bluuebunny/crossref_metadata_2025 huggingface dataset:
Collagen Type I Induces Disruption of E-Cadherin–Mediated Cell-Cell Contacts and Promotes Proliferation of Pancreatic Carcinoma Cells
Authors: Koenig Alexander , Mueller Claudia , Hasel Cornelia , Adler Guido , Menke Andre
Published: May 2006

Pancreatic cancer is characterized by its invasiveness, early metastasis, and the production of large amounts of extracellular matrix (ECM). We analyzed the influence of type I collagen and fibronectin on the regulation of cellular adhesion in pancreatic cancer cell lines to characterize the role of ECM proteins in the development of pancreatic cancer. We show that collagen type I is able to initiate a disruption of the E-cadherin adhesion complex in pancreatic carcinoma cells. This is due to the increased tyrosine phosphorylation of the complex protein β-catenin, which correlates with collagen type I–dependent activation of the focal adhesion kinase and its association with the E-cadherin complex. The activation and recruitment of focal adhesion kinase to the E-cadherin complex depends on the interaction of type I collagen with β1-containing integrins and an integrin-mediated activation of the cellular kinase Src. The disassembly of the E-cadherin adhesion complex correlates with the nuclear translocation of β-catenin, which leads to an increasing expression of the β-catenin-Lef/Tcf target genes, cyclin D1 and c-myc. In addition to that, cells grown on collagen type I show enhanced cell proliferation. We show that components of the ECM, produced by the tumor, contribute to invasiveness and metastasis by reducing E-cadherin–mediated cell-cell adhesion and enhance proliferation in pancreatic tumor cells. (Cancer Res 2006; 66(9): 4662-71)
Gefitinib Modulates the Function of Multiple ATP-Binding Cassette Transporters In vivo
Authors: Leggas Markos , Panetta John C. , Zhuang Yanli , Schuetz John D. , Johnston Brad , Bai Feng , Sorrentino Brian , Zhou Sheng , Houghton Peter J. , Stewart Clinton F.
Published: May 2006

The 4-anilinoquinazoline (4-AQ) derivative gefitinib (Iressa) is an oral epidermal growth factor receptor tyrosine kinase inhibitor. Oral administration of 4-AQ molecules, such as gefitinib, inhibits ATP-binding cassette (ABC) transporter–mediated drug efflux and strongly increases the apparent bioavailability of coadministered drug molecules that are transporter substrates. Based on in vitro studies investigating 4-AQ interactions with several transporters, these effects have primarily been attributed to the inhibition of breast cancer resistance protein (BCRP; ABCG2). Although 4-AQ shows in vitro inhibition of P-glycoprotein [multidrug resistance protein (MDR1); ABCB1], the in vivo effect on this and other transporters is not known. In our studies, pretreatment of Abcg2−/− and Mdr1(a/b)−/− mice with gefitinib increased oral absorption and decreased systemic clearance of topotecan, a model substrate, indicating that additional transporters were inhibited. These results were extended to human orthologues using engineered cell lines to show that gefitinib inhibited the efflux of BCRP and MDR1 substrates and restored vincristine sensitivity in MDR1-expressing cells. Although gefitinib inhibited BCRP more potently than MDR1 (10-fold), the inhibition of both transporters occurred at clinically relevant concentrations (e.g., 1-5 μmol/L). These studies illustrate the broad implications for the therapeutic combination of gefitinib or other 4-AQ molecules with agents that are BCRP and MDR1 substrates. 4-AQ molecules may offer a means to increase the low and variable oral drug absorption of transporter substrates while decreasing interpatient variability and reversing tumor drug resistance. (Cancer Res 2006; 66(9): 4802-7)
Attenuation of Mitogen- and Stress-Activated Protein Kinase-1–Driven Nuclear Factor-κB Gene Expression by Soy Isoflavones Does Not Require Estrogenic Activity
Authors: Vanden Berghe Wim , Dijsselbloem Nathalie , Vermeulen Linda , Ndlovu 'Matladi N. , Boone Elke , Haegeman Guy
Published: May 2006

We have analyzed in molecular detail how soy isoflavones (genistein, daidzein, and biochanin A) suppress nuclear factor-κB (NF-κB)–driven interleukin-6 (IL6) expression. In addition to its physiologic immune function as an acute stress cytokine, sustained elevated expression levels of IL6 promote chronic inflammatory disorders, aging frailty, and tumorigenesis. Our results in estrogen-unresponsive fibroblasts, mitogen- and stress-activated protein kinase (MSK) knockout cells, and estrogen receptor (ER)–deficient breast tumor cells show that phytoestrogenic isoflavones can selectively block nuclear NF-κB transactivation of specific target genes (in particular IL6), independently of their estrogenic activity. This occurs via attenuation of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) and ERK activity, which further down-regulates MSK-dependent NF-κB p65 and histone H3 phosphorylation. As constitutive NF-κB and MSK activity are hallmarks of aggressive metastatic ER-deficient breast cancer, the MSK signaling pathway may become an attractive target for chemotherapy. (Cancer Res 2006; 66(9): 4852-62)
Ex vivoCulture with Interleukin (IL)-12 Improves CD8+ T-Cell Adoptive Immunotherapy for Murine Leukemia Independent of IL-18 or IFN-γ but Requires Perforin
Authors: MacGregor Jennifer N. , Li Qiao , Chang Alfred E. , Braun Thomas M. , Hughes Dennis P.M. , McDonagh Kevin T.
Published: May 2006

