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Sample records for erbb2 receptor status

  1. Gastric Cancer Cell Glycosylation as a Modulator of the ErbB2 Oncogenic Receptor

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    Henrique O. Duarte

    2017-10-01

    Full Text Available Aberrant expression and hyperactivation of the human epidermal growth factor receptor 2 (ErbB2 constitute crucial molecular events underpinning gastric neoplastic transformation. Despite ErbB2 extracellular domain being a well-known target for glycosylation, its glycosylation profile and the molecular mechanisms through which it actively tunes tumorigenesis in gastric cancer (GC cells remain elusive. We aimed at disclosing relevant ErbB2 glycan signatures and their functional impact on receptor’s biology in GC cells. The transcriptomic profile of cancer-relevant glycosylation enzymes, and the expression and activation of the ErbB receptors were characterized in four GC cell lines. Cellular- and receptor-specific glycan profiling of ErbB2-overexpressing NCI-N87 cells unveiled a heterogeneous glycosylation pattern harboring the tumor-associated sialyl Lewis a (SLea antigen. The expression of SLea and key enzymes integrating its biosynthetic pathway were strongly upregulated in this GC cell line. An association between the expression of ERBB2 and FUT3, a central gene in SLea biosynthesis, was disclosed in GC patients, further highlighting the crosstalk between ErbB2 and SLea expression. Moreover, cellular deglycosylation and CA 19.9 antibody-mediated blocking of SLea drastically altered ErbB2 expression and activation in NCI-N87 cells. Altogether, NCI-N87 cell line constitutes an appealing in vitro model to address glycan-mediated regulation of ErbB2 in GC.

  2. ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor

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    Alvarado, Diego; Klein, Daryl E.; Lemmon, Mark A.; (UPENN-MED)

    2009-09-25

    The orphan receptor tyrosine kinase ErbB2 (also known as HER2 or Neu) transforms cells when overexpressed, and it is an important therapeutic target in human cancer. Structural studies have suggested that the oncogenic (and ligand-independent) signalling properties of ErbB2 result from the absence of a key intramolecular 'tether' in the extracellular region that autoinhibits other human ErbB receptors, including the epidermal growth factor (EGF) receptor. Although ErbB2 is unique among the four human ErbB receptors, here we show that it is the closest structural relative of the single EGF receptor family member in Drosophila melanogaster (dEGFR). Genetic and biochemical data show that dEGFR is tightly regulated by growth factor ligands, yet a crystal structure shows that it, too, lacks the intramolecular tether seen in human EGFR, ErbB3 and ErbB4. Instead, a distinct set of autoinhibitory interdomain interactions hold unliganded dEGFR in an inactive state. All of these interactions are maintained (and even extended) in ErbB2, arguing against the suggestion that ErbB2 lacks autoinhibition. We therefore suggest that normal and pathogenic ErbB2 signalling may be regulated by ligands in the same way as dEGFR. Our findings have important implications for ErbB2 regulation in human cancer, and for developing therapeutic approaches that target novel aspects of this orphan receptor.

  3. ERBB2 regulation by Estrogen Receptor-Pax2 determines tamoxifen response

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    Hurtado, Antoni; Holmes, Kelly A.; Geistlinger, Timothy R.; Hutcheson, Iain R.; Nicholson, Robert I.; Brown, Myles; Jiang, Jie; Howat, William J.; Ali, Simak; Carroll, Jason S.

    2010-01-01

    Cross talk between the Estrogen Receptor (ER) and ErbB2/HER-2 pathways have long been implicated in breast cancer aetiology and drug response1, yet no direct connection at a transcriptional level has been shown. We now show that estrogen-ER and tamoxifen-ER complexes directly repress ErbB2 transcription via a cis-regulatory element within the ERBB2 gene. We implicate the Paired Box 2 gene product (Pax2), in a novel role, as a crucial mediator of ER repression of ErbB2 by the anti-cancer drug tamoxifen. We show that Pax2 and the ER co-activator AIB-1/SRC-3 compete for binding and regulation of ErbB2 transcription, the outcome of which determines tamoxifen response in breast cancer cells. The repression of ErbB2 by ER-Pax2 links these two important breast cancer subtypes and suggests that aggressive ErbB2 positive tumours can originate from ER positive luminal tumours by circumventing this repressive mechanism. These data provide mechanistic insight into the molecular basis of endocrine resistance in breast cancer. PMID:19005469

  4. Human CD3+ T-Cells with the Anti-ERBB2 Chimeric Antigen Receptor Exhibit Efficient Targeting and Induce Apoptosis in ERBB2 Overexpressing Breast Cancer Cells.

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    Munisvaradass, Rusheni; Kumar, Suresh; Govindasamy, Chandramohan; Alnumair, Khalid S; Mok, Pooi Ling

    2017-09-08

    Breast cancer is a common malignancy among women. The innate and adaptive immune responses failed to be activated owing to immune modulation in the tumour microenvironment. Decades of scientific study links the overexpression of human epidermal growth factor receptor 2 (ERBB2) antigen with aggressive tumours. The Chimeric Antigen Receptor (CAR) coding for specific tumour-associated antigens could initiate intrinsic T-cell signalling, inducing T-cell activation, and cytotoxic activity without the need for major histocompatibility complex recognition. This renders CAR as a potentially universal immunotherapeutic option. Herein, we aimed to establish CAR in CD3+ T-cells, isolated from human peripheral blood mononucleated cells that could subsequently target and induce apoptosis in the ERBB2 overexpressing human breast cancer cell line, SKBR3. Constructed CAR was inserted into a lentiviral plasmid containing a green fluorescent protein tag and produced as lentiviral particles that were used to transduce activated T-cells. Transduced CAR-T cells were then primed with SKBR3 cells to evaluate their functionality. Results showed increased apoptosis in SKBR3 cells co-cultured with CAR-T cells compared to the control (non-transduced T-cells). This study demonstrates that CAR introduction helps overcome the innate limitations of native T-cells leading to cancer cell apoptosis. We recommend future studies should focus on in vivo cytotoxicity of CAR-T cells against ERBB2 expressing tumours.

  5. Human CD3+ T-Cells with the Anti-ERBB2 Chimeric Antigen Receptor Exhibit Efficient Targeting and Induce Apoptosis in ERBB2 Overexpressing Breast Cancer Cells

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    Munisvaradass, Rusheni; Kumar, Suresh; Govindasamy, Chandramohan; Alnumair, Khalid S.; Mok, Pooi Ling

    2017-01-01

    Breast cancer is a common malignancy among women. The innate and adaptive immune responses failed to be activated owing to immune modulation in the tumour microenvironment. Decades of scientific study links the overexpression of human epidermal growth factor receptor 2 (ERBB2) antigen with aggressive tumours. The Chimeric Antigen Receptor (CAR) coding for specific tumour-associated antigens could initiate intrinsic T-cell signalling, inducing T-cell activation, and cytotoxic activity without the need for major histocompatibility complex recognition. This renders CAR as a potentially universal immunotherapeutic option. Herein, we aimed to establish CAR in CD3+ T-cells, isolated from human peripheral blood mononucleated cells that could subsequently target and induce apoptosis in the ERBB2 overexpressing human breast cancer cell line, SKBR3. Constructed CAR was inserted into a lentiviral plasmid containing a green fluorescent protein tag and produced as lentiviral particles that were used to transduce activated T-cells. Transduced CAR-T cells were then primed with SKBR3 cells to evaluate their functionality. Results showed increased apoptosis in SKBR3 cells co-cultured with CAR-T cells compared to the control (non–transduced T-cells). This study demonstrates that CAR introduction helps overcome the innate limitations of native T-cells leading to cancer cell apoptosis. We recommend future studies should focus on in vivo cytotoxicity of CAR-T cells against ERBB2 expressing tumours. PMID:28885562

  6. A single amino acid substitution is sufficient to modify the mitogenic properties of the epidermal growth factor receptor to resemble that of gp185erbB-2

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    Di Fiore, P P; Helin, K; Kraus, M H

    1992-01-01

    The epidermal growth factor (EGF) receptor (EGFR) and the erbB-2 gene product, gp185erbB-2, exhibit distinct abilities to stimulate mitogenesis in different target cells. By using chimeric molecules between these two receptors, we have previously shown that their intracellular juxtamembrane regio...

  7. Truncated ErbB2 receptor enhances ErbB1 signaling and induces reversible, ERK-independent loss of epithelial morphology

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    Egeblad, M; Mortensen, Ole Hartvig; Jäättelä, M

    2001-01-01

    Shedding of the extracellular domain of the ErbB2 tyrosine kinase receptor and expression of the remaining NH(2)-terminally truncated ErbB2 correlates with lymph node metastases and adverse outcome in human breast cancer. To study the possible signaling from such a truncated receptor, MCF-7 human...... breast cancer cells expressing NH(2)-terminally truncated ErbB2 (DeltaNErbB2) were compared with cells overexpressing wild-type ErbB2. Expression of DeltaNErbB2 in MCF-7 cells resulted in sustained activation of extracellular signal-regulated kinases (ERK) 1/2, extensive loss of the epithelial morphology......, appearance of vesicles and long protrusions as well as pronounced scattering of the cells. Similar alterations were observed upon ErbB2 overexpression but at much lower levels. Employing cell clones with inducible expression of DeltaNErbB2, it was revealed that the morphological changes were fully reversible...

  8. ErbB-2 signaling plays a critical role in regulating androgen-sensitive and castration-resistant androgen receptor-positive prostate cancer cells.

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    Muniyan, Sakthivel; Chen, Siu-Ju; Lin, Fen-Fen; Wang, Zhengzhong; Mehta, Parmender P; Batra, Surinder K; Lin, Ming-Fong

    2015-11-01

    While androgen deprivation therapy (ADT) reduces tumor burden, autocrine growth factor loops such as human epidermal growth factor receptor 2 (HER2/ErbB-2/neu) have been proposed to contribute to prostate cancer (PCa) survival and relapse. However, the role of ErbB-2 in regulating androgen-sensitive (AS) and castration-resistant (CR) cell proliferation remains unclear. Here, we determined the role of ErbB-2 in PCa progression and survival under steroid-reduced conditions using two independent PCa cell progression models. In AR-positive androgen-independent (AI) PCa cells that exhibit the CR phenotype, ErbB-2 was constitutively activated, compared to corresponding AS PCa cells. In AS LNCaP C-33 cells, androgen-induced ErbB-2 activation through ERK1/2 mediates PCa cell proliferation. Further, the ErbB-2-specific but not EGFR-specific inhibitor suppresses basal and androgen-stimulated cell proliferation and also blocks ERK1/2 activation. ErbB-2 ectopic expression and cPAcP siRNA transfection of LNCaP C-33 cells each increases ErbB-2 tyrosine phosphorylation, correlating with increased AI PSA secretion and cell proliferation. Conversely, trapping ErbB-2 by transfected endoplasmic reticulum-targeting ScFv5R expression vector abolished DHT-induced LNCaP C-33 cell growth. Moreover, inhibition of ErbB-2 but not EGFR in AI LNCaP C-81 and MDA PCa2b-AI PCa cells significantly abolished AI cell growth. In contrast to androgens via ErbB-2/ERK1/2 signaling in AS PCa cells, the inhibition of ErbB-2 abrogated AI cell proliferation by inhibiting the cell survival protein Akt in those AI cells. These results suggest that ErbB-2 is a prominent player in mediating the ligand-dependent and -independent activation of AR in AS and AI/CR PCa cells respectively for PCa progression and survival. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. A Functionally Significant Cross-talk between Androgen Receptor and ErbB2 Pathways in Estrogen Receptor Negative Breast Cancer

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    Ali Naderi

    2008-06-01

    Full Text Available Recent studies have identified novel subgroups in ER-negative breast cancer based on the expression pattern of androgen receptor (AR. One subtype (molecular apocrine has an over-expression of steroid-response genes and ErbB2. Using breast cancer cell lines with molecular apocrine features, we demonstrate a functional cross-talk between AR and ErbB2 pathways. We show that stimulation of AR and ErbB2 pathways leads to the cross-regulation of gene expression for AR, ErbB2, FOXA1, XBP1, TFF3, and KLK3. As opposed to the physiologic transient phosphorylation of extracellular signal–regulated kinase (ERK1/2 observed with the testosterone treatment, we demonstrate that the addition of ErbB2 inhibition leads to a persistent phosphorylation of ERK1/2, which negatively regulates the downstream signaling and cell growth. This suggests a mechanism for the cross-talk involving the ERK pathway. Moreover, testosterone stimulates the proliferation of molecular apocrine breast cell lines, and this effect can be reversed using antiandrogen flutamide and anti-ErbB2 AG825. Conversely, the growth stimulatory effect of heregulin can also be inhibited with flutamide, suggesting a cross-talk between the AR and ErbB2 pathways affecting cell proliferation. Importantly, there is a synergy with the combined use of flutamide and AG825 on cell proliferation and apoptosis, which indicates a therapeutic advantage in the combined blockage of AR and ErbB2 pathways.

  10. ErbB2 receptor over-expression improves post-traumatic peripheral nerve regeneration in adult mice.

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    Ronchi, Giulia; Gambarotta, Giovanna; Di Scipio, Federica; Salamone, Paolina; Sprio, Andrea E; Cavallo, Federica; Perroteau, Isabelle; Berta, Giovanni N; Geuna, Stefano

    2013-01-01

    In a transgenic mice (BALB-neuT) over-expressing ErbB2 receptor, we investigated the adult mouse median nerve in physiological and pathological conditions. Results showed that, in physiological conditions, the grip function controlled by the median nerve in BALB-neuT mice was similar to wild-type (BALB/c). Stereological assessment of ErbB2-overexpressing intact nerves revealed no difference in number and size of myelinated fibers compared to wild-type mice. By contrast, after a nerve crush injury, the motor recovery was significantly faster in BALB-neuT compared to BALB/c mice. Moreover, stereological assessment revealed a significant higher number of regenerated myelinated fibers with a thinner axon and fiber diameter and myelin thickness in BALB-neuT mice. At day-2 post-injury, the level of the mRNAs coding for all the ErbB receptors and for the transmembrane (type III) Neuregulin 1 (NRG1) isoforms significantly decreased in both BALB/c and BALB-neuT mice, as shown by quantitative real time PCR. On the other hand, the level of the mRNAs coding for soluble NRG1 isoforms (type I/II, alpha and beta) increased at the same post-traumatic time point though, intriguingly, this response was significantly higher in BALB-neuT mice with respect to BALB/c mice. Altogether, these results suggest that constitutive ErbB2 receptor over-expression does not influence the physiological development of peripheral nerves, while it improves nerve regeneration following traumatic injury, possibly through the up-regulation of soluble NRG1 isoforms.

