bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cyclin D1 Is Necessary for Tamoxifen-Induced Cell Cycle Progression in Human Breast Cancer Cells
Authors: Kilker Robin L. , Planas-Silva Maricarmen D. 
Published: December 2006

Abstract
Despite the success of tamoxifen in treating hormone-responsive breast cancer, its use is limited by the development of resistance to the drug. Understanding the pathways involved in the growth of tamoxifen-resistant cells may lead to new ways to treat tamoxifen-resistant breast cancer. Here, we investigate the role of cyclin D1, a mediator of estrogen-dependent proliferation, in growth of tamoxifen-resistant cells using a cell culture model of acquired resistance to tamoxifen. We show that tamoxifen and 4-hydroxytamoxifen (OHT) promoted cell cycle progression of tamoxifen-resistant cells after growth-arrest mediated by the estrogen receptor down-regulator ICI 182,780. Down-regulation of cyclin D1 with small interfering RNA blocked basal cell growth of tamoxifen-resistant cells and induction of cell proliferation by OHT. In addition, pharmacologic inhibition of phosphatidylinositol 3-kinase/Akt or mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 pathways decreased basal cyclin D1 expression and impaired OHT-mediated cyclin D1 induction and cell cycle progression. These findings indicate that cyclin D1 expression is necessary for proliferation of tamoxifen-resistant cells and for tamoxifen-induced cell cycle progression. These results suggest that therapeutic strategies to block cyclin D1 expression or function may inhibit development and growth of tamoxifen-resistant tumors. (Cancer Res 2006; 66(23): 11478-84)
p50 Nuclear Factor-κB Overexpression in Tumor-Associated Macrophages Inhibits M1 Inflammatory Responses and Antitumor Resistance
Authors: Saccani Alessandra , Schioppa Tiziana , Porta Chiara , Biswas Subhra K. , Nebuloni Manuela , Vago Luca , Bottazzi Barbara , Colombo Mario P. , Mantovani Alberto , Sica Antonio 
Published: December 2006

AbstractTumor-associated macrophages (TAM) are a major inflammatory infiltrate in tumors and a major component of the protumor function of inflammation. TAM in established tumors generally have an M2 phenotype with defective production of interleukin-12 (IL-12) and high IL-10. Here, we report that defective responsiveness of TAM from a murine fibrosarcoma and human ovarian carcinoma to M1 activation signals was associated with a massive nuclear localization of the p50 nuclear factor-κB (NF-κB) inhibitory homodimer. p50 overexpression inhibited IL-12 expression in normal macrophages. TAM isolated from p50−/− mice showed normal production of M1 cytokines, associated with reduced growth of transplanted tumors. Bone marrow chimeras showed that p50 inactivation in hematopoietic cells was sufficient to result in reduced tumor growth. Thus, p50 NF-κB overexpression accounts for the inability of TAM to mount an effective M1 antitumor response capable of inhibiting tumor growth. (Cancer Res 2006; 66(23): 11432-40)
Loss of Nrdp1 Enhances ErbB2/ErbB3–Dependent Breast Tumor Cell Growth
Authors: Yen Lily , Cao Zhongwei , Wu Xiuli , Ingalla Ellen R.Q. , Baron Colin , Young Lawrence J.T. , Gregg Jeffrey P. , Cardiff Robert D. , Borowsky Alexander D. , Sweeney Colleen , Carraway Kermit L. 
Published: December 2006