In animal models and clinical trials, adoptive transfer of activated, antigen-specific CD8+ T cells mediates tumor regression in a cell dose-dependent manner. The cytokine interleukin (IL)-12 promotes CD8+ T-cell cytotoxicity and, with IL-18, synergistically up-regulates IFN-γ release. We have shown that culturing CD8+ T cells ex vivo with IL-12 and IL-18 enhanced antitumor responses in vivo and in vitro using a model of C1498/ovalbumin, a murine acute myeloid leukemia cell line expressing the antigen ovalbumin. Activated ovalbumin-specific CD8+ T cells cultured with IL-12, IL-18, both, or neither were assayed for antigen-specific cytokine production and cytolytic activity and adoptively transferred to C57BL/6 mice with established tumors. Maximal IFN-γ release occurred after T-cell culture with IL-12 and IL-18. Tumor-specific in vitro cytotoxicity was enhanced by IL-12, unaffected by addition of IL-18, and abrogated in perforin-deficient T cells irrespective of cytokine exposure. T cells cultured with IL-12 more effectively eliminated tumors, and addition of IL-18 did not further augment responses. IFN-γ-deficient CD8+ T cells showed effective antitumor activity that was enhanced by IL-12 with or without IL-18. Perforin-deficient CD8+ T cells were poor mediators of antitumor activity, though, and showed no improvement after culture with IL-12 and/or IL-18. Thus, ex vivo culture with IL-12 was sufficient to augment antigen-specific in vitro cytotoxicity and antitumor activity in vivo in an IFN-γ-independent but perforin-dependent manner. Ex vivo culture with IL-12 may improve CD8+ T-cell immunotherapy of cancer in the absence of donor cell–derived IFN-γ via perforin-mediated cytolysis. (Cancer Res 2006; 66(9): 4913-21)
Disruption of the Y-Box Binding Protein-1 Results in Suppression of the Epidermal Growth Factor Receptor and HER-2
Authors: Wu Joyce , Lee Cathy , Yokom Daniel , Jiang Helen , Cheang Maggie C.U. , Yorida Erika , Turbin Dmitry , Berquin Isabelle M. , Mertens Peter R. , Iftner Thomas , Gilks C. Blake , Dunn Sandra E.
Published: May 2006

The overexpression of the epidermal growth factor receptor (EGFR) and HER-2 underpin the growth of aggressive breast cancer; still, it is unclear what governs the regulation of these receptors. Our laboratories recently determined that the Y-box binding protein-1 (YB-1), an oncogenic transcription/translation factor, induced breast tumor cell growth in monolayer and in soft agar. Importantly, mutating YB-1 at Ser102, which resides in the DNA-binding domain, prevented growth induction. We reasoned that the underlying cause for growth attenuation by YB-1(Ser102) is through the regulation of EGFR and/or HER-2. The initial link between YB-1 and these receptors was sought by screening primary tumor tissue microarrays. We determined that YB-1 (n = 389 cases) was positively associated with EGFR (P < 0.001, r = 0.213), HER-2 (P = 0.008, r = 0.157), and Ki67 (P < 0.0002, r = 0.219). It was inversely linked to the estrogen receptor (P < 0.001, r = −0.291). Overexpression of YB-1 in a breast cancer cell line increased HER-2 and EGFR. Alternatively, mutation of YB-1 at Ser102 > Ala102 prevented the induction of these receptors and rendered the cells less responsive to EGF. The mutant YB-1 protein was also unable to optimally bind to the EGFR and HER-2 promoters based on chromatin immunoprecipitation. Furthermore, knocking down YB-1 with small interfering RNA suppressed the expression of EGFR and HER-2. This was coupled with a decrease in tumor cell growth. In conclusion, YB-1(Ser102) is a point of molecular vulnerability for maintaining the expression of EGFR and HER-2. Targeting YB-1 or more specifically YB-1(Ser102) are novel approaches to inhibiting the expression of these receptors to ultimately suppress tumor cell growth. (Cancer Res 2006; 66(9): 4872-9)
Noninvasive Bioluminescence Imaging of Normal and Spontaneously Transformed Prostate Tissue in Mice
Authors: Lyons Scott K. , Lim Ed , Clermont Anne O. , Dusich Joan , Zhu Lingyun , Campbell Kenneth D. , Coffee Richard J. , Grass David S. , Hunter John , Purchio Tony , Jenkins Darlene
Published: May 2006

Several transgenic mouse models of prostate cancer have been developed recently that are able to recapitulate many key biological features of the human condition. It would, therefore, be desirable to employ these models to test the efficacy of new therapeutics before clinical trial; however, the variable onset and nonvisible nature of prostate tumor development limit their use for such applications. We now report the generation of a transgenic reporter mouse that should obviate these limitations by enabling noninvasive in vivo bioluminescence imaging of normal and spontaneously transformed prostate tissue in the mouse. We used an 11-kb fragment of the human prostate-specific antigen (PSA) promoter to achieve specific and robust expression of firefly luciferase in the prostate glands of transgenic mice. Ex vivo bioluminescence imaging and in situ hybridization analysis confirmed that luciferase expression was restricted to the epithelium in all four lobes of the prostate. We also show that PSA-Luc mice exhibit decreased but readily detectable levels of in vivo bioluminescence over extended time periods following androgen ablation. These results suggest that this reporter should enable in vivo imaging of both androgen-dependent and androgen-independent prostate tumor models. As proof-of-principle, we show that we could noninvasively image SV40 T antigen–induced prostate tumorigenesis in mice with PSA-Luc. Furthermore, we show that our noninvasive imaging strategy can be successfully used to image tumor response to androgen ablation in transgenic mice and, as a result, that we can rapidly identify individual animals capable of sustaining tumor growth in the absence of androgen. (Cancer Res 2006; 66(9): 4701-7)
The Interaction Mode of Premalignant Schwann and Immune Effector Cells during Chemically Induced Carcinogenesis in the Rat Peripheral Nervous System Is Strongly Influenced by Genetic Background
Authors: Gering Katharina M. , Marx Judith A.M. , Lennartz Klaus , Fischer Christine , Rajewsky Manfred F. , Kindler-Röhrborn Andrea
Published: May 2006