  11. Intermittent hypoxia induces the proliferation of rat vascular smooth muscle cell with the increases in epidermal growth factor family and erbB2 receptor

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    Kyotani, Yoji, E-mail: cd147@naramed-u.ac.jp [Department of Pharmacology, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan); Department of Pharmacy, Nara Medical University Hospital, Kashihara 634-8522 (Japan); Ota, Hiroyo [Second Department of Internal Medicine, Nara Medical University School of Medicine, Kashihara 634-8522 (Japan); Department of Biochemistry, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan); Itaya-Hironaka, Asako; Yamauchi, Akiyo; Sakuramoto-Tsuchida, Sumiyo [Department of Biochemistry, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan); Zhao, Jing; Ozawa, Kentaro; Nagayama, Kosuke; Ito, Satoyasu [Department of Pharmacology, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan); Takasawa, Shin [Department of Biochemistry, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan); Kimura, Hiroshi [Second Department of Internal Medicine, Nara Medical University School of Medicine, Kashihara 634-8522 (Japan); Uno, Masayuki [Department of Pharmacy, Nara Medical University Hospital, Kashihara 634-8522 (Japan); Yoshizumi, Masanori [Department of Pharmacology, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan)

    2013-11-15

    Obstructive sleep apnea is characterized by intermittent hypoxia (IH), and associated with cardiovascular diseases, such as stroke and heart failure. These cardiovascular diseases have a relation to atherosclerosis marked by the proliferation of vascular smooth muscle cells (VSMCs). In this study, we investigated the influence of IH on cultured rat aortic smooth muscle cell (RASMC). The proliferation of RASMC was significantly increased by IH without changing the level of apoptosis. In order to see what induces RASMC proliferation, we investigated the influence of normoxia (N)-, IH- and sustained hypoxia (SH)-treated cell conditioned media on RASMC proliferation. IH-treated cell conditioned medium significantly increased RASMC proliferation compared with N-treated cell conditioned medium, but SH-treated cell conditioned medium did not. We next investigated the epidermal growth factor (EGF) family as autocrine growth factors. Among the EGF family, we found significant increases in mRNAs for epiregulin (ER), amphiregulin (AR) and neuregulin-1 (NRG1) in IH-treated cells and mature ER in IH-treated cell conditioned medium. We next investigated the changes in erbB family receptors that are receptors for ER, AR and NRG1, and found that erbB2 receptor mRNA and protein expressions were increased by IH, but not by SH. Phosphorylation of erbB2 receptor at Tyr-1248 that mediates intracellular signaling for several physiological effects including cell proliferation was increased by IH, but not by SH. In addition, inhibitor for erbB2 receptor suppressed IH-induced cell proliferation. These results provide the first demonstration that IH induces VSMC proliferation, and suggest that EGF family, such as ER, AR and NRG1, and erbB2 receptor could be involved in the IH-induced VSMC proliferation. - Highlights: ●In vitro system for intermittent hypoxia (IH) and sustained hypoxia (SH). ●IH, but not SH, induces the proliferation of rat vascular smooth muscle cell. ●Epiregulin m

  12. Self-renewal of human embryonic stem cells requires insulin-like growth factor-1 receptor and ERBB2 receptor signaling

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    Wang, Linlin; Schulz, Thomas C.; Sherrer, Eric S.; Dauphin, Derek S.; Shin, Soojung; Nelson, Angelique M.; Ware, Carol B.; Zhan, Mei; Song, Chao-Zhong; Chen, Xiaoji; Brimble, Sandii N.; McLean, Amanda; Galeano, Maria J.; Uhl, Elizabeth W.; D'Amour, Kevin A.; Chesnut, Jonathan D.; Rao, Mahendra S.

    2007-01-01

    Despite progress in developing defined conditions for human embryonic stem cell (hESC) cultures, little is known about the cell-surface receptors that are activated under conditions supportive of hESC self-renewal. A simultaneous interrogation of 42 receptor tyrosine kinases (RTKs) in hESCs following stimulation with mouse embryonic fibroblast (MEF) conditioned medium (CM) revealed rapid and prominent tyrosine phosphorylation of insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R); less prominent tyrosine phosphorylation of epidermal growth factor receptor (EGFR) family members, including ERBB2 and ERBB3; and trace phosphorylation of fibroblast growth factor receptors. Intense IGF1R and IR phosphorylation occurred in the absence of MEF conditioning (NCM) and was attributable to high concentrations of insulin in the proprietary KnockOut Serum Replacer (KSR). Inhibition of IGF1R using a blocking antibody or lentivirus-delivered shRNA reduced hESC self-renewal and promoted differentiation, while disruption of ERBB2 signaling with the selective inhibitor AG825 severely inhibited hESC proliferation and promoted apoptosis. A simple defined medium containing an IGF1 analog, heregulin-1β (a ligand for ERBB2/ERBB3), fibroblast growth factor-2 (FGF2), and activin A supported long-term growth of multiple hESC lines. These studies identify previously unappreciated RTKs that support hESC proliferation and self-renewal, and provide a rationally designed medium for the growth and maintenance of pluripotent hESCs. PMID:17761519

  13. Electrocardiographic Characterization of Cardiac Hypertrophy in Mice that Overexpress the ErbB2 Receptor Tyrosine Kinase

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    Sysa-Shah, Polina; Sørensen, Lars L; Abraham, M Roselle

    2015-01-01

    Electrocardiography is an important method for evaluation and risk stratification of patients with cardiac hypertrophy. We hypothesized that the recently developed transgenic mouse model of cardiac hypertrophy (ErbB2(tg)) will display distinct ECG features, enabling WT (wild type) mice...... in other rodent models of cardiac hypertrophy. Furthermore, with appropriate modifications, this method might be translated for use in other species....

  14. Selective Inhibition of Tumor Growth by Clonal NK Cells Expressing an ErbB2/HER2-Specific Chimeric Antigen Receptor

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    Schönfeld, Kurt; Sahm, Christiane; Zhang, Congcong; Naundorf, Sonja; Brendel, Christian; Odendahl, Marcus; Nowakowska, Paulina; Bönig, Halvard; Köhl, Ulrike; Kloess, Stephan; Köhler, Sylvia; Holtgreve-Grez, Heidi; Jauch, Anna; Schmidt, Manfred; Schubert, Ralf; Kühlcke, Klaus; Seifried, Erhard; Klingemann, Hans G; Rieger, Michael A; Tonn, Torsten; Grez, Manuel; Wels, Winfried S

    2015-01-01

    Natural killer (NK) cells are an important effector cell type for adoptive cancer immunotherapy. Similar to T cells, NK cells can be modified to express chimeric antigen receptors (CARs) to enhance antitumor activity, but experience with CAR-engineered NK cells and their clinical development is still limited. Here, we redirected continuously expanding and clinically usable established human NK-92 cells to the tumor-associated ErbB2 (HER2) antigen. Following GMP-compliant procedures, we generated a stable clonal cell line expressing a humanized CAR based on ErbB2-specific antibody FRP5 harboring CD28 and CD3ζ signaling domains (CAR 5.28.z). These NK-92/5.28.z cells efficiently lysed ErbB2-expressing tumor cells in vitro and exhibited serial target cell killing. Specific recognition of tumor cells and antitumor activity were retained in vivo, resulting in selective enrichment of NK-92/5.28.z cells in orthotopic breast carcinoma xenografts, and reduction of pulmonary metastasis in a renal cell carcinoma model, respectively. γ-irradiation as a potential safety measure for clinical application prevented NK cell replication, while antitumor activity was preserved. Our data demonstrate that it is feasible to engineer CAR-expressing NK cells as a clonal, molecularly and functionally well-defined and continuously expandable cell therapeutic agent, and suggest NK-92/5.28.z cells as a promising candidate for use in adoptive cancer immunotherapy. PMID:25373520

  15. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor.

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    Schönfeld, Kurt; Sahm, Christiane; Zhang, Congcong; Naundorf, Sonja; Brendel, Christian; Odendahl, Marcus; Nowakowska, Paulina; Bönig, Halvard; Köhl, Ulrike; Kloess, Stephan; Köhler, Sylvia; Holtgreve-Grez, Heidi; Jauch, Anna; Schmidt, Manfred; Schubert, Ralf; Kühlcke, Klaus; Seifried, Erhard; Klingemann, Hans G; Rieger, Michael A; Tonn, Torsten; Grez, Manuel; Wels, Winfried S

    2015-02-01

    Natural killer (NK) cells are an important effector cell type for adoptive cancer immunotherapy. Similar to T cells, NK cells can be modified to express chimeric antigen receptors (CARs) to enhance antitumor activity, but experience with CAR-engineered NK cells and their clinical development is still limited. Here, we redirected continuously expanding and clinically usable established human NK-92 cells to the tumor-associated ErbB2 (HER2) antigen. Following GMP-compliant procedures, we generated a stable clonal cell line expressing a humanized CAR based on ErbB2-specific antibody FRP5 harboring CD28 and CD3ζ signaling domains (CAR 5.28.z). These NK-92/5.28.z cells efficiently lysed ErbB2-expressing tumor cells in vitro and exhibited serial target cell killing. Specific recognition of tumor cells and antitumor activity were retained in vivo, resulting in selective enrichment of NK-92/5.28.z cells in orthotopic breast carcinoma xenografts, and reduction of pulmonary metastasis in a renal cell carcinoma model, respectively. γ-irradiation as a potential safety measure for clinical application prevented NK cell replication, while antitumor activity was preserved. Our data demonstrate that it is feasible to engineer CAR-expressing NK cells as a clonal, molecularly and functionally well-defined and continuously expandable cell therapeutic agent, and suggest NK-92/5.28.z cells as a promising candidate for use in adoptive cancer immunotherapy.

  16. Reliable PCR quantitation of estrogen, progesterone and ERBB2 receptor mRNA from formalin-fixed, paraffin-embedded tissue is independent of prior macro-dissection

    DEFF Research Database (Denmark)

    Tramm, Trine; Hennig, Guido; Kyndi, Marianne

    2013-01-01

    Gene expression analysis on messenger RNA (mRNA) purified from formalin-fixed, paraffin-embedded tissue is increasingly used for research purposes. Tissue heterogeneity may question specificity and interpretation of results from mRNA isolated from a whole slide section, and thresholds for minimal...... tumor content in the paraffin block or macrodissection are used to avoid contamination from non-neoplastic tissue. The aim was to test if mRNA from tissue surrounding breast cancer affected quantification of estrogen receptor α (ESR1), progesterone receptor (PGR) and human epidermal growth factor...... receptor 2 (ERBB2), by comparing gene expression from whole slide and tumor-enriched sections, and correlating gene expression from whole slide sections with corresponding immunohistochemistry. Gene expression, based on mRNA extracted from a training set (36 paraffin blocks) and two validation sets (133...

  17. Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib.

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    Rama Krishna Kancha

    Full Text Available BACKGROUND: Overexpression of the ERBB2 kinase is observed in about one-third of breast cancer patients and the dual ERBB1/ERBB2 kinase inhibitor lapatinib was recently approved for the treatment of advanced ERBB2-positive breast cancer. Mutations in the ERBB2 receptor have recently been reported in breast cancer at diagnosis and also in gastric, colorectal and lung cancer. These mutations may have an impact on the clinical responses achieved with lapatinib in breast cancer and may also have a potential impact on the use of lapatinib in other solid cancers. However, the sensitivity of lapatinib towards clinically observed ERBB2 mutations is not known. METHODOLOGY/PRINCIPAL FINDINGS: We cloned a panel of 8 clinically observed ERBB2 mutations, established stable cell lines and characterized their sensitivity towards lapatinib and alternative ERBB2 inhibitors. Both lapatinib-sensitive and lapatinib-resistant ERBB2 mutations were observed. Interestingly, we were able to generate lapatinib resistance mutations in wt-ERBB2 cells incubated with lapatinib for prolonged periods of time. This indicates that these resistance mutations may also cause secondary resistance in lapatinib-treated patients. Lapatinib-resistant ERBB2 mutations were found to be highly resistant towards AEE788 treatment but remained sensitive towards the dual irreversible inhibitors CL-387785 and WZ-4002. CONCLUSIONS/SIGNIFICANCE: Patients harbouring certain ERBB2 kinase domain mutations at diagnosis may not benefit from lapatinib treatment. Moreover, secondary lapatinib resistance may develop due to kinase domain mutations. Irreversible ERBB2 inhibitors may offer alternative treatment options for breast cancer and other solid tumor patients harbouring lapatinib resistance mutations. In addition, these inhibitors may be of interest in the scenario of secondary lapatinib resistance.

  18. Effect of estradiol on estrogen receptor-alpha gene expression and activity can be modulated by the ErbB2/PI 3-K/Akt pathway.

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    Stoica, Gerald E; Franke, Thomas F; Moroni, Maria; Mueller, Susette; Morgan, Elisha; Iann, Mary C; Winder, Abigail D; Reiter, Ronald; Wellstein, Anton; Martin, Mary Beth; Stoica, Adriana

    2003-09-11

    Epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), and heregulin-beta1 (HRG-beta1), can modulate the expression and activity of the estrogen receptor-alpha (ER-alpha) via the phosphatidylinositol 3-kinase (PI 3-K)/Akt pathway in the ER-alpha-positive breast cancer cell line, MCF-7. Estradiol can also rapidly activate PI 3-K/Akt in these cells (nongenomic effect). The recent study examines whether Akt is involved in the ER-alpha regulation by estradiol (genomic effect). Stable transfection of parental MCF-7 cells with a dominant-negative Akt mutant, as well as the PI 3-K inhibitors wortmannin and LY 294,002, blocked the effect of estradiol on ER-alpha expression and activity by 70-80 and 55-63%, respectively. Stable transfection of MCF-7 cells with a constitutively active Akt mimicked the effect of estradiol. The changes in ER-alpha expression and activity were abrogated in response to estradiol by an arginine to cysteine mutation in the pleckstrin homology (PH) domain of Akt (R25C), suggesting the involvement of this amino acid in the interaction between Akt and ER-alpha. Experiments employing selective ErbB inhibitors demonstrate that the effect of estradiol on ER-alpha expression and activity is mediated by ErbB2 and not by EGFR. Moreover, anchorage-dependent and -independent growth assays, cell cycle and membrane ruffling analyses showed that Akt exerts estrogen-like activity on cell growth and membrane ruffling and that a selective ErbB2 inhibitor, but not anti-ErbB2 antibodies directed to the extracellular domain, can block these effects. In the presence of constitutively active Akt, tamoxifen only partially inhibits cell growth. In contrast, in cells stably transfected with either a dominant-negative Akt or with R25C-Akt, as well as in parental cells in the presence of a selective ErbB2 inhibitor, the effect of estradiol on anchorage-dependent and -independent cell growth was inhibited by 50-75 and 100%, respectively. Dominant-negative Akt

  19. Novel targeted approaches to treating biliary tract cancer: the dual epidermal growth factor receptor and ErbB-2 tyrosine kinase inhibitor NVP-AEE788 is more efficient than the epidermal growth factor receptor inhibitors gefitinib and erlotinib.