Abstract
Dysregulation of ErbB receptor tyrosine kinases is thought to promote mammary tumor progression by stimulating tumor cell growth and invasion. Overexpression and aberrant activation of ErbB2/HER2 confer aggressive and malignant characteristics to breast cancer cells, and patients displaying ErbB2-amplified breast cancer face a worsened prognosis. Recent studies have established that ErbB2 and ErbB3 are commonly co-overexpressed in breast tumor cell lines and in patient samples. ErbB2 heterodimerizes with and activates the ErbB3 receptor, and the two receptors synergize in promoting growth factor–induced cell proliferation, transformation, and invasiveness. Our previous studies have shown that the neuregulin receptor degradation protein-1 (Nrdp1) E3 ubiquitin ligase specifically suppresses cellular ErbB3 levels by marking the receptor for proteolytic degradation. Here, we show that overexpression of Nrdp1 in human breast cancer cells results in the suppression of ErbB3 levels, accompanied by the inhibition of cell growth and motility and the attenuation of signal transduction pathways. In contrast, either Nrdp1 knockdown or the overexpression of a dominant-negative form enhances ErbB3 levels and cellular proliferation. Additionally, Nrdp1 expression levels inversely correlate with ErbB3 levels in primary human breast cancer tissue and in a mouse model of ErbB2 mammary tumorigenesis. Our observations suggest that Nrdp1-mediated ErbB3 degradation suppresses cellular growth and motility, and that Nrdp1 loss in breast tumors may promote tumor progression by augmenting ErbB2/ErbB3 signaling. (Cancer Res 2006; 66(23): 11279-86)
Genome-Wide Allelic Imbalance Analysis of Pediatric Gliomas by Single Nucleotide Polymorphic Allele Array
Authors: Wong Kwong-Kwok , Tsang Yvonne T.M. , Chang Yi-Mieng , Su Jack , Di Francesco Angela M. , Meco Daniela , Riccardi Riccardo , Perlaky Laszlo , Dauser Robert C. , Adesina Adekunle , Bhattacharjee Meenakshi , Chintagumpala Murali , Lau Ching C. 
Published: December 2006

Abstract
Using single nucleotide polymorphic (SNP) allele arrays, we analyzed 28 pediatric gliomas consisting of 14 high-grade gliomas and 14 low-grade gliomas. Most of the low-grade gliomas had no detectable loss of heterozygosity (LOH) in any of the 11,562 SNP loci; exceptions were two gangliogliomas (3q and 9p), one astrocytoma (6q), and two subependymal giant cell astrocytomas (16p and 21q). On the other hand, all high-grade gliomas had various degrees of LOH affecting 52 to 2,168 SNP loci on various chromosomes. LOH occurred most frequently in regions located at 4q (54%), 6q (46%), 9p (38%), 10q (38%), 11p (38%), 12 (38%), 13q (69%), 14q (54%), 17 (38%), 18p (46%), and 19q (38%). We also detected amplifications of epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor α (PDGFRα) in a few of the 13 cases of glioblastoma multiforme analyzed. Interestingly, the amplified EGFR and PDGFRα were located within regions of LOH. SNP loci with LOH and copy number changes were validated by sequencing and quantitative PCR, respectively. Our results indicate that, in some pediatric glioblastoma multiforme, one allele each of EGFR and PDGFRα was lost but the remaining allele was amplified. This may represent a new molecular mechanism underlying tumor progression. (Cancer Res 2006; 66(23): 11172-8)
Inhibition of Growth and Metastasis of Human Hepatocellular Carcinoma by Antisense Oligonucleotide Targeting Signal Transducer and Activator of Transcription 3
Authors: Li Wen-Chang , Ye Sheng-Long , Sun Rui-Xia , Liu Yin-Kun , Tang Zhao-You , Kim Youngsoo , Karras James G. , Zhang Hong 
Published: December 2006

