bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-Resolution Analysis of Chromosomal Breakpoints and Genomic Instability Identifies PTPRD as a Candidate Tumor Suppressor Gene in Neuroblastoma
Authors: Stallings Raymond L. , Nair Prakash , Maris John M. , Catchpoole Daniel , McDermott Michael , O'Meara Anne , Breatnach Fin 
Published: April 2006

Abstract
Although neuroblastoma is characterized by numerous recurrent, large-scale chromosomal imbalances, the genes targeted by such imbalances have remained elusive. We have applied whole-genome oligonucleotide array comparative genomic hybridization (median probe spacing 6 kb) to 56 neuroblastoma tumors and cell lines to identify genes involved with disease pathogenesis. This set of tumors was selected for having either 11q loss or MYCN amplification, abnormalities that define the two most common genetic subtypes of metastatic neuroblastoma. Our analyses have permitted us to map large-scale chromosomal imbalances and high-level amplifications at exon-level resolution and to identify novel microdeletions and duplications. Chromosomal breakpoints (n = 467) generating imbalances &gt;2 Mb were mapped to intervals ranging between 6 and 50 kb in size, providing substantial information on each abnormality. For example, breakpoints leading to large-scale hemizygous loss of chromosome 11q were highly clustered and preferentially associated with segmental duplications. High-level amplifications of MYCN were extremely complex, often resulting in a series of discontinuous regions of amplification. Imbalances (n = 540) &lt;2 Mb long were also detected. Although the majority (78%) of these imbalances mapped to segmentally duplicated regions and primarily reflect constitutional copy number polymorphisms, many subtle imbalances were detected that are likely somatically acquired alterations and include genes involved with tumorigenesis, apoptosis, or neural cell differentiation. The most frequent microdeletion involved the PTPRD locus, indicating a possible tumor suppressor function for this gene. (Cancer Res 2006; 66(7): 3673-80)
Frequent Met Oncogene Amplification in a Brca1/Trp53 Mouse Model of Mammary Tumorigenesis
Authors: Smolen Gromoslaw A. , Muir Beth , Mohapatra Gayatry , Barmettler Anne , Kim Woo J. , Rivera Miguel N. , Haserlat Sara M. , Okimoto Ross A. , Kwak Eunice , Dahiya Sonika , Garber Judy E. , Bell Daphne W. , Sgroi Dennis C. , Chin Lynda , Deng Chu-Xia , Haber Daniel A. 
Published: April 2006

Abstract
In a screen for gene copy number alterations in mouse mammary tumors initiated by loss of the Brca1 and Trp53 genes, we observed that the majority (11 of 15; 73%) had high-level amplification of wild-type Met, encoding a growth factor receptor implicated in tumor progression. Met amplification was localized to unstable double minute chromosomes and was uniquely found in mouse breast tumors driven by loss of Brca1 and Trp53. Whereas analogous MET amplification was not found in human breast cancers, the identification of a dominant somatic genetic lesion in the Brca1/Trp53 mouse model suggests that recurrent secondary hits may also exist in BRCA1-initiated human breast cancer. (Cancer Res 2006; 66(7): 3452-5)
Transcription Analysis of Human Equilibrative Nucleoside Transporter-1 Predicts Survival in Pancreas Cancer Patients Treated with Gemcitabine
Authors: Giovannetti Elisa , Del Tacca Mario , Mey Valentina , Funel Niccola , Nannizzi Sara , Ricci Sergio , Orlandini Cinzia , Boggi Ugo , Campani Daniela , Del Chiaro Marco , Iannopollo Mauro , Bevilacqua Generoso , Mosca Franco , Danesi Romano 
Published: April 2006

