analysis of total cellular RNA revealed overexpression of these transcripts in 6 of 7 HNSCC cell lines compared with normal epidermal keratinocytes. In contrast, no differences were observed in HeLa (cervical carcinoma) or HCT116 (colon carcinoma) cells. Immunostaining of HNSCC cells derived from primary (HN4) and metastatic (HN12) tumors indicated elevated levels of endogenous laminin‐γ2 protein. Furthermore, HNSCC tissues demonstrated strong laminin‐γ2 staining, particularly in the peripheral basaloid cells of tumor islands at the invasion front. In contrast, only minimal staining of laminin‐γ2 was detected in basal cells of the normal epithelium. The data indicate that laminin‐γ2 is frequently overexpressed in HNSCCs and derivative cell lines and that its overexpression is likely to be useful as a marker of head‐and‐neck squamous malignancy. © 2002 Wiley‐Liss, Inc.
Expression of UPA and UPAR is associated with the clinical course of urinary bladder neoplasms
Authors: Seddighzadeh Maria , Steineck Gunnar , Larsson Per , Wijkström Hans , Norming Ulf , Onelöv Erik , Linder Stig
Published: August 2002

The expression of urokinase plasminogen activator (uPA) and its receptor (uPAR) mRNA was determined in 194 subjects with newly detected bladder neoplasms, selected from a larger population‐based series. An association was found between uPA and uPAR expression (n = 172; Spearman rs = 0.60, p < 0.001). Both uPA and uPAR mRNA levels were higher in muscle invasive (T2+) tumors than in noninvasive mucosal tumors (Ta) or those invading submucosa (T1). The relative hazard ratios (RHRs) for cancer‐specific death associated with elevated expression (95% CI), adjusted for age and gender in a Cox proportional hazard model, were 1.8 (1.0–3.3) for uPA (upper quartile cut‐line), 2.2 (1.3–4.0) for uPAR (median quartile cut‐line) and 2.5 (1.3–4.9) for uPA + uPAR. An RHR for metastatic disease of 4.0 (1.6–9.9) was observed for uPAR. Restricting the analyses to T2+ tumors, the corresponding figures were: 2.1 (1.1–3.9) for uPA, 1.6 (0.8–3.3) for uPAR and 2.5 (1.1–5.6) for both. We conclude that expression of uPA and uPAR is associated with the clinical behaviour of bladder neoplasms, possibly providing means for refined staging of muscle invasive tumors and target proteins for novel therapies. © 2002 Wiley‐Liss, Inc.
Cancer risk in persons receiving prescriptions for paracetamol: A Danish cohort study
Authors: Friis Søren , Nielsen Gunnar Lauge , Mellemkjær Lene , McLaughlin Joseph K. , Thulstrup Ane Marie , Blot William J. , Lipworth Loren , Vilstrup Hendrik , Olsen Jørgen H.
Published: August 2002

The use of paracetamol has been associated with increased risks for urinary tract cancers and decreased risk for ovarian cancer, although results have been inconsistent. We conducted a population‐based cohort study using data from the Prescription Database of North Jutland County and the Danish Cancer Registry. Cancer incidence among 39,946 individuals receiving prescriptions for paracetamol was compared with expected incidence based on the North Jutland population who did not receive paracetamol prescriptions, during a 9‐year follow‐up period. Standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (95% CIs) were calculated for cancers overall and at selected sites. Overall, 2,173 cancers were observed with 1,973 expected, yielding a SIR of 1.10 (95% CI, 1.06–1.15). Significantly elevated SIRs were found for cancers of the esophagus (1.9; 95% CI, 1.3–2.8) and lung (1.6; 95% CI, 1.4–1.7). Nonsignificantly increased SIRs were observed for cancers of the liver (1.5; 95% CI, 0.96–2.2), renal parenchyma (1.3; 95% CI, 0.9–1.7) and renal pelvis/ureter (1.6; 95% CI, 0.96–2.6), whereas the SIR for cancer of the urinary bladder was close to unity (1.1; 95% CI, 0.9–1.4). For ovarian cancer, the SIR was close to expectation (0.9; 95% CI, 0.6–1.2) with no evidence of trends with duration of follow‐up or number of prescriptions. A similar risk pattern was observed after exclusion of person‐time experience following prescription for aspirin or other nonsteroidal antiinflammatory drugs in the study cohort and reference population. Our results do not support a major role for paracetamol in the development of cancers of the urinary tract, and we found little evidence of a protective effect of paracetamol against ovarian cancer. The elevated risks for cancers of the esophagus, lung and liver are most likely a result of confounding variables, but may warrant further investigation. © 2002 Wiley‐Liss, Inc.
Proficient mismatch repair protein expression in Hodgkin and Reed Sternberg cells
Authors: Re Daniel , Benenson Lena , Wickenhauser Claudia , Starostik Petr , Staratschek‐Jox Andrea , Müller‐Hermelink Hans Konrad , Diehl Volker , Wolf Jürgen
Published: August 2002