Contrary to rats of the highly sensitive inbred strain BDIX, BDIV rats are resistant to the induction of malignant schwannomas by N-ethyl-N-nitrosourea, arising predominantly in the trigeminal nerves. A point mutation of the neu/erbB-2 gene diagnostic of N-ethyl-N-nitrosourea–induced rat schwannomas is an early marker of Schwann precursor cells at high risk of subsequent malignant transformation. Neu-mutant cells initially arise at a similar frequency in sensitive and resistant animals. However, these cells disappear from the trigeminal nerves of resistant rats while giving rise to highly malignant schwannomas in susceptible animals. The resistance of BDIV rats obviously includes mechanisms to recognize and eliminate premalignant cells. The involvement of a cellular immune response was investigated in trigeminal nerves of both strains at different times after neonatal carcinogen exposure. An inflammatory reaction involving sequentially CD4+ macrophages and T helper cells, CD8+ cytotoxic T cells, and ED1+ and ED2+ macrophages was detected as a consequence of N-ethyl-N-nitrosourea treatment as early as postnatal day 40, briefly after the emergence of premalignant neu-mutant Schwann cells. It persisted throughout the observation period (40-250 days). However, there were no gross differences in immune cell counts between tumor-susceptible and tumor-resistant rats, except for a moderate increase of ED2+ macrophages in N-ethyl-N-nitrosourea–treated BDIX rats only. Differential interactions of immune effector cells with premalignant Schwann cells may thus be involved in genetically determined tumor susceptibility or resistance, which could include functional differences of immune effector cells and/or a differential capability of premalignant Schwann cells to escape or counteract the cellular immune response. (Cancer Res 2006; 66(9): 4708-14)
Gene Expression Profiling Revealed Survivin as a Target of 3,3′-Diindolylmethane-Induced Cell Growth Inhibition and Apoptosis in Breast Cancer Cells
Authors: Rahman KM Wahidur , Li Yiwei , Wang Zhiwei , Sarkar Sarah H. , Sarkar Fazlul H.
Published: May 2006

The phytochemical indole-3-carbinol (I3C), found in cruciferous vegetables, and its major acid-catalyzed reaction product 3,3′-diindolylmethane (DIM) showed anticancer activity mediated by its pleiotropic effects on cell cycle progression, apoptosis, carcinogen bioactivation, and DNA repair. To further elucidate the molecular mechanism(s) by which 3,3′-diindolylmethane exerts its effects on breast cancer cells, we have used microarray gene expression profiling analysis. We found a total of 1,238 genes altered in 3,3′-diindolylmethane-treated cells, among which 550 genes were down-regulated and 688 genes were up-regulated. Clustering analysis showed significant alterations in some genes that are critically involved in the regulation of cell growth, cell cycle, apoptosis, and signal transduction, including down-regulation of survivin. Previous studies have shown that antiapoptotic protein survivin is overexpressed in many human cancers, including breast cancer. However, very little or no information is available regarding the consequence of down-regulation of survivin for cancer therapy. We, therefore, hypothesized that down-regulation of survivin as observed by 3,3′-diindolylmethane could be an important approach for the treatment of breast cancer. We have tested our hypothesis using multiple molecular approaches and found that 3,3′-diindolylmethane inhibited cell growth and induced apoptosis in MDA-MB-231 breast cancer cells by down-regulating survivin, Bcl-2, and cdc25A expression and also caused up-regulation of p21WAF1 expression, which could be responsible for cell cycle arrest. Down-regulation of survivin by small interfering RNA before 3,3′-diindolylmethane treatment resulted in enhanced cell growth inhibition and apoptosis, whereas overexpression of survivin by cDNA transfection abrogated 3,3′-diindolylmethane-induced cell growth inhibition and apoptosis. These results suggest that targeting survivin by 3,3′-diindolylmethane could be a new and novel approach for the prevention and/or treatment of breast cancer. (Cancer Res 2006; 66(9): 4952-60)
Estradiol and Tamoxifen Regulate Endostatin Generation via Matrix Metalloproteinase Activity in Breast CancerIn vivo
Authors: Nilsson Ulrika W. , Dabrosin Charlotta
Published: May 2006