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    Wiedmann, Marcus; Feisthammel, Jürgen; Blüthner, Thilo; Tannapfel, Andrea; Kamenz, Thomas; Kluge, Annett; Mössner, Joachim; Caca, Karel

    2006-08-01

    Aberrant activation of the epidermal growth factor receptor is frequently observed in neoplasia, notably in tumors of epithelial origin. Attempts to treat such tumors with epidermal growth factor receptor antagonists resulted in remarkable success in recent studies. Little is known, however, about the efficacy of this therapy in biliary tract cancer. Protein expression of epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor-2 was assessed in seven human biliary tract cancer cell lines by immunoblotting. In addition, histological sections from 19 patients with extrahepatic cholangiocarcinoma were analyzed for epidermal growth factor receptor, ErbB-2 and vascular endothelial growth factor receptor-2 expression by immunohistochemistry. Moreover, we sequenced the cDNA products representing the entire epidermal growth factor receptor coding region of the seven cell lines, and searched for genomic epidermal growth factor receptor amplifications and polysomy by fluorescence in-situ hybridization. Cell growth inhibition by gefitinib erlotinib and NVP-AEE788 was studied in vitro by automated cell counting. In addition, the anti-tumoral effect of erlotinib and NVP-AEE788 was studied in a chimeric mouse model. The anti-tumoral drug mechanism in this model was assessed by MIB-1 antibody staining, terminal deoxynucleotidyl transfer-mediated dUTP nick end-labelling assay, von Willebrand factor staining, and immunoblotting for p-p42/44 (p-Erk1/2, p-MAPK) and p-AKT. Immunoblotting revealed expression of epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor-2 in all biliary tract cancer cell lines. EGFR was detectable in six of 19 (32%) extrahepatic human cholangiocarcinoma tissue samples, ErbB-2 in 16 of 19 (84%), and vascular endothelial growth factor receptor-2 in nine of 19 (47%). Neither epidermal growth factor receptor mutations nor amplifications or polysomy were found in the seven biliary tract cancer

  20. Inhibition of ErbB2 by receptor tyrosine kinase inhibitors causes myofibrillar structural damage without cell death in adult rat cardiomyocytes

    International Nuclear Information System (INIS)

    Pentassuglia, Laura; Graf, Michael; Lane, Heidi; Kuramochi, Yukio; Cote, Gregory; Timolati, Francesco; Sawyer, Douglas B.; Zuppinger, Christian; Suter, Thomas M.

    2009-01-01

    Inhibition of ErbB2 (HER2) with monoclonal antibodies, an effective therapy in some forms of breast cancer, is associated with cardiotoxicity, the pathophysiology of which is poorly understood. Recent data suggest, that dual inhibition of ErbB1 (EGFR) and ErbB2 signaling is more efficient in cancer therapy, however, cardiac safety of this therapeutic approach is unknown. We therefore tested an ErbB1-(CGP059326) and an ErbB1/ErbB2-(PKI166) tyrosine kinase inhibitor in an in-vitro system of adult rat ventricular cardiomyocytes and assessed their effects on 1. cell viability, 2. myofibrillar structure, 3. contractile function, and 4. MAPK- and Akt-signaling alone or in combination with Doxorubicin. Neither CGP nor PKI induced cardiomyocyte necrosis or apoptosis. PKI but not CGP caused myofibrillar structural damage that was additive to that induced by Doxorubicin at clinically relevant doses. These changes were associated with an inhibition of excitation-contraction coupling. PKI but not CGP decreased p-Erk1/2, suggesting a role for this MAP-kinase signaling pathway in the maintenance of myofibrils. These data indicate that the ErbB2 signaling pathway is critical for the maintenance of myofibrillar structure and function. Clinical studies using ErbB2-targeted inhibitors for the treatment of cancer should be designed to include careful monitoring for cardiac dysfunction.

  1. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial

    DEFF Research Database (Denmark)

    Regan, M.M.; Lykkesfeldt, A.E.; Dell'Orto, P.

    2008-01-01

    Background The Breast International Group (BIG) 1-98 trial (a randomised double-blind phase III trial) has shown that letrozole significantly improves disease-free survival (DFS) compared with tamoxifen in postmenopausal women with endocrine-responsive early breast cancer. Our aim was to establish...... over tamoxifen was noted, irrespective of ERBB2 status of the tumour, and, therefore, ERBB2 status does not seem to be a selection criterion for treatment with letrozole versus tamoxifen in postmenopausal women with endocrine-responsive early breast cancer Udgivelsesdato: 2008/1...... was the primary endpoint, and to assess treatment-by-covariate interactions. The BIG 1-98 trial is registered on the clinical trials site of the US National Cancer institute website http://www.clinicaltrials.gov/ct/show/NCT00004205. Findings By central assessment 7% (257 of 3650) of tumours were classified...

  2. Active G protein-coupled receptors (GPCR), matrix metalloproteinases 2/9 (MMP2/9), heparin-binding epidermal growth factor (hbEGF), epidermal growth factor receptor (EGFR), erbB2, and insulin-like growth factor 1 receptor (IGF-1R) are necessary for trenbolone acetate-induced alterations in protein turnover rate of fused bovine satellite cell cultures.

    Science.gov (United States)

    Thornton, K J; Kamanga-Sollo, E; White, M E; Dayton, W R

    2016-06-01

    Trenbolone acetate (TBA), a testosterone analog, increases protein synthesis and decreases protein degradation in fused bovine satellite cell (BSC) cultures. However, the mechanism through which TBA alters these processes remains unknown. Recent studies indicate that androgens improve rate and extent of muscle growth through a nongenomic mechanism involving G protein-coupled receptors (GPCR), matrix metalloproteinases (MMP), heparin-binding epidermal growth factor (hbEGF), the epidermal growth factor receptor (EGFR), erbB2, and the insulin-like growth factor-1 receptor (IGF-1R). We hypothesized that TBA activates GPCR, resulting in activation of MMP2/9 that releases hbEGF, which activates the EGFR and/or erbB2. To determine whether the proposed nongenomic pathway is involved in TBA-mediated alterations in protein turnover, fused BSC cultures were treated with TBA in the presence or absence of inhibitors for GPCR, MMP2/9, hbEGF, EGFR, erbB2, or IGF-1R, and resultant protein synthesis and degradation rates were analyzed. Assays were replicated at least 9 times for each inhibitor experiment utilizing BSC cultures obtained from at least 3 different steers that had no previous exposure to steroid compounds. As expected, fused BSC cultures treated with 10 n TBA exhibited increased ( GPCR, MMP2/9, hbEGF, EGFR, erbB2, or IGF-1R suppressed ( GPCR, MMP2/9, hbEGF, EGFR, erbB2, or IGF-1R in the presence of 10 n TBA each had no ( > 0.05) effect on TBA-mediated decreases in protein degradation. However, inhibition of both EGFR and erbB2 in the presence of 10 n TBA resulted in decreased ( GPCR, MMP2/9, hbEGF, EGFR, erbB2, and IGF-1R. However, the mechanism through which TBA mediates changes in protein degradation is different and appears to involve only the EGFR and erbB2. Furthermore, it appears the protein kinase B pathway is involved in TBA's effects on fused BSC cultures.

  3. Role of Erbin in ErbB2-dependent breast tumor growth

    Science.gov (United States)

    Tao, Yanmei; Shen, Chengyong; Luo, Shiwen; Traoré, Wilfried; Marchetto, Sylvie; Santoni, Marie-Josée; Xu, Linlin; Wu, Biao; Shi, Chao; Mei, Jinghong; Bates, Ryan; Liu, Xihui; Zhao, Kai; Xiong, Wen-Cheng; Borg, Jean-Paul; Mei, Lin

    2014-01-01

    ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2), a receptor tyrosine kinase of the ErbB family, is overexpressed in around 25% of breast cancers. In addition to forming a heterodimer with other ErbB receptors in response to ligand stimulation, ErbB2 can be activated in a ligand-independent manner. We report here that Erbin, an ErbB2-interacting protein that was thought to act as an antitumor factor, is specifically expressed in mammary luminal epithelial cells and facilitates ErbB2-dependent proliferation of breast cancer cells and tumorigenesis in MMTV-neu transgenic mice. Disruption of their interaction decreases ErbB2-dependent proliferation, and deletion of the PDZ domain in Erbin hinders ErbB2-dependent tumor development in MMTV-neu mice. Mechanistically, Erbin forms a complex with ErbB2, promotes its interaction with the chaperon protein HSP90, and thus prevents its degradation. Finally, ErbB2 and Erbin expression correlates in human breast tumor tissues. Together, these observations establish Erbin as an ErbB2 regulator for breast tumor formation and progression. PMID:25288731

  4. ERBB2 influences the subcellular localization of the estrogen receptor in tamoxifen-resistant MCF-7 cells leading to the activation of AKT and RPS6KA2.

    Science.gov (United States)

    Pancholi, Sunil; Lykkesfeldt, Anne E; Hilmi, Caroline; Banerjee, Susana; Leary, Alexandra; Drury, Suzanne; Johnston, Stephen; Dowsett, Mitch; Martin, Lesley-Ann

    2008-12-01

    Acquired resistance to endocrine therapies remains a major clinical obstacle in hormone-sensitive breast tumors. We used an MCF-7 breast tumor cell line (Tam(R)-1) resistant to tamoxifen to investigate this mechanism. We demonstrate that Tam(R)-1 express elevated levels of phosphorylated AKT and MAPK3/1-activated RPS6KA2 compared with the parental MCF-7 cell line (MCF-7). There was no change in the level of total ESR between the two cell lines; however, the Tam(R)-1 cells had increased phosphorylation of ESR1 ser(167). SiRNA blockade of AKT or MAPK3/1 had little effect on ESR1 ser(167) phosphorylation, but a combination of the two siRNAs abrogated this. Co-localization studies revealed an association between ERBB2 and ESR1 in the Tam(R)-1 but not MCF-7 cells. ESR1 was redistributed to extranuclear sites in Tam(R)-1 and was less transcriptionally competent compared with MCF-7 suggesting that nuclear ESR1 activity was suppressed in Tam(R)-1. Tamoxifen resistance in the Tam(R)-1 cells could be partially overcome by the ERBB2 inhibitor AG825 in combination with tamoxifen, and this was associated with re-localization of ESR1 to the nucleus. These data demonstrate that tamoxifen-resistant cells have the ability to switch between ERBB2 or ESR1 pathways promoting cell growth and that pharmacological inhibition of ERBB2 may be a therapeutic strategy for overcoming tamoxifen resistance.

  5. Preubiquitinated chimeric ErbB2 is constitutively endocytosed and subsequently degraded in lysosomes

    International Nuclear Information System (INIS)

    Vuong, Tram Thu; Berger, Christian; Bertelsen, Vibeke; Rødland, Marianne Skeie; Stang, Espen; Madshus, Inger Helene

    2013-01-01

    The oncoprotein ErbB2 is endocytosis-deficient, probably due to its interaction with Heat shock protein 90. We previously demonstrated that clathrin-dependent endocytosis of ErbB2 is induced upon incubation of cells with Ansamycin derivatives, such as geldanamycin and its derivative 17-AAG. Furthermore, we have previously demonstrated that a preubiquitinated chimeric EGFR (EGFR-Ub 4 ) is constitutively endocytosed in a clathrin-dependent manner. We now demonstrate that also an ErbB2-Ub 4 chimera is endocytosed constitutively and clathrin-dependently. Upon expression, the ErbB2-Ub 4 was further ubiquitinated, and by Western blotting, we demonstrated the formation of both Lys48-linked and Lys63-linked polyubiquitin chains. ErbB2-Ub 4 was constitutively internalized and eventually sorted to late endosomes and lysosomes where the fusion protein was degraded. ErbB2-Ub 4 was not cleaved prior to internalization. Interestingly, over-expression of Ubiquitin Interaction Motif-containing dominant negative fragments of the clathrin adaptor proteins epsin1 and Eps15 negatively affected endocytosis of ErbB2. Altogether, this argues that ubiquitination is sufficient to induce clathrin-mediated endocytosis and lysosomal degradation of the otherwise plasma membrane localized ErbB2. Also, it appears that C-terminal cleavage is not required for endocytosis. -- Highlights: ► A chimera containing ErbB2 and a tetra-Ubiquitin chain internalizes constitutively. ► Receptor fragmentation is not required for endocytosis of ErbB2. ► Ubiquitination is sufficient to induce endocytosis and degradation of ErbB2. ► ErbB2-Ub4 is internalized clathrin-dependently.

  6. EGF Regulation of VEGF: Role in Progression of ErbB2 Overexpressing Mammary Tumors

    National Research Council Canada - National Science Library

    Loureiro, Robyn

    2004-01-01

    .... ErbB2, an epidermal growth factor receptor family member whose overexpression in mammary tumors is correlated with poor patient prognosis, has been previously implicated as a positive modulator of VEGF expression...

  7. ERBB2 in Cat Mammary Neoplasias Disclosed a Positive Correlation between RNA and Protein Low Expression Levels: A Model for erbB-2 Negative Human Breast Cancer

    Science.gov (United States)

    Abreu, Rui M. V.; Bastos, Estela; Amorim, Irina; Gut, Ivo G.; Gärtner, Fátima; Chaves, Raquel

    2013-01-01

    Human ERBB2 is a proto-oncogene that codes for the erbB-2 epithelial growth factor receptor. In human breast cancer (HBC), erbB-2 protein overexpression has been repeatedly correlated with poor prognosis. In more recent works, underexpression of this gene has been described in HBC. Moreover, it is also recognised that oncogenes that are commonly amplified or deleted encompass point mutations, and some of these are associated with HBC. In cat mammary lesions (CMLs), the overexpression of ERBB2 (27%–59.6%) has also been described, mostly at the protein level and although cat mammary neoplasias are considered to be a natural model of HBC, molecular information is still scarce. In the present work, a cat ERBB2 fragment, comprising exons 10 to 15 (ERBB2_10–15) was achieved for the first time. Allelic variants and genomic haplotype analyses were also performed, and differences between normal and CML populations were observed. Three amino acid changes, corresponding to 3 non-synonymous genomic sequence variants that were only detected in CMLs, were proposed to damage the 3D structure of the protein. We analysed the cat ERBB2 gene at the DNA (copy number determination), mRNA (expression levels assessment) and protein levels (in extra- and intra protein domains) in CML samples and correlated the last two evaluations with clinicopathological features. We found a positive correlation between the expression levels of the ERBB2 RNA and erbB-2 protein, corresponding to the intracellular region. Additionally, we detected a positive correlation between higher mRNA expression and better clinical outcome. Our results suggest that the ERBB2 gene is post-transcriptionally regulated and that proteins with truncations and single point mutations are present in cat mammary neoplastic lesions. We would like to emphasise that the recurrent occurrence of low erbB-2 expression levels in cat mammary tumours, suggests the cat mammary neoplasias as a valuable model for erbB-2 negative HBC

  8. ERBB2 in cat mammary neoplasias disclosed a positive correlation between RNA and protein low expression levels: a model for erbB-2 negative human breast cancer.

    Science.gov (United States)

    Santos, Sara; Baptista, Cláudia S; Abreu, Rui M V; Bastos, Estela; Amorim, Irina; Gut, Ivo G; Gärtner, Fátima; Chaves, Raquel

    2013-01-01

    Human ERBB2 is a proto-oncogene that codes for the erbB-2 epithelial growth factor receptor. In human breast cancer (HBC), erbB-2 protein overexpression has been repeatedly correlated with poor prognosis. In more recent works, underexpression of this gene has been described in HBC. Moreover, it is also recognised that oncogenes that are commonly amplified or deleted encompass point mutations, and some of these are associated with HBC. In cat mammary lesions (CMLs), the overexpression of ERBB2 (27%-59.6%) has also been described, mostly at the protein level and although cat mammary neoplasias are considered to be a natural model of HBC, molecular information is still scarce. In the present work, a cat ERBB2 fragment, comprising exons 10 to 15 (ERBB2_10-15) was achieved for the first time. Allelic variants and genomic haplotype analyses were also performed, and differences between normal and CML populations were observed. Three amino acid changes, corresponding to 3 non-synonymous genomic sequence variants that were only detected in CMLs, were proposed to damage the 3D structure of the protein. We analysed the cat ERBB2 gene at the DNA (copy number determination), mRNA (expression levels assessment) and protein levels (in extra- and intra protein domains) in CML samples and correlated the last two evaluations with clinicopathological features. We found a positive correlation between the expression levels of the ERBB2 RNA and erbB-2 protein, corresponding to the intracellular region. Additionally, we detected a positive correlation between higher mRNA expression and better clinical outcome. Our results suggest that the ERBB2 gene is post-transcriptionally regulated and that proteins with truncations and single point mutations are present in cat mammary neoplastic lesions. We would like to emphasise that the recurrent occurrence of low erbB-2 expression levels in cat mammary tumours, suggests the cat mammary neoplasias as a valuable model for erbB-2 negative HBC.

