bluuebunny/crossref_metadata_2025_split huggingface dataset:
β‐Catenin activates a coordinated expression of the proinvasive factors laminin‐5 γ2 chain and MT1‐MMP in colorectal carcinomas
Authors: Hlubek Falk , Spaderna Simone , Jung Andreas , Kirchner Thomas , Brabletz Thomas 
Published: June 2004

AbstractIn colorectal carcinomas, loss‐of‐function mutations of the adenomatous polyposis coli (APC) tumor suppressor gene lead to a nuclear accumulation of the oncogenic transcriptional activator β‐catenin, predominantly at the invasive front within the tumor host interface. Various identified genes activated by β‐catenin are associated with tumor invasion. One prerequisite for malignant tumor invasion is the ability of tumor cells to migrate. We recently described the γ2 chain of laminin as another β‐catenin target gene. Fragments of the laminin γ2 chain, resulting from cleavage by the membrane type 1 matrix metalloproteinase (MT1‐MMP), are strong inducers of epithelial cell migration. We here show a coordinated expression of nuclear β‐catenin, its target gene and MT1‐MMP substrate laminin γ2 chain, as well as MT1‐MMP in tumor cells at invasive regions of colorectal carcinomas. We further demonstrate that MT1‐MMP expression is regulated by β‐catenin/TCF through a TCF binding site in its promoter. These results suggest that nuclear β‐catenin activates the coordinated expression of the interacting proinvasive proteins laminin γ2 chain and MT1‐MMP, thereby leading to a promigratory activity at the invasive front of colorectal cancers. This further supports an important role of β‐catenin for invasion and metastasis of colorectal carcinomas. © 2003 Wiley‐Liss, Inc.
The fibroblast: Sentinel cell and local immune modulator in tumor tissue
Authors: Silzle Tobias , Randolph Gwendalyn J. , Kreutz Marina , Kunz‐Schughart Leoni A. 
Published: June 2004

AbstractDevelopment and progression of epithelial malignancies are frequently accompanied by complex phenotypic alterations of resident tissue fibroblasts. Some of these changes, such as myofibroblastic differentiation and an oncofetal extracellular matrix (ECM) expression profile, are also implicated in inflammation and tissue repair. Studies over the past decade revealed the relevance of reciprocal interactions between tumor cells and tumor‐associated host fibroblasts (TAF) in the malignant process. In many tumors, a considerable fraction of the inflammatory infiltrate is located within the fibroblast‐ and ECM‐rich stromal compartment. However, while fibroblasts are known as “sentinel cells” in various nonneoplastic diseases, where they often regulate the composition and function of recruited leucocytes, they are hardly considered active participants in the inflammatory host response in tumors. This article focuses on the functional impact of TAF on immune cells. The complex network of immune‐modulating effects transduced by TAF and TAF‐derived factors is highlighted, and recent reports that support the hypothesis that TAF are involved in the inflammatory response and immune suppression in tumors are reviewed. The role of TAF‐dependent ECM remodeling and TAF‐derived peptide growth factors, cytokines, and chemokines in the immune modulation is stressed and the idea of TAF as an important therapeutic target is emphasized. © 2003 Wiley‐Liss, Inc.
Synergy between anti‐endoglin (CD105) monoclonal antibodies and TGF‐β in suppression of growth of human endothelial cells
Authors: She Xinwei , Matsuno Fumihiko , Harada Naoko , Tsai Hilda , Seon Ben K. 
Published: June 2004

AbstractEndoglin (CD105) is a proliferation‐associated cell membrane antigen of endothelial cells and strongly expressed in the angiogenic vasculature of solid tumors. Endoglin is essential for angiogenesis/vascular development and an ancillary transforming growth factor β (TGF‐β) receptor. Certain anti‐endoglin monoclonal antibodies (mAbs), termed SN6 series mAbs, inhibited angiogenesis, tumor growth and metastasis in mice. We investigated the mechanisms by which anti‐endoglin mAbs suppress growth of proliferating endothelial cells. We found that 4 SN6 series mAbs suppressed growth of human umbilical vein endothelial cells (HUVECs) in a dose‐dependent manner in the absence of any effector cells or complement. Significant differences in the growth suppression between the 4 anti‐endoglin mAbs defining different epitopes were observed. These differences were not determined by antigen‐binding avidities of the mAbs. Combination of TGF‐β1 and each of the 4 anti‐endoglin mAbs exerted synergistic growth suppression of HUVECs. Binding of anti‐endoglin mAbs to endoglin‐expressing cells did not block the subsequent binding of TGF‐β1. Conversely, preincubation of HUVECs with TGF‐β1 did not change cell surface expression of endoglin. The present results suggest that direct suppression of the endothelial cell growth by SN6 series mAbs is one of the underlying mechanisms by which anti‐endoglin mAbs exert antiangiogenic and tumor‐suppressive activity in vivo. The results further suggest that TGF‐β1 plays an important role in the in vivo antiangiogenic efficacy of anti‐endoglin mAbs by synergistically enhancing the activity of these mAbs. Further studies of the present novel findings may provide valuable information about the functional roles of endoglin and anti‐endoglin mAbs in the TGF‐β‐mediated cell regulation. © 2003 Wiley‐Liss, Inc.
High α‐fetoprotein level correlates with high stage, early recurrence and poor prognosis of hepatocellular carcinoma: Significance of hepatitis virus infection, age, p53 and β‐catenin mutations
Authors: Peng Shian‐Yang , Chen Wei J. , Lai Po‐Lin , Jeng Yun‐Ming , Sheu Jin‐Chuan , Hsu Hey‐Chi 
Published: June 2004