Matrix metalloproteinases (MMP) are important regulators of tumor progression and angiogenesis. MMPs generate both proangiogenic and antiangiogenic fragments, such as vascular endothelial growth factor and endostatin. The in vivo activation of MMPs and endostatin generation occur mainly in the extracellular environment by interactions of different cell types. Therefore, these processes are necessary to study in the extracellular space in vivo. Sex steroids play a dominant role in breast carcinogenesis, by largely unknown mechanisms. In the present study, we used in vivo microdialysis to directly quantify MMP-2 and MMP-9 activity and sample endostatin from both stroma (murine) and tumor (human) cells in vivo in solid MCF-7 tumors in nude mice. We found that tamoxifen in combination with estradiol increased tumor MMP-2/MMP-9 in vivo activity, endostatin levels, and decreased tumor vascularization compared with estradiol treatment only. The stroma-derived endostatin was three to five times higher than cancer cell–generated endostatin. After inhibition of MMP-2/MMP-9, endostatin levels decreased, providing evidence that these proteases are highly involved in the generation of endostatin. Our results support the previously reported concept that MMPs may serve as negative regulators of angiogenesis. The regulation of endostatin generation by modulation of MMP-2/MMP-9 activities suggests a previously unrecognized mechanism of estradiol and tamoxifen, which may have implications for the pathogenesis of breast cancer. (Cancer Res 2006; 66(9): 4789-94)
β-Catenin/Wnt Signaling Regulates Expression of the Membrane Type 3 Matrix Metalloproteinase in Gastric Cancer
Authors: Lowy Andrew M. , Clements Wilson M. , Bishop John , Kong Ling , Bonney Tera , Sisco Karena , Aronow Bruce , Fenoglio-Preiser Cecilia , Groden Joanna
Published: May 2006

Activation of Wnt signaling through β-catenin dysregulation occurs in numerous human tumors, including gastric cancer. The specific consequences of Wnt signaling in gastric cancer, however, are not well characterized. This study shows that the introduction of mutant β-catenin into gastric cancer cell lines by adenoviral infection enhances invasiveness and proliferation and up-regulates the expression of the gene encoding the matrix metalloproteinase (MMP) family member membrane type 3 MMP (MT3-MMP). Up-regulation of MT3-MMP is critical to the invasive phenotype as shown by small interfering RNA (siRNA) studies. Immunohistochemical staining also showed that MT3-MMP was highly expressed in gastric cancers with activating β-catenin mutations. These observations suggest that Wnt activation may contribute to gastric cancer progression by increasing the invasiveness of neoplastic cells in the stomach via up-regulation of MT3-MMP expression. (Cancer Res 2006; 66(9): 4734-41)
Integrative Genomic Analysis of Protein Kinase C (PKC) Family Identifies PKCι as a Biomarker and Potential Oncogene in Ovarian Carcinoma
Authors: Zhang Lin , Huang Jia , Yang Nuo , Liang Shun , Barchetti Andrea , Giannakakis Antonis , Cadungog Mark G. , O'Brien-Jenkins Ann , Massobrio Marco , Roby Katherine F. , Katsaros Dionyssios , Gimotty Phyllis , Butzow Ralf , Weber Barbara L. , Coukos George
Published: May 2006

The protein kinase C (PKC) family plays a key regulatory role in a wide range of cellular functions as well as in various cancer-associated signal transduction pathways. Here, we investigated the genomic alteration and gene expression of most known PKC family members in human ovarian cancer. The DNA copy number of PKC family genes was screened by a high-resolution array-based comparative genomic hybridization in 89 human ovarian cancer specimens. Five PKC genes exhibited significant DNA copy number gains, including PKCι (43.8%), PKCβ1 (37.1%), PKCγ (27.6%), PKCζ (22.5%), and PKC𝛉 (21.3%). None of the PKC genes exhibited copy number loss. The mRNA expression level of PKC genes was analyzed by microarray retrieval approach. Two of the amplified PKC genes, PKCι and PKC𝛉, were significantly up-regulated in ovarian cancer compared with normal ovary. Increased PKCι expression correlated with tumor stage or grade, and PKCι overexpression was seen mostly in ovarian carcinoma but not in other solid tumors. The above results were further validated by real-time reverse transcription-PCR with 54 ovarian cancer specimens and 24 cell lines; overexpression of PKCι protein was also confirmed by tissue array and Western blot. Interestingly, overexpressed PKCι did not affect ovarian cancer cell proliferation or apoptosis in vitro. However, decreased PKCι expression significantly reduced anchorage-independent growth of ovarian cancer cells, whereas overexpression of PKCι contributed to murine ovarian surface epithelium transformation in cooperation with mutant Ras. We propose that PKCι may serve as an oncogene and a biomarker of aggressive disease in human ovarian cancer. (Cancer Res 2006; 66(9): 4627-35)
Celastrol, a Triterpene Extracted from the Chinese “Thunder of God Vine,” Is a Potent Proteasome Inhibitor and Suppresses Human Prostate Cancer Growth in Nude Mice
Authors: Yang Huanjie , Chen Di , Cui Qiuzhi Cindy , Yuan Xiao , Dou Q. Ping
Published: May 2006