  9. Chimeric DNA Vaccines against ErbB2{sup +} Carcinomas: From Mice to Humans

    Energy Technology Data Exchange (ETDEWEB)

    Quaglino, Elena; Riccardo, Federica; Macagno, Marco; Bandini, Silvio; Cojoca, Rodica; Ercole, Elisabetta [Molecular Biotechnology Center, Department of Clinical and Biological Sciences, University of Turin, 10126 Turin (Italy); Amici, Augusto [Department of Molecular Cellular and Animal Biology, University of Camerino, 62032 Camerino (Italy); Cavallo, Federica, E-mail: federica.cavallo@unito.it [2 Department of Molecular Cellular and Animal Biology, University of Camerino, 62032 Camerino (Italy)

    2011-08-10

    DNA vaccination exploits a relatively simple and flexible technique to generate an immune response against microbial and tumor-associated antigens (TAAs). Its effectiveness is enhanced by the application of an electrical shock in the area of plasmid injection (electroporation). In our studies we exploited a sophisticated electroporation device approved for clinical use (Cliniporator, IGEA, Carpi, Italy). As the target antigen is an additional factor that dramatically modulates the efficacy of a vaccine, we selected ErbB2 receptor as a target since it is an ideal oncoantigen. It is overexpressed on the cell membrane by several carcinomas for which it plays an essential role in driving their progression. Most oncoantigens are self-tolerated molecules. To circumvent immune tolerance we generated two plasmids (RHuT and HuRT) coding for chimeric rat/human ErbB2 proteins. Their immunogenicity was compared in wild type mice naturally tolerant for mouse ErbB2, and in transgenic mice that are also tolerant for rat or human ErbB2. In several of these mice, RHuT and HuRT elicited a stronger anti-tumor response than plasmids coding for fully human or fully rat ErbB2. The ability of heterologous moiety to blunt immune tolerance could be exploited to elicit a significant immune response in patients. A clinical trial to delay the recurrence of ErbB2{sup +} carcinomas of the oral cavity, oropharynx and hypopharynx is awaiting the approval of the Italian authorities.

  10. Activating mutations in ERBB2 and their impact on diagnostics and treatment

    Directory of Open Access Journals (Sweden)

    Grit Sophie Herter-Sprie

    2013-04-01

    Full Text Available Despite the ongoing ‘war on cancer’, cancer remains one of the major causes of human morbidity and mortality. A new paradigm of targeted therapies holds the most promise for the future, making identification of tumor-specific therapeutic targets of prime importance. ERBB2, best known for its role in breast cancer tumorigenesis, can be targeted by two types of pharmacological manipulation: antibody therapy against the extracellular receptor domain and small molecule compounds against the intracellular tyrosine kinase domain. Aberrant activation of ERBB2 by gene amplification has been shown to participate in the pathophysiology of breast, ovarian, gastric, colorectal, lung, brain and head and neck tumors. However, the advent of next-generation sequencing technologies has enabled efficient identification of activating molecular alterations of ERBB2. In this review, we will focus on the functional role of these somatic mutations that cause ERBB2 receptor activation. We will additionally discuss the current preclinical and clinical therapeutic strategies for targeting mutationally activated ERBB2.

  11. ERBB2/HER2-SPECIFIC NATURAL KILLER CELLS FOR ADOPTIVE IMMUNOTHERAPY OF GLIOBLASTOMA

    Science.gov (United States)

    Steinbach, Joachim P.; Zhang, Congcong; Burger, Michael; Jennewein, Lukas; Schönfeld, Kurt; Genßler, Sabrina; Sahm, Christiane; Brendel, Christian; Naundorf, Sonja; Odendahl, Marcus; Köhl, Ulrike; Nowakowska, Paulina; Seifried, Erhard; Bönig, Halvard; Tonn, Torsten; Grez, Manuel; Mittelbronn, Michel; Wels, Winfried S.

    2014-01-01

    BACKGROUND: While EGFRvIII appears a logical target for immunotherapy, only a subpopulation of tumor cells express EGFRvIII and immune escape has been demonstrated. ErbB2 is overexpressed in a substantial proportion of glioblastomas and has been successfully utilized in immunotherapies. Natural killer (NK) cells are the first line of defense against viral infections and malignant cells. The continuously growing cytotoxic cell line NK-92 holds promise for cancer immunotherapy. Safety of infusion of high doses of NK-92 was established in previous phase I clinical trials utilizing irradiated cells to prevent permanent engraftment. METHODS: To provide NK-92 cells with pre-determined tumor-cell specificity, we generated a lentiviral second generation chimeric antigen receptor (CAR) construct (5.28.z) employing the ErbB2 (HER2)-specific scFv(FRP5) antibody fragment for target cell recognition, and human CD28-CD3 ζ as a composite signaling moiety. An ErbB2-specific single cell clone (NK-92/5.28.z) was isolated, which showed high and selective cytotoxicity towards ErbB2-expressing tumor cells of various origins in vitro. We evaluated the cytotoxicity of NK-93/5.28.z cells against a panel of glioblastoma cell lines and primary glioblastoma cultures with different levels of Erb2 expression in vitro and in vivo. RESULTS: To provide NK-92 cells with pre-determined tumor-cell specificity, we generated a lentiviral second generation chimeric antigen receptor (CAR) construct (5.28.z) employing the ErbB2 (HER2)-specific scFv(FRP5) antibody fragment for target cell recognition, and human CD28-CD3 ζ as a composite signaling moiety. An ErbB2-specific single cell clone (NK-92/5.28.z) was isolated, which showed high and selective cytotoxicity towards ErbB2-expressing tumor cells of various origins in vitro. We evaluated the cytotoxicity of NK-93/5.28.z cells against a panel of glioblastoma cell lines and primary glioblastoma cultures with different levels of Erb2 expression in vitro

  12. Integrin-Associated CD151 Drives ErbB2-Evoked Mammary Tumor Onset and Metastasis

    Directory of Open Access Journals (Sweden)

    Xinyu Deng

    2012-08-01

    Full Text Available ErbB2+ human breast cancer is a major clinical problem. Prior results have suggested that tetraspanin CD151 might contribute to ErbB2-driven breast cancer growth, survival, and metastasis. In other cancer types, CD151 sometimes supports tumor growth and metastasis. However, a definitive test of CD151 effects on de novo breast cancer initiation, growth, and metastasis has not previously been done. We used CD151 gene-deleted mice expressing the MMTV-ErbB2 transgene to show that CD151 strongly supports ErbB2+ mammary tumor initiation and metastasis. Delayed tumor onset (by 70–100 days in the absence of CD151 was accompanied by reduced survival of mammary epithelial cells and impaired activation of FAK- and MAPK-dependent pathways. Both primary tumors and metastatic nodules showed smooth, regular borders, consistent with a less invasive phenotype. Furthermore, consistent with impaired oncogenesis and decreased metastasis, CD151-targeted MCF-10A/ErbB2 cells showed substantial decreases in three-dimensional colony formation, EGF-stimulated tumor cell motility, invasion, and transendothelial migration. These CD151-dependent functions were largely mediated through α6β4 integrin. Moreover, CD151 ablation substantially prevented PKC- and EGFR/ERK-dependent α6β4 integrin phosphorylation, consistent with retention of epithelial cell polarity and intermediate filament cytoskeletal connections, which helps to explain diminished metastasis. Finally, clinical data analyses revealed a strong correlation between CD151 and ErbB2 expression and metastasis-free survival of breast cancer patients. In conclusion, we provide strong evidence that CD151 collaborates with LB integrins (particularly α6β4 and ErbB2 (and EGFR receptors to regulate multiple signaling pathways, thereby driving mammary tumor onset, survival, and metastasis. Consequently, CD151 is a useful therapeutic target in malignant ErbB2+ breast cancer.

  13. Increased level of phosphorylated akt measured by chemiluminescence-linked immunosorbent assay is a predictor of poor prognosis in primary breast cancer overexpressing ErbB-2

    International Nuclear Information System (INIS)

    Cicenas, Jonas; Urban, Patrick; Vuaroqueaux, Vincent; Labuhn, Martin; Küng, Willy; Wight, Edward; Mayhew, Mark; Eppenberger, Urs; Eppenberger-Castori, Serenella

    2005-01-01

    Akt1, Akt2 and Akt3 kinases are downstream components of phosphoinositol 3-kinase derived signals from receptor tyrosine kinases, which influence cell growth, proliferation and survival. Akt2 overexpression and amplification have been described in breast, ovarian and pancreatic cancers. The present study was designed to investigate the prognostic significance of activated Akt in primary breast cancer and its association with other tumour biomarkers. Using a two-site chemiluminescence-linked immunosorbent assay, we measured the quantitative expression levels of total phosphorylated (P-S473) Akt (Akt1/Akt2/Akt3) on cytosol fractions obtained from fresh frozen tissue samples of 156 primary breast cancer patients. Akt phosphorylation was not associated with nodal status or ErbB-2 protein expression levels. High levels of phosphorylated Akt correlated (P < 0.01) with poor prognosis, and the significance of this correlation increased (P < 0.001) in the subset of patients with ErbB-2 overexpressing tumours. In addition, phosphorylated Akt was found to be associated with mRNA expression levels of several proliferation markers (e.g. thymidylate synthase), measured using quantitative real-time RT-PCR. Our findings demonstrate that, in breast cancer patients, Akt activation is associated with tumour proliferation and poor prognosis, particularly in the subset of patients with ErbB2-overexpressing tumours

  14. Hsp90 inhibitor 17-AAG reduces ErbB2 levels and inhibits proliferation of the trastuzumab resistant breast tumor cell line JIMT-1.

    Science.gov (United States)

    Zsebik, Barbara; Citri, Ami; Isola, Jorma; Yarden, Yosef; Szöllosi, János; Vereb, György

    2006-04-15

    ErbB2, a member of the EGF receptor family of tyrosine kinases is overexpressed on many tumor cells of epithelial origin and is the molecular target of trastuzumab (Herceptin), the first humanized antibody used in the therapy of solid tumors. Trastuzumab, which is thought to act, at least in part, by downregulating ErbB2 expression is only effective in approximately 30-40% of ErbB2 positive breast tumors. Geldanamycin and its derivative 17-AAG are potential antitumor agents capable of downregulating client proteins of Hsp90, including ErbB2. To investigate the ability of 17-AAG to downregulate ErbB2 in trastuzumab resistant breast cancer cells and the possibility of 17-AAG and trastuzumab potentiating each other's effect, the recently established trastuzumab resistant breast cancer cell line, JIMT-1 was compared to the known trastuzumab sensitive SKBR-3 line. Baseline and stimulus-evoked dimerization and activation levels of ErbB2, and the effects of trastuzumab and 17-AAG alone and in combination on cell proliferation and apoptosis, as well as on ErbB2 expression and phosphorylation have been measured. Baseline activation and amenability to activation and downregulation by trastuzumab was much lower in the resistant line. However, 17-AAG enhanced ErbB2 homodimerization after 5-10 min of treatment in both cell lines, and decreased proliferation with an IC50 of 70 nM for SKBR-3 and 10nM for JIMT-1. Thus, 17-AAG may be a useful drug in trastuzumab resistant ErbB2 overexpressing tumors. The antiproliferative effect of 17-AAG was positively correlated with phosphorylation and downregulation of ErbB2 and was dominated by apoptosis, although, especially at higher doses, necrosis was also present. Interestingly, IC50 values for ErbB2 downregulation and phosphorylation, in the 30-40 nM range, were not significantly different for the two cell lines. This observation and the negative correlation between resting ErbB2 levels and the antiproliferative effect of 17-AAG may

  15. Expression and function of Neuregulin 1 and its signaling system ERBB2/3 in the enteric nervous system

    Directory of Open Access Journals (Sweden)

    Martina eBarrenschee

    2015-09-01

    Full Text Available Neuregulin 1 (NRG1 is suggested to promote the survival and maintenance of the enteric nervous system (ENS. As deficiency in its corresponding receptor signaling complex ERBB2/ERBB3 leads to postnatal colonic hypo/aganglionosis we assessed the distributional and expressional pattern of the NRG1-ERBB2/ERBB3 system in the human colon and explored the neurotrophic capacity of NRG1 on cultured enteric neurons.Site-specific mRNA expression of the NRG1-ERBB2/3 system was determined in microdissected samples harvested from enteric musculature and ganglia. Localization of NRG1, ERBB2 and ERBB3 was determined by dual-label-immunohistochemistry using pan-neuronal and pan-glial markers. Morphometric analysis was performed on NRG1-stimulated rat enteric nerve cultures to evaluate neurotrophic effects. mRNA expression of the NRG1-ERBB2/3 system was determined by qPCR. Co-localization of NRG1 with neuronal or synaptic markers was analyzed in enteric nerve cultures stimulated with glial cell line-derived neurotrophic factor (GDNF. The NRG1 system was expressed in both neurons and glial cells of enteric ganglia and in nerve fibers. NRG1 significantly enhanced growth parameters in enteric nerve cell cultures and ErB3 mRNA expression was down-regulated upon NRG1 stimulation. GDNF negatively regulates ErbB2 and ErbB3 mRNA expressionThe NRG1-ERBB2/3 system is physiologically present in the human ENS and NRG1 acts as a neurotrophic factor for the ENS. The down-regulation of ErbB3/ErbB2 in GDNF stimulated nerve cell cultures points to an interaction of both neurotrophic factors. Thus, the data may provide a basis to assess disturbed signaling components of the NRG1 system in enteric neuropathies.