Abstract
Gene expression analysis may help the management of cancer patients, allowing the selection of subjects responding to treatment. The aim of this study was the characterization of expression pattern of genes involved in gemcitabine activity in pancreas tumor specimens and its correlation with treatment outcome. The role of drug transport and metabolism on gemcitabine cytotoxicity was examined with specific inhibitors, whereas transcription analysis of human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (dCK), 5′-nucleotidase (5′-NT), cytidine deaminase (CDA), and ribonucleotide reductase subunits M1 and M2 (RRM1 and RRM2) was done by quantitative reverse transcription-PCR in tumor tissue isolated by laser microdissection from surgical or biopsy samples of 102 patients. Association between clinical outcome and gene expression levels was estimated using Kaplan-Meier method and Cox's proportional hazards model. Transport and metabolism had a key role on gemcitabine sensitivity in vitro; moreover, hENT1, dCK, 5′-NT, CDA, RRM1, and RRM2 were detectable in most tumor specimens. hENT1 expression was significantly correlated with clinical outcome. Patients with high levels of hENT1 had a significantly longer overall survival [median, 25.7; 95% confidence interval (95% CI), 17.6-33.7 months in the higher expression tertile versus median, 8.5; 95% CI, 7.0-9.9 months in the lower expression tertile]. Similar results were obtained with disease-free survival and time to disease progression, and the multivariate analysis confirmed the prognostic significance of hENT1. This study suggests that the expression levels of hENT1 may allow the stratification of patients based on their likelihood of survival, thus offering a potential new tool for treatment optimization. (Cancer Res 2006; 66(7): 3928-35)
Tumor B7-H1 Is Associated with Poor Prognosis in Renal Cell Carcinoma Patients with Long-term Follow-up
Authors: Thompson R. Houston , Kuntz Susan M. , Leibovich Bradley C. , Dong Haidong , Lohse Christine M. , Webster W. Scott , Sengupta Shomik , Frank Igor , Parker Alexander S. , Zincke Horst , Blute Michael L. , Sebo Thomas J. , Cheville John C. , Kwon Eugene D. 
Published: April 2006

Abstract
B7-H1 participates in T-cell costimulation functioning as a negative regulator of immunity. Recent observations suggest that B7-H1 is expressed by renal cell carcinoma (RCC) tumor cells and is associated with poor prognosis. However, outcome analyses have been restricted to patients with fresh-frozen tissue and limited follow-up. We report the clinical effect of B7-H1 in RCC patients with a median of 10 years of follow-up. Between 1990 and 1994, 306 patients underwent nephrectomy for clear cell RCC and had paraffin tissue available for review. We did immunohistochemistry with anti-B7-H1 and conducted outcome analyses. Among the 306 patients, 73 (23.9%) harbored tumors with B7-H1 expression. Patients with tumor B7-H1 were at a significantly increased risk of both death from RCC [risk ratio (RR), 3.92; P &lt; 0.001] and overall mortality (RR, 2.37; P &lt; 0.001). The 5-year cancer-specific survival rates were 41.9% and 82.9% for patients with and without tumor B7-H1, respectively. In a multivariate model, tumor B7-H1 remained associated with cancer-specific death even after adjusting for tumor-node-metastasis stage, grade, and performance status (RR, 2.00; P = 0.003). In the subset of 268 patients with localized RCC, tumor B7-H1 was significantly associated with metastatic cancer progression (RR, 3.46; P &lt; 0.001) and death from RCC (RR, 4.13; P &lt; 0.001) even after adjusting for stage, grade, and performance status (RR, 1.78, P = 0.036). RCC patients with tumor B7-H1 are at significant risk of rapid cancer progression and accelerated rates of mortality. B7-H1 may function as a key determinant in RCC, abrogating immune responses directed against this immunogenic tumor. (Cancer Res 2006; 66(7): 3381-5)
Activation of Mitogen-Activated Protein Kinase in Estrogen Receptor α–Positive Breast Cancer Cells In vitro Induces an In vivo Molecular Phenotype of Estrogen Receptor α–Negative Human Breast Tumors
Authors: Creighton Chad J. , Hilger Amy M. , Murthy Shalini , Rae James M. , Chinnaiyan Arul M. , El-Ashry Dorraya 
Published: April 2006

