bluuebunny/crossref_metadata_2025 huggingface dataset:
Robust evaluation of fixed‐event forecast rationality
Authors: Clements Michael P. , Taylor Nick
Published: September 2002

In this paper we introduce a new testing procedure for evaluating the rationality of fixed‐event forecasts based on a pseudo‐maximum likelihood estimator. The procedure is designed to be robust to departures in the normality assumption. A model is introduced to show that such departures are likely when forecasters experience a credibility loss when they make large changes to their forecasts. The test is illustrated using monthly fixed‐event forecasts produced by four UK institutions. Use of the robust test leads to the conclusion that certain forecasts are rational while use of the Gaussian‐based test implies that certain forecasts are irrational. The difference in the results is due to the nature of the underlying data. Copyright © 2001 John Wiley & Sons, Ltd.
Homozygous deletion in a neuroblastoma cell line defined by a high‐density STS map spanning human chromosome band 1p36
Authors: Chen Ying Zhang , Soeda Eiichi , Yang Hong Wei , Takita Junko , Chai Ling , Horii Akira , Inazawa Johji , Ohki Misao , Hayashi Yasuhide
Published: September 2002

Recent molecular studies have shown a relatively high rate of loss of heterozygosity (LOH) in neuroblastoma (NB) as well as other types of tumors in human chromosome band 1p36. To identify candidate tumor suppressor genes in NB, we searched for homozygous deletions in NB cell lines with PCR according to a high‐density sequence tagged site (STS)‐content map spanning 1p35–36. Among 25 NB cell lines examined, only one cell line, NB‐1, showed no signal with 27 STSs in a 480 kb region in 1p36.2. The sequence analysis has revealed that the defective region included seven known genes (E4, KIF1B, SCYA5, PGD, Cortistatin, DFF45, and PEX14), nine expressed sequence tags (ESTs), and two microsatellite markers. These genes are related to apoptosis, an ubiquitin‐proteasome pathway, a neuronal microtubule‐associated motor molecule, and components of a common translocation machinery. The region between the DFF45 and KIF1B genes was defined as homozygous deletion by Southern blotting. The search in LOH regions with high‐density STSs may be useful for the isolation and identification of tumor suppressor genes in other tumors as well as NBs. © 2001 Wiley‐Liss, Inc.
Clinical impact of molecular and cytogenetic findings in synovial sarcoma
Authors: Panagopoulos Ioannis , Mertens Fredrik , Isaksson Margareth , Limon Janusz , Gustafson Pelle , Skytting Björn , Åkerman Måns , Sciot Raf , Dal Cin Paola , Samson Ignace , Iliszko Mariola , Ryoe Janusz , Dêbiec‐Rychter Maria , Szadowska Anna , Brosjö Otte , Larsson Olle , Rydholm Anders , Mandahl Nils
Published: September 2002

Synovial sarcoma is an aggressive soft‐tissue tumor that accounts for up to 10% of soft‐tissue sarcomas. Cytogenetically, synovial sarcoma is characterized by the t(X;18)(p11;q11), found in more than 95% of the tumors. This translocation results in rearrangements of the SYT gene in 18q11 and one of the SSX1, SSX2, or SSX4 genes in Xp11, creating a SYT/SSX1, SYT/SSX2, or SYT/SSX4 chimeric gene. It has been shown that patients with SYT/SSX1 fusion genes have a shorter metastasis‐free survival than do patients with SYT/SSX2. Previous studies have also suggested that clonal evolution may be associated with disease progression. In the present study, RT‐PCR analysis showed that all 64 examined synovial sarcomas from 54 patients had SYT‐SSX chimeric genes. SYT/SSX1 was found in 40 tumors from 33 patients, SYT/SSX2 in 23 tumors from 20 patients, and SYT/SSX4 in one case. Two patients had variant SYT/SSX2 transcripts, with 57 bp and 141 bp inserts, respectively, between the known SYT and SSX2 sequences. Patients with tumors with SYT/SSX1 fusions had a higher risk of developing metastases compared to those with SYT/SSX2 fusions (P = 0.01). The reciprocal transcripts SSX1/SYT and SSX2/SYT were detected using nested PCR in 11 of the 40 samples with SYT/SSX1 and 5 of the 23 samples with SYT/SSX2, respectively. Among 20 blood samples, SYT/SSX1 and SYT/SSX2 were detected in one sample each. The t(X;18), or variants thereof, was found cytogenetically in all patients but three. Among 32 primary tumors, the t(X;18) or a variant translocation was the sole anomaly in 10. In contrast, of the seven metastatic lesions that were investigated prior to radiotherapy, only one had a t(X;18) as the sole anomaly; all other tumors displayed complex karyotypes. Cytogenetic complexity in primary tumors was, however, not associated with the development of metastases. Tumors with SYT/SSX2 less often (4/12 vs. 7/15) showed complex karyotypes than did tumors with SYT/SSX1, but the difference was not significant. Combining cytogenetic complexity and transcript data, we found that the subgroup of patients with tumors showing simple karyotypes and SYT/SSX2 fusion had the best clinical outcome (2/8 patients developed metastases), and those with tumors showing complex karyotypes together with SYT/SSX1 fusion the worst (6/7 patients developed metastases). This corresponded to 5‐year metastasis‐free survival rates of 0.58 and 0.0, respectively (P = 0.02). © 2001 Wiley‐Liss, Inc.
A plains ceramic clay source characterization by comparative geochemical and petrographic analyses: Results from the Calhan Paint Mines, Colorado, U.S.A.
Authors: Phillips Scott C. , Morgenstein Maury
Published: September 2002