Interest in the use of traditional medicines for cancer prevention and treatment is increasing. In vitro, in vivo, and clinical studies suggest the potential use of proteasome inhibitors as novel anticancer drugs. Celastrol, an active compound extracted from the root bark of the Chinese medicine “Thunder of God Vine” (Tripterygium wilfordii Hook F.), was used for years as a natural remedy for inflammatory conditions. Although Celastrol has been shown to induce leukemia cell apoptosis, the molecular target involved has not been identified. Furthermore, whether Celastrol has antitumor activity in vivo has never been conclusively shown. Here, we report, for the first time, that Celastrol potently and preferentially inhibits the chymotrypsin-like activity of a purified 20S proteasome (IC50 = 2.5 μmol/L) and human prostate cancer cellular 26S proteasome (at 1-5 μmol/L). Inhibition of the proteasome activity by Celastrol in PC-3 (androgen receptor- or AR-negative) or LNCaP (AR-positive) cells results in the accumulation of ubiquitinated proteins and three natural proteasome substrates (IκB-α, Bax, and p27), accompanied by suppression of AR protein expression (in LNCaP cells) and induction of apoptosis. Treatment of PC-3 tumor–bearing nude mice with Celastrol (1-3 mg/kg/d, i.p., 1-31 days) resulted in significant inhibition (65-93%) of the tumor growth. Multiple assays using the animal tumor tissue samples from both early and end time points showed in vivo inhibition of the proteasomal activity and induction of apoptosis after Celastrol treatment. Our results show that Celastrol is a natural proteasome inhibitor that has a great potential for cancer prevention and treatment. (Cancer Res 2006; 66(9): 4758-65)
The Regulation of Exosome Secretion: a Novel Function of the p53 Protein
Authors: Yu Xin , Harris Sandra L. , Levine Arnold J.
Published: May 2006

The p53 protein responds to stress signals by regulating the transcription of a variety of genes. Some of these genes encode secreted proteins that may be involved in the communication between adjacent cells. In this study, a proteomics approach was employed to identify proteins secreted by cells in a p53-dependent manner after DNA damage. In addition to the known transcriptional targets of p53, a set of proteins encoded by genes that are not transcriptional targets of p53 were found to increase in the culture medium after p53 activation. These proteins exit the cell via small, secreted vesicles called exosomes and exosome production by cells was found to be regulated by the p53 response. A p53-regulated gene product, TSAP6, was shown to enhance exosome production in cells undergoing a p53 response to stress. Thus, the p53 pathway regulates the production of exosomes into the medium and these vesicles can communicate with adjacent cells and even cells of the immune system. (Cancer Res 2006; 66(9): 4795-801)
Gene Expression Profiling Shows Medullary Breast Cancer Is a Subgroup of Basal Breast Cancers
Authors: Bertucci François , Finetti Pascal , Cervera Nathalie , Charafe-Jauffret Emmanuelle , Mamessier Emilie , Adélaïde José , Debono Stéphane , Houvenaeghel Gilles , Maraninchi Dominique , Viens Patrice , Charpin Colette , Jacquemier Jocelyne , Birnbaum Daniel
Published: May 2006

Medullary breast cancer (MBC) is a rare but enigmatic pathologic type of breast cancer. Despite features of aggressiveness, MBC is associated with a favorable prognosis. Morphologic diagnosis remains difficult in many cases. Very little is known about the molecular alterations involved in MBC. Notably, it is not clear whether MBC and ductal breast cancer (DBC) represent molecularly distinct entities and what genes/proteins might account for their differences. Using whole-genome oligonucleotide microarrays, we compared gene expression profiles of 22 MBCs and 44 grade III DBCs. We show that MBCs are less heterogeneous than DBCs. Whereas different molecular subtypes (luminal A, luminal B, basal, ERBB2-overexpressing, and normal-like) exist in DBCs, 95% MBCs display a basal profile, similar to that of basal DBCs. Supervised analysis identified gene expression signatures that discriminated MBCs from DBCs. Discriminator genes are associated with various cellular processes related to MBC features, in particular immune reaction and apoptosis. As compared with MBCs, basal DBCs overexpress genes involved in smooth muscle cell differentiation, suggesting that MBCs are a distinct subgroup of basal breast cancer with limited myoepithelial differentiation. Finally, MBCs overexpress a series of genes located on the 12p13 and 6p21 chromosomal regions known to contain pluripotency genes. Our results contribute to a better understanding of MBC and of mammary oncogenesis in general. (Cancer Res 2006; (66)9: 4634-44)
Gefitinib Inhibits the Growth and Invasion of Urothelial Carcinoma Cell Lines in which Akt and MAPK Activation Is Dependent on Constitutive Epidermal Growth Factor Receptor Activation
Authors: Nicolle Gaëlle , Daher Ahmad , Maillé Pascale , Vermey Marcel , Loric Sylvain , Bakkar Ashraf , Wallerand Hervé , Vordos Dimitrios , Vacherot Francis , de Medina Sixtina Gil Diez , Abbou Claude C. , Kwast Theodore Van der , Thiery Jean-Paul , Radvanyi François , Chopin Dominique K.
Published: May 2006

Purpose: Abnormally high levels of epidermal growth factor receptor (EGFR) protein are associated with advanced tumor stage/grade. The objective of this study was to evaluate the effects of the specific EGFR tyrosine kinase inhibitor gefitinib on activation of the Akt and mitogen-activated protein kinase (MAPK) pathways in human urothelial cell carcinoma (UCC) cell lines and to identify potential markers of gefitinib responsiveness in biopsy samples of UCC.

Experimental Design: Changes in markers of UCC growth and invasion after exposure to gefitinib were studied in six human UCC cell lines expressing various levels of EGFR. The findings were related to activation of Akt and MAPK. We studied the influence of gefitinib on intraepithelial expansion of the responsive 1207 cell line. EGFR, Akt, and MAPK activation was studied by Western blot analysis of a panel of 57 human UCC.