  16. Marked enhancement of lysosomal targeting and efficacy of ErbB2-targeted drug delivery by HSP90 inhibition.

    Science.gov (United States)

    Raja, Srikumar M; Desale, Swapnil S; Mohapatra, Bhopal; Luan, Haitao; Soni, Kruti; Zhang, Jinjin; Storck, Matthew A; Feng, Dan; Bielecki, Timothy A; Band, Vimla; Cohen, Samuel M; Bronich, Tatiana K; Band, Hamid

    2016-03-01

    Targeted delivery of anticancer drugs to tumor cells using monoclonal antibodies against oncogenic cell surface receptors is an emerging therapeutic strategy. These strategies include drugs directly conjugated to monoclonal antibodies through chemical linkers (Antibody-Drug Conjugates, ADCs) or those encapsulated within nanoparticles that in turn are conjugated to targeting antibodies (Antibody-Nanoparticle Conjugates, ANPs). The recent FDA approval of the ADC Trastuzumab-TDM1 (Kadcyla; Genentech; San Francisco) for the treatment of ErbB2-overexpressing metastatic breast cancer patients has validated the strong potential of these strategies. Even though the activity of ANPs and ADCs is dependent on lysosomal traffic, the roles of the endocytic route traversed by the targeted receptor and of cancer cell-specific alterations in receptor dynamics on the efficiency of drug delivery have not been considered in these new targeted therapies. For example, constitutive association with the molecular chaperone HSP90 is thought to either retard ErbB2 endocytosis or to promote its recycling, traits undesirable for targeted therapy with ANPs and ADCs. HSP90 inhibitors are known to promote ErbB2 ubiquitination, targeting to lysosome and degradation. We therefore hypothesized that ErbB2-targeted drug delivery using Trastuzumab-conjugated nanoparticles could be significantly improved by HSP90 inhibitor-promoted lysosomal traffic of ErbB2. Studies reported here validate this hypothesis and demonstrate, both in vitro and in vivo, that HSP90 inhibition facilitates the intracellular delivery of Trastuzumab-conjugated ANPs carrying a model chemotherapeutic agent, Doxorubicin, specifically into ErbB2-overexpressing breast cancer cells, resulting in improved antitumor activity. These novel findings highlight the need to consider oncogene-specific alterations in receptor traffic in the design of targeted drug delivery strategies. We suggest that combination of agents that enhance receptor

  17. Mechanisms of Trastuzumab resistance in ErbB2-driven breast cancer and newer opportunities to overcome therapy resistance

    Directory of Open Access Journals (Sweden)

    Tameka A Bailey

    2011-01-01

    Full Text Available The Human Epidermal Growth Factor Receptor 2 (Her2, ErbB2 or Neu is overexpressed in about 20 - 25% of breast cancers and is causally linked to oncogenesis, providing opportunities for targeted therapy. Trastuzumab (Herceptin™, Genentech Inc, San Francisco, CA, a humanized monoclonal antibody against ErbB2, is a successful example of this concept and has vastly improved the response to treatment and overall survival in a majority of ErbB2+ breast cancer patients. However, lack of response in some patients as well as relapse during the course of therapy in others, continue to challenge researchers and clinicians alike towards a better understanding of the fundamental mechanisms of Trastuzumab action and resistance to treatment. The exact in vivo mechanism of action of Trastuzumab remains enigmatic, given its direct effects on the ErbB2 signaling pathway as well as indirect contributions from the immune system, by virtue of the ability of Trastuzumab to elicit Antibody-Dependent Cellular Cytotoxicity. Consequently, multiple mechanisms of resistance have been proposed. We present here a comprehensive review of our current understanding of the mechanisms, both of Trastuzumab action and clinical resistance to Trastuzumab-based therapies. We also review newer strategies (based on ErbB2 receptor biology that are being explored to overcome resistance to Trastuzumab therapy.

  18. Bispecific antibody to ErbB2 overcomes trastuzumab resistance through comprehensive blockade of ErbB2 heterodimerization.

    Science.gov (United States)

    Li, Bohua; Meng, Yanchun; Zheng, Lei; Zhang, Xunmin; Tong, Qing; Tan, Wenlong; Hu, Shi; Li, Hui; Chen, Yang; Song, Jinjing; Zhang, Ge; Zhao, Lei; Zhang, Dapeng; Hou, Sheng; Qian, Weizhu; Guo, Yajun

    2013-11-01

    The anti-ErbB2 antibody trastuzumab has shown significant clinical benefits in metastatic breast cancer. However, resistance to trastuzumab is common. Heterodimerization between ErbB2 and other ErbBs may redundantly trigger cell proliferation signals and confer trastuzumab resistance. Here, we developed a bispecific anti-ErbB2 antibody using trastuzumab and pertuzumab, another ErbB2-specific humanized antibody that binds to a distinct epitope from trastuzumab. This bispecific antibody, denoted as TPL, retained the full binding activities of both parental antibodies and exhibited pharmacokinetic properties similar to those of a conventional immunoglobulin G molecule. Unexpectedly, TPL showed superior ErbB2 heterodimerization-blocking activity over the combination of both parental monoclonal antibodies, possibly through steric hindrance and/or inducing ErbB2 conformational change. Further data indicated that TPL potently abrogated ErbB2 signaling in trastuzumab-resistant breast cancer cell lines. In addition, we showed that TPL was far more effective than trastuzumab plus pertuzumab in inhibiting the growth of trastuzumab-resistant breast cancer cell lines, both in vitro and in vivo. Importantly, TPL treatment eradicated established trastuzumab-resistant tumors in tumor-bearing nude mice. Our results suggest that trastuzumab-resistant breast tumors remain dependent on ErbB2 signaling and that comprehensive blockade of ErbB2 heterodimerization may be an effective therapeutic avenue. The unique potential of TPL to overcome trastuzumab resistance warrants its consideration as a promising treatment in the clinic.

  19. The role of ERBB2 gene polymorphisms in leprosy susceptibility

    Directory of Open Access Journals (Sweden)

    Jamile Leão Rêgo

    2015-03-01

    Full Text Available Mycobacterium leprae infects skin and peripheral nerves causing deformities and disability. The M. leprae bacterium binds to ErbB2 on the Schwann cell surface causing demyelination and favoring spread of the bacilli and causing nerve injury. Polymorphisms at the ERBB2 gene were previously investigated as genetic risk factors for leprosy in two Brazilian populations but with inconsistent results. Herein we extend the analysis of ERBB2 variants to a third geographically distinct population in Brazil. Our results show that there is no association between the genotyped SNPs and the disease (p > 0.05 in this population. A gene set or pathway analysis under the genomic region of ERBB2 will be necessary to clarify its regulation under M. leprae stimulus.

  20. ERBB2 mutations associated with solid variant of high-grade invasive lobular breast carcinomas.

    Science.gov (United States)

    Deniziaut, Gabrielle; Tille, Jean Christophe; Bidard, François-Clément; Vacher, Sophie; Schnitzler, Anne; Chemlali, Walid; Trémoulet, Laurence; Fuhrmann, Laetitia; Cottu, Paul; Rouzier, Roman; Bièche, Ivan; Vincent-Salomon, Anne

    2016-11-08

    ERBB2 and ERBB3 somatic gain-of-function mutations, which may be targeted by anti-ERBB2 therapies, were reported by high-throughput sequencing studies in 1% and 2% of invasive breast cancers respectively. Our study aims to determine ERBB2 and ERBB3 mutations frequencies in grade 3 and/or ERBB2-positive invasive lobular breast carcinomas (ILC). All the 529 ILC surgically-excised registered at Institut Curie in the years 2005 to 2008 were reviewed. Thirty-nine grade 3 ERBB2-negative ILC and 16 ERBB2-positive ILC were retrieved and subjected to Sanger sequencing of the ERBB2 and ERBB3 activation mutation hotspots (ERBB2: exons 8, 17, 19, 20, 21; ERBB3: exons 3, 6, 7, 8). Among the 39 grade 3 ERBB2-negative ILC, six tumors were found to have at least one detectable ERBB2 activating mutation (incidence rate: 15%, 95%CI [4%-27%]). No ERBB2 mutation was found among the 16 ERBB2-positive ILC. No ERBB3 mutation was found in any of the 55 ILC. ERBB2 mutations were statistically associated with solid ILC features (p=0.01). Survival analyses showed no significant prognostic impact of ERBB2 mutations. Our study demonstrates that high grade ERBB2-negative ILC display a high frequency of ERBB2 mutations, and should be subjected to systematic genetic screening.

  1. Activation of EGFR and ERBB2 by Helicobacter pylori Results in Survival of Gastric Epithelial Cells with DNA Damage

    Science.gov (United States)

    Chaturvedi, Rupesh; Asim, Mohammad; Piazuelo, M. Blanca; Yan, Fang; Barry, Daniel P.; Sierra, Johanna Carolina; Delgado, Alberto G.; Hill, Salisha; Casero, Robert A.; Bravo, Luis E.; Dominguez, Ricardo L.; Correa, Pelayo; Polk, D. Brent; Washington, M. Kay; Rose, Kristie L.; Schey, Kevin L.; Morgan, Douglas R.; Peek, Richard M.; Wilson, Keith T.

    2014-01-01

    BACKGROUND & AIMS The gastric cancer-causing pathogen Helicobacter pylori upregulates spermine oxidase (SMOX) in gastric epithelial cells, causing oxidative stress-induced apoptosis and DNA damage. A subpopulation of SMOXhigh cells are resistant to apoptosis, despite their high levels of DNA damage. Because epidermal growth factor receptor (EGFR) activation can regulate apoptosis, we determined its role in SMOX-mediated effects. METHODS SMOX, apoptosis, and DNA damage were measured in gastric epithelial cells from H pylori-infected Egfrwa5 mice (which have attenuated EGFR activity), Egfr wild-type mice, or in infected cells incubated with EGFR inhibitors or deficient in EGFR. Phosphoproteomic analysis was performed. Two independent tissue microarrays containing each stage of disease, from gastritis to carcinoma, and gastric biopsies from Colombian and Honduran cohorts were analyzed by immunohistochemistry. RESULTS SMOX expression and DNA damage were decreased, and apoptosis increased in H pylori-infected Egfrwa5 mice. H pylori-infected cells with deletion or inhibition of EGFR had reduced levels of SMOX, DNA damage, and DNA damagehigh apoptosislow cells. Phosphoproteomic analysis revealed increased EGFR and ERBB2 signaling. Immunoblot analysis demonstrated the presence of a phosphorylated (p)EGFR–ERBB2 heterodimer and pERBB2; knockdown of ErbB2 facilitated apoptosis of DNA damagehigh apoptosislow cells. SMOX was increased in all stages of gastric disease, peaking in tissues with intestinal metaplasia, whereas pEGFR, pEGFR–ERBB2, and pERBB2 were increased predominantly in tissues demonstrating gastritis or atrophic gastritis. Principal component analysis separated gastritis tissues from patients with cancer vs those without cancer. pEGFR, pEGFR–ERBB2, pERBB2, and SMOX were increased in gastric samples from patients whose disease progressed to intestinal metaplasia or dysplasia, compared with patients whose disease did not progress. CONCLUSIONS In an analysis

  2. Poly (A+ transcriptome assessment of ERBB2-induced alterations in breast cell lines.

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    Dirce Maria Carraro

    Full Text Available We report the first quantitative and qualitative analysis of the poly (A⁺ transcriptome of two human mammary cell lines, differentially expressing (human epidermal growth factor receptor an oncogene over-expressed in approximately 25% of human breast tumors. Full-length cDNA populations from the two cell lines were digested enzymatically, individually tagged according to a customized method for library construction, and simultaneously sequenced by the use of the Titanium 454-Roche-platform. Comprehensive bioinformatics analysis followed by experimental validation confirmed novel genes, splicing variants, single nucleotide polymorphisms, and gene fusions indicated by RNA-seq data from both samples. Moreover, comparative analysis showed enrichment in alternative events, especially in the exon usage category, in ERBB2 over-expressing cells, data indicating regulation of alternative splicing mediated by the oncogene. Alterations in expression levels of genes, such as LOX, ATP5L, GALNT3, and MME revealed by large-scale sequencing were confirmed between cell lines as well as in tumor specimens with different ERBB2 backgrounds. This approach was shown to be suitable for structural, quantitative, and qualitative assessment of complex transcriptomes and revealed new events mediated by ERBB2 overexpression, in addition to potential molecular targets for breast cancer that are driven by this oncogene.

  3. Genetic Polymorphisms in the EGFR (R521K and Estrogen Receptor (T594T Genes, EGFR and ErbB-2 Protein Expression, and Breast Cancer Risk in Tunisia

    Directory of Open Access Journals (Sweden)

    Imen Kallel

    2009-01-01

    Full Text Available We evaluated the association of epidermal growth factor receptor (EGFR 142285G>A (R521K and estrogen receptor alpha (ESR1 2014G>A (T594T single nucleotide polymorphisms with breast cancer risk and prognosis in Tunisian patients. EGFR 142285G>A and ESR1 2014G>A were genotyped in a sample of 148 Tunisian breast cancer patients and 303 controls using PCR-RFLP method. Immunohistochemitsry was used to evaluate the expression levels of EGFR, HER2, ESR1, progesterone receptor and BCL2 in tumors. We found no evidence for an association between EGFR R521K polymorphism and breast cancer risk. However, we found that the homozygous GG (Arg genotype was more prevalent in patients with lymph node metastasis (=.03 and high grade tumors (=.011. The ESR1 2014G allele showed significant association with breast cancer risk (=.025. The GG genotype was associated with HER2 overexpression and this association withstood univariate and multivariate analyses (=.009; =.021, resp.. These data suggest that the R521K might be a prognostic factor, because it correlates with both tumor grade and nodule status. The higher expression of HER2 in ESR1 T594T GG patients suggests the possibility that ESR1 gene polymorphisms accompanied by HER2 expression might influence the pathogenesis of breast cancers.

  4. ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini

    Energy Technology Data Exchange (ETDEWEB)

    Muthuswamy, Senthil K; Li, Dongmei; Lelievre, Sophie; Bissell, Mina J; Brugge, Joan S

    2001-08-08

    Both ErbB1 and ErbB2 are overexpressed or amplified in breast tumors. To examine the effects of activating ErbB receptors in a context that mimics polarized epithelial cells in vivo, we activated ErbB1 and ErbB2 homodimers in preformed, growth-arrested mammary acini cultured in three-dimensional basement membrane gels. Activation of ErbB2, but not that of ErbB1, led to a reinitiation of cell proliferation and altered the properties of mammary acinar structures. These altered structures share several properties with early-stage tumors, including a loss of proliferative suppression, an absence of lumen, retention of the basement membrane and a lack of invasive properties. ErbB2 activation also disrupted tight junctions and the cell polarity of polarized epithelia, whereas ErbB1 activation did not have any effect. Our results indicate that ErbB receptors differ in their ability to induce early stages of mammary carcinogenesis in vitro and this three-dimensional model system can reveal biological activities of oncogenes that cannot be examined in vitro in standard transformation assays.

  5. Direct binding of Copine3 with Jab1 activates downstream ErbB2 signaling and motility in SKBr3 breast cancer cells.

    Science.gov (United States)

    Choi, Hye Young; Park, Nammi; Na, Jae Boem; Ko, Eun Sook; Park, Jae-Yong; Yoo, Jae Cheal

    2016-02-01

    Copine3, a known calcium-dependent membrane binding protein, contains two tandem C2 domains and an A domain. This protein has been shown to interact with receptor tyrosine kinase 2 (ErbB2), but little is known concerning the physiological function of Copine3. To better understand its cellular function, we carried out a yeast two-hybrid screen to find Copine3 binding partners. Among the identified proteins, Jun activation domain-binding protein 1 (Jab1) appears to directly interact with Copine3. This physical interaction between Copine3 and Jab1 as well as the specific binding regions of both proteins were confirmed in vitro and in vivo. Our results also demonstrate that binding of Copine3 to ErbB2 is increased when Jab1 is overexpressed in SKBr3 breast cancer cells. Furthermore, two ErbB2 downstream signaling proteins [phosphatidylinositol 3 (PI3) kinase and protein kinase B (AKT)] were also activated by Jab1 overexpression in these cells. These data suggest that binding of Copine3 and Jab1 regulates, at least to some extent, the ErbB2 signaling pathway. Moreover, overexpression of both Copine3 and Jab1 in SKBr3 cells effectively increased cellular migration. Collectively, our findings indicating that Jab1 enhances the ErbB2 binding ability of Copine3, further activating the ErbB2 signaling pathways involved in breast cancer cell pathogenesis.