The Calhan Paint Mines District, 5EP3258, Colorado, presents exposures of an exceptional clay source. When the area also produced prehistoric Ceramic stage sites, it provided the opportunity for both pottery and potential clay source analysis by optical petrography, X‐ray diffraction, and neutron activation. Although the main purpose of this study is the characterization of the ceramics and outcrop clays, results from a limited number of samples suggest that the colorful clays, the figurative “paints,” of the Calhan Paint Mines were purposely used in prehistoric times as clay source materials for ceramic production. The Calhan Paint Mines are quite possibly the only prehistoric Plains Ceramic stage clay source currently confirmed within the state of Colorado. © 2002 Wiley Periodicals, Inc.
Studies on low‐coordinated nitrogen, phosphorus, sulfur, and selenium compounds
Authors: Inamoto Naoki
Published: September 2002

The major studies of my laboratory on heteroatom chemistry are briefly outlined and include the following topics: (1) novel radical reactions to kinetic stabilization of organosulfur and selenium compounds, (2) novel reactions of organophosphorus compounds, (3) reaction of the S atom to stabilization of o‐thioquinonemethides, (4) N‐nitrosoimines stabilized by heterocycles to hypervalent sulfur compounds, and (5) phosphinidenes (R‐P) to kinetic stabilization of low‐coordinated organophosphorus compounds. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:183–194, 2001
Radico‐catalysis: possible involvement of a cobalt(II) complex in the free radical reactions of sulfur functions
Authors: Tada Masaru
Published: September 2002

A cobalt(II) complex is paramagnetic and can be coordinated with sulfur functions; the coordination complex delocalizes an unpaired electron from cobalt(II) to the sulfur functions such as thioester and vinyl sulfide. Thus, the generation of partial unpaired electron density on the sulfur functions induces or modifies the reactions of the organo free radical containing the sulfur function. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:204–208, 2001
Formation of antimony–sulfur double‐bond compounds and their trapping with nitrile oxides
Authors: Tokitoh Norihiro , Arai Yoshimitsu , Sasamori Takahiro , Takeda Nobuhiro , Okazaki Renji
Published: September 2002

The reaction of a highly crowded dihydrostibine [2,4,6‐tris[bis(trimethylsilyl)methyl]phenyl‐SbH2 (TbtSbH2) (1)] with elemental sulfur in the presence of nitrile oxides resulted in the formation of [2 + 3] cycloaddition reaction products of a thioxostibine [TbtSb=S (6)] and a dithioxostiborane [TbtSb(S)=S (7)], which are among a novel class of antimony–sulfur double‐bond compounds. The structures of the [2 + 3] cycloadducts of dithioxostiborane 7 with nitrile oxides were determined by X‐ray structural analysis. Desulfurization of highly crowded antimony‐containing cyclic polysulfides [TbtSbSx (4: x = 5; 5: x = 7)] with phosphine reagents also resulted in the formation of 6 and 7. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:244–249, 2001
Additional Resources
Authors: Ikeda Elaine K.
Published: September 2002

A number of core resources can help faculty begin or improve service‐learning at their institution.
Networks
Authors: Maughan George R. , Petitto Karen R. , McLaughlin Don
Published: September 2002

Campus leaders must understand the connectivity features and options of modern campus communication and information systems networks to make sound future‐oriented decisions.
Leadership
Authors: Poley Janet K.
Published: September 2002

Leadership in guiding the evolution of a college's or university's technology must recognize a context of complex collaborations.
Ifosamide, epirubicin and granulocyte colony‐stimulating factor: a regimen for successful mobilization of peripheral blood progenitor cells in patients with multiple myeloma
Authors: Arland M. , Leuner S. , Lange S. , Bartsch R. , Kahl C. , Florschütz A. , Franke A. , Höffkes H.‐G.
Published: September 2002

In general, the mobilization of peripheral blood progenitor cells (PBPC) in multiple myeloma (MM) patients is poor and is achieved in most cases by combined cyclophosphamide and G‐CSF. This study was performed to examine the efficacy of combined ifosfamide/epirubicine and G‐CSF for PBPC mobilization and purging. Sixteen patients suffering from multiple myeloma in stage II/A and III/A according to Durie and Salmon underwent chemotherapy consisting of a total of three cycles of ifosfamide (3 g/m2 on days 1 and 2 and epirubicine 80 mg/m2 on day 1) and G‐CSF (10 or 20 µg/kg body weight (BW) daily until harvesting). PBPC harvesting was performed after the first and third cycle of chemotherapy. The median number of PBPC after the first cycle of chemotherapy was 7.79×106 CD34+ cells/kg BW (ranging from 0.94–26.36×106) and 6.38×106 CD34+ cells/kg BW (ranging from 0.79–29.31×106) after the third cycle of chemotherapy. Clinical re‐evaluation after three cycles of chemotherapy showed 13 (81 per cent) patients in partial remission (PR), two (12 per cent) in complete remission (CR) and one (6.25 per cent) in stable disease (SD). No major side‐effects were observed, six patients developed hematological toxicity stage IV WHO for a median of 3.9 days but no serious infection episodes occurred. Combined ifosfamide/epirubicin and standard G‐CSF is able to mobilize sufficient PBPC without serious side‐effects for patients with MM and for purging procedures resulting in a high proportion of complete remissions after tandem high‐dose melphalan chemotherapy. Copyright © 2001 John Wiley & Sons, Ltd.
Organizational socialization as instrument and symbol: An extended institutional theory perspective
Authors: Fogarty Timothy J. , Dirsmith Mark W.
Published: September 2002

Organizational socialization can be viewed from the perspective of institutional theory, and institutional theory plays a key role in helping organizations achieve their missions. This article applies a framework to suggest that socialization can be interpreted as a symbolic response to societal expectations. Research propositions are presented that can be used to guide future research on the role of socialization.
Self‐report of memory and affective dysfunction in association with medication use in a sample of individuals with chronic sleep disturbance
Authors: McAndrews Mary Pat , Kayumov Leonid , Phillipson Ron , Shapiro Colin M.
Published: September 2002

