bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractClinicopathologically, 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

AbstractAberrant 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

AbstractThe 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

AbstractOsteolytic 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

AbstractThe 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

AbstractWe 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

AbstractThe 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

AbstractA 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

AbstractThis 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

AbstractThis 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

AbstractRevision 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

AbstractMuscle 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
Resorbable defect analog PLGA scaffolds using CO2 as solvent: Structural characterization
Authors: Maspero F. A. , Ruffieux K. , Müller B. , Wintermantel E. 
Published: September 2002

AbstractAfter tooth extraction, the immediate wound treatment by implanting an exact copy of the root could prevent alveolar bone atrophy. The implant should have an interconnected porosity in order to promote tissue in‐growth. This communication reports a novel method to realize such net‐shaped porous scaffolds fabricated within a few minutes. Porosity and micro‐architecture are evaluated by Hg‐porosimetry and by image analysis of electron and light microscopy as well as by computed micro‐tomography. The total porosity of the scaffold corresponds to (63 ± 3)%, mainly related to open interconnected porosity. Micro‐tomography, as a noninvasive 3D method, is best suited to uncover pores of about 100 μm, a diameter especially important for tissue in‐growth. The differentiation between open and closed porosity, however, depends on the method chosen. This effect is attributed to the spherical pores with an orifice only detected in the 3D analysis. Consequently, the closed porosity is overestimated by 8% evaluating 2D images. Finally, the mean pore diameter is found to be 106 and 100 μm for 2D and 3D analysis, respectively. Although the porosity of the scaffold needs to be further optimized for clinical applications, the procedure proposed is a promising route in manufacturing open porous implants without the use of any organic solvent. © 2002 Wiley Periodicals, Inc. J Biomed Mater Res 62: 89–98, 2002
Synthesis of functionally graded MgCO3 apatite accelerating osteoblast adhesion
Authors: Yamasaki Y. , Yoshida Y. , Okazaki M. , Shimazu A. , Uchida T. , Kubo T. , Akagawa Y. , Hamada Y. , Takahashi J. , Matsuura N. 
Published: September 2002

AbstractAs a means of improving the biological properties of materials for use as bone substitutes, functionally graded carbonate apatite containing Mg, FGMgCO3Ap, was synthesized at 60°C and pH 7.4 using a gradient magnesium supply system. X‐ray diffraction analysis of FGMgCO3Ap showed a poorly crystallized apatitic pattern, similar to that of human bone. ESCA analysis clearly showed the negative gradient distribution in Mg1s intensity (atomic concentration) of magnesium from the crystal surface toward the inner core. When the FGMgCO3Ap crystals were mixed with collagen, the resulting FGMgCO3Ap‐collagen composite, irradiated with UV light for 4 h, retained their features in the saline solution. After washing away the nonadhesive cells, a cell adhesion assay showed that the optical density of the FGMgCO3Ap‐collagen composite was higher than that of the CO3Ap‐collagen composite. SEM observation showed that the osteoblast‐like cells adhered well to the surface of the FGMgCO3Ap‐collagen composite. Staining with hematoxylin‐eosin and alizarin red confirmed the existence of a great many more cells and a thicker extracellular matrix layer on the FGMgCO3Ap‐collagen composite than on the CO3Ap‐collagen composite. This result demonstrated the acceleration effect of magnesium ions on osteoblast adhesion on the FGMgCO3Ap‐collagen composite. © 2002 Wiley Periodicals, Inc. J Biomed Mater Res 62: 99–105, 2002