AbstractPurpose: Hepatocellular carcinoma (HCC) is an aggressive malignancy and is a devastating clinical complication of chronic liver disease. Therapeutic options are limited mainly because the genetic and biochemical understanding of this disease remains fragmented. We intended to study the role of signal transducer and activator of transcription 3 (STAT3) aberrant signaling in HCC malignancy, and the therapeutic potential of inhibition of STAT3 expression for HCC.Experimental Design: A 2′-O-methoxyethylribose–modified phosphorothioate antisense oligonucleotide (ASO) was used to knock down STAT3 expression in different human HCC cell lines, including the highly metastatic HCCLM3 derived from orthotopic implantation and subsequent lung metastasis in athymic mice. The effects of STAT3 ASO treatment on HCC cells, metastasis, and animal survival following HCCLM3 orthotopic implantation were evaluated.Results: Specific suppression of phosphorylated STAT3 reduced its DNA-binding activity, inhibited the expression of vascular endothelial growth factor, survivin, matrix metalloproteinases 2 and 9, reduced cell proliferation and migratory potential, induced apoptosis in vitro, and inhibited intradermal angiogenesis and s.c. tumorigenesis upon injection in mice. In mice bearing orthotopically implanted HCCLM3, STAT3 inhibition following therapeutic treatment with STAT3 ASO reduced circulating vascular endothelial growth factor and basic fibroblast growth factor, decreased intratumor CD34-positive microvessel density, intrahepatic and intraperitoneal transmission, and lung metastasis. HCC tumor volume and weight were reduced and the survival time of mice bearing orthotopically xenografted HCC was approximately doubled in STAT3 ASO–treated mice (P &lt; 0.05).Conclusions: Constitutively activated STAT3 is essential for the growth, survival, and metastasis of HCC, suggesting that STAT3-targeted therapy may have utility for HCC.
In vivo Radioprotection by the Fullerene Nanoparticle DF-1 as Assessed in a Zebrafish Model
Authors: Daroczi Borbala , Kari Gabor , McAleer Mary Frances , Wolf Jeffrey C. , Rodeck Ulrich , Dicker Adam P. 
Published: December 2006

Abstract
Purpose: We have previously shown that zebrafish (Danio rerio) embryos can be used as an in vivo model to validate modifiers of the radiation response. Here, we evaluated the radioprotective effect of the nanoparticle DF-1, a fullerene with antioxidant properties, in zebrafish embryos.
Experimental Design: Zebrafish embryos were exposed to different doses of ionizing radiation ranging from 20 to 80 Gy in the presence and absence of DF-1. Toxicity and radioprotective effects were assessed by monitoring overall survival and morphology as well as organ functions by employing assays to measure kidney excretory function and development of sensory nerve cells (neuromasts). Antioxidant properties of DF-1 were assessed in whole fish.
Results: DF-1 had no apparent adverse effects on normal zebrafish morphology or viability throughout the concentration range tested (1-1,000 μmol/L). Ionizing radiation (10-40 Gy) caused time-dependent and dose-dependent perturbations of normal zebrafish morphology and physiology, notably defective midline development resulting in dorsal curvature of the body axis (“curly-up”), neurotoxicity, impaired excretory function, and decreased survival of the exposed embryos. DF-1 (100 μmol/L) markedly attenuated overall and organ-specific radiation-induced toxicity when given within 3 hours before or up to 15 minutes after radiation exposure. By contrast, DF-1 afforded no protection when given 30 minutes after ionizing radiation. The degree of radioprotection provided by DF-1 was comparable with that provided by the Food and Drug Administration–approved radioprotector amifostine (4 mmol/L). Protection against radiation-associated toxicity using DF-1 in zebrafish embryos was associated with marked reduction of radiation-induced reactive oxygen species.
Conclusion: The fullerene DF-1 protects zebrafish embryos against deleterious effects of ionizing radiation due, in part, to its antioxidant properties.
Flt3 Internal Tandem Duplication and P-Glycoprotein Functionality in 171 Patients with Acute Myeloid Leukemia
Authors: Marzac Christophe , Teyssandier I. , Calendini Ors'Anton , Perrot Jean-Yves , Faussat Anne-Marie , Tang Ruoping , Casadevall Nicole , Marie Jean-Pierre , Legrand Ollivier 
Published: December 2006

