bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of the Peptidyl-Prolyl-Isomerase Pin1 Enhances the Responses of Acute Myeloid Leukemia Cells to Retinoic Acid via Stabilization of RARα and PML-RARα
Authors: Gianni' Maurizio , Boldetti Andrea , Guarnaccia Valeria , Rambaldi Alessandro , Parrella Edoardo , Raska Ivan , Rochette-Egly Cecile , Del Sal Giannino , Rustighi Alessandra , Terao Mineko , Garattini Enrico 
Published: January 2009

Abstract
The peptidyl-prolyl-isomerase Pin1 interacts with phosphorylated proteins, altering their conformation. The retinoic acid receptor RARα and the acute-promyelocytic-leukemia–specific counterpart PML-RARα directly interact with Pin1. Overexpression of Pin1 inhibits ligand-dependent activation of RARα and PML-RARα. Inhibition is relieved by Pin1-targeted short interfering RNAs and by pharmacologic inhibition of the catalytic activity of the protein. Mutants of Pin1 catalytically inactive or defective for client-protein–binding activity are incapable of inhibiting ligand-dependent RARα transcriptional activity. Functional inhibition of RARα and PML-RARα by Pin1 correlates with degradation of the nuclear receptors via the proteasome-dependent pathway. In the acute myelogenous leukemia cell lines HL-60 and NB4, Pin1 interacts with RARα in a constitutive fashion. Suppression of Pin1 by a specific short hairpin RNA in HL-60 or NB4 cells stabilizes RARα and PML-RARα, resulting in increased sensitivity to the cytodifferentiating and antiproliferative activities of all-trans retinoic acid. Treatment of the two cell lines and freshly isolated acute myelogenous leukemia blasts (M1 to M4) with ATRA and a pharmacologic inhibitor of Pin1 causes similar effects. Our results add a further layer of complexity to the regulation of nuclear retinoic acid receptors and suggest that Pin1 represents an important target for strategies aimed at increasing the therapeutic index of retinoids. [Cancer Res 2009;69(3):1016–26
Glucocorticoid-Induced Tumor Necrosis Factor Receptor–Related Protein Ligand Subverts Immunosurveillance of Acute Myeloid Leukemia in Humans
Authors: Baessler Tina , Krusch Matthias , Schmiedel Benjamin Joachim , Kloss Mercedes , Baltz Katrin Miriam , Wacker Alexander , Schmetzer Helga Maria , Salih Helmut Rainer 
Published: January 2009

Abstract
The reciprocal interaction of tumor cells with the immune system is influenced by various members of the tumor necrosis factor (TNF)/TNF receptor (TNFR) family, and recently, glucocorticoid-induced TNFR-related protein (GITR) was shown to stimulate antitumor immunity in mice. However, GITR may mediate different effects in mice and men and impairs the reactivity of human natural killer (NK) cells. Here, we studied the role of GITR and its ligand (GITRL) in human acute myeloid leukemia (AML). Surface expression of GITRL was observed on AML cells in six of seven investigated cell lines, and 34 of 60 investigated AML patients whereas healthy CD34+ cells did not express GITRL. Furthermore, soluble GITRL (sGITRL) was detectable in AML patient sera in 18 of 55 investigated cases. While the presence of GITRL was not restricted to a specific AML subtype, surface expression was significantly associated with monocytic differentiation. Signaling via GITRL into patient AML cells induced the release of TNF and interleukin-10 (IL-10), and this was blocked by the inhibition of mitogen-activated protein kinases extracellular signal-regulated kinase 1/2. Furthermore, triggering GITR by surface-expressed and sGITRL impaired NK cell cytotoxicity and IFN-γ production in cocultures with leukemia cells, and NK cell reactivity could be restored by blocking GITR and neutralization of sGITRL and IL-10. Thus, whereas a stimulatory role of the GITR-GITRL system in mouse antitumor immunity has been reported, our data show that in humans GITRL expression subverts NK cell immunosurveillance of AML. Our results provide useful information for therapeutic approaches in AML, which, like haploidentical stem cell transplantation, rely on a sufficient NK cell response. [Cancer Res 2009;69(3):1037–45]
Tamoxifen Induces Expression of Immune Response–Related Genes in Cultured Normal Human Mammary Epithelial Cells
Authors: Schild-Hay Laura J. , Leil Tarek A. , Divi Rao L. , Olivero Ofelia A. , Weston Ainsley , Poirier Miriam C. 
Published: January 2009