Abstractα‐Fetoprotein (AFP) is often elevated in hepatocellular carcinoma (HCC). This study was to elucidate the significance and related factors of AFP elevation in HCC in 781 unifocal HCCs receiving curative hepatectomy. We showed that high AFP (> 200 ng/ml), which was associated with AFP mRNA expression in HCC (p = 0.00001), correlated with major clinicopathologic factors. Younger age (≤ 55 years; p = 0.00001), hepatitis B surface antigen (HBsAg) in serum (p = 0.00001), p53 mutation (p = 0.008), large tumor (p = 0.00001), vascular invasion (p = 0.00001) and early tumor recurrence (p = 0.00001) were significant associates of high AFP, while anti‐HCV in serum and β‐catenin mutation in HCC had less frequent high AFP (p = 0.013 and < 0.0001, respectively). We also showed that HCC with high AFP had a lower 10‐year survival (p < 0.0001), particularly in large HCC (p < 0.0001). At univariate analysis, high AFP (p < 0.0001), HBsAg positivity (p = 0.05), p53 mutation (p = 0.0004), liver cirrhosis (p = 0.0094), large tumor (p = 0.0003), vascular invasion (p < 0.0001) and early recurrence (p < 0.0001) were significant unfavorable prognostic factors. In Cox proportional hazards regression analysis, high AFP remained a borderline significance (OR = 1.2; CI = 1.0–1.4) after adjustment for the effect of tumor size and tumor stage (p = 0.0821). Furthermore, the detection of AFP mRNA in the liver of AFP mRNA‐positive HCC was associated with more frequent early recurrence (p = 0.0026) and might be a useful marker of intrahepatic spread. We therefore conclude that AFP elevation, more than a coincidental epiphenomenon, appears to contribute to vascular invasion and HCC progression and help to identify subsets of HCC patients with increased risk for early recurrence and poor prognosis after hepatectomy. © 2004 Wiley‐Liss, Inc.
Detection of cancer‐related gene expression profiles in severe cervical neoplasia
Authors: Sopov Igor , Sörensen Till , Magbagbeolu Mandy , Jansen Lars , Beer Katrin , Kühne‐Heid Rosemarie , Kirchmayr Richard , Schneider Achim , Dürst Matthias 
Published: June 2004

AbstractThe molecular signatures of 20 severe cervical intraepithelial neoplasia (CIN3) cases and 10 cervical squamous cell cancers were determined to define cancer‐related gene expression profiles. RNAs extracted from microdissected tissues were amplified by SMART technology and used as probes for hybridization of commercially available cDNA array filters comprising 1,176 cancer‐related genes. Ninety‐two differentially expressed genes were identified by comparison of pooled cDNA from CIN3 vs. cervical cancer. Heterogeneity in expression of this subset of genes was then analyzed for each biopsy using an algorithm for self‐organizing maps. For several gene clusters, the expression pattern for CIN3 differed significantly from that of cancer. Moreover, hierarchical clustering revealed significant differences in distribution of CIN and cancer. Several CIN cases were more strongly related to cancer, suggesting that gene expression profiling may be useful for subdividing pathologically indistinguishable precancers into different biologic entities. This approach also provides a basis for the identification of putative prognostic markers and for targeted molecular therapy. © 2004 Wiley‐Liss, Inc.
Expression and activity of IL‐17 in cutaneous T‐cell lymphomas (mycosis fungoides and sezary syndrome)
Authors: Cirée Arnaud , Michel Laurence , Camilleri‐Bröet Sophie , Jean Louis Francette , Oster Michèle , Flageul Beatrice , Senet Patricia , Fossiez Francois , Fridman Wolf H. , Bachelez Hervé , Tartour Eric 
Published: June 2004