Results: Gefitinib had a growth-inhibitory and anti-invasive effect in two of six UCC cell lines (i.e., 647V and 1207). Gefitinib was also able to block the expansion of 1207 at the expense of normal urothelial cells. These effects did not depend on the level of expression of EGFR but they were associated with the down-regulation of MAPK and Akt activity; in 1207 cells, gefitinib activity was associated with p27 up-regulation and p21 and matrix metalloproteinase-9 down-regulation. Similarly, the Akt and MAPK pathways were found to be strongly phosphorylated in association with EGFR activation in a subset of human UCC specimens.

Conclusions: Activation of EGFR, Akt, and MAPK defines a subset of UCC which might provide information for the identification of gefitinib responders.
Bisphosphonates Inhibit the Growth of Mesothelioma Cells In vitro and In vivo
Authors: Wakchoure Savita , Merrell Melinda A. , Aldrich Wayne , Millender-Swain Telisha , Harris Kevin W. , Triozzi Pierre , Selander Katri S.
Published: May 2006

Purpose: Bisphosphonates (such as risedronate and zoledronate) are widely used inhibitors of bone resorption. Despite their in vitro antiproliferative effects in various cancer cells, bisphosphonates have not exhibited significant antitumor efficacy in animal models of visceral cancer, which may be due to their poor bioavailability. The diagnostic use of radioactive bisphosphonates has revealed the accumulation of bisphosphonates in mesothelioma, which prompted us to test the antitumor efficacy of bisphosphonates in this disease.

Experimental Design and Results: Treatment with either risedronate or zoledronate (2 × 10−4 to 2 × 10−6 mol/L) inhibited the growth of AB12 and AC29 mouse mesothelioma cells and induced the accumulation of unprenylated Rap1A in these cells. Both these in vitro effects were reversed by geranygeraniol, an end product of the mevalonate pathway that these bisphosphonates inhibit. Both bisphosphonates also induced the phosphorylation of the p38 mitogen-activated protein kinase in AB12 and AC29 cells. The inhibition of p38 augmented bisphosphonate-induced growth inhibition in these cells. Bisphosphonate-induced p38 phosphorylation was not reversible by geranylgeraniol. Risedronate (15 mg/kg) and zoledronate (0.5 mg/kg) inhibited the growth of s.c. tumors and increased the median survival of mice with i.p. mesothelioma tumors in vivo.

Discussion: In conclusion, risedronate and zoledronate inhibit the mevalonate pathway and induce p38 activation in mesothelioma cells in vitro. The effects on the mevalonate pathway dominate because the net result is growth inhibition. Both bisphosphonates also inhibit mesothelioma tumor growth in vivo and prolong the survival of mesothelioma-bearing mice. These results support further study of bisphosphonates in the management of mesothelioma.
Simulating Competition and Coexistence between Plant Functional Types in a Dynamic Vegetation Model
Authors: Arora Vivek K. , Boer George J.
Published: May 2006

The global distribution of vegetation is broadly determined by climate, and where bioclimatic parameters are favorable for several plant functional types (PFTs), by the competition between them. Most current dynamic global vegetation models (DGVMs) do not, however, explicitly simulate inter-PFT competition and instead determine the existence and fractional coverage of PFTs based on quasi-equilibrium climate–vegetation relationships. When competition is explicitly simulated, versions of Lotka–Volterra (LV) equations developed in the context of interaction between animal species are almost always used. These equations may, however, exhibit unrealistic behavior in some cases and do not, for example, allow the coexistence of different PFTs in equilibrium situations. Coexistence may, however, be obtained by introducing features and mechanisms such as temporal environmental variation and disturbance, among others.

A generalized version of the competition equations is proposed that includes the LV equations as a special case, which successfully models competition for a range of climate and vegetation regimes and for which coexistence is a permissible equilibrium solution in the absence of additional mechanisms. The approach is tested for boreal forest, tropical forest, savanna, and temperate forest locations within the framework of the Canadian Terrestrial Ecosystem Model (CTEM) and successfully simulates the observed successional behavior and the observed near-equilibrium distribution of coexisting PFTs.
War Crimes, Democracy, and the Rule of Law in Belgrade, the Former Yugoslavia, and Beyond
Authors: Hagan John , Ivković Sanja Kutnjak
Published: May 2006

The creation and operation of the International Criminal Tribunal for the Former Yugoslavia (ICTY) is an advance in the rule of law and arguably part of a larger process of the globalization of democratic norms. Yet support for the ICTY is increasingly influenced by local processes in which these norms are contested by indigenous parties and forces. We explore this issue with regard to support of Serbs living in and outside of Serbia for the ICTY in comparison to local courts. Serbs in Belgrade are distinctive in insisting that war criminals be tried in their places of origin, while Serbs in Sarajevo and Vukovar agree with other groups in these settings that war criminals should be tried in the locations where their crimes occurred. This is compelling evidence of the localized influence of cultural norms on ethnic and national group members in post-war crime settings.
Democracy and Crime: A Multilevel Analysis of Homicide Trends in Forty-Four Countries, 1950-2000
Authors: Lafree Gary , Tseloni Andromachi
Published: May 2006