Abstract
Use of tamoxifen is associated with a 50% reduction in breast cancer incidence and an increase in endometrial cancer incidence. Here, we documented tamoxifen-induced gene expression changes in cultured normal human mammary epithelial cells (strains 5, 16, and 40), established from tissue taken at reduction mammoplasty from three individuals. Cells exposed to 0, 10, or 50 μmol/L of tamoxifen for 48 hours were evaluated for (E)-α-(deoxyguanosine-N2-yl)-tamoxifen (dG-N2-TAM) adduct formation using TAM-DNA (DNA modified with dG-N2-TAM) chemiluminescence immunoassay, gene expression changes using National Cancer Institute DNA-oligonucleotide microarray, and real-time PCR. At 48 hours, cells exposed to 10 and 50 μmol/L of tamoxifen were 85.6% and 48.4% viable, respectively, and there were no measurable dG-N2-TAM adducts. For microarrays, cells were exposed to 10 μmol/L of tamoxifen and genes with expression changes of &gt;3-fold were as follows: 13 genes up-regulated and 1 down-regulated for strain 16; 17 genes up-regulated for strain 5, and 11 genes up-regulated for strain 40. Interferon-inducible genes (IFITM1, IFIT1, MXI, and GIP3), and a potassium ion channel (KCNJ1) were up-regulated in all three strains. No significant expression changes were found for genes related to estrogen or xenobiotic metabolism. Real-time PCR revealed the up-regulation of IFNA1 and confirmed the tamoxifen-induced up-regulation of the five other genes identified by microarray, with the exception of GIP3 and MX1, which were not up-regulated in strain 40. Induction of IFN-related genes in the three normal human mammary epithelial cell strains suggests that, in addition to hormonal effects, tamoxifen exposure may enhance immune response in normal breast tissue. [Cancer Res 2009;69(3):1150–5]
MicroRNA-101, Down-regulated in Hepatocellular Carcinoma, Promotes Apoptosis and Suppresses Tumorigenicity
Authors: Su Hang , Yang Jian-Rong , Xu Teng , Huang Jun , Xu Li , Yuan Yunfei , Zhuang Shi-Mei 
Published: January 2009

Abstract
Although aberrant microRNA (miRNA) expressions have been observed in different types of cancer, their pathophysiologic role and their relevance to tumorigenesis are still largely unknown. In this study, we first evaluated the expression of 308 miRNAs in human hepatocellular carcinoma (HCC) and normal hepatic tissues and identified 29 differentially expressed miRNAs in HCC tissues. miR-101, a significantly down-regulated miRNA, was further studied in greater detail because the signal pathway(s) regulated by miR-101 and the role of miR-101 in tumorigenesis have not yet been elucidated. Interestingly, decreased expression of miR-101 was found in all six hepatoma cell lines examined and in as high as 94.1% of HCC tissues, compared with their nontumor counterparts. Furthermore, ectopic expression of miR-101 dramatically suppressed the ability of hepatoma cells to form colonies in vitro and to develop tumors in nude mice. We also found that miR-101 could sensitize hepatoma cell lines to both serum starvation– and chemotherapeutic drug–induced apoptosis. Further investigation revealed that miR-101 significantly repressed the expression of luciferase carrying the 3′-untranslated region of Mcl-1 and reduced the endogenous protein level of Mcl-1, whereas the miR-101 inhibitor obviously up-regulated Mcl-1 expression and inhibited cell apoptosis. Moreover, silencing of Mcl-1 phenocopied the effect of miR-101 and forced expression of Mcl-1 could reverse the proapoptotic effect of miR-101. These results indicate that miR-101 may exert its proapoptotic function via targeting Mcl-1. Taken together, our data suggest an important role of miR-101 in the molecular etiology of cancer and implicate the potential application of miR-101 in cancer therapy. [Cancer Res 2009;69(3):1135–42]
Positron Emission Tomography (PET) Imaging with [11C]-Labeled Erlotinib: A Micro-PET Study on Mice with Lung Tumor Xenografts
Authors: Memon Ashfaque A. , Jakobsen Steen , Dagnaes-Hansen Frederik , Sorensen Boe S. , Keiding Susanne , Nexo Ebba 
Published: January 2009