Hodgkin and Reed‐Sternberg (H/RS) cells are characterized by chromosomal instability. Nevertheless, neither specific nor consistent chromosomal alterations could be characterized in H/RS cells. Microsatellite instability (MSI) is another form of genomic instability but its role in the pathogenesis of classical Hodgkin's disease (cHD) has not been investigated so far. We analyzed MSI and mismatch repair (MMR) protein expression in H/RS cells of cHD in order to assess genomic instability in these cells. Using a sensitive single cell approach, MSI‐low was detected in a portion of single cells of the H/RS cell line L1236. Mutations of genes encoding for hMSH2 and hMLH1 were excluded by RT‐PCR in L1236 cells. An analysis of pooled single H/RS cells of seven primary cases of cHD showed loss of heterozygosity for some allelic markers but absence of MSI in all 7 cases. Owing to a tight correlation between MSI‐high, inactivating mutations of MMR genes and MMR protein expression in colon cancer, MMR protein expression commonly is used as a marker for MSI. In order to screen additional primary cases of cHD for MSI, we performed immunohistochemistry for hMSH2 and hMLH1 in 6 of the 7 cases analyzed by single cell PCR and 20 additional cases of cHD. H/RS cells from 25 out of 26 cases showed a nuclear staining pattern for hMSH2 and hMLH1 similar to germinal center B cells of non‐malignant lymph nodes. These results indicate a proficient MMR system in most H/RS cells. It is concluded that a defect MMR system is unlikely to contribute to the malignant phenotype and genomic instability of H/RS cells in cHD. © 2002 Wiley‐Liss, Inc.
Diet, reproductive factors and lung cancer risk among Chinese women in Singapore: Evidence for a protective effect of soy in nonsmokers
Authors: Seow Adeline , Poh Wee‐Teng , Teh Ming , Eng Philip , Wang Yee‐Tang , Tan Wan‐Cheng , Chia Kee‐Seng , Yu Mimi C. , Lee Hin‐Peng
Published: August 2002

The factors associated with risk of lung cancer among nonsmokers have not been fully elucidated, but dietary factors have consistently been shown to play a role. Chinese women are unique in having a high incidence of lung cancer despite a low smoking prevalence. This population is also known to have a high intake of soy, a dietary source of phytoestrogens. We conducted a hospital‐based case‐control study among Singapore Chinese women, comprising 303 cases and 765 age‐matched controls, of whom 176 cases and 663 controls were lifetime nonsmokers. Data on demographic background, reproductive factors and dietary intake of fruit, vegetables and soy foods were obtained by in‐person interview. We observed an inverse association between intake of total, cruciferous and non‐cruciferous vegetables and risk of lung cancer among smokers. Although smokers in the highest tertile of fruit intake also had a lower risk, this was not statistically significant. Higher intake of soy foods significantly reduced risk of lung cancer among lifetime nonsmokers, but not among smokers. When soy isoflavonoid intake in mg/week was computed based on frequency and portion size of intake of eight common local soy foods, the adjusted OR among nonsmokers for the highest tertile compared to the lowest was 0.56, 95% CI 0.37–0.85 (p for trend <0.01). Fruit intake was also significantly associated with reduced lung cancer risk among nonsmokers, but the effect was not significant after adjustment for soy intake. On the other hand, soy intake remained an independent predictor of risk after controlling for fruit intake. Reproductive effects were also primarily confined to lifetime nonsmokers, among whom having 3 or more livebirths (adjusted OR 0.65, 0.44–0.96) and a menstrual cycle length of more than 30 days (OR 0.46, 0.25–0.84) accorded a significantly reduced risk of lung cancer. Place of birth was significantly associated with risk among nonsmokers (OR 2.6, 1.7–3.9 for China‐born vs. local born) but not among smokers. When analysis was restricted to nonsmokers with adenocarcinomas, the dietary effects were consistent or enhanced. On stepwise regression, soy intake and cycle length emerged as the independent dietary and reproductive predictors of lung cancer risk in nonsmokers. These findings are consistent with other evidence suggesting an involvement of estrogen‐related pathways in lung cancer among non‐smoking women. © 2001 Wiley‐Liss, Inc.
Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population
Authors:   German Consortium for Hereditary Breast and Ovarian Cancer
Published: August 2002