Abstract
Breast cancer presents as either estrogen receptor α (ERα) positive or negative, with ERα+ tumors responding to antiestrogen therapy and having a better prognosis. By themselves, mRNA expression signatures of estrogen regulation in ERα+ breast cancer cells do not account for the vast molecular differences observed between ERα+ and ERα− cancers. In ERα− tumors, overexpression of epidermal growth factor receptor (EGFR) or c-erbB-2, leading to increased growth factor signaling, is observed such that mitogen-activated protein (MAP) kinase (MAPK) is significantly hyperactivated compared with ERα+ breast cancer. In ERα+/progesterone receptor–positive, estrogen-dependent MCF-7 breast cancer cells, we stably overexpressed EGFR or constitutively active erbB-2, Raf, or MAP/extracellular signal-regulated kinase kinase, resulting in cell lines exhibiting hyperactivation of MAPK, estrogen-independent growth, and the reversible down-regulation of ERα expression. By global mRNA profiling, we found a “MAPK signature” of ∼400 genes consistently up-regulated or down-regulated in each of the MAPK+ cell lines. In several independent profile data sets of human breast tumors, the in vitro MAPK signature was able to accurately distinguish ER+ from ER− tumors. In addition, our in vitro mRNA profile data revealed distinct mRNA signatures specific to either erbB-2 or EGFR activation. A subset of breast tumor profiles was found to share extensive similarities with either the erbB-2-specific or the EGFR-specific signatures. Our results confirm that increased MAPK activation causes loss of ERα expression and suggest that hyperactivation of MAPK plays a role in the generation of the ERα− phenotype in breast cancer. These MAPK+ cell lines are excellent models for investigating the underlying mechanisms behind the ERα− phenotype. (Cancer Res 2006; 66(7): 3903-11)
Highly Efficacious Nontoxic Preclinical Treatment for Advanced Metastatic Breast Cancer Using Combination Oral UFT-Cyclophosphamide Metronomic Chemotherapy
Authors: Munoz Raquel , Man Shan , Shaked Yuval , Lee Christina R. , Wong John , Francia Giulio , Kerbel Robert S. 
Published: April 2006

Abstract
Metronomic antiangiogenic chemotherapy, the prolonged administration of relatively low drug doses, at close regular intervals with no significant breaks, has been mainly studied at the preclinical level using single chemotherapeutic drugs, frequently in combination with a targeted antiangiogenic drug, and almost always evaluated on primary localized tumors. We tested a “doublet” combination metronomic chemotherapy treatment using two oral drugs, UFT, a 5-fluorouracil (5-FU) prodrug administered by gavage, and cyclophosphamide, for efficacy and toxicity in a new mouse model of advanced, terminal, metastatic human breast cancer. The optimal biological dose of each drug was first determined by effects on levels of circulating endothelial progenitor cells as a surrogate marker for angiogenesis, which was assessed to be 15 mg/kg for UFT and 20 mg/kg for cyclophosphamide. A combination treatment was then evaluated in mice with advanced metastatic disease using a serially selected metastatic variant of the MDA-MB-231 breast cancer-cell line, 231/LM2-4. UFT or cyclophosphamide treatment showed only very modest survival advantages whereas a combination of the two resulted in a remarkable prolongation of survival, with no evidence of overt toxicity despite 140 days of continuous therapy, such that a significant proportion of mice survived for over a year. In contrast, this striking therapeutic effect of the combination treatment was not observed when tested on primary orthotopic tumors. We conclude that combination oral low-dose daily metronomic chemotherapy, using cyclophosphamide and UFT, is superior to monotherapy and seems to be a safe and highly effective experimental antimetastatic therapy, in this case, for advanced metastatic breast cancer. (Cancer Res 2006; 66(7): 3386-91)
Estrogen Induces Lung Metastasis through a Host Compartment–Specific Response
Authors: Banka Carole L. , Lund Caren V. , Nguyen Mai T.N. , Pakchoian Andrew J. , Mueller Barbara M. , Eliceiri Brian P. 
Published: April 2006