Benzodiazepines produce memory disturbance after acute administration. It is not clear whether chronic use of benzodiazepines is hazardous to memory processes. Epidemiological data indicate that a large proportion (10–30 per cent) of individuals with sleep dysfunction take hypnotic aids for a year or longer. The purpose of the present study was to evaluate self‐reported memory dysfunction in a sample of individuals who considered their sleep disturbance sufficiently severe to seek investigation in sleep clinics. It was hypothesized that individuals taking benzodiazepines for sleep would report greater perceived everyday memory failures than individuals taking other sleep aids or no medication. Questionnaires were given to 368 individuals referred into the study by investigators in six sleep disorders clinics. All respondents completed a lengthy (700‐item) questionnaire, which included scales assessing memory difficulties, affective status and sleep disturbance. Respondents also reported any medication use for sleep problems and duration of use of the current drug. Information on medication use was reported by 289 participants. Fifty‐six per cent of respondents reported using some form of psychoactive medication (antidepressants, benzodiazepines, Zopiclone). Twenty‐two per cent reported using no medication. Analysis of covariance showed that these medications had no detectable effect on subjective memory difficulties during chronic use, F(4,226)=1·34, p=0·25. Copyright © 2000 John Wiley & Sons, Ltd.
Enhancement of cisplatin‐induced apoptosis by infection with adeno‐associated virus type 2
Authors: Duverger Valerie , Sartorius Ute , Klein‐Bauernschmitt Petra , Krammer Peter H. , Schlehofer Jörg R.
Published: September 2002

The non‐pathogenic human adeno‐associated virus, AAV, has been shown to sensitize human cancer cells and experimental tumors towards the action of chemotherapeutic agents such as cisplatin. Since chemotherapeutic drugs mainly involve the induction of apoptosis, we investigated whether 1 possible mechanism of AAV‐mediated sensitization of human tumor cells may result from an enhancement of cisplatin‐induced apoptosis. In HeLa and A549 cells, infection with AAV type 2 (AAV‐2) increased cisplatin‐induced DNA fragmentation but had no cytotoxic effect by itself. This enhanced apoptosis appeared to be mediated at least in part by a component of the viral capsid since empty or UV‐inactivated AAV‐2 particles were also able to boost cisplatin‐induced DNA fragmentation. Interestingly, these effects were not observed after infection with AAV type 5 (AAV‐5) or the autonomous parvovirus, H‐1. AAV‐2‐mediated enhancement of apoptosis was not associated with a modification of the expression of CD95 ligand, CD95 receptor or other death receptors, as shown by RT‐PCR and RNase protection assay. In contrast, using the mitochondrial fluorescent dye, JC‐1 in flow cytometry, AAV‐2 infection was found to further reduce the mitochondrial transmembrane potential after treatment with cisplatin in a caspase‐independent manner, suggesting that increase of apoptosis by AAV‐2 occurred at the mitochondrial level. In contrast, in cells of the small cell lung cancer line, P693, an enhancement of cisplatin‐induced DNA fragmentation was not observed after infection with AAV‐2. In these cells, sensitization to cisplatin‐toxicity was associated with cell cycle arrest in G2/M. The data indicate that in the absence of viral gene expression, AAV‐2‐mediated sensitization to cisplatin involves multiple cellular pathways promoting cell death signals in a cell type‐dependent manner. The results further support that AAV‐2 particles may be appropriate adjuvants for improving cancer chemotherapy and may also have consequences regarding AAV‐2‐based vectors for gene therapy. © 2001 Wiley‐Liss, Inc.
Dominant‐negative inhibition of breast cancer resistance protein as drug efflux pump through the inhibition of S‐S dependent homodimerization
Authors: Kage Kumie , Tsukahara Satomi , Sugiyama Tomomi , Asada Sakiyo , Ishikawa Etsuko , Tsuruo Takashi , Sugimoto Yoshikazu
Published: September 2002

Breast cancer resistance protein (BCRP) is a half‐molecule ABC transporter highly expressed in mitoxantrone‐resistant cells. In our study we established PA317 transfectants expressing Myc‐tagged BCRP (MycBCRP) or HA‐tagged BCRP (HABCRP). The exogenous BCRP protein migrated as a 70‐kDa protein in SDS‐PAGE under reducing condition, but migrated as a 140‐kDa complex in the absence of reducing agents. The 140‐kDa BCRP complex was heat‐stable but dissociated into 70‐kDa BCRP with the addition of 2‐mercaptoethanol. The 140‐kDa BCRP complex was immunoprecipitated with anti‐Myc antibody from the lysates of PA317 cells double‐transfected with MycBCRP and HABCRP. The 140‐kDa complex reacted with anti‐HA and anti‐BCRP antibodies and after the addition of reducing agents, a 70‐kDa protein reacting with anti‐Myc, anti‐HA and anti‐BCRP antibodies was detected. These results clearly indicate that BCRP forms a homodimer bridged by disulfide bonds. To assess the possible dominant‐negative inhibition of BCRP drug efflux pump, various mutant BCRP cDNAs were isolated by PCR mutagenesis. First, mutant BCRP cDNAs were introduced to parental PA317 cells and tested for their function as drug‐resistance genes. Next, inactive BCRP cDNA clones were introduced to MycBCRP‐transfected cells and tested for the ability to lower drug resistance. Among the 8 inactive mutant cDNA clones tested, HABCRP cDNA clone 15 with an amino acid change from Leu to Pro at residue 554 in the fifth transmembrane domain of BCRP partially reversed the drug resistance of MycBCRP‐transfected cells. These results suggest that homodimer formation is essential for BCRP drug resistance, implicating this dominant‐negative inhibition as a new strategy to circumvent drug resistance. © 2001 Wiley‐Liss, Inc.
RPR‐115135, a farnesyltransferase inhibitor, increases 5‐FU‐ cytotoxicity in ten human colon cancer cell lines: Role of p53
Authors: Russo Patrizia , Malacarne Davide , Falugi Carla , Trombino Sonya , O'Connor Patrick M.
Published: September 2002

