bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

AbstractThe 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

AbstractMatrix 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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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.
Combining evidence, biomedical literature and statistical dependence: new insights for functional annotation of gene sets
Authors: Aubry Marc , Monnier Annabelle , Chicault Celine , de Tayrac Marie , Galibert Marie-Dominique , Burgun Anita , Mosser Jean 
Published: May 2006

AbstractBackgroundLarge-scale genomic studies based on transcriptome technologies provide clusters of genes that need to be functionally annotated. The Gene Ontology (GO) implements a controlled vocabulary organised into three hierarchies: cellular components, molecular functions and biological processes. This terminology allows a coherent and consistent description of the knowledge about gene functions. The GO terms related to genes come primarily from semi-automatic annotations made by trained biologists (annotation based on evidence) or text-mining of the published scientific literature (literature profiling).ResultsWe report an original functional annotation method based on a combination of evidence and literature that overcomes the weaknesses and the limitations of each approach. It relies on the Gene Ontology Annotation database (GOA Human) and the PubGene biomedical literature index. We support these annotations with statistically associated GO terms and retrieve associative relations across the three GO hierarchies to emphasise the major pathways involved by a gene cluster. Both annotation methods and associative relations were quantitatively evaluated with a reference set of 7397 genes and a multi-cluster study of 14 clusters. We also validated the biological appropriateness of our hybrid method with the annotation of a single gene (cdc2) and that of a down-regulated cluster of 37 genes identified by a transcriptome study of anin vitroenterocyte differentiation model (CaCo-2 cells).ConclusionThe combination of both approaches is more informative than either separate approach: literature mining can enrich an annotation based only on evidence. Text-mining of the literature can also find valuable associated MEDLINE references that confirm the relevance of the annotation. Eventually, GO terms networks can be built with associative relations in order to highlight cooperative and competitive pathways and their connected molecular functions.