Despite simultaneous increases in democratization and violent crime rates in many countries during the second half of the twentieth century, the authors could find no prior studies that have directly examined possible connections between these two processes. The civilization perspective predicts that violent crime rates will decline along with the civilizing effects of democratization, the conflict perspective predicts that violent crime rates will increase along with the brutalizing effects of the market economies that so far have universally accompanied democratization, and the modernization perspective predicts that violent crime rates will initially increase with the transition to democracy but then decline as democracies mature. Our analysis of data from forty-four countries from 1950 to 2000 shows the most support for a modernization perspective: violent crime rates are highest for transitional democracies. However, as predicted by the conflict perspective, we also find that during the second half of the twentieth century homicide rates gradually increased for full democracies.
A Comparison of Compact Yarn Properties Produced on Different Systems
Authors: Göktepe Fatma , Yilmaz Demet , Göktepe Özer
Published: May 2006

It is well known that yarn produced using the compact spinning technique, which has been introduced as one of the best spinning innovations of this century, has superior yarn structure and quality, especially in terms of hairiness and strength. However, there are different compact spinning systems on the market from different manufacturers and information concerning the favorable and unfavorable properties of each would be of great interest. In this study, we compared the properties of yarn spun on the three main compact spinning systems commonly used today. To maintain impartiality it was preferable to refer to these three systems as system A, system B, and system C instead of using their trade names. It was found that system B seemed to be more suitable for finer yarns whereas system A generally gave better results for medium to coarse counts.
Basis Functions of the Total Radiance Factor of Fluorescent Whitening Agents
Authors: Amirshahi Seyed Hossein , Agahian Farnaz
Published: May 2006

This paper describes the representation of the total radiance factor of fluorescent whitening agents by up to three basis components. Applying the dimensionality reduction technique to the total radiance factor of 84 cotton samples treated with different fluorescent whitening agents, it was possible to reconstruct the spectral behavior of specimens by using a very small number of basis functions, accurately. In order to study the properties of the basis function, a three-dimensional Euclidean spectral space was implemented to represent the samples. The orientation of the samples that confirmed the whiteness index limitations of CIE1982 were along a line in this space, as expected from a set of white specimens. The perfect correlation was also found between the CIE1982 whiteness index, W, and the first derived principal component coordinates of the samples.
Differential Associations and Daily Smoking of Adolescents
Authors: Nofziger Stacey , Lee Hye-Ryeon
Published: May 2006

This article examines whether the importance of parents, siblings, best friends, and romantic interests are sex-specific in predicting daily juvenile smoking. Juveniles who smoke daily are strongly influenced by prosmoking attitudes and behaviors of same-sex family members. However, peers remain the most important associations in predicting daily smoking. An important finding is that juveniles without same-sex family role models, or close peers, are at higher risk. Policy implications for prevention and cessation programs are discussed.
Factors Precipitating Suicidality among Homeless Youth
Authors: Kidd Sean A.
Published: May 2006

Homeless youth are a population at a high risk for suicidal behavior. A previous exploratory study emphasized the importance of feeling trapped or helpless, which appeared to mediate the impact of other risk variables. Confirmatory work was needed to test this inductively derived model. Two hundred eight homeless youths completed surveys on the streets and in agencies in New York City and Toronto. Structural equation modeling was used to test a theoretical model developed from exploratory work, and regression analyses were used to examine the influence of home and street contextual variables. The centrality of the trapped experience in a model incorporating drug use and dependence, abusive family history, loneliness, low self-esteem, and suicidality was confirmed. Other findings included a marked reduction in reported suicidal behavior following participants’ leaving home, with family violence, being thrown out of the home, neglect, poor physical health, and having suicidal friends showing strong relationships with suicidality.
Authority at Work: Reflections and Recollections
Authors: Knights David
Published: May 2006

This article summarizes, in a style that I have never before been brave enough to adopt, my work as an academic over the last 30 years. I have come closer here to practising what I have preached concerning the idea of being in the text as a self-reflexive, embodied subject rather than representing the world as a detached observer. Our self-imposed, but also heavily institutionalized, pressure to conform to certain modes of writing can produce standardized and anodyne accounts. While we often pretend that personal life is distant from our intellectual endeavours, this is rarely the case, for personal and professional lives are interdependent. I have also tried to offer more conventional accounts of those ideas and theories that have informed my work yet have also been intertwined with personally meaningful experiences. I am grateful to Organization Studies for offering me this opportunity.
Theoretical Limology: Postmodern Analytical Approaches
Authors: Kolossov Vladimir
Published: May 2006

In the field of geographical limology, the new science of international borders, it is possible to distinguish several consecutive theoretical approaches that can be seen as either traditional or postmodern. At each consecutive stage new approaches have been applied together with, not in place of, the traditional, in order to continue to perfect the discipline (see, for instance, Minghi, 1963; Rumley and Minghi, 1991). Traditional approaches, such as historical mapping, the typological, the functional and the political, have been described in previous theoretical works (e.g. Kolossov and O'Loughlin, 1998; Kolossov and Turovsky, 1998; Kolossov and Mironenko, 2001). Here we are concerned with the postmodern approaches, which have been emerging mostly during the 1990s and the present decade.
Bearing Strength Analysis of Single Mechanically Fastened Joint in Stitched Laminates
Authors: Wang Dong , Chen Gang , Li Zhengneng , Kou Changhe
Published: May 2006