AbstractInterleukin‐17 (IL‐17) is a proinflammatory cytokine mainly produced by activated CD4+ CD45RO T cells. In mice, we have demonstrated that, depending on the model, IL‐17 may act as a tumor growth‐promoting or ‐inhibiting factor. In order to address the relevance of these models in human tumors, we look for the natural expression and activity of IL‐17 in mycosis fungoides (MF) and Sezary syndrome (SS). These cutaneous T‐cell lymphomas were selected because they are usually CD3+ CD4+ CD45RO+, a phenotype similar to nontransformed T cells producing IL‐17. We show that in vitro activated malignant T cells derived from MF or SS patients express IL‐17 mRNA and secrete this cytokine. However, IL‐17 does not act in vitro as a growth factor for MF or SS cell lines. In addition, 5 out of 10 MF/SS biopsies expressed IL‐17 mRNA, while this cytokine was not detected in normal skin. IL‐17 was not observed in the biopsies derived from 2 patients initially identified as MF, whereas an upregulation of this cytokine was clearly demonstrated during progression of the disease in these patients. An association between IL‐17 expression and polymorphonuclear neutrophil infiltration was also recorded in this group of MF/SS patients. A more detailed analysis of 2 patients with a pustular form of MF and SS revealed that IL‐17 may participate in the recruitment of polymorphonuclear neutrophils via a paracrine mechanism involving keratinocyte‐released IL‐8. This study is the first report demonstrating that some human tumor cells could express IL‐17, a cytokine that represents an early event in the development of the inflammatory reaction within the tumor microenvironment, a process that may influence tumor phenotype and growth. © 2004 Wiley‐Liss, Inc.
Hydroxyapatite and fluor‐hydroxyapatite layered film on titanium processed by a sol–gel route for hard‐tissue implants
Authors: Kim Hae‐Won , Knowles Jonathan C. , Salih Vehid , Kim Hyoun‐Ee 
Published: June 2004

AbstractA double‐layered coating, consisting of a hydroxyapatite (HA) outer film and a fluor‐hydroxyapatite (FHA) inner film, was produced on a Ti substrate by a sol–gel route to improve the biocompatibility and functionality of the system. Dissolution behavior of and in vitro cellular responses to the layered film were investigated. Calcium nitrate and triethyl phosphite were used for calcium and phosphate precursors, respectively, and ammonium fluoride was added as a fluorine‐ion source for FHA. The FHA layer was deposited on Ti by spin coating and subsequent heat treatment at 550°C for 30 min in air, and then the HA layer was laid down over the FHA‐coated Ti under the same conditions. After heat treatment, characteristic apatite structures and phases were developed on both FHA and HA films. The cross‐section view of the HA/FHA film clearly showed a double‐layered structure on Ti with each layer approximately 0.6–0.8‐μm thickness. The coating layer was highly uniform and dense, and adhered to Ti substrate strongly with an adhesion strength of about 40 MPa. The in vitro solubility of the HA/FHA layered film in a physiological solution was between that of HA and FHA pure film, and the dissolution profile was quite biphasic, that is, an initial rapid period and a slowdown with increasing time, reflecting the gradient solubility of the fast HA outer structure/slow FHA inner structure. The human osteoblast‐like HOS TE85 cells cultured on the HA/FHA layered film attached, spread, and grew favorably. The proliferation rate of the cells on the layered film was significantly higher (considered at p < 0.05 for n = 6) than that on Ti substrate and was similar to that on pure HA film. The alkaline phosphatase (ALP) activity and osteocalcin (OC) produced by the cells on the layered film were significantly higher (considered at p < 0.05 for n = 6) than those on Ti substrate. Moreover, the ALP and OC levels of cells on the layered film showed the trends of HA outer/FHA inner structure with respect to culture period, that is, HA initially and FHA later. These observations suggest that the HA/FHA layered film on Ti obtained by a sol–gel route possesses gradient functionality in terms of solubility and cellular responses, and find that those parameters can be tailored for specific use in hard‐tissue implants. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 71B: 66–76, 2004
Extending the treatment of backbone energetics in protein force fields: Limitations of gas‐phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations
Authors: Mackerell Alexander D. , Feig Michael , Brooks Charles L. 
Published: June 2004