  6. Hyaluronan-induced masking of ErbB2 and CD44-enhanced trastuzumab internalisation in trastuzumab resistant breast cancer.

    Science.gov (United States)

    Pályi-Krekk, Zsuzsanna; Barok, Márk; Isola, Jorma; Tammi, Markku; Szöllosi, János; Nagy, Peter

    2007-11-01

    Although trastuzumab, a recombinant humanised anti-ErbB2 antibody, is widely used in the treatment of breast cancer, neither its mechanism of action, nor the factors leading to resistance are fully understood. We have previously shown that antibody-dependent cellular cytotoxicity is pivotal in the in vivo effect of trastuzumab against JIMT-1, a cell line showing in vitro resistance to the antibody, and suggested that masking of the trastuzumab-binding epitope by MUC-4, a cell surface mucin, took place. Here, we further explored the role of masking of ErbB2 in connection with CD44 expression and synthesis of its ligand, hyaluronan. We show that high expression of CD44 observed in JIMT-1 cells correlates with ErbB2 downregulation in vivo, while siRNA-mediated inhibition of CD44 expression leads to decreased rate of trastuzumab internalisation and low cell proliferation in vitro. An inhibitor of hyaluronan synthesis, 4-methylumbelliferon (4-MU) significantly reduced the hyaluronan level of JIMT-1 cells both in vivo and in vitro leading to enhanced binding of trastuzumab to ErbB2 and increased ErbB2 down-regulation. Furthermore, the inhibitory effect of trastuzumab on the growth of JIMT-1 xenografts was significantly increased by 4-MU treatment. Our results point to the importance of the CD44-hyaluronan pathway in the escape of tumour cells from receptor-oriented therapy.

  7. Structure-Based Design of erbB-2 Selective Small Molecule Kinase Inhibitors

    National Research Council Canada - National Science Library

    Wang, Shaomeng

    2003-01-01

    .... Among these initial lead compounds, B-17 has excellent activity in inhibition of erbB-2 auto-phosphorylation and inhibition of cell proliferation using MDA-453 human breast cancer cells with erbB-2 overexpression...

  8. ERBB-2 overexpression as a risk factor for malignant phaeochromocytomas and paraganglinomas.

    Science.gov (United States)

    Wang, Weiqing; Zhong, Xu; Ye, Lei; Qi, Yan; Su, TingWei; Wei, Qing; Xie, Jing; Jiang, Lei; Jiang, Yiran; Zhou, Weiwei; Cui, Bin; Ning, Guang

    2016-06-01

    There are currently no good histological or molecular markers to differentiate benign from malignant phaeochromocytomas and paraganglinomas (PPGLs). Our previous cross-sectional study observed that ERBB-2 overexpression was associated with malignant PPGLs. This study aimed to evaluate the predictive value of ERBB-2 overexpression for metastasis in PPGLs in a large population. A total of 262 patients diagnosed as PPGLs in our institution between 2002 and 2012 were included. We analysed ERBB-2 protein expression in the primary PPGL tumours by immunohistochemistry (IHC) and ERBB-2 amplification by fluorescence in situ hybridization (FISH). Direct Sanger sequencing was performed to examine ERBB-2 exon 20 mutations. The occurrence of malignant PPGLs was documented in the follow-up period. Kaplan-Meier analysis and Cox proportional hazard models were used to evaluate the association between ERBB-2 overexpression and metastasis of PPGLs. Twenty-six (9·9%) patients had ERBB-2 overexpression in their primary PPGL tumours, which was significantly associated with ERBB-2 amplification (17/25, 68%). No ERBB-2 mutation was found. At a median follow-up of 4·5 years, a total of 23 malignant PPGLs were documented, including eight (30·8%) patients in the ERBB-2 overexpression group and 15 (6·4%) patients in the ERBB-2-negative group. The incidence rate of metastasis was 5·3 per 100 person-years vs 1·4 per 100 person-years in the ERBB-2 overexpression and ERBB-2-negative groups (P overexpression was associated with decreased metastasis-free survival (P = 0·001, log-rank test). After adjusting for primary tumour size and location, Cox regression analysis revealed that ERBB-2 overexpression was independently associated with risk of malignant PPGLs (HR = 2·78; 95% CI, 1·12-6·90; P = 0·028). Patients harbouring tumours with ERBB-2 overexpression have a significantly higher risk of developing malignant PPGLs. © 2016 John Wiley & Sons Ltd.

  9. Estradiol rapidly activates Akt via the ErbB2 signaling pathway.

    Science.gov (United States)

    Stoica, Gerald E; Franke, Thomas F; Wellstein, Anton; Czubayko, Frank; List, Heinz-Joachim; Reiter, Ronald; Morgan, Elisha; Martin, Mary Beth; Stoica, Adriana

    2003-05-01

    Previously, we have demonstrated that the two mitogenic growth factors epidermal growth factor and IGF-I can activate Akt and estrogen receptor-alpha (ERalpha) in the hormone-dependent breast cancer cell line, MCF-7. In this report we now show that estradiol can also rapidly activate phosphatidylinositol 3-kinase (PI 3-K)/Akt and that this effect is mediated by the ErbB2 signaling pathway. Treatment of cells with estradiol resulted in phosphorylation of Akt and a 9-fold increase in Akt activity in 10 min. Akt activation was blocked by wortmannin and LY 294,002, two inhibitors of PI 3-K; by genistein, a protein tyrosine kinase inhibitor and an ER agonist; by AG825, a selective ErbB2 inhibitor; and by the antiestrogens ICI 182,780 and 4-hydroxy-tamoxifen; but not by rapamycin, an inhibitor of the ribosomal protein kinase p70S6K; nor by AG30, a selective epidermal growth factor receptor inhibitor. Akt activation by estradiol was abrogated by an arginine-to-cysteine mutation in the pleckstrin homology domain of Akt (R25C). Growth factors also activated Akt in the ER-negative variant of MCF-7, MCF-7/ADR, but estradiol did not induce Akt activity in these cells. Transient transfection of ERalpha into these cells restored Akt activation by estradiol, suggesting that estradiol activation of Akt requires the ERalpha. Estradiol did not activate Akt in MCF-7 cells stably transfected with an anti-ErbB2-targeted ribozyme, further confirming a role for ErbB2. In vitro kinase assays using immunoprecipitation and anti-Akt1, -Akt2, and -Akt3-specific antibodies demonstrated that Akt1 is activated by estradiol in MCF-7 cells whereas Akt3 is the activated isoform in ER-negative MDA-MB231 cells, implying that selective activation of Akt subtypes plays a role in the actions of estradiol. Taken together, our data suggest that estradiol, bound to membrane ERalpha, interacts with and activates an ErbB dimer containing ErbB2, inducing activation of PI 3-K/Akt.

  10. Anti-metastasis activity of black rice anthocyanins against breast cancer: analyses using an ErbB2 positive breast cancer cell line and tumoral xenograft model.

    Science.gov (United States)

    Luo, Li-Ping; Han, Bin; Yu, Xiao-Ping; Chen, Xiang-Yan; Zhou, Jie; Chen, Wei; Zhu, Yan-Feng; Peng, Xiao-Li; Zou, Qiang; Li, Sui-Yan

    2014-01-01

    Increasing evidence from animal, epidemiological and clinical investigations suggest that dietary anthocyanins have potential to prevent chronic diseases, including cancers. It is also noteworthy that human epidermal growth factor receptor 2 (ErbB2) protein overexpression or ErbB2 gene amplification has been included as an indicator for metastasis and higher risk of recurrence for breast cancer. The present experiments investigated the anti-metastasis effects of black rice anthocyanins (BRACs) on ErbB2 positive breast cancer cells in vivo and in vitro. Oral administration of BRACs (150 mg/kg/day) reduced transplanted tumor growth, inhibited pulmonary metastasis, and decreased lung tumor nodules in BALB/c nude mice bearing ErbB2 positive breast cancer cell MDA-MB-453 xenografts. The capacity for migration, adhesion, motility and invasion was also inhibited by BRACs in MDA-MB-453 cells in a concentration dependent manner, accompanied by decreased activity of a transfer promoting factor, urokinase-type plasminogen activator (u-PA). Together, our results indicated that BRACs possess anti-metastasis potential against ErbB2 positive human breast cancer cells in vivo and in vitro through inhibition of metastasis promoting molecules.

  11. Inhibition of eIF2α dephosphorylation inhibits ErbB2-induced deregulation of mammary acinar morphogenesis

    Directory of Open Access Journals (Sweden)

    Avivar-Valderas Alvaro

    2009-09-01

    Full Text Available Abstract Background The ErbB2/Her2/Neu receptor tyrosine kinase is amplified in ~30% of human breast cancers. Phosphorylation of the translation initiation factor, eIF2α inhibits global protein synthesis and activates a stress signaling and growth suppressive program. We have shown that forced phosphorylation of eIF2α can suppress head and neck, colorectal carcinoma and multiple myeloma tumor growth and/or survival. Here we explore whether ErbB2 modulates eIF2α phosphorylation and whether forced phosphorylation of the latter can antagonize ErbB2 deregulation of mammary acinar morphogenesis. Results We tested whether ErbB2 signaling influenced eIF2α signaling and whether enhanced phosphorylation of the latter affected ErbB2-deregulated mammary acinar development. We obtained stable MCF10A cells overexpressing wild-type (Wt Neu/ErbB2 or a constitutively active (CA variant via retroviral delivery or mammary tumor cells from MMTV-Neu tumors. Western blotting, RT-PCR and confocal microscopy were used to analyze the effects of ErbB2 activation on eIF2α signaling and the effect of the GADD34-PP1C inhibitor salubrinal. Wt- and MMTV-Neu cells formed aberrant acini structures resembling DCIS, while CA-ErbB2 overexpression induced invasive lesions. In these structures we found that CA-ErbB2 but not the Wt variant significantly down-regulated the pro-apoptotic gene CHOP. This occurred without apparent modulation of basal phosphorylation of PERK and eIF2α or induction of its downstream target ATF4. However, inhibition of eIF2α dephosphorylation with salubrinal was sufficient to inhibit Wt- and CA-ErbB2- as well as MMTV-Neu-induced deregulation of acinar growth. This was linked to enhanced CHOP expression, inhibition of proliferation, induction of apoptosis and luminal clearing in Wt-ErbB2 and to inhibition of cyclin D1 levels and subsequent proliferation in CA-ErbB2 cells. Conclusion Depending on the strength of ErbB2 signaling there is a differential

  12. The ectodomain of cadherin-11 binds to erbB2 and stimulates Akt phosphorylation to promote cranial neural crest cell migration.

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    Ketan Mathavan

    Full Text Available During development, a multi-potent group of cells known as the cranial neural crest (CNC migrate to form craniofacial structures. Proper migration of these cells requires proteolysis of cell adhesion molecules, such as cadherins. In Xenopus laevis, preventing extracellular cleavage of cadherin-11 impairs CNC migration. However, overexpression of the soluble cleavage product (EC1-3 is capable of rescuing this phenotype. The mechanism by which EC1-3 promotes CNC migration has not been investigated until now. Here we show that EC1-3 stimulates phosphorylation of Akt, a target of PI3K, in X.laevis CNC. Through immunoprecipitation experiments, we determined that EC1-3 interacts with all ErbB receptors, PDGFRα, and FGFR1. Of these receptors, only ErbB2 was able to produce an increase in Akt phosphorylation upon treatment with a recombinant EC1-3. This increase was abrogated by mubritinib, an inhibitor of ErbB2. We were able to recapitulate this decrease in Akt phosphorylation in vivo by knocking down ErbB2 in CNC cells. Knockdown of the receptor also significantly reduced CNC migration in vivo. We confirmed the importance of ErbB2 and ErbB receptor signaling in CNC migration using mubritinib and canertinib, respectively. Mubritinib and the PI3K inhibitor LY294002 significantly decreased cell migration while canertinib nearly prevented it altogether. These data show that ErbB2 and Akt are important for CNC migration and implicate other ErbB receptors and Akt-independent signaling pathways. Our findings provide the first example of a functional interaction between the extracellular domain of a type II classical cadherin and growth factor receptors.

  13. Polysomy of chromosome 17 in breast cancer tumors showing an overexpression of ERBB2: a study of 175 cases using fluorescence in situ hybridization and immunohistochemistry

    International Nuclear Information System (INIS)

    Salido, Marta; Solé, Francesc; Tusquets, Ignasi; Corominas, Josep M; Suarez, Marta; Espinet, Blanca; Corzo, Cristina; Bellet, Meritxell; Fabregat, Xavier; Serrano, Sergi

    2005-01-01

    One of the most common genetic aberrations associated with breast cancer is the amplification and overexpression of the ERBB2 proto-oncogene located at chromosome 17, bands q12-21. The amplification/overexpression occurs in 25 to 30% of all breast cancers. In breast cancer, aneusomy of chromosome 17, either monosomy or polysomy, is frequently observed by conventional cytogenetics and fluorescence in situ hybridization (FISH). The aim of this study was to discover whether or not numerical aberrations on chromosome 17 have a correlation to the amplification or overexpression of the ERBB2 gene and to analyze their clinical implications in subgroups showing 2+ or 3+ positive scores by immunohistochemistry (IHC). We used FISH on a series of 175 formalin-fixed paraffin-embedded breast carcinomas to detect ERBB2 amplification, using a dual-probe system for the simultaneous enumeration of the ERBB2 gene and the centromeric region of chromosome 17, as well as using IHC to detect overexpression. We analyzed clinical and pathological variables in a subgroup of patients with 2+ and 3+ IHC scores (147 patients), to describe any differences in clinicopathological characteristics between polysomic and non-polysomic cases with the use of the χ 2 test. We found 13% of cases presenting polysomy, and three cases presented monosomy 17 (2%). According to the status of the ERBB2 gene, instances of polysomy 17 were more frequently observed in non-amplified cases than in FISH-amplified cases, suggesting that the mechanism for ERBB2 amplification is independent of polysomy 17. Polysomy 17 was detected in patients with 2+ and 3+ IHC scores. We found that nodal involvement was more frequent in polysomic than in non-polysomic cases (P = 0.046). The determination of the copy number of chromosome 17 should be incorporated into the assesment of ERBB2 status. It might also be helpful to differentiate a subgroup of breast cancer patients with polysomy of chromosome 17 and overexpression of ERBB2

  14. Flotillins as regulators of ErbB2 levels in breast cancer

    DEFF Research Database (Denmark)

    Pust, S; Klokk, T I; Musa, N

    2013-01-01

    -induced mechanisms. Here we show that flotillins are involved in the stabilization of ErbB2 at the plasma membrane. In SKBR3 breast cancer cells and breast cancer tissue, a positive correlation between flotillin and ErbB2 expression levels could be demonstrated. Moreover, the tissue microarray analyses of biopsies...