Abstract
Purpose: Patients with adult acute myeloid leukemia (AML) with intermediate cytogenetics remain a heterogeneous group with highly variable individual prognoses. New molecular markers could help to refine cytogenetic stratification.
Experimental Design: We assessed P-glycoprotein (Pgp) activity and Flt3 internal tandem duplication (ITD+) because of their known prognostic value and because they might lead to targeted therapy. We did a multivariate analysis on 171 patients with adult AML treated in the European Organization for Research and Treatment of Cancer protocols.
Results: ITD+ and high Pgp activity (Pgp+) were found in 26 of 171 (15%) and 55 of 171 (32%) of all patients, respectively. ITD and Pgp activities were negative in 94 of 171 (55%, Pgp−ITD− group), mutually exclusive in 73 of 171 (43%, Pgp−ITD+ and Pgp+ITD− groups), and only 4 of 171 (2%, Pgp+ITD+ group) patients were positive for both. In multivariate analyses, Pgp+ITD+ (P &lt; 0.0001) and age (P = 0.0022) were independent prognostic factors for the achievement of complete remission (CR). Overall survival (OS), CR achievement (P &lt; 0.0001), WHO performance status (P = 0.0007), and Pgp+ITD+ status (P = 0.0014) were also independent prognostic factors. In 95 patients with intermediate cytogenetics, the CR rates of ITD+ patients were 40% versus 62% for ITD− (P = 0.099) and 41% versus 67% (P = 0.014) for Pgp+ versus Pgp− patients. In the Pgp−ITD− group (41 of 95), CR rates were 70% versus 44% for others (P = 0.012), OS achieved 48% versus 16% (P &lt; 0.0001) and disease-free survival was 56% versus 27% (P = 0.024), respectively. Furthermore, the OS curves of the intermediate cytogenetics-Pgp−ITD− group were not significantly different from the favorable cytogenetic group.
Conclusion: Flt3/ITD and Pgp activity are independent and additive prognostic factors which provide a powerful risk classification that can be routinely used to stratify the treatment of patients with intermediate cytogenetic AML. ITD+ and Pgp+ patients should be considered for targeted therapy.
Antitumor Activity of the Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor Gefitinib (ZD1839, Iressa) in Non–Small Cell Lung Cancer Cell Lines Correlates with Gene Copy Number and EGFR Mutations but not EGFR Protein Levels
Authors: Helfrich Barbara A. , Raben David , Varella-Garcia Marileila , Gustafson Dan , Chan Daniel C. , Bemis Lynne , Coldren Chris , Barón Anna , Zeng Chan , Franklin Wilbur A. , Hirsch Fred R. , Gazdar Adi , Minna John , Bunn Paul A. 
Published: December 2006

Abstract
Purpose: Recognition that the epidermal growth factor receptor (EGFR) was a therapeutic target in non–small cell lung cancer (NSCLC) and other cancers led to development of the small-molecule receptor tyrosine kinase inhibitors gefitinib and erlotinib. Clinical trials established that EGFR tyrosine kinase inhibitors produced objective responses in a minority of NSCLC patients. We examined the sensitivity of 23 NSCLC lines with wild-type or mutated EGFR to gefitinib to determine genes/proteins related to sensitivity, including EGFR and HER2 cell surface expression, phosphorylated EGFR expression, EGFR gene copy number, and EGFR mutational status. Downstream cell cycle and signaling events were compared with growth-inhibitory effects.
Experimental Design: We determined gefitinib sensitivity by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, EGFR expression by fluorescence-activated cell sorting and immunohistochemistry, phosphorylated EGFR by Western blotting, EGFR gene copy number by fluorescence in situ hybridization, and EGFR mutation by sequencing. The cellular effects of gefitinib on cell cycle were determined by flow cytometry and the molecular effects of gefitinib EGFR inhibition on downstream signal proteins by Western blotting. Gefitinib in vivo effects were evaluated in athymic nude mice bearing sensitive and resistant NSCLC xenografts.
Results: There was a significant correlation between EGFR gene copy number, EGFR gene mutations, and gefitinib sensitivity. EGFR protein was necessary but not sufficient for predicting sensitivity. Gefitinib-sensitive lines showed a G1 cell cycle arrest and inactivation of downstream signaling proteins; resistant cell lines had no changes. The in vivo effects mirrored the in vitro effects.
Conclusions: This panel of NSCLC lines characterized for gefitinib response was used to identify predictive molecular markers of response to gefitinib. Several of these have subsequently been shown to identify NSCLC patients likely to benefit from gefitinib therapy.
Synergistic Antitumor Activity of ZD6474, An Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling, with Gemcitabine and Ionizing Radiation against Pancreatic Cancer
Authors: Bianco Cataldo , Giovannetti Elisa , Ciardiello Fortunato , Mey Valentina , Nannizzi Sara , Tortora Giampaolo , Troiani Teresa , Pasqualetti Francesco , Eckhardt Gail , de Liguoro Mario , Ricciardi Simona , Del Tacca Mario , Raben David , Cionini Luca , Danesi Romano 
Published: December 2006