Abstract
Erlotinib (Tarceva) targets the epidermal growth factor receptor (EGFR), which is commonly overexpressed in human cancers, including lung cancer. We show that erlotinib can be labeled with [11C] by reacting the normethyl precursor with [11C]-methyl iodide. By using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay, two lung cancer cell lines (A549 and NCI358) were shown to be less sensitive to erlotinib compared with the lung cancer cell line HCC827. This correlated with higher expression and activity of the EGFR in HCC827 cells as compared with the less sensitive cell lines. Micro–positron emission tomography (PET) and biodistribution of erlotinib was performed with [11C]-erlotinib in nude mice bearing xenografts of A549, NCI358, and HCC827 cells. Dynamic micro-PET showed that HCC827 tumors had the highest [11C]-erlotinib uptake and retained the activity significantly longer as compared with A549 and NCI358 tumors. Biodistribution of [11C]-erlotinib in the xenograft models of lung cancer showed the highest accumulation in the liver. In mice carrying the sensitive cancer cells, the accumulation of [11C]-erlotinib was higher in tumors than in the other organs. In contrast, the drug accumulated to a comparable extent in tumors from the less sensitive cancer cells and the other organs. Uptake of [11C]-erlotinib in the tumors was 1.6%, 0.7%, and 3.7% (percentage of injected dose/g), in A549, NCI358, and HCC827 cells, respectively. We show for the first time that [11C]-erlotinib identifies erlotinib-sensitive tumors. These results pave the road for studies examining the benefit of [11C]-erlotinib PET in patients with lung tumors or other tumors overexpressing EGFR. [Cancer Res 2009;69(3):873–8]
Transient Receptor Potential Type Vanilloid 1 Suppresses Skin Carcinogenesis
Authors: Bode Ann M. , Cho Yong-Yeon , Zheng Duo , Zhu Feng , Ericson Marna E. , Ma Wei-Ya , Yao Ke , Dong Zigang 
Published: January 2009

Abstract
Blockade of the transient receptor potential channel vanilloid subfamily 1 (TRPV1) is suggested as a therapeutic approach to pain relief. However, TRPV1 is a widely expressed protein whose function might be critical in various nonneuronal physiologic conditions. The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is overexpressed in many human epithelial cancers and is a potential target for anticancer drugs. Here, we show that TRPV1 interacts with EGFR, leading to EGFR degradation. Notably, the absence of TRPV1 in mice results in a striking increase in skin carcinogenesis. The TRPV1 is the first membrane receptor shown to have a tumor-suppressing effect associated with the down-regulation of another membrane receptor. The data suggest that, although a great deal of interest has focused on TRPV1 as a target for pain relief, the chronic blockade of this pain receptor might increase the risk for cancer development. [Cancer Res 2009;69(3):905–13]
Consistent Deregulation of Gene Expression between Human and Murine MLL Rearrangement Leukemias
Authors: Li Zejuan , Luo Roger T. , Mi Shuangli , Sun Miao , Chen Ping , Bao Jingyue , Neilly Mary Beth , Jayathilaka Nimanthi , Johnson Deborah S. , Wang Lili , Lavau Catherine , Zhang Yanming , Tseng Charles , Zhang Xiuqing , Wang Jian , Yu Jun , Yang Huanming , Wang San Ming , Rowley Janet D. , Chen Jianjun , Thirman Michael J. 
Published: January 2009