AbstractComputational studies of proteins based on empirical force fields represent a powerful tool to obtain structure–function relationships at an atomic level, and are central in current efforts to solve the protein folding problem. The results from studies applying these tools are, however, dependent on the quality of the force fields used. In particular, accurate treatment of the peptide backbone is crucial to achieve representative conformational distributions in simulation studies. To improve the treatment of the peptide backbone, quantum mechanical (QM) and molecular mechanical (MM) calculations were undertaken on the alanine, glycine, and proline dipeptides, and the results from these calculations were combined with molecular dynamics (MD) simulations of proteins in crystal and aqueous environments. QM potential energy maps of the alanine and glycine dipeptides at the LMP2/cc‐pVxZ//MP2/6‐31G* levels, where x = D, T, and Q, were determined, and are compared to available QM studies on these molecules. The LMP2/cc‐pVQZ//MP2/6‐31G* energy surfaces for all three dipeptides were then used to improve the MM treatment of the dipeptides. These improvements included additional parameter optimization via Monte Carlo simulated annealing and extension of the potential energy function to contain peptide backbone ϕ, ψ dihedral crossterms or a ϕ, ψ grid‐based energy correction term. Simultaneously, MD simulations of up to seven proteins in their crystalline environments were used to validate the force field enhancements. Comparison with QM and crystallographic data showed that an additional optimization of the ϕ, ψ dihedral parameters along with the grid‐based energy correction were required to yield significant improvements over the CHARMM22 force field. However, systematic deviations in the treatment of ϕ and ψ in the helical and sheet regions were evident. Accordingly, empirical adjustments were made to the grid‐based energy correction for alanine and glycine to account for these systematic differences. These adjustments lead to greater deviations from QM data for the two dipeptides but also yielded improved agreement with experimental crystallographic data. These improvements enhance the quality of the CHARMM force field in treating proteins. This extension of the potential energy function is anticipated to facilitate improved treatment of biological macromolecules via MM approaches in general. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1400–1415, 2004
Geldanamycin induces mitotic catastrophe and subsequent apoptosis in human glioma cells
Authors: Nomura Motohiro , Nomura Naoko , Newcomb Elizabeth W. , Lukyanov Yevgeniy , Tamasdan Cristina , Zagzag David 
Published: June 2004

AbstractGeldanamycin (GA) binds to heat shock protein 90 (Hsp90) and interferes with its function which is to protect various cellular proteins involved in signaling, growth control, and survival from ubiquitination and subsequent degradation by the proteasome. Recently, we demonstrated that GA inhibited migration of glioma cells in vitro associated with downregulation of hypoxia‐inducible factor (HIF‐1α) and phosphorylation of focal adhesion kinase (FAK) (Zagzag et al., 2003, J Cell Physiol 196:394–402). Here, we have investigated the mechanisms through which GA treatment of the T98G glioma cell line induces apoptosis. We found that GA treatment induced cell death in a caspase‐dependent manner through activation of caspase‐3 and PARP cleavage together with release of cytochrome c and apoptosis inducing factor (AIF) from the mitochondria. Use of synchronized T98G cells showed that GA treatment of glioma cells during S‐phase enhanced cytotoxicity followed by M‐phase arrest, resulting in mitotic catastrophe. In addition, apoptosis was associated with the downregulation of the survival protein, phosphorylated Akt (pAkt), an important signaling protein in the PI3K pathway, that is overexpressed in many cancers including gliomas. Given that many glioma tumors show deregulation of the PI3K signaling pathway, either through loss of the tumor suppressor protein PTEN or overexpression of the growth factor EGFR, the ability to identify different subsets of patients using simple immunohistochemistry for the presence of absence of pAkt could enable selection of the appropriate kinase inhibitor, such as GA, for drug therapy. Based on our data presented here, GA or its analogs may have potential in the treatment of glioma. © 2004 Wiley‐Liss, Inc.
Progression elevated gene‐3 (PEG‐3) induces pleiotropic effects on tumor progression: Modulation of genomic stability and invasion
Authors: Emdad Luni , Sarkar Devanand , Su Zao‐Zhong , Boukerche Habib , Bar‐Eli Menashe , Fisher Paul B. 
Published: June 2004