A new non peptidic farnesyltransferase inhibitor, RPR‐115135, in combination with 5‐FU was studied in 10 human colon cancer cell lines (HCT‐116, RKO, DLD‐1, Colo‐320, LoVo, SW‐620, HT‐29, HCT‐15, Colo‐205 and KM‐12) carrying several mutations but well characterized for p53 and Ras status. We found that there was a slight tendency (not statistically significant) for the p53 inactivated cells to be less sensitive to 5‐FU after 6 days continuous treatment. Simultaneous administration of RPR‐115135 and 5‐FU, at subtoxic concentrations, resulted in a synergistic enhancement of 5‐FU cytotoxicity in the p53 wildtype cells (HCT‐116, RKO, DLD‐1, Colo‐320, LoVo). In the p53 mutated cells (SW‐620, HT‐29, HCT‐15, Colo‐205, KM‐12) the effect was very complicated. In HCT‐15 the combination resulted in antagonism, in KM‐12 in antagonism or in synergy (at different concentrations) and in SW‐620, HT‐29 and Colo‐205 cells in synergy but only when 5‐FU was administered at high concentrations. Growth inhibition could be accounted for on the basis of a specific cell cycle arrest phenotype (G2‐M arrest), as assayed by flow cytometry, only in the p53 functioning cell lines. The combination RPR‐115135 + 5‐FU increases apoptotic events only in these cell lines. In the mutated cell lines no major alterations on cell cycle arrest phenotype and no induction of apoptosis was observed. Although RPR‐115135 can potentiate the effect of 5‐FU in cells in which p53 function is disrupted, these data suggest strongly that RPR‐115135 significantly enhances the efficacy of 5‐FU only when p53 is functioning. © 2002 Wiley‐Liss, Inc.
Food groups and laryngeal cancer risk: A case‐control study from Italy and Switzerland
Authors: Bosetti Cristina , La Vecchia Carlo , Talamini Renato , Negri Eva , Levi Fabio , Dal Maso Luigino , Franceschi Silvia
Published: September 2002

Besides tobacco and alcohol, diet has been thought to be associated with laryngeal cancer risk. We thus analyzed the role of various food groups, as well as specific seasoning fats, in a case‐control study conducted in Northern Italy and the Swiss Canton of Vaud from 1992 to 2000. Our study included 527 incident, histologically confirmed cases and 1,297 frequency‐matched controls, selected among patients admitted to the same hospitals as cases for acute, nonneoplastic conditions, unrelated to smoking, alcohol consumption and long‐term modifications of diet. The subjects' usual diet was investigated through a validated food frequency questionnaire, including 78 foods and beverages. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional multiple logistic regression models. After adjustment for major confounding factors, a significant trend of increasing risk was observed for eggs (OR = 1.7 for the highest compared to the lowest quintile), red meat (OR = 3.1), processed meat (OR = 1.7), fish (OR = 1.6) and sugars (OR = 1.6). Significant inverse associations were observed for pulses (OR = 0.7), raw vegetables (OR = 0.2), cooked vegetables (OR = 0.3), citrus fruit (OR = 0.6) and other fruit (OR = 0.5). In regard to seasoning fats, a significant reduction of cancer risk was observed for olive oil (OR = 0.4) and specific seed oils (OR = 0.6), while mixed seed oils were directly associated with laryngeal cancer risk (OR = 2.2). Our study suggests that increasing vegetables and fruit, decreasing meat consumption and perhaps substituting olive oil or specific seed oils for other types of seasoning lipids might help reduce laryngeal cancer risk. © 2002 Wiley‐Liss, Inc.
Human breast adenocarcinoma cell lines promote angiogenesis by providing cells with uPA‐PAI‐1 and by enhancing their expression
Authors: Bajou Khalid , Lewalle Jean‐Marc , Martinez Christian Rodriguez , Soria Claudine , Lu He , Noël Agnès , Foidart Jean‐Michel
Published: September 2002

During angiogenesis, endothelial cells use uPA and PAI‐1 to migrate and degrade the basement membrane surrounding capillary blood vessels. Invasive tumor cells produce a large amount of uPA that could bind uPAR present at the endothelial cell surface to facilitate their invasion. To verify this hypothesis, endothelial cells were incubated with conditioned medium (CM) from two breast cancer cell lines (MCF7 and MDA MB 231 cells). Within a short incubation period (30 min) with both CM, an increase of uPA, PAI‐1 and uPA‐PAI‐1 complex was detected in endothelial cell layer as assessed by casein zymography, ELISA and uPA immunostaining. The extent of this enhancement was related to the levels of uPA secreted by tumor cells (high in MDA MB 231 cells and low in MCF7 cells). After 2 hr of incubation, the CM from both tumor cells upregulated uPA and PAI‐1 mRNA levels in endothelial cells in a time‐dependent manner. The uPA increase in the cell layer could not be attributable to an increase of uPAR level. Only the CM from highly invasive MDA MB 231 cells increased the angiogenic morphotype of endothelial cells assessed in a collagen gel. A single addition of amino‐terminal fragment of uPA (ATF) was able to abolish the angiogenic effect induced by MDA MB 231 cell CM. Our data demonstrate that the interactions occurring between breast tumor cells and endothelial cells can modulate tumor angiogenesis at least by two mechanisms: an increase of uPA and PAI‐1 cell surface‐binding and of their expression by endothelial cells. © 2002 Wiley‐Liss, Inc.
Protein phosphatase‐2A regulates endothelial cell motility and both the phosphorylation and the stability of focal adhesion complexes
Authors: Young M. Rita I. , Kolesiak Kristin , Meisinger Jeremy
Published: September 2002