Experimental investigation is carried out to understand the bearing strength of stitched and unstitched uniweave T300/QY9512 laminates with single-lap single-bolt joint configuration in this article. The objectives of the studies are to determine the effects of stitching node position, stacking sequence, and hygrothermal environment on the bearing strength and the load–displacement curves of stitched laminates. A three-dimensional finite element model is also developed to investigate the bearing properties of mechanically fastened joints in unstitched and stitched laminates. Hashin's three-dimensional failure criterion is used to predict the progressive ply failure. The stitching node position effect is of primary interest. A good agreement between experimental results and numerical predictions is observed. The results show that the bearing strength decreased when the stitching node position was close to the hole boundary.
Should Donors Care About Overhead Costs? Do They Care?
Authors: Bowman Woods
Published: May 2006

This article reports on a theory-based experiment to determine whether there is an observable relationship between changes in charitable giving to an organization and changes in the proportion of revenue it spends on administration and fund-raising (“overhead ratio”). This article argues that overhead ratios are meaningless for comparing organizations, but changes in overhead ratios communicate useful, though incomplete, information to donors. Empirical studies have used organization-level data with mixed results. This research improves on past work by using donor-level information on federal employees in the Chicago area who donate through the Combined Federal Campaign with ready access to information on the overhead ratios of all participating charities. Donations are aggregated by charity and compared over time. Statistical tests give evidence of an inverse relationship between changes in overhead ratios and changes in giving that are robust with respect to model specification; however, collectively other factors are much more important.
Giving and Volunteering as Distinct Forms of Civic Engagement: The Role of Community Integration and Personal Resources in Formal Helping
Authors: Jones Keely S.
Published: May 2006

Despite the debate over the value of giving versus volunteering and the implications that they may be connected to public life in distinct ways, there is little work that compares how factors related to civic engagement may encourage greater volunteering and greater charitable giving in different ways. Moreover, there is a need for a theoretical framework to understand why these helping behaviors relate differently to civic engagement when placed in the context of social ties and community participation. Using data from The Survey of Giving and Volunteering in the United States, the author finds that greater volunteering is most strongly promoted by community ties and increased giving is best explained by personal resources and helping values. As a result, the author argues that giving and volunteering represent distinct means of engagement and the potential substitution of money for time in formal helping has important implications for the civic life.
Exploring the Processes Underlying Within-Group Homogeneity
Authors: Mason Claire M.
Published: May 2006

Many group-level constructs are based on within-group homogeneity in attitudes, affect, beliefs, and perceptions. In this article, three models for the development of within-group homogeneity are delineated. These models are shown to have implications both for differences between variables in their level of homogeneity and the conditions under which relatively high and low homogeneity should be observed. The models are explored in a small sample ( N = 24 groups), where homogeneity in job satisfaction, positive affect, potency beliefs, and task-identity perceptions is examined. The results indicate that variables differ in their mean level of homogeneity and suggest that homogeneity may be the product of a combination of processes. A hierarchical framework for the investigation of homogeneity is suggested for further research.
The Effects of Team Leader Race on Performance Evaluations
Authors: Ellis Aleksander P. J. , Ilgen Daniel R. , Hollenbeck John R.
Published: May 2006

Using attribution theory, this study examined the effects of team leader race on subordinate performance evaluations. The authors found that the team leader’s performance was a major determinant of subordinate performance ratings. However, the team leader’s performance, in combination with race, also affected performance attributions. In high performing teams with a Black leader, subordinates were more likely to attribute the leader’s performance to internal causes (i.e., ability and effort) rather than external causes (i.e., luck and the ease of the game). Alternatively, in low performing teams with a Black leader, subordinates were more likely to attribute the leader’s performance to external causes. These causal attributions then tempered the direct effect of the team leader’s performance on subordinate performance ratings. Leaders who performed well received higher ratings when performance was attributed to internal rather than external factors. On the other hand, leaders who performed poorly received higher ratings when performance was attributed to external rather than internal factors.
Grounded Learning From a Strategy Case Competition
Authors: Corner Patricia Doyle , Bowden Stephen , Clark Delwyn , Collins Eva , Gibb Jenny , Kearins Kate , Pavlovich Kathryn
Published: May 2006

This article describes a case competition that reflects the four elements of a grounded learning exercise. These elements include creating a real-world experience, optimizing learning transfer, integrating theory and practice, and shifting learning responsibility to the students. The authors also provide details on implementing this exercise in an undergraduate capstone strategy course and using a real-time case that brings the competition to life.
The Use of Simulation to Improve the Effectiveness of Training in Performance Management
Authors: Rachman-Moore Dalia , Kenett Ron S.
Published: May 2006

Performance management is an important managerial tool that directs employees’ goals and behavior toward the organization’s strategic goals. This article focuses on simulation-based training in performance management systems. The simulation developed at the School of Business Administration of the College of Management in Israel is based on a typical life insurance firm. It is designed to promote understanding of the process of performance management. The simulation involves assessing performance of supervisors using multirater assessment and an organizational Balanced Scorecard. Student feedback showed that the simulation significantly enhanced the effectiveness of the performance-management teaching program.
Emotional Episodes at Work: An Experiential Exercise in Feeling and Expressing Emotions
Authors: Gibson Donald E.
Published: May 2006

This exercise explores how organizations affect individuals’ feelings and expressions of emotion. Although recent attention by management theorists suggests that emotions are an important aspect of organizational life, people’s actual experience of emotions at work often do not reflect this emphasis: Work-place emotions remain, in large part, undiscussable. The purpose of this experiential exercise is to emphasize emotions as a central, rather than hidden, part of work life. In the exercise, students explore and discuss emotional “episodes” from their work lives to learn about how organizations generate display rules for emotional expression and what this means for individual and organizational effectiveness.