Abstract
Direct proliferative effects of estrogen (E2) on estrogen receptor–positive tumors are well documented; however, the potential for E2 to mediate effects selective for the host (i.e., angiogenesis, vascular permeability, or stromal effects), which influence tumor growth and/or metastasis, has received less attention. In this study, we examine the capacity for E2 to promote tumor growth and/or metastasis independent of direct effects on tumor cells. In these studies, we distinguish host versus tumor compartment components of E2 action in tumor growth and metastasis by analysis of E2-nonresponsive tumor cells implanted in ovariectomized (OVX) mice that contain s.c. implants of placebo (OVX) or E2-containing slow-release pellets (OVX + E2). We show that the D121 lung carcinoma cell line is E2-nonresponsive, and following s.c. implantation in OVX versus OVX + E2 mice, E2 action on the host compartment leads to an increase in spontaneous metastasis but not primary tumor growth or neovascularization. Similarly, experimental lung metastasis of E2-nonresponsive 4T1 mammary carcinoma cells also leads to increased tumor burden in the lungs of OVX + E2 mice. These results suggest that the E2 status of the host compartment influences late steps in tumor cell metastasis that can provide important insights into the role of E2 in the tumor versus host compartments. (Cancer Res 2006; 66(7): 3667-72)
Mitosis-Independent Survivin Gene Expression In vivo and Regulation by p53
Authors: Xia Fang , Altieri Dario C. 
Published: April 2006

Abstract
Survivin is an essential mitotic gene, and this has been speculated to reflect its primary function in development and cancer. Here, we generated a knock-in transgenic mouse (SVVp-GFP) in which a green fluorescent protein (GFP) reporter gene was placed under the control of the survivin promoter that regulates transcription at mitosis. The expression of endogenous survivin was widespread in mouse tissues during development and shortly after birth. In contrast, GFP reactivity was undetectable in transgenic mouse embryos, and was largely limited postnatally to mitotic cells in the testes. Double transgenic mice generated in the tumor-prone Min/+ background exhibited intestinal adenomas that strongly expressed endogenous survivin, but only isolated GFP-positive cells. Conversely, dysplastic adenomas (16%) stained intensely for GFP, and revealed focal reactivity for mutant, but not wild-type, p53. The expression of GFP was increased by ∼10-fold in p53−/− as opposed to p53+/+ HCT116 colorectal cancer cells, and reintroduction of p53 in p53−/− cells abolished GFP expression. Therefore, the mitotic transcription of the survivin gene is highly restricted in vivo, and unexpectedly negatively regulated by p53. Contrary to a commonly held view, the dominant function(s) of survivin in development and tumor ontogeny are largely cell cycle–independent. (Cancer Res 2006; (66)7: 3392-5)
The Oxygen Sensor Factor-Inhibiting Hypoxia-Inducible Factor-1 Controls Expression of Distinct Genes through the Bifunctional Transcriptional Character of Hypoxia-Inducible Factor-1α
Authors: Dayan Frédéric , Roux Danièle , Brahimi-Horn M. Christiane , Pouyssegur Jacques , Mazure Nathalie M. 
Published: April 2006