Solid cancers must stimulate expansion of the vascular network for continued growth. The process of angiogenesis involves endothelial cell migration so as to reorganize into vessel structures. The extent of cellular motility is regulated in part by the balance between serine/threonine kinases and protein phosphatases. In the present study, we show a decline in the activity of the serine/threonine phosphatase PP‐2A in endothelial cells whose motility is stimulated by exposure to medium conditioned by either murine LLC cells or human HNSCC cells. Inhibition of endothelial cell PP‐2A pharmacologically by treatment with okadaic acid also stimulated endothelial cell motility. Identification of mechanisms by which PP‐2A inhibition might stimulate endothelial cell motility focused on proteins of the focal adhesions. Inhibition of PP‐2A caused hyperphosphorylation of the paxillin serine residues and dephosphorylation of its tyrosine residues, dissolution of FAK/Src/paxillin complexes and decreased phosphorylation of the inhibitory Y529 residue of Src, suggesting increased Src activity. Inhibition of Src activity prevented the stimulation of PP‐2A‐inhibited cell motility. Our results suggest an interrelationship between tumor inhibition of PP‐2A, dissolution of focal adhesion complexes and stimulated motility of endothelial cells. © 2002 Wiley‐Liss, Inc.
SH2D1A expression in Burkitt lymphoma cells is restricted to EBV positive group I lines and is downregulated in parallel with immunoblastic transformation
Authors: Nagy Noémi , Maeda Akihiko , Bandobashi Kentaro , Kis Loránd L. , Nishikawa Jun , Trivedi Pankaj , Faggioni Alberto , Klein George , Klein Eva
Published: September 2002

The SH2 domain containing SH2D1A protein has been characterized in relation to the X‐linked lymphoproliferative disease (XLP), a primary immunodeficiency that leads to serious clinical conditions after Epstein‐Barr virus (EBV) infection. The SH2D1A gene is mutated in the majority of XLP patients. We previously detected SH2D1A in activated T and NK cells, but not in B lymphocytes. We have found SH2D1A protein in Burkitt lymphoma (BL) lines, but only in those that carried EBV and had a Group I (germinal center) phenotype. All the EBV‐carrying Group III (immunoblastic) and the EBV‐negative BL lines tested were SH2D1A‐negative. Motivated by these differences, we studied the impact of EBV and the cellular phenotype on SH2D1A expression. We approached the former question with BL sublines after both the loss of the virus and subsequent reinfection. We also tested original EBV‐negative BL lines carrying transfected EBV genes, such as EBNA1, EBNA2, EBNA6, EBER1, 2 and LMP1, respectively. In our experiments, no direct relationship could be seen between EBV and SH2D1A expression. We modified the phenotype of the Group I BL cells by LMP1 transfection or CD40 ligation. The phenotypic changes, indicated by expression of immunoblastic markers, e.g., SLAM, were accompanied by downregulation of SH2D1A. It seems, therefore, that the presence of EBV and the phenotype of the cell together regulate SH2D1A expression in the BL cells. It is possible that SH2D1A is expressed in a narrow window of B cell development represented by germinal center cells. © 2002 Wiley‐Liss, Inc.
Mucin phenotype and microsatellite instability in early multiple gastric cancers
Authors: Takahashi Hiroaki , Endo Takao , Yamashita Kentaroh , Arimura Yoshiaki , Yamamoto Hiroyuki , Sasaki Shigeru , Itoh Fumio , Hirata Koichi , Imamura Akimichi , Kondo Masafumi , Sato Toshihiro , Imai Kohzoh
Published: September 2002

Clinicopathologically, multiple gastric cancers (MGCs) are reported to involve predominantly intestinal‐type adenocarcinoma and frequently to be associated with severe intestinal metaplasia. However, there are few reports concerning the characteristic biomarkers of early MGCs. The aim of our study was to identify the cellular lineage defined by mucin phenotypes and the relationships among mucin phenotypes, background mucosa and microsatellite instability (MSI) of early MGCs. We examined mucin phenotypes of 63 surgically resected carcinomas from 25 patients with early MGCs and 39 early solitary gastric cancers (SGCs) by immunohistochemical analysis using a panel of monoclonal antibodies. MSI and the degree of intestinal metaplasia (IM) on the background mucosa were also examined. In early MGCs, the incidence of cancer exhibiting the gastric phenotype (G‐type) was 59% (37 of 63 cancers), which was higher than that in early SGCs (23%, 9 of 39 cancers). There was a significant difference between the distributions of mucin phenotypes in early MGCs and early SGCs (p = 0.001). Whereas half of the G‐type cancers in early MGCs were related to severe IM, none of the G‐type cancers in early SGCs were related to severe IM. In the early MGCs, MSI was observed in 21 of 63 cancers (33.3%). In contrast, MSI was observed in only 3 of the 39 (7.7%) early SGCs, indicating a significant difference between these 2 groups (p < 0.01). Our results suggest that the characteristic features of early MGCs are the gastric mucin dominant phenotype and high frequency of MSI. © 2002 Wiley‐Liss, Inc.
Molecular genetic analysis of malignant melanomas for aberrations of the WNT signaling pathway genes CTNNB1, APC, ICAT and BTRC
Authors: Reifenberger Julia , Knobbe Christiane B. , Wolter Marietta , Blaschke Britta , Schulte Klaus W. , Pietsch Torsten , Ruzicka Thomas , Reifenberger Guido
Published: September 2002