The main focus of this German‐wide multi‐center study was to establish a BRCA1/2 mutation profile and to determine family types with high frequencies of mutations in these genes. In a comprehensive study, the entire coding sequences of the breast cancer genes BRCA1 and BRCA2 were analyzed in 989 unrelated patients from German breast/ovarian cancer families. A total of 77 BRCA1 and 63 BRCA2 distinct deleterious mutations were found in 302 patients. More than ⅓ of these mutations are novel and might be specific for the German population. Eighteen common mutations were found in 68% of cases in BRCA1 and 13 recurrent mutations in 44% of cases in BRCA2, facilitating prescreening approaches. Haplotype analysis indicate that 14 out of 20 recurrent mutations are likely originating from a common founder. An additional 50 different rare sequence variants with unknown relevance for tumorigenesis were found in 72 families. Correlation of BRCA1/BRCA2 detection rates with family history identified families with both breast and ovarian cancer to be at highest risk for BRCA1/BRCA2 mutations (43% and 10%, respectively), followed by families with at least 2 premenopausal cases of breast cancer (24% BRCA1 and 13% BRCA2 mutations). These data provide strong evidence for further predisposing genes in the German population. In breast cancer families with 2 or 3 affected females but only a single or no premenopausal case, mutations were detected with low frequencies (about 10% or less for both genes). The decision for or against molecular diagnosis is now aided by considering the expected mutation detection rates that greatly depend on family history and structure. © 2001 Wiley‐Liss, Inc.
The myxoid liposarcoma specific TLS‐CHOP fusion protein localizes to nuclear structures distinct from PML nuclear bodies
Authors: Thelin‐Järnum Sofia , Göransson Melker , Burguete Alondra Schweizer , Olofsson Anita , Åman Pierre
Published: August 2002

CHOP in 12q13, also called GADD153 or DDIT3, encodes a transcription factor of the C/EBP type. As a result of t(12;16) translocations, CHOP is rearranged and fused to TLS in 16p11 in about 90% of myxoid liposarcomas/round cell liposarcomas (MLS/RCLS). The TLS‐CHOP protein consists of the N‐terminal half of TLS juxtaposed to the N‐terminal of the entire CHOP. It is capable of forming dimers with the natural dimer partners of CHOP. Here we report that recombinant TLS‐CHOP‐green fluorescence protein localizes to nuclear structures, similar to, but distinct from, PML nuclear bodies. The TLS‐CHOP‐green fluorescent protein nuclear structures are resistant to high salt concentration and nuclease treatment. Transfection of TLS‐CHOP to normal fibroblasts causes a rapid down regulation and relocation of PML nuclear bodies. An abnormal extra nuclear localization of PML bodies was also found in TLS‐CHOP carrying cell lines established from myxoid liposarcomas. Transfection of TLS‐CHOP induced a rapid disappearance of PCNA. TLS‐CHOP may disturb the nuclear machinery by binding and sequestering important factors from their natural sites. © 2001 Wiley‐Liss, Inc.
Leaving Home in Europe: The Experience of Cohorts Born Around 1960
Authors: Billari Francesco C. , Philipov Dimiter , Baizán Pau
Published: August 2002

In the paper we analyse the leaving‐home experience of men and women born around 1960 in 16 European countries. We use extensive empirical evidence from Fertility and Family Survey data, providing a large‐scale comparison. We focus on some key indicators of the process of leaving home: the timing, sequencing and synchronisation of leaving home with the end of education and the formation of a first union. As far as these dimensions of leaving home are concerned, Europe appears to be extremely heterogeneous, and explaining this will undoubtedly be a challenge. The complex interplay between the present economic situation of young people and long‐term institutional and cultural factors is thought to be the main driving factor. Our findings constitute a benchmark against which subsequent behaviour, such as that of cohorts coming of age after the fall of the Iron Curtain, could be compared. Copyright © 2001 John Wiley & Sons, Ltd.
Scilab as an econometric programming system
Authors: Mrkaic Mico
Published: August 2002