Abstract
The function of the hypoxia-inducible factor-1 (HIF-1), the key transcription factor involved in cellular adaptation to hypoxia, is restricted to low oxygen tension (pO2). As such, this transcription factor is central in modulating the tumor microenvironment, sensing nutrient availability, and controlling anaerobic glycolysis, intracellular pH, and cell survival. Degradation and inhibition of the limiting HIF-1α subunit are intimately connected in normoxia. Hydroxylation of two proline residues by prolyl hydroxylase domain (PHD) 2 protein earmarks the protein for degradation, whereas hydroxylation of an asparagine residue by factor-inhibiting HIF-1 (FIH-1 or FIH) reduces its transcriptional activity. Indeed, silencing of either PHD2 or FIH in normoxia partially induced hypoxic genes, whereas combined PHD2/FIH silencing generated a full hypoxic gene response. Given the fact that HIF-1α possesses two transcriptional activation domains [TAD; NH2-terminal (N-TAD) and COOH-terminal (C-TAD)], we hypothesized on a possible bifunctional activity of HIF-1α that could be discriminated by FIH, an inhibitor of the C-TAD. In human cell lines engineered to overexpress or silence FIH in response to tetracycline, we show by quantitative reverse transcription-PCR that a set of hypoxic genes (ca9, phd3, pgk1, and bnip3) respond differently toward FIH expression. This finding, extended to 26 hypoxia-induced genes, indicates differential gene expression by the N-TAD and C-TAD in response to the hypoxic gradient. We propose that the oxygen-sensitive attenuator FIH, together with two distinct TADs, is central in setting the gene expression repertoire dictated by the cell pO2. (Cancer Res 2006; 66(7): 3688-98)
TMPRSS2:ETV4 Gene Fusions Define a Third Molecular Subtype of Prostate Cancer
Authors: Tomlins Scott A. , Mehra Rohit , Rhodes Daniel R. , Smith Lisa R. , Roulston Diane , Helgeson Beth E. , Cao Xuhong , Wei John T. , Rubin Mark A. , Shah Rajal B. , Chinnaiyan Arul M. 
Published: April 2006

Abstract
Although common in hematologic and mesenchymal malignancies, recurrent gene fusions have not been well characterized in epithelial carcinomas. Recently, using a novel bioinformatic approach, we identified recurrent gene fusions between TMPRSS2 and the ETS family members ERG or ETV1 in the majority of prostate cancers. Here, we interrogated the expression of all ETS family members in prostate cancer profiling studies and identified marked overexpression of ETV4 in 2 of 98 cases. In one such case, we confirmed the overexpression of ETV4 using quantitative PCR, and by rapid amplification of cDNA ends, quantitative PCR, and fluorescence in situ hybridization, we show that the TMPRSS2 (21q22) and ETV4 (17q21) loci are fused in this case. This result defines a third molecular subtype of prostate cancer and supports the hypothesis that dysregulation of ETS family members through fusions with TMRPSS2 may be an initiating event in prostate cancer development. (Cancer Res 2006; 66(7): 3396-400)
US.India.China
Authors: Gupta Amit 
Published: April 2006

With the rise of India and China to potential great power status, there is now talk of the United States, India and China being the three poles in the international system of 2050. This article argues that the three countries are on different power trajectories and that two of these trajectories—those of the United States and China—will lead to a strategic rivalry. On the other hand, India's power trajectory, while faced with conflict at the South Asian level of analysis, may well allow it to play the role of a ‘swing state’. As a swing state, India could work as a facilitator to get China to work in a cooperative security arrangement to secure energy supplies, maintain freedom of navigation on the high seas, and play according to the rules that make it a status quo power in the international system. In return, India would expect China to settle the border dispute to India's advantage, delink from Pakistan, and be more considerate of India's own quest for securing energy resources.
E2f4 regulates fetal erythropoiesis through the promotion of cellular proliferation
Authors: Kinross Kathryn M. , Clark Allison J. , Iazzolino Rosa M. , Humbert Patrick Orson 
Published: April 2006