  15. Transducer of ERBB2.1 (TOB1 as a Tumor Suppressor: A Mechanistic Perspective

    Directory of Open Access Journals (Sweden)

    Hun Seok Lee

    2015-12-01

    Full Text Available Transducer of ERBB2.1 (TOB1 is a tumor-suppressor protein, which functions as a negative regulator of the receptor tyrosine-kinase ERBB2. As most of the other tumor suppressor proteins, TOB1 is inactivated in many human cancers. Homozygous deletion of TOB1 in mice is reported to be responsible for cancer development in the lung, liver, and lymph node, whereas the ectopic overexpression of TOB1 shows anti-proliferation, and a decrease in the migration and invasion abilities on cancer cells. Biochemical studies revealed that the anti-proliferative activity of TOB1 involves mRNA deadenylation and is associated with the reduction of both cyclin D1 and cyclin-dependent kinase (CDK expressions and the induction of CDK inhibitors. Moreover, TOB1 interacts with an oncogenic signaling mediator, β-catenin, and inhibits β-catenin-regulated gene transcription. TOB1 antagonizes the v-akt murine thymoma viral oncogene (AKT signaling and induces cancer cell apoptosis by activating BCL2-associated X (BAX protein and inhibiting the BCL-2 and BCL-XL expressions. The tumor-specific overexpression of TOB1 results in the activation of other tumor suppressor proteins, such as mothers against decapentaplegic homolog 4 (SMAD4 and phosphatase and tensin homolog-10 (PTEN, and blocks tumor progression. TOB1-overexpressing cancer cells have limited potential of growing as xenograft tumors in nude mice upon subcutaneous implantation. This review addresses the molecular basis of TOB1 tumor suppressor function with special emphasis on its regulation of intracellular signaling pathways.

  16. FASN, ErbB2-mediated glycolysis is required for breast cancer cell migration.

    Science.gov (United States)

    Zhou, Lan; Jiang, Sufang; Fu, Qiang; Smith, Kelly; Tu, Kailing; Li, Hua; Zhao, Yuhua

    2016-05-01

    Both fatty acid synthase (FASN) and ErbB2 have been shown to promote breast cancer cell migration. However, the underlying molecular mechanism remains poorly understood and there is no reported evidence that directly links glycolysis to breast cancer cell migration. In this study, we investigated the role of FASN, ErbB2-mediated glycolysis in breast cancer cell migration. First, we compared lactate dehydrogenase A (LDHA) protein levels, glycolysis and cell migration between FASN, ErbB2-overexpressing SK-BR-3 cells and FASN, ErbB2-low-expressing MCF7 cells. Then, SK-BR-3 cells were treated with cerulenin (Cer), an inhibitor of FASN, and ErbB2, LDHA protein levels, glycolysis, and cell migration were detected. Next, we transiently transfected ErbB2 plasmid into MCF7 cells and detected FASN, LDHA protein levels, glycolysis and cell migration. Heregulin-β1 (HRG-β1) is an activator of ErbB2 and 2-deoxyglucose (2-DG) and oxamate (OX) are inhibitors of glycolysis. MCF7 cells were treated with HRG-β1 alone, HRG-β1 plus 2-DG, OX or cerulenin and glycolysis, and cell migration were measured. We found that FASN, ErbB2-high-expressing SK-BR-3 cells displayed higher levels of glycolysis and migration than FASN, ErbB2-low-expressing MCF7 cells. Inhibition of FASN by cerulenin impaired glycolysis and migration in SK-BR-3 cells. Transient overexpression of ErbB2 in MCF7 cells promotes glycolysis and migration. Moreover, 2-deoxyglucose (2-DG), oxamate (OX), or cerulenin partially reverses heregulin-β1 (HRG-β1)-induced glycolysis and migration in MCF7 cells. In conclusion, this study demonstrates that FASN, ErbB2-mediated glycolysis is required for breast cancer cell migration. These novel findings indicate that targeting FASN, ErbB2-mediated glycolysis may be a new approach to reverse breast cancer cell migration.

  17. A combination of Trastuzumab and 17-AAG induces enhanced ubiquitinylation and lysosomal pathway-dependent ErbB2 degradation and cytotoxicity in ErbB2-overexpressing breast cancer cells.

    Science.gov (United States)

    Raja, Srikumar M; Clubb, Robert J; Bhattacharyya, Mitra; Dimri, Manjari; Cheng, Hao; Pan, Wei; Ortega-Cava, Cesar; Lakku-Reddi, Alagarsamy; Naramura, Mayumi; Band, Vimla; Band, Hamid

    2008-10-01

    ErbB2 (or Her2/Neu) overexpression in breast cancer signifies poorer prognosis, yet it has provided an avenue for targeted therapy as demonstrated by the success of the humanized monoclonal antibody Trastuzumab (Herceptin). Resistance to Trastuzumab and eventual failure in most cases, however, necessitate alternate ErbB2-targeted therapies. HSP90 inhibitors such as 17-allylaminodemethoxygeldanamycin (17-AAG), potently downregulate the cell surface ErbB2. While the precise mechanisms of Trastuzumab or 17-AAG action remain unclear, ubiquitinylation-dependent proteasomal or lysosomal degradation of ErbB2 appears to play a substantial role. As Trastuzumab and 17-AAG induce the recruitment of distinct E3 ubiquitin ligases, Cbl and CHIP respectively, to ErbB2, we hypothesized that 17-AAG and Trastuzumab combination could induce a higher level of ubiquitinylation and downregulation of ErbB2 as compared to single drug treatments. We present biochemical and cell biological evidence that combined 17-AAG and Trastuzumab treatment of ErbB2-overexpressing breast cancer cell lines leads to enhanced ubiquitinylation, downregulation from the cell surface and lysosomal degradation of ErbB2. Importantly, combined 17-AAG and Trastuzumab treatment induced synergistic growth arrest and cell death specifically in ErbB2-overexpressing but not in ErbB2-low breast cancer cells. Our results suggest the 17-AAG and Trastuzumab combination as a mechanism-based combinatorial targeted therapy for ErbB2-overexpressing breast cancer patients.

  18. ErbB2 Regulation of c-src Activity in Breast Cancer

    National Research Council Canada - National Science Library

    Sheffield, Lewis

    1999-01-01

    ErbB2 transformation of mammary epithelial cells activated c-src. C-src activation was associated with decreased phosphorylation of tyrosine 527, but not by a decrease in C-terminal-src-kinase (CSK) activity...

  19. Novel Peptide/Protein Delivery System Targeting erbB2-Overexpressing Breast Cancer Cells

    National Research Council Canada - National Science Library

    Yu, Dihua

    2002-01-01

    .... During this funding year, we focused on the delivery of erbB2 signal-blocking ESP peptides (objective 2) . Because of the complexity of biotin-penetratin-AHNP-ESP, the synthesis was unsuccessful...

  20. Overexpression of ErbB2 induces invasion of MCF10A human breast epithelial cells via MMP-9.

    Science.gov (United States)

    Kim, In-Young; Yong, Hae-Young; Kang, Keon Wook; Moon, Aree

    2009-03-18

    Metastasis is the principal cause of death from breast cancer. ErbB2 (HER-2/neu) has been identified as an important regulator of metastatic potential of breast cancer. The present study investigated the molecular mechanism underlying the role of ErbB2 in malignant phenotypic conversion of MCF10A human breast epithelial cells which originally have 'normal' cell character. Here we report that ErbB2 induces invasion and migration of MCF10A cells though up-regulation of matrix metalloproteinase (MMP)-9. We also observed a marked reduction of an epithelial cell marker, E-cadherin, and an induction of vimentin in ErbB2-MCF10A cells, suggesting that epithelial-mesenchymal transition may play a role in the ErbB2-induced invasion and migration of MCF10A cells. Overexpression of ErbB2 significantly activated p38 MAPK and Akt, while Raf-1/MEK/ERK pathway was not activated by ErbB2. Using pharmacological inhibitors, we further show that p38 MAPK and Akt signaling pathways are crucial for the ErbB2-induced MMP-9 up-regulation, invasion and migration of MCF10A cells. Given that ErbB2 is one of the most important oncogenes in human breast cancer and thus is an attractive therapeutic target, our findings may provide a molecular basis for the promoting role of ErbB2 in breast cancer progression.

  1. Mek activity is required for ErbB2 expression in breast cancer cells detached from the extracellular matrix.

    Science.gov (United States)

    Khan, Iman A; Yoo, Byong H; Rak, Janusz; Rosen, Kirill V

    2017-12-01

    Detachment of non-malignant epithelial cells from the extracellullar matrix (ECM) triggers their growth arrest and apoptosis. Conversely, carcinoma cells can grow without adhesion to the ECM. This capacity for anchorage-independent growth is thought to be critical for tumor progression. ErbB2/Her2 oncoprotein is overproduced by a significant fraction of breast cancers and promotes anchorage-independent tumor cell growth by poorly understood mechanisms. In an effort to understand them we found that in order to produce ErbB2, detached breast cancer cells require the activity of an ErbB2 effector protein kinase Mek and that Mek-driven ErbB2 expression is neccesary for anchorage-independent growth of such cells. We observed that Mek inhibition does not alter ErbB2 mRNA levels in detached cancer cells and that ErbB2 protein loss induced by this inhibition can be blocked by a lysosomal inhibitor. We also noticed that an increase of the density of cancer cells detached from the ECM downregulates a Mek effector protein kinase Erk and causes ErbB2 loss. Those cells that survive after ErbB2 loss display resistance to trastuzumab, an anti-ErbB2 antibody used for ErbB2-positive breast cancer treatment. Thus, Mek-induced ErbB2 stabilization in detached breast cancer cells is critical for their ability to grow anchorage-independently and their trastuzumab sensitivity.

  2. ErbB2 Activation Upregulates Glutaminase 1 Expression Which Promotes Breast Cancer Cell Proliferation

    Science.gov (United States)

    Qie, Shuo; Chu, Clarissa; Li, Weihua; Wang, Chenguang; Sang, Nianli

    2015-01-01

    Active glutamine utilization is critical for tumor cell proliferation. Glutaminolysis represents the first and rate-limiting step of glutamine utilization and is catalyzed by glutaminase (GLS). Activation of ErbB2 is one of the major causes of breast cancers, the second most common cause of death for women in many countries. However, it remains unclear whether ErbB2 signaling affects glutaminase expression in breast cancer cells. In this study, we show that MCF10A-NeuT cell line has higher GLS1 expression at both mRNA and protein levels than its parental line MCF10A, and knockdown of ErbB2 decreases GLS1 expression in MCF10A-NeuT cells. We further show that in these cells, ErbB2-mediated upregulation of GLS1 is not correlated to c-Myc expression. Moreover, activation of neither PI3K-Akt nor MAPK pathway is sufficient to upregulate GLS1 expression. Interestingly, inhibition of NF-κB blocks ErbB2-stimulated GLS1 expression, whereas stimulation of NF-κB is sufficient to enhance GLS1 levels in MCF10A cells, suggesting a PI3K-Akt-independent activation of NF-κB upregulates GLS1 in ErbB2-positive breast cancer cells. Finally, knockdown or inhibition of GLS1 significantly decreased the proliferation of breast cancer cells with high GLS1 levels. Taken together, our data indicate that ErbB2 activation promotes GLS1 expression via a PI3K-Akt-independent NF-κB pathway in breast cancer cells, identifying another oncogenic signaling pathway which stimulates GLS1 expression, and thus promoting glutamine utilization in cancer cells. These findings, if validated by in vivo model, may facilitate the identification of novel biochemical targets for cancer prevention and therapy. PMID:24122876

  3. Cooperative antitumor activities of carnosic acid and Trastuzumab in ERBB2+ breast cancer cells

    Directory of Open Access Journals (Sweden)

    Carolina D’Alesio

    2017-11-01

    Full Text Available Abstract Background ERBB2 is overexpressed in up to 20–30% of human breast cancers (BCs, and it is associated with aggressive disease. Trastuzumab (Tz, a humanized monoclonal antibody, improves the prognosis associated with ERBB2-amplified BCs. However, the development of resistance remains a significant challenge. Carnosic acid (CA is a diterpene found in rosemary and sage, endowed with anticancer properties. In this in vitro study, we have investigated whether Tz and CA have cooperative effects on cell survival of ERBB2 overexpressing (ERBB2+ cells and whether CA might restore Tz sensitivity in Tz-resistant cells. Methods We have studied BC cell migration and survival upon CA and Tz treatment. In particular, migration ability was assessed by transwell assay while cell survival was assessed by MTT assay. In addition, we have performed cell cycle and apoptosis analysis by high-resolution DNA flow cytometry and annexin-V, resazurin and sytox blue staining by flow cytometry, respectively. The expression of proteins involved in cell cycle progression, ERBB2 signaling pathway, and autophagy was evaluated by immunoblot and immunofluorescence analysis. Cellular structures relevant to the endosome/lysosome and autophagy pathways have been studied by immunofluorescence and transmission electron microscopy. Results We report that, in ERBB2+ BC cells, CA reversibly enhances Tz inhibition of cell survival, cooperatively inhibits cell migration and induces cell cycle arrest in G0/G1. These events are accompanied by ERBB2 down-regulation, deregulation of the PI3K/AKT/mTOR signaling pathway and up-regulation of both CDKN1A/p21WAF1 and CDKN1B/p27KIP1. Furthermore, we have demonstrated that CA impairs late autophagy and causes derangement of the lysosomal compartment as shown by up-regulation of SQSTM1/p62 and ultrastructural analysis. Accordingly, we have found that CA restores, at least in part, sensitivity to Tz in SKBR-3 Tz-resistant cell line

  4. ERBB2 mutation is associated with a worse prognosis in patients with CDH1 altered invasive lobular cancer of the breast.

    Science.gov (United States)

    Ping, Zheng; Siegal, Gene P; Harada, Shuko; Eltoum, Isam-Eldin; Youssef, Mariam; Shen, Tiansheng; He, Jianbo; Huang, Yingjie; Chen, Dongquan; Li, Yiping; Bland, Kirby I; Chang, Helena R; Shen, Dejun

    2016-12-06

    E-cadherin (CDH1) is a glycoprotein that mediates adhesion between epithelial cells and also suppresses cancer invasion. Mutation or deletion of the CDH1 gene has been reported in 30-60% cases of invasive lobular carcinoma (ILC). However, little is known about genomic differences between ILC with and without a CDH1 alteration. Therefore, we analyzed whole genome sequencing data of 169 ILC cases from The Cancer Genome Atlas (TCGA) to address this deficiency. Our study shows that CDH1 gene was altered in 59.2% (100/169) of ILC. No significant difference was identified between CDH1-altered and -unaltered ILC cases for any of the examined demographic, clinical or pathologic characteristics, including histologic grade, tumor stage, lymph node metastases, or ER/PR/HER2 states. Seven recurrent mutations (PTEN, MUC16, ERBB2, FAT4, PCDHGA2, HERC1 and FLNC) and four chromosomal changes with recurrent copy number variation (CNV) (11q13, 17q12-21, 8p11 and 8q11) were found in ILC, which correlated with a positive or negative CDH1 alteration status, respectively. The prevalence of the most common breast cancer driver abnormalities including TP53 and PIK3CA mutations and MYC and ERBB2 amplifications showed no difference between the two groups. However, CDH1-altered ILC with an ERBB2 mutation shows a significantly worse prognosis compared to its counterparts without such a mutation. Our study suggests that CDH1-altered ILC patients with ERBB2 mutations may represent an actionable group of patients who could benefit from targeted breast cancer therapy.