Aberrant activation of the Wnt signaling pathway has been reported in different human tumor types, including malignant melanomas. We investigated 37 malignant melanomas (15 primary tumors and 22 metastases) for alterations of 4 genes encoding members of this pathway, i.e.,
CTNNB1 (β‐catenin gene, 3p22.1), APC (adenomatous polyposis coli gene, 5q22.2), BTRC (β‐transducin repeat–containing protein gene, 10q24.3) and ICAT (inhibitor of β‐catenin and Tcf‐4, 1p36.2). Mutational analysis of CTNNB1 identified somatic mutations in 1 primary melanoma and 1 melanoma metastasis from 2 different patients (5%). Both mutations affected the N‐terminal degradation box of β‐catenin, which is important for the regulation of β‐catenin homeostasis. Another primary melanoma carried a somatic APC missense mutation within the known mutation cluster region in exon 15. Fourteen tumors (40%) showed LOH at microsatellite markers on 1p36. None of the tumors had lost both copies of the ICAT gene, but 1 melanoma metastasis carried a somatic point mutation altering the translation start codon of ICAT. Real‐time RT‐PCR showed markedly reduced ICAT transcript levels (≤20% relative to normal skin and benign melanocytic nevi) in 28/36 malignant melanomas (78%), including 13/14 tumors with LOH on 1p36. Allelic loss on 10q was detected in 15 tumors (44%). We found neither mutations nor complete loss of expression of the BTRC gene in our melanoma series. Taken together, our results indicate that the Wnt pathway may be altered in malignant melanomas by different mechanisms, including rare somatic mutations in CTNNB1, APC or ICAT, as well as low or absent expression of ICAT transcripts. © 2002 Wiley‐Liss, Inc.
The antifungal drug ciclopirox inhibits deoxyhypusine and proline hydroxylation, endothelial cell growth and angiogenesis in vitro
Authors: Clement Paul M.J. , Hanauske‐Abel Hartmut M. , Wolff Edith C. , Kleinman Hynda K. , Park Myung Hee
Published: September 2002

The hypusine biosynthetic steps represent novel targets for intervention in cell proliferation. Hypusine is a rare amino acid, formed posttranslationally in one cellular protein, eIF5A, and is essential for cell proliferation. Deoxyhypusine hydroxylase, the metalloenzyme catalyzing the final step in hypusine biosynthesis, and prolyl 4‐hydroxylase, a non‐heme iron enzyme critical for collagen processing, can be inhibited by small chelating molecules that target their essential metal atom. We examined the effects of 5 compounds (ciclopirox, deferiprone, deferoxamine, mimosine and 2,2′‐dipyridyl) on these protein hydroxylases in HUVECs, on cell proliferation and on angiogenesis using 2 model assays: tube‐like vessel formation on Matrigel and the chick aortic arch sprouting assay. These compounds inhibited cellular deoxyhypusine hydroxylase in a concentration‐dependent manner, but their efficacy varied widely in the following order: ciclopirox→ deferoxamine→2,2′‐dipyridyl→deferiprone→mimosine (IC50 5–200 μM). Inhibition of DNA synthesis, following the same order (IC50 10–450 μM), correlated with G1 arrest of the cell cycle. These compounds also inhibited proline hydroxylation and maturation of collagen in HUVECs and caused inhibition of angiogenesis in vitro. Of the compounds tested, ciclopirox was by far the most effective inhibitor of HUVEC proliferation and angiogenesis. The strong antiangiogenic activity of this readily available antifungal drug along with its antiproliferative effects suggests a new potential application for ciclopirox in the treatment of solid tumors. Published 2002 Wiley‐Liss, Inc.
Ipriflavone inhibits osteolytic bone metastasis of human breast cancer cells in a nude mouse model
Authors: Iwasaki Teruo , Mukai Mutsuko , Tsujimura Tohru , Tatsuta Masaharu , Nakamura Hiroyuki , Terada Nobuyuki , Akedo Hitoshi
Published: September 2002

Osteolytic bone metastasis is a frequent problem in the treatment of cancer. Ipriflavone, a synthetic isoflavone that inhibits osteoclastic bone resorption, has been used for the treatment of osteoporosis in some countries. Some other isoflavones also exhibit an antitumor effect in vitro and in vivo. Here, we studied the effects of ipriflavone on osteolytic bone metastasis of MDA‐231 human breast cancer cells injected intracardially into athymic nude mice (ICR‐nu/nu). Daily oral administration of ipriflavone at 12 mg/mouse significantly inhibited the development of new osteolytic bone metastases (p < 0.05) and the progression of established osteolytic lesions (p = 0.01), prolonging the life of tumor‐bearing mice (p = 0.01 vs. control). In addition, ipriflavone reduced the number of osteoclasts at the bone–cancer interface with no severe adverse effects on the host. In vitro, ipriflavone inhibited the proliferation and DNA synthesis of MDA‐231 cells and blocked the ligand‐induced phosphorylation of Tyr845 of the EGFR. Ipriflavone did not promote apoptosis of MDA‐231 cells. Our results show that ipriflavone not only directly inhibits the growth of cancer cells but also reduces osteoclasts to prevent the soft tissue tumor burden and osteolytic bone metastases. These findings raise the possibility that ipriflavone may be of use as a therapeutic agent against osteolytic bone metastasis. © 2002 Wiley‐Liss, Inc.
Is growth inhibition and induction of apoptosis in lung cancer cell lines by fenretinide [N‐(4‐hydroxyphenyl)retinamide] sufficient for cancer therapy?
Authors: Ohlmann Carsten‐Henning , Jung Christine , Jaques Gabriele
Published: September 2002