AbstractPurpose: Standard treatments have modest effect against pancreatic cancer, and current research focuses on agents targeting molecular pathways involved in tumor growth and angiogenesis. This study investigated the interactions between ZD6474, an inhibitor of tyrosine kinase activities of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor (EGFR), gemcitabine, and ionizing radiation in human pancreatic cancer cells and analyzed the molecular mechanisms underlying this combination.Experimental Design: ZD6474, ionizing radiation, and gemcitabine, alone or in combination, were given in vitro to MIA PaCa-2, PANC-1, and Capan-1 cells and in vivo to MIA PaCa-2 tumor xenografts. The effects of treatments were studied by the evaluation of cytotoxicity, apoptosis, cell cycle, EGFR and Akt phosphorylation, modulation of gene expression of enzymes related to gemcitabine activity (deoxycytidine kinase and ribonucleotide reductase), as well as vascular endothelial growth factor immunohistochemistry and microvessel count.Results: In vitro, ZD6474 dose dependently inhibited cell growth, induced apoptosis, and synergistically enhanced the cytotoxic activity of gemcitabine and ionizing radiation. Moreover, ZD6474 inhibited phosphorylation of EGFR and Akt and triggered cell apoptosis. PCR analysis showed that ZD6474 increased the ratio between gene expression of deoxycytidine kinase and ribonucleotide reductase. In vivo, ZD6474 showed significant antitumor activity alone and in combination with radiotherapy and gemcitabine, and the combination of all three modalities enhanced MIA PaCA-2 tumor growth inhibition compared with gemcitabine alone.Conclusions: ZD6474 decreases EGFR and Akt phosphorylation, enhances apoptosis, favorably modulates gene expression in cancer cells, and acts synergistically with gemcitabine and radiotherapy to inhibit tumor growth. These findings support the investigation of this combination in the clinical setting.
Increased Frequency of CD4+ Cells Expressing CD161 in Cancer Patients
Authors: Iliopoulou Eleni G. , Karamouzis Michalis V. , Missitzis Ioannis , Ardavanis Alexandros , Sotiriadou Nectaria N. , Baxevanis Constantin N. , Rigatos Gerasimos , Papamichail Michael , Perez Sonia A. 
Published: December 2006