Abstract
Important biological and pathologic properties are often conserved across species. Although several mouse leukemia models have been well established, the genes deregulated in both human and murine leukemia cells have not been studied systematically. We performed a serial analysis of gene expression in both human and murine MLL-ELL or MLL-ENL leukemia cells and identified 88 genes that seemed to be significantly deregulated in both types of leukemia cells, including 57 genes not reported previously as being deregulated in MLL-associated leukemias. These changes were validated by quantitative PCR. The most up-regulated genes include several HOX genes (e.g., HOX A5, HOXA9, and HOXA10) and MEIS1, which are the typical hallmark of MLL rearrangement leukemia. The most down-regulated genes include LTF, LCN2, MMP9, S100A8, S100A9, PADI4, TGFBI, and CYBB. Notably, the up-regulated genes are enriched in gene ontology terms, such as gene expression and transcription, whereas the down-regulated genes are enriched in signal transduction and apoptosis. We showed that the CpG islands of the down-regulated genes are hypermethylated. We also showed that seven individual microRNAs (miRNA) from the mir-17-92 cluster, which are overexpressed in human MLL rearrangement leukemias, are also consistently overexpressed in mouse MLL rearrangement leukemia cells. Nineteen possible targets of these miRNAs were identified, and two of them (i.e., APP and RASSF2) were confirmed further by luciferase reporter and mutagenesis assays. The identification and validation of consistent changes of gene expression in human and murine MLL rearrangement leukemias provide important insights into the genetic base for MLL-associated leukemogenesis. [Cancer Res 2009;69(3):OF1109–16]
Svalbard's Maritime Zones: The End of Legal Uncertainty?
Authors: Pedersen Torbjørn , Henriksen Tore 
Published: January 2009

AbstractThis paper argues that Norway, by fixing the extension of the continental shelf around the Svalbard archipelago according to criteria set by the Law of the Sea Convention, may see an end to some of the legal controversies regarding the maritime zones around Svalbard. The process of determining the outer limits of the continental shelf area adjacent to Svalbard is adduced as supporting the view that Norway is entitled to establish maritime zones around the archipelago, including an exclusive economic zone. It does not settle whether the provisions of the Svalbard Treaty apply to such zones, but is adduced as supporting the view that Norway may exercise coastal state jurisdiction in these areas.
Balancing a Child's Best Interests and a Child's Views
Authors: Archard David , Skivenes Marit 
Published: January 2009

AbstractWe consider the problem of reconciling the two commitments to hear a child and to promote a child's best interests by identifying the principal issues at stake and illustrating them by reference to legal decision-making in the domains of health in the United Kingdom and custody and child protection in Norway. We agree that a child's views are not authoritative but dispute Harry Brighouse's claim that they are only of consultative value, affirming the fundamental right of a child capable of expressing a view of doing so and of thereby participating in the procedures where decisions affecting his or her interests are made. In conclusion we offer a checklist of questions that need to be asked about the way in which jurisdictions combine their explicit commitments to the two principles of best interests and hearing the child's views.
Analysis of errors in degree days for building energy analysis using Meteorological Office weather station data
Authors: Layberry RL 
Published: January 2009

Heating degree days are widely used in building energy management for weather normalization of energy use. Degree days are normally calculated at Meteorological Office weather stations sited some distance from the building of interest and this can introduce errors between the degree days used in the calculations and the actual degree days at the building. This paper analyses the major sources of errors in the degree days derived from a newly available data set of Met. Office stations supplied by the British Atmospheric Data Survey (BADC) and compares these errors against those from other available data sets. The BADC data set consists of hourly temperatures for 242 weather stations in the UK from January 2001 until November 2007 and has been converted to monthly degree days for the analysis. The errors have been analysed in terms of measurement and recording errors, errors due to altitude and errors due to spatial separation between weather station and building. The largest error is due to spatial separation between building and weather station. It is therefore important to use data sets with high numbers of weather stations. The data set used in this analysis has been made available on the internet at http:// www.eci.ox.ac.uk/research/energy/degreedays.php and consists of daily, weekly and monthly degree days for over 200 UK weather stations at a range of building base temperatures for the years 1987—2006. Also included is the 20-year mean for the 55 stations with unbroken records for benchmarking purposes. Practical application: The paper discusses how errors arise in degree day data when using Met. Office weather stations sited some distance from the building of interest. The paper discusses both the method and the extent of reductions in errors that are possible by using spatially rich weather station degree day data sets. The paper makes the data set used — the best for UK degree day monitoring of buildings — available through a website, daily, weekly and monthly, over a range of building base temperatures, back to 1986.
Performance evaluation of dual-flush WC cistern in a multifamily building in Brazil
Authors: Oliveira LH , Gonçalves OM , Uchida C. 
Published: January 2009