The synthetic retinoid fenretinide [N‐(4‐hydroxyphenyl)retinamide, 4‐HPR] has demonstrated growth inhibition and induction of apoptosis of various malignant cells, including lung cancer cell lines. 4‐HPR is now being investigated in several clinical trials. In our study, we show that 4‐HPR inhibits growth on a broad panel of lung cancer cell lines (12/12 small cell lung cancer and 9/12 nonsmall cell lung cancer cell lines), including cell lines unresponsive to all‐trans‐retinoic acid (ATRA). 4‐HPR revealed a higher potency than ATRA in inhibiting cell growth with IC50 values ranging from 3.3–8.5 μM. Furthermore, 4‐HPR induces apoptosis in lung cancer cell lines as proven by TUNEL and annexin V assay. Despite this, we observed stimulation of growth in 2 SCLC cell lines at 1 μM 4‐HPR. In advance to the clinical application of 4‐HPR, we demonstrate that growth inhibition is reversible after removal of 4‐HPR and that long‐term application is necessary. Through long‐term stimulation with 4‐HPR, we cultivated 3 resistant cell lines that were still inhibited by 4‐HPR after several weeks, however, exhibited almost no apoptosis. These cell lines exhibited morphologic changes, which in the case of the SCLC cell lines suggested differentiation. Our data show that 4‐HPR inhibits growth in lung cancer cell lines by varying mechanisms including (i) cytostasis, (ii) apoptosis and (iii) presumably, differentiation. In contrast, the observed growth stimulation, reversibility of growth inhibition and development of resistance to apoptosis make successful cancer therapy uncertain and may limit clinical application of 4‐HPR in lung cancer patients, although its inhibitory effects last over several weeks. © 2002 Wiley‐Liss, Inc.
Clustering of cancer‐related mutations in a subset of BRCA1 alleles: A study in the Spanish population
Authors: de La hoya Miguel , Sulleiro Sara , Osorio Ana , Díez Orland , Baiget Montserrat , Benítez Javier , Díaz‐Rubio Eduardo , Caldés Trinidad
Published: September 2002

We have observed that the frequency of D17S855 short alleles (139 bp and 141 bp) in individuals carrying BRCA1 germline mutations is higher than in controls (54% vs. 31%, p = 0.0004). By unambiguously establishing mutation/D17S855 phase in 18 BRCA1‐positive families, we find that most (11 of 15 different mutations) BRCA1 defects are linked to chromosomes with short alleles (OR = 8.21, 95% CI 1.97–39.32, p = 0.0007). We suggest that BRCA1 mutations are not randomly distributed but clustered in a subset of BRCA1 alleles that can be identified by D17S855 genotyping. Further analysis involving a larger set of mutations and different populations are needed to clarify the relevance of this unexpected finding. © 2002 Wiley‐Liss, Inc.
Effect of O6‐(4‐bromothenyl)guanine on different temozolomide schedules in a human melanoma xenograft model
Authors: Middleton Mark R. , Thatcher Nicholas , McMurry T. Brian H. , McElhinney R. Stanley , Donnelly Dorothy J. , Margison Geoffrey P.
Published: September 2002

The DNA repair protein O6‐alkylguanine DNA alkyltransferase (ATase) is a major component of resistance to treatment with methylating agents and nitrosoureas. Inactivation of the protein, via the administration of pseudosubstrates, prior to chemotherapy has been shown to improve the latter's therapeutic index in animal models of human tumours. We have also shown that rational scheduling of temozolomide, so that drug is administered at the ATase nadir after the preceding dose, increases tumour growth delay in these models. We now report the results of combining these two approaches. Nude mice bearing A375M human melanoma xenografts were treated with vehicle or 100 mg/kg temozolomide ip for 5 doses spaced 4, 12 or 24 hr apart. Each dose was preceded by the injection of vehicle or 20 mg/kg 4BTG. All treatments resulted in significant delays in tumour quintupling time compared with controls: by 6.2, 5.9 and 16.8 days, respectively, for 24‐, 12‐ and 4‐hourly temozolomide alone and by 22.3, 21.3 and 22.1 days, respectively, in combination with 4BTG. Weight loss due to TMZ was unaffected by the presence of 4BTG. This was of the order of 6.2–10.6% with 24‐ and 12‐hourly administration and 17.4–20.1% (p < 0.0001) with 4‐hourly treatment. In our model, combining daily temozolomide with 4‐BTG confers increased antitumour activity equivalent to that achieved by compressing the temozolomide schedule but with less toxicity. Using temozolomide schedule compression with 4‐BTG does not improve on this result, suggesting that ATase inactivation with pseudosubstrates is a more promising means of enhancing the activity of temozolomide than compressed scheduling. © 2002 Wiley‐Liss, Inc.
Application of differential display to identify genes for lung cancer detection in peripheral blood
Authors: Matsunaga Hiroko , Hangai Nanae , Aso Yoshimasa , Okano Kazunori , Kawamura Masafumi , Kobayashi Kouichi , Kambara Hideki , Hoger Jeff H. , Mitsuhashi Masato
Published: September 2002

A blood assay for detection of lung cancer biomarkers could significantly improve cancer patient prognosis and survival rates. Amplified fragment length polymorphism‐differential display (AFLP‐DD) was used to identify gene transcripts found in lung cancer tissue and the peripheral blood of lung cancer patients. The clones were evaluated for gene expression in lung cancer tissue, peripheral blood of lung cancer patients and healthy volunteers' blood. The isolated gene transcript clones were found to be from the syndecan 1 gene, collagen 1 gene and 2 novel genes. All 4 transcripts were expressed in normal lung tissue, 4 cultured primary lung cells and 6 lung cancer cell lines. RNA was isolated from peripheral blood samples of 69 lung cancer patients. Reverse transcriptase polymerase chain reaction (RT‐PCR) was used to test for the presence of cytokeratin 19 and the 4 gene mRNA transcripts in blood RNA. The positive detection rate of at least 1 of the 5 transcripts was 79% for lung adenocarcinoma and 62% for squamous carcinoma. Using RT‐PCR, at least 1 of the markers was found in 53% of stage I patients, 100% of stage II, 71% of stage III and 81% of stage IV lung cancer patients. Blood samples from 20 healthy volunteers were also tested, but only 1 of the 5 transcripts was found in 1 patient. These new molecular markers may aid early detection, staging and follow‐up of lung cancer patients by RNA isolated from blood. © 2002 Wiley‐Liss, Inc.
Earnings, unemployment, and housing in Britain
Authors: Cameron Gavin , Muellbauer John
Published: September 2002