AbstractProgression elevated gene‐3 (PEG‐3) is a novel rodent gene, identified and cloned by subtraction hybridization, that associates with transformation progression in virus‐ and oncogene‐transformed rat embryo (RE) cells. Previous reports document that ectopic expression of PEG‐3 in rodent or human tumor cells produces an aggressive transformed/tumorigenic phenotype. Moreover, PEG‐3 expression in rodent tumor cells correlates directly with genomic instability, as indicated by chromosomal alterations and gene amplification, and it promotes angiogenesis. The present studies were designed to further elucidate the functional significance and role of PEG‐3 in cancer progression with a specific focus on genomic instability and cancer invasion. Genomic instability was assessed by micronucleus assays and staining of centrosomes to define centrosomal amplification. Immunocytochemical observations revealed that overexpression of PEG‐3 in transformed rodent cells induced a loss of chromosomes as established by the appearance of micronuclei and staining of the centrosomes with γ‐tubulin antibody, thereby confirming centrosome amplification. Overexpression of PEG‐3 modulated the expression of several genes involved in centrosomal duplication, such as p21CIP1/WAF1/MDA‐6, nucleophosmin (NPM), and aurora‐A kinase. In vitro invasion of transformed rodent cells was augmented by PEG‐3, which correlated with an increase in the transcription and activity of matrix metalloproteinase‐2 and ‐9 (MMP‐2 and MMP‐9), which play important roles in local invasion during cancer progression. These findings demonstrate that PEG‐3 plays a central role in augmenting tumor progression by modulating several critical parameters of the carcinogenic process, such as genomic stability and local tumor cell invasion. © 2005 Wiley‐Liss, Inc.
Sea‐surface temperature and salinity changes in the northwest Pacific since the Last Glacial Maximum
Authors: Oba Tadamichi , Murayama Masafumi 
Published: June 2004

AbstractThe oxygen isotope records of both benthic and planktonic Foraminifera in five piston cores, collected from the region between the Oyashio and Kuroshio Currents near Japan, clearly show the marked latitudinal shifts of these two currents during the past 25 kyr. Under the present hydrographic condition, a clear relationship between the sea‐surface temperature (SST) and oxygen isotope differences from benthic to planktonic Foraminifera is observed in this region. Using this relationship, we find decreased SSTs of 12–13°C (maximum 15°C) in the southernmost core site at the Last Glacial Maximum (LGM), indicating the Oyashio Current shifted southward. The SSTs at the southern two core sites abruptly increased more than 10°C at 10–11 ka, suggesting the Kuroshio Current shifted northward over these sites at 10–11 ka. In contrast, the northern two core sites have remained under the influence of the cold Oyashio Current for the past 25 kyr. With the reasonable estimate of bottom‐water temperature decrease of 2.5°C at the LGM, the SSTs estimated by this new method give exactly the same SST values calculated from Mg/Ca ratio of planktonic Foraminifera, allowing palaeosea‐surface salinities to be reconstructed. The result suggests that the ice volume effect was 1.0 ± 0.1‰ at the LGM. Copyright © 2004 John Wiley & Sons, Ltd.
Late Neogene–Quaternary evolution of the intermontane Clusone Basin (Southern Alps, Italy): integration of seismic and geological data
Authors: de Franco R. , Berra F. , Biella G. , Boniolo G. , Caielli G. , Corsi A. , Forcella F. , Lazzati F. , Lozej A. , Morrone A. , Tondi R. 
Published: June 2004

AbstractIn the Clusone Basin (a large intermontane basin filled by thick late Neogene–Quaternary sediments in the Middle Val Seriana, Southern Alps), two high‐resolution seismic profiles have been acquired in order to reconstruct the geometries of the sediments that fill the depression, with a maximum thickness of more than 200 m as documented by available well data, and to define their relationships with the bedrock, consisting of Late Triassic carbonates. In addition to standard seismic reflection processing, a seismic refraction inversion technique has been applied. The integration of geological (both surface and well data) and seismic data indicates a complex history of the drainage patterns of the Clusone Basin, documenting a shift of the Serio River from a palaeodrainage toward the southeast (Val Borlezza) to the present situation, toward the south (Val Seriana): between the older and the present‐day drainages an important depositional stage occurred, as documented by the thick sediments that fill the Clusone Basin, controlling the capture of the Serio River along the Val Seriana. Copyright © 2004 John Wiley & Sons, Ltd.
Practices of managing knowledge sharing: towards a second wave of knowledge management
Authors: Huysman Marleen , de Wit Dirk 
Published: June 2004

AbstractThis paper presents case study findings on practices of knowledge sharing in 10 large companies, each with more than 1000 employees. All initiatives belong to the so‐called ‘first wave of knowledge management’, where the focus is on knowledge acquisition, exchange and creation by individual employees, supported by information and communications technologies and introduced by management. We found various biases and traps that seem to be general within the ‘first wave’ of managing knowledge. Based on this research, we discuss conditions of the ‘second wave of knowledge management’ that might overcome the various problems that we encountered. Copyright © 2004 John Wiley & Sons, Ltd.