The performance assessment as to water consumption in WC cisterns has contributed to the development of flushing system technologies, which allow smaller flushing volumes. The purpose of this work is to assess the performance of the the low water consumption requirement of WC cisterns with dual flushing system (6/3 L), when compared to 6 L flushing volume WC cisterns in multifamily buildings. The research methodology consisted of a case study in a multifamily residential building with submetering system, by monitoring the total water consumption and the two flushing systems using water meters installed in WC cisterns. By means of a mathematical model, a comparison of the design flowrate in the main branch was carried out considering the two types of WC cisterns. The results indicated that the water consumption in the 6 L WC cistern was 20% in relation to the total domestic consumption, whereas the water consumption observed in the dual-flush WC cistern (6/3 L) was 16%. The dual flushing system (6/3 L) presented about 18% consumption reduction impact as compared to the 6 L system. The design flowrate values in the main branch, obtained by the mathematical model, were 0.35 L/s for systems with 6 L WC cistern and 0.34 L/s with dual-flush WC cistern (6/3 L), that is, a reduction of ~3%. Practical application: The knowledge of the performance in field of dual-flush WC cistern contributes to industry to improve this system and to users to aid their choice of technologies aimed at water conservation, and so assisting to the development of sustainable buildings.
Morphologic and Immunohistochemical Features of the Cynomolgus Macaque Cervix
Authors: Wood Charles E. 
Published: January 2009

Female macaques serve as an important model for the study of reproductive diseases in women. Here we summarize characteristics of the macaque cervix, with a particular emphasis on the cynomolgus macaque. Key anatomic features include a stratified squamous exocervix, squamocolumnar junction and transformation zone, and glandular endocervix with prominent colliculi. Endocervical eversion occurs with onset of ovarian cycling and regresses to varying degrees based on age, hormonal status, and individual conformation. The cervical epithelium in macaques is highly responsive to estrogens, which induce marked squamous epithelial maturation and glandular hypertrophy. Progestogen effects include further induction of endocervical secretory activity and release of viscous mucus, which functions in both mucosal immunity and fertility regulation. On immunohistochemistry, the squamous cervix shows strong expression of estrogen receptor α, the proliferation marker Ki67/MIB1, and cytokeratin 14, whereas endocervical epithelium strongly expresses estrogen and progesterone receptors and cytokeratins 18 and 19. These patterns of expression are altered in cervical intraepithelial neoplasia, which is a common spontaneous lesion of the macaque cervix associated with specific types of oncogenic papillomaviruses. This report highlights important similarities with human cervix that should be useful for future studies of genital infection, neoplasia, and immunity in the macaque model. Competing Interests: This article was sponsored by Covance Inc. and Schering-Plough. The author did not declare any other competing interests.
The Macaque Endometrium, with Special Reference to the Cynomolgus Monkey (Macaca fascicularis)
Authors: van Esch Eric , Cline J. Mark , Buse Eberhard , Weinbauer Gerhard F. 
Published: January 2009

The macaque endometrium undergoes dramatic morphologic and functional changes during the menstrual cycle that are nearly identical to those of the human endometrium. The sequential events that take place in the endometrium are mainly driven by the ovarian steroids and their respective receptors. To be able to interpret the changes and effects induced by mammalian or synthetic hormones and other compounds that could have influence on the hormonal status of the animal, a thorough knowledge of the anatomy, physiology, and histology of the cyclic hormone-mediated processes within the endometrium is indispensable. In this paper we give an overview of uterine growth and development, anatomy, basic histology, aging, spontaneous pathology, and the techniques to study the endometrium in-life. In addtion, a comprehensive description of the receptor-mediated, hormone-driven morphological changes during the menstrual cycle in the cynomolgus monkey (Macaca fascicularis) is given. Where possible, differences between the macaque and human endometria are discussed. Competing Interests: This article was sponsored by Covance Inc. and Schering-Plough. Gerhard F. Weinbauer and Eberhard Buse are employed by Covance Inc. Eric Van Esch is employed by Schering-Plough. No other competing interests were declared.