This paper models regional earnings and unemployment in the ten regions of Great Britain between 1972 and 1995, paying particular attention to their interaction and to the important influence of the housing market. In contrast to Blanchard and Katz (1992, 1997) for the United States, we find less persistence in British regional earnings differentials but greater persistence in regional unemployment rates. We find no evidence of a negative effect of the overall unemployment rate on the earnings of men in non‐manual, or women in full‐time, employment. However, for manual men, we find a significant elasticity of around −0.07, comparable with Blanchflower and Oswald (1994). Copyright © 2001 John Wiley & Sons, Ltd.
Estimating shocks and impulse response functions
Authors: Wickens Michael R. , Motto Roberto
Published: September 2002

This paper examines the issue of how to identify the shocks in a cointegrated VAR when the following assumptions are made: the variables can be classified as endogenous or exogenous, there are as many cointegrating relations as endogenous variables, the cointegrating vectors are identified and they contain at least one exogenous variable. It is shown that with these assumptions it is possible to identify the shocks without the use of further restrictions on the covariance matrix of the disturbances or the short‐run dynamics. If the long‐run parameters are known the whole model can be estimated by OLS. The analysis is extended to allow the VAR to have both stationary and non‐stationary variables. An illustration of the method is provided using the traditional benchmark VAR model involving US data on output, prices, interest rates and money. A liquidity effect is not found using this VAR methodology. Copyright © 2001 John Wiley & Sons, Ltd.
In vivo evaluation of a bioactive scaffold for bone tissue engineering
Authors: Livingston T. , Ducheyne P. , Garino J.
Published: September 2002

Revision cases of total hip implants are complicated by the significant amount of bone loss. New materials and/or approaches are needed to provide stability to the site, stimulate bone formation, and ultimately lead to fully functional bone tissue. Porous bioactive glasses (prepared from 45S5 granules, 45% SiO2, 24.5% Na2O, 24.5% CaO, and 6% P2O5) have been developed as scaffolds for bone tissue engineering and have been studied in vitro. In this study, we investigated the incorporation of tissue‐engineered constructs utilizing these scaffolds in large, cortical bone defects in the rat simulating revision conditions. With implantation times of 2, 4, and 12 weeks the results were compared to those using the bioactive ceramic scaffold alone. Two tissue‐engineered constructs were studied: osteoprogenitor cells that were either seeded onto the scaffold prior to implantation (“primary”) or those that were culture expanded to form bonelike tissue on the scaffold prior to implantation (“hybrid”). Defects treated with the hybrid had the greatest amount of bone in the available pore space of the defect over all other groups at 2 weeks (p < 0.05). For both the primary and hybrid groups, woven and lamellar bone was present along the interface of the scaffold and the host cortex and within the porous space of the scaffold at 2 weeks. By 4 weeks, very uniform, lamellar bone was present throughout the scaffold for both tissue‐engineered groups. The amount of bone significantly increased over time for all groups while the bioactive ceramic gradually resorbed by 40% at 12 weeks (p < 0.05). Structural properties of the treated long bones improved over time. Long bones treated with the hybrid had an early return in torsional stiffness by 2 weeks. Both tissue‐engineered constructs achieved normal torsional strength and stiffness by 4 weeks as compared to the scaffold alone, which achieved this by 12 weeks. Porous, surface modified bioactive ceramic is a promising scaffold material for tissue‐engineered bone repair. © 2002 Wiley Periodicals, Inc. J Biomed Mater Res 62: 1–13, 2002
Glycosaminoglycan mimetics (RGTA) modulate adult skeletal muscle satellite cell proliferation in vitro
Authors: Papy‐Garcia Dulce , Barbosa Isabelle , Duchesnay Arlette , Saadi Sihem , Caruelle Jean‐Pierre , Barritault Denis , Martelly Isabelle
Published: September 2002

Muscle regeneration occurs through the activation of satellite cells, which are stimulated to proliferate and to fuse into myofibers that will reconstitute the damaged muscle. We have previously reported that a family of new compounds called “regenerating agents” (RGTAs), which are polymers engineered to mimic heparan sulfates, stimulate in vivo tissue repair. One of these agents, RG1192, a dextran derivative substituted by CarboxyMethyl, Benzylamide, and Sulfate (noted CMBS, RGTA type), was shown to improve greatly the regeneration of rat skeletal muscle after severe crushing, denervation, and acute ischemia. In vitro, these compounds mimic the protecting and stabilizing properties of heparin or heparan sulfates toward heparin‐binding growth factors (HBGFs). We hypothesized that RGTA could act by increasing the bioavailability of some HBGF involved in myoblast growth and thus asked whether RGTA would alter the ability of satellite cells to proliferate. Its effect was tested on primary cultures of rat satellite cells. The RG1192 stimulated the proliferation of satellite cells in vitro in a dose‐dependent manner. It appeared to be as efficient as natural glycosaminoglycans (GAGs; heparan sulfate, dermatan sulfate, or keratan sulfate) in stimulating satellite cell proliferation but was about 100 times more efficient than heparin. RG1192 stimulated satellite cell proliferation by increasing the potency of fibroblast growth factor 2 and scatter factor–hepatocyte growth factor. It also partially restored myoblast proliferation of satellite cells with chlorate‐induced hyposulfation. Taken together, our results explain to some extent the improving effect of RGTA with a CMBS structure, such as the RG1192, on muscle regeneration in vivo by providing support for the hypothesis that RGTA may act by increasing the potency of some HBGFs during the proliferation phase of the regenerating muscle. © 2002 Wiley Periodicals, Inc. J Biomed Mater Res 62: 46–55, 2002