  5. RhNRG-1β Protects the Myocardium against Irradiation-Induced Damage via the ErbB2-ERK-SIRT1 Signaling Pathway.

    Directory of Open Access Journals (Sweden)

    Anxin Gu

    Full Text Available Radiation-induced heart disease (RIHD, which is a serious side effect of the radiotherapy applied for various tumors due to the inevitable irradiation of the heart, cannot be treated effectively using current clinical therapies. Here, we demonstrated that rhNRG-1β, an epidermal growth factor (EGF-like protein, protects myocardium tissue against irradiation-induced damage and preserves cardiac function. rhNRG-1β effectively ameliorated irradiation-induced myocardial nuclear damage in both cultured adult rat-derived cardiomyocytes and rat myocardium tissue via NRG/ErbB2 signaling. By activating ErbB2, rhNRG-1β maintained mitochondrial integrity, ATP production, respiratory chain function and the Krebs cycle status in irradiated cardiomyocytes. Moreover, the protection of irradiated cardiomyocytes and myocardium tissue by rhNRG-1β was at least partly mediated by the activation of the ErbB2-ERK-SIRT1 signaling pathway. Long-term observations further showed that rhNRG-1β administered in the peri-irradiation period exerts continuous protective effects on cardiac pump function, the myocardial energy metabolism, cardiomyocyte volume and interstitial fibrosis in the rats receiving radiation via NRG/ErbB2 signaling. Our findings indicate that rhNRG-1β can protect the myocardium against irradiation-induced damage and preserve cardiac function via the ErbB2-ERK-SIRT1 signaling pathway.

  6. Continuous requirement of ErbB2 kinase activity for loss of cell polarity and lumen formation in a novel ErbB2/Neu-driven murine cell line model of metastatic breast cancer

    Directory of Open Access Journals (Sweden)

    Cesar F Ortega-Cava

    2011-01-01

    Full Text Available Background: Well over a quarter of human breast cancers are ErbB2-driven and constitute a distinct subtype with substantially poorer prognosis. Yet, there are substantial gaps in our understanding of how ErbB2 tyrosine kinase activity unleashes a coordinated program of cellular and extracellular alterations that culminate in aggressive breast cancers. Cellular models that exhibit ErbB2 kinase dependency and can induce metastatic breast cancer in immune competent hosts are likely to help bridge this gap. Materials and Methods: Here, we derived and characterized a cell line model obtained from a transgenic ErbB2/Neu-driven mouse mammary adenocarcinoma. Results: The MPPS1 cell line produces metastatic breast cancers when implanted in the mammary fat pads of immune-compromised as well as syngeneic immune-competent hosts. MPPS1 cells maintain high ErbB2 overexpression when propagated in DFCI-1 or related media, and their growth is ErbB2-dependent, as demonstrated by concentration-dependent inhibition of proliferation with the ErbB kinase inhibitor Lapatinib. When grown in 3-dimensional (3-D culture on Matrigel, MPPS1 cells predominantly form large irregular cystic and solid structures. Remarkably, low concentrations of Lapatinib led to a switch to regular acinar growth on Matrigel. Immunofluorescence staining of control vs. Lapatinib-treated acini for markers of epithelial polarity revealed that inhibition of ErbB2 signaling led to rapid resumption of normal mammary epithelium-like cell polarity. Conclusions: The strict dependence of the MPPS1 cell system on ErbB2 signals for proliferation and alterations in cell polarity should allow its use to dissect ErbB2 kinase-dependent signaling pathways that promote loss of cell polarity, a key component of the epithelial mesenchymal transition and aggressiveness of ErbB2-driven breast cancers.

  7. ERalpha and ErbB-2 Cross-talk in Mammary Tumorigenesis and Metastasis

    National Research Council Canada - National Science Library

    Muller, William J

    2006-01-01

    .... The results of these analyses did not show any influence of the expression of an activated form of ER on ErbB-2 induced mammary tumor formation. No evidence of c- Src or Akt-1 acting synergistically with ER to accelerate mammary tumor progression has been observed either.

  8. Detection of erbB2 copy number variations in plasma of patients with esophageal carcinoma

    International Nuclear Information System (INIS)

    Andolfo, Immacolata; Orditura, Michele; Ciardiello, Fortunato; De Vita, Fernando; Zollo, Massimo; Petrosino, Giuseppe; Vecchione, Loredana; De Antonellis, Pasqualino; Capasso, Mario; Montanaro, Donatella; Gemei, Marica; Troncone, Giancarlo; Iolascon, Achille

    2011-01-01

    Mortality is high in patients with esophageal carcinoma as tumors are rarely detected before the disease has progressed to an advanced stage. Here, we sought to isolate cell-free DNA released into the plasma of patients with esophageal carcinoma, to analyze copy number variations of marker genes in the search for early detection of tumor progression. Plasma of 41 patients with esophageal carcinoma was prospectively collected before tumor resection and chemotherapy. Our dataset resulted heterogeneous for clinical data, resembling the characteristics of the tumor. DNA from the plasma was extracted to analyze copy number variations of the erbB2 gene using real-time PCR assays. The real-time PCR assays for erbB2 gene showed significant (P = 0.001) copy number variations in the plasma of patients with esophageal carcinoma, as compared to healthy controls with high sensitivity (80%) and specificity (95%). These variations in erbB2 were negatively correlated to the progression free survival of these patients (P = 0.03), and revealed a further risk category stratification of patients with low VEGF expression levels. The copy number variation of erbB2 gene from plasma can be used as prognostic marker for early detection of patients at risk of worse clinical outcome in esophageal cancer

  9. A novel mutation in the tyrosine kinase domain of ERBB2 in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Bekaii-Saab, Tanios; Williams, Nita; Plass, Christoph; Calero, Miguel Villalona; Eng, Charis

    2006-01-01

    Several studies showed that gain-of-function somatic mutations affecting the catalytic domain of EGFR in non-small cell lung carcinomas were associated with response to gefitinib and erlotinib, both EGFR-tyrosine kinase inhibitors. In addition, 4% of non-small cell lung carcinomas were shown to have ERBB2 mutations in the kinase domain. In our study, we sought to determine if similar respective gain-of-function EGFR and ERBB2 mutations were present in hepatoma and/or biliary cancers. We extracted genomic DNA from 40 hepatoma (18) and biliary cancers (22) samples, and 44 adenocarcinomas of the lung, this latter as a positive control for mutation detection. We subjected those samples to PCR-based semi-automated double stranded nucleotide sequencing targeting exons 18–21 of EGFR and ERBB2. All samples were tested against matched normal DNA. We found 11% of hepatoma, but no biliary cancers, harbored a novel ERBB2 H878Y mutation in the activating domain. These newly described mutations may play a role in predicting response to EGFR-targeted therapy in hepatoma and their role should be explored in prospective studies

  10. Negative transcriptional control of ERBB2 gene by MBP-1 and HDAC1: diagnostic implications in breast cancer

    International Nuclear Information System (INIS)

    Contino, Flavia; Mazzarella, Claudia; Ferro, Arianna; Lo Presti, Mariavera; Roz, Elena; Lupo, Carmelo; Perconti, Giovanni; Giallongo, Agata; Feo, Salvatore

    2013-01-01

    The human ERBB2 gene is frequently amplified in breast tumors, and its high expression is associated with poor prognosis. We previously reported a significant inverse correlation between Myc promoter-binding protein-1 (MBP-1) and ERBB2 expression in primary breast invasive ductal carcinoma (IDC). MBP-1 is a transcriptional repressor of the c-MYC gene that acts by binding to the P2 promoter; only one other direct target of MBP-1, the COX2 gene, has been identified so far. To gain new insights into the functional relationship linking MBP-1 and ERBB2 in breast cancer, we have investigated the effects of MBP-1 expression on endogenous ERBB2 transcript and protein levels, as well as on transcription promoter activity, by transient-transfection of SKBr3 cells. Reporter gene and chromatin immunoprecipitation assays were used to dissect the ERBB2 promoter and identify functional MBP-1 target sequences. We also investigated the relative expression of MBP-1 and HDAC1 in IDC and normal breast tissues by immunoblot analysis and immunohistochemistry. Transfection experiments and chromatin immunoprecipitation assays in SKBr3 cells indicated that MBP-1 negatively regulates the ERBB2 gene by binding to a genomic region between nucleotide −514 and −262 of the proximal promoter; consistent with this, a concomitant recruitment of HDAC1 and loss of acetylated histone H4 was observed. In addition, we found high expression of MBP-1 and HDAC1 in normal tissues and a statistically significant inverse correlation with ErbB2 expression in the paired tumor samples. Altogether, our in vitro and in vivo data indicate that the ERBB2 gene is a novel MBP-1 target, and immunohistochemistry analysis of primary tumors suggests that the concomitant high expression of MBP-1 and HDAC1 may be considered a diagnostic marker of cancer progression for breast IDC

  11. Integrin α3β1-CD151 complex regulates dimerization of ErbB2 via RhoA.

    Science.gov (United States)

    Novitskaya, V; Romanska, H; Kordek, R; Potemski, P; Kusińska, R; Parsons, M; Odintsova, E; Berditchevski, F

    2014-05-22

    Integrin α3β1 regulates adhesive interactions of cells with laminins and have a critical role in adhesion-dependent cellular responses. Here, we examined the role of α3β1-integrin in ErbB2-dependent proliferation of breast cancer cells in three-dimensional laminin-rich extracellular matrix (3D lr-ECM). Depletion of α3β1 in ErbB2-overexpressing breast cancer cells suppressed growth and restore cell polarity in 3D lr-ECM. The phenotype of α3β1-depleted cells was reproduced upon depletion of tetraspanin CD151 and mirrored that of the cells treated with Herceptin, an established ErbB2 antagonist. Breast cancer cells expressing the α3β1-CD151 complex have higher steady-state phosphorylation of ErbB2 and show enhanced dimerization of the protein when compared with α3β1-/CD151-depleted cells. Furthermore, Herceptin-dependent dephosphorylation of ErbB2 was only observed in α3β1-CD151-expressing cells. Importantly, the inhibitory activity of Herceptin was more pronounced when cells expressed both α3β1 and CD151. We also found that the level of active RhoA was increased in α3β1- and CD151-depleted cells and that Rho controls dimerization of ErbB2. Expression of α3β1 alone did not have significant prognostic value in patients with invasive ductal carcinoma of the breast. However, expression of α3β1 in combination with CD151 represented a more stringent indicator of poor survival than CD151 alone. Taken together, these results demonstrate that the α3β1-CD151 complex has a critical regulatory role in ErbB2-dependent signalling and thereby may be involved in breast cancer progression.

  12. Schwann cell-specific deletion of the endosomal PI 3-kinase Vps34 leads to delayed radial sorting of axons, arrested myelination, and abnormal ErbB2-ErbB3 tyrosine kinase signaling.

    Science.gov (United States)

    Logan, Anne M; Mammel, Anna E; Robinson, Danielle C; Chin, Andrea L; Condon, Alec F; Robinson, Fred L

    2017-09-01

    The PI 3-kinase Vps34 (Pik3c3) synthesizes phosphatidylinositol 3-phosphate (PI3P), a lipid critical for both endosomal membrane traffic and macroautophagy. Human genetics have implicated PI3P dysregulation, and endosomal trafficking in general, as a recurring cause of demyelinating Charcot-Marie-Tooth (CMT) peripheral neuropathy. Here, we investigated the role of Vps34, and PI3P, in mouse Schwann cells by selectively deleting Vps34 in this cell type. Vps34-Schwann cell knockout (Vps34 SCKO ) mice show severe hypomyelination in peripheral nerves. Vps34 -/- Schwann cells interact abnormally with axons, and there is a delay in radial sorting, a process by which large axons are selected for myelination. Upon reaching the promyelinating stage, Vps34 -/- Schwann cells are significantly impaired in the elaboration of myelin. Nerves from Vps34 SCKO mice contain elevated levels of the LC3 and p62 proteins, indicating impaired autophagy. However, in the light of recent demonstrations that autophagy is dispensable for myelination, it is unlikely that hypomyelination in Vps34 SCKO mice is caused by impaired autophagy. Endosomal trafficking is also disturbed in Vps34 -/- Schwann cells. We investigated the activation of the ErbB2/3 receptor tyrosine kinases in Vps34 SCKO nerves, as these proteins, which play essential roles in Schwann cell myelination, are known to traffic through endosomes. In Vps34 SCKO nerves, ErbB3 was hyperphosphorylated on a tyrosine known to be phosphorylated in response to neuregulin 1 exposure. ErbB2 protein levels were also decreased during myelination. Our findings suggest that the loss of Vps34 alters the trafficking of ErbB2/3 through endosomes. Abnormal ErbB2/3 signaling to downstream targets may contribute to the hypomyelination observed in Vps34 SCKO mice. © 2017 Wiley Periodicals, Inc.

  13. Pertuzumab Increases 17-AAG-Induced Degradation of ErbB2, and This Effect Is Further Increased by Combining Pertuzumab with Trastuzumab

    Science.gov (United States)

    Hughes, Juliana Bentes; Rødland, Marianne Skeie; Hasmann, Max; Madshus, Inger Helene; Stang, Espen

    2012-01-01

    ErbB2 is an important oncogenic protein involved in carcinogenesis of, among others, breast, gastric, and ovarian carcinoma. Over-expression of ErbB2 is found in almost 20% of breast cancers, and this results in proliferative and anti-apoptotic signalling. ErbB2 is therefore an important treatment target. Antibodies recognizing full-length ErbB2 are clinically established, and drugs targeting the ErbB2 stabilizing heat shock protein 90 (Hsp90) are under clinical evaluation. We have investigated effects of the ErbB2-binding antibodies trastuzumab and pertuzumab alone and in combination, as well as the effect of the antibodies in combination with the Hsp90 inhibitor 17-AAG. Our results confirm the notion that combination of different ErbB2-binding antibodies more efficiently down-regulates ErbB2 than does one antibody in isolation. Additionally, our data demonstrate that ErbB2 is most efficiently down-regulated upon incubation with anti-ErbB2 antibodies in combination with Hsp90 inhibitors. The combination of anti-ErbB2 antibodies, and especially the combination of antibodies with 17-AAG, did also increase the inhibition of Akt activation of either agent, which could suggest an anti-proliferative effect. In such case, combining these agents could be beneficial in treatment of tumors not responding to trastuzumab only. PMID:24281706

  14. Pertuzumab Increases 17-AAG-Induced Degradation of ErbB2, and This Effect Is Further Increased by Combining Pertuzumab with Trastuzumab

    Directory of Open Access Journals (Sweden)

    Juliana Bentes Hughes

    2012-06-01

    Full Text Available ErbB2 is an important oncogenic protein involved in carcinogenesis of, among others, breast, gastric, and ovarian carcinoma. Over-expression of ErbB2 is found in almost 20% of breast cancers, and this results in proliferative and anti-apoptotic signalling. ErbB2 is therefore an important treatment target. Antibodies recognizing full-length ErbB2 are clinically established, and drugs targeting the ErbB2 stabilizing heat shock protein 90 (Hsp90 are under clinical evaluation. We have investigated effects of the ErbB2-binding antibodies trastuzumab and pertuzumab alone and in combination, as well as the effect of the antibodies in combination with the Hsp90 inhibitor 17-AAG. Our results confirm the notion that combination of different ErbB2-binding antibodies more efficiently down-regulates ErbB2 than does one antibody in isolation. Additionally, our data demonstrate that ErbB2 is most efficiently down-regulated upon incubation with anti-ErbB2 antibodies in combination with Hsp90 inhibitors. The combination of anti-ErbB2 antibodies, and especially the combination of antibodies with 17-AAG, did also increase the inhibition of Akt activation of either agent, which could suggest an anti-proliferative effect. In such case, combining these agents could be beneficial in treatment of tumors not responding to trastuzumab only.

  15