AbstractPurpose: Although the function of natural killer receptors on T cells infiltrating tumors and their potential effect on antitumor immunity has been investigated, little is known about T cells expressing NKR-P1A (CD161) in cancer patients. In the present study, we examined T cells expressing CD161 in the peripheral blood, the tumor tissue and in malignant effusions of patients with several types of malignancies.Experimental Design: Expression of CD161 in CD4+ or CD8+ (lacking CD56) T cells isolated from peripheral blood (n = 61), tumor specimens (n = 8), and malignant effusions (n = 37) of cancer patients was examined using four-color flow cytometry. Proliferative capacity and cytokine production of purified CD4+CD161+CD56− cells were studied after weak or strong stimulation, with or without costimulation, in the presence or absence of interleukin 2. The possible regulatory function of activated CD4+CD161+CD56− cells on T-cell alloresponses was also investigated.Results: CD4+ cells expressing CD161 were increased in cancer patients, compared with healthy individuals. This increase in the peripheral blood of cancer patients positively correlated with disease stage and was augmented at the tumor site. Phenotypic analysis revealed that CD4+CD161+ cells are memory T cells, with low expression of activation markers. CD4+CD161+ cells play an immunoregulatory role through cytokine production, because upon receiving costimulatory signals via CD28, they exert suppressive activity on autologous peripheral blood mononuclear cell alloresponses.Conclusions: CD4+CD161+CD56− cells represent a distinct memory T-cell population significantly increased in cancer patients. Depending on the type of signals provided by the tumor microenvironment, CD4+CD161+ cells may regulate the immune response.
Chelators at the Cancer Coalface: Desferrioxamine to Triapine and Beyond
Authors: Yu Yu , Wong Jacky , Lovejoy David B. , Kalinowski Danuta S. , Richardson Des R. 
Published: December 2006

Abstract
The importance of iron and copper in cancer biology has been well established. Iron plays a fundamental role in cellular proliferation and copper has been shown to be a significant cofactor for angiogenesis. Early observations with the chelator used for the treatment of iron overload, desferrioxamine, showed that it had promise as an anticancer agent. These results sparked great interest in the possibility of developing more effective iron chelators for cancer therapy. The recent entry into clinical trials of the iron-binding drug, Triapine, provides evidence of the potential of this antitumor strategy. Likewise, chelators originally designed to treat disorders of copper overload, such as penicillamine, trientine, and tetrathiomolybdate, have also emerged as potential anticancer drugs, as they are able to target the key angiogenic cofactor, copper. In this review, we will discuss the development of these and other chelators that show potential as anticancer agents.
What Difference Does Ius Inter Gentes Make? Changing Diplomatic Rights and Duties and the Modern European States-System
Authors: Lechner Silviya 
Published: December 2006

AbstractThe legal status of diplomats underwent a dramatic change between the sixteenth and eighteenth centuries as a consequence of a transformed European states-system. Its transformation is linked to ius inter gentes, a 'law between nations' whose emergence not only created a Europe of sovereign states but simultaneously affected the scope, definition and justification of rights and duties held by diplomatic representatives. It is generally acknowledged that diplomacy as an institution exists by virtue of rules that are embodied in the modern system of states and defined as 'international society' or the 'society of states'. What needs to be better understood is that diplomatic rights and duties are made possible by this framework of an international society, which has discernible historical and analytical boundaries, and that the relationship between such a framework and its diplomatic institutions is not contingent but logical.
A Case Study in Summitry: The Experience of Britain's Edward Heath, 1970-74
Authors: Young John 
Published: December 2006

AbstractWhile summits are well served in the literature on diplomacy, the focus tends to be on specific, high-profile occasions such as Munich and Yalta or on the broad experience of multilateral conferences. Such approaches may obscure the full range of summits that were taking place by the later twentieth century. By focusing on a four-year period in the experience of a particular leader, this article provides a case study of summitry, which might serve as the basis for comparisons with other countries and time periods. It draws out the frequency, type and geographical range of summits experienced by Edward Heath as British premier and, in doing so, also raises issues about how types of summits are defined, the relationship between bilateral and multilateral meetings and the way that summitry has evolved as a diplomatic practice. In particular it emerges that summits were frequent and ofen perfunctory affairs, sometimes held as a simple courtesy to leaders who were passing through London. In this sense the British experience may have been unusual, but it is also evident from the number of Heath's interlocutors and the multilateral conferences that he attended that summits had become an integral part of political life for world leaders in the jet age.