This article reviews Scilab, a free MATLAB‐like programming system. Scilab can be used for data analysis and applied numerical work in both research and teaching. Scilab is an interesting alternative to some commercial programming environments. Copyright © 2001 John Wiley & Sons, Ltd.
Modelling the trend and seasonals within an AIDS model of the demand for alcoholic beverages in the United Kingdom
Authors: Moosa I. A. , Baxter J. L.
Published: August 2002

The argument that is put forward in this paper is that failure to represent stochastic trend and stochastic seasonality in an AIDS model leads to a misspecified and possibly structurally unstable model. This proposition is verified by estimating an AIDS model of the demand for alcoholic beverages in the United Kingdom. Three versions of the model are estimated, and it is demonstrated that the version allowing for stochastic trend and stochastic seasonality performs better than the other two versions of the model in terms of the diagnostics tests and goodness of fit measures. The best estimated model turns out to possess the properties of having common components and being homogenous. Further empirical testing reveals the presence of stochastic trends and cointegration between the budget shares of beer and wine. The results clearly indicate that there has been a shift away from the consumption of beer towards wine. Copyright © 2002 John Wiley & Sons, Ltd.
Cytokine fingerprinting and hazard assessment of chemical respiratory allergy
Authors: Dearman R. J. , Kimber I.
Published: August 2002

Allergic sensitization of the respiratory tract resulting in occupational asthma and other symptoms can be caused by a variety of chemicals and represents an important occupational health problem. Although there is a need to identify and characterize those chemicals that are able to cause respiratory allergy, there are currently no well validated or widely accepted predictive test methods. Some progress has been made with guinea pig assays, but our attention in this laboratory has focused instead on the development of novel approaches based on an understanding of the nature of immune responses induced in mice by chemical allergens. We have shown that whereas contact allergens provoke in mice selective type 1 immune responses, characterized by the secretion by draining lymph node cells (LNC) of high levels of the cytokine interferon γ (IFN‐γ), chemical respiratory allergens stimulate instead preferential type 2 responses associated with comparatively high levels of interleukins 4 and 10 (IL‐4 and IL‐10). The divergent immune responses provoked by different classes of chemical allergens, and the phenotypes of selective cytokine secretion that characterize such responses, form the basis of a novel method—cytokine fingerprinting—that permits chemicals that have the potential to cause respiratory allergy to be identified and distinguished from those that are associated primarily with contact sensitization. In this article the immunobiological basis for cytokine fingerprinting is considered and the development, evaluation and practical application of the assay are reviewed. Copyright © 2001 John Wiley & Sons, Ltd.
Structure–hepatoprotective activity relationship of 3,4‐dihydroxycinnamic acid (caffeic acid) derivatives
Authors: Pérez‐Alvarez V. , Bobadilla R. A. , Muriel P.
Published: August 2002

3,4‐Dihydroxycinnamic acid (caffeic acid, CAF) is a natural product containing a catechol group with an α,β‐unsaturated carboxylic acid chain that has shown hepatoprotective properties. The aim of this work was to determine the importance of the 4‐hydroxy, 3‐hydroxy, 3,4‐dihydroxy substituents and the double bond moiety on the hepatic pharmacological effects of the molecule. We compared the ability of the caffeic, 4‐hydroxycinnamic, 3‐hydroxycinnamic, cinnamic and 3,4‐dihydroxyhydrocinnamic (a caffeic acid analogue without the double bond) acids at a dose of 50 mg kg−1, p.o., to reduce the liver damage produced by CCl4 (4 g kg−1, p.o.) intoxication in the rat. Cinnamic acid, the non‐hydroxylated analogue, only modestly protected the experimental animals challenged with CCl4, suggesting that hydroxyl groups participate in the pharmacological properties of CAF. The 3,4‐dihydroxyhydrocinnamic derivative did not show any significant differences when compared with the CAF effect in this model, suggesting that the double bond does not account for the liver pharmacological properties of CAF. In contrast, the 4‐hydroxy substituent seems to be very important for hepatoprotective activity because the 4‐hydroxy analogue improved almost every hepatic injury marker altered by CCl4, and in a better way than CAF did. Copyright © 2001 John Wiley & Sons, Ltd.