AbstractThe E2F proteins are major regulators of the transcriptional program required to coordinate cell cycle progression and exit. In particular, E2f4 has been proposed to be the principal family member responsible for the regulation of cell cycle exit chiefly through its transcriptional repressive properties. We have previously shown that E2f4–/– mice display a marked macrocytic anemia implicating E2f4 in the regulation of erythropoiesis. However, these studies could not distinguish whether E2f4 was required for differentiation, survival, or proliferation control. Here, we describe a novel function for E2f4 in the promotion of erythroid proliferation. We show that loss of E2f4 results in an impaired expansion of the fetal erythroid compartment in vivo that is associated with impaired cell cycle progression and decreased erythroid proliferation. Consistent with these observations, cDNA microarray analysis reveals cell cycle control genes as one of the major class of genes down-regulated in E2f4–/– FLs, and we provide evidence that E2f4 may directly regulate the transcriptional expression of a number of these genes. We conclude that the macrocytic anemia of E2f4–/– mice results primarily from impaired cellular proliferation and that the major role of E2f4 in fetal erythropoiesis is to promote cell cycle progression and cellular proliferation.
Proper levels of c-Myb are discretely defined at distinct steps of hematopoietic cell development
Authors: Sakamoto Hiroshi , Dai Guoyou , Tsujino Kaori , Hashimoto Kazuaki , Huang Xin , Fujimoto Tetsuhiro , Mucenski Michael , Frampton Jon , Ogawa Minetaro 
Published: April 2006

AbstractThe definitive hematopoietic cell lineages have been proposed to originate from hemogenic endothelial cells during mouse embryogenesis. c-Myb is a transcription factor that is essential for the development of definitive hematopoiesis. To investigate the functional role of c-Myb in hematopoietic cell development from endothelial cells, we introduced a c-myb transgene expressed under the control of a tetracycline-regulated promoter into the c-myb–/– embryonic stem (ES) cell line, with the aim of inducing c-Myb expression at any stage and at any level. Induction of c-Myb expression after replating c-myb–/– endothelial cells rescued the generation and proliferation of definitive hematopoietic progenitor cells, suggesting that c-Myb expression in developing endothelial cells is not a prerequisite for their hematogenic potential. Overexpression of c-Myb, however, prevented the terminal differentiation of erythrocytes and megakaryocytes and completely abolished B-lymphocyte development. Our results indicate that c-Myb is a major factor that controls differentiation as well as proliferation of hematopoietic progenitor cells derived from hemogenic endothelial cells, and that appropriate levels of c-Myb protein are strictly defined at distinct differentiation steps of each hematopoietic cell lineage.
The role of interleukin-17 during acute rejection after lung transplantation
Authors: Vanaudenaerde B. M. , Dupont L. J. , Wuyts W. A. , Verbeken E. K. , Meyts I. , Bullens D. M. , Dilissen E. , Luyts L. , Van Raemdonck D. E. , Verleden G. M. 
Published: April 2006

Acute rejection (AR) is an important complication that can occur after lung transplantation and constitutes a risk factor for bronchiolitis obliterans syndrome, which is characterised by a neutrophilic airway inflammation. The specific aim of this study was to investigate the role of interleukin (IL)-17, which promotes chemotaxis of neutrophils by inducing IL-8 production, in AR.Cell differentials, mRNA and protein levels were quantified in bronchoalveolar lavages (BALs) taken from patients at 28 and 90 days after lung transplantation. The patient's rejection status was assessed by transbronchial biopsy.An AR was found in nine out of the 26 patients examined, 28 days after transplantation. The number of BAL neutrophils and lymphocytes were increased in these patients. IL-17 mRNA and protein levels in the BAL were increased in patients with AR. Analysis of BAL obtained at day 90 after transplantation, demonstrated that the increase in IL-17 had disappeared, whereas the increase in neutrophils and lymphocytes persisted.These data showed that interleukin-17 is temporarily upregulated in bronchoalveolar lavage during acute rejection. The number of lymphocytes and neutrophils are increased in bronchoalveolar lavage during acute rejection and may persist up to 2 months after acute rejection. These findings suggest that interleukin-17 is important in the pathophysiology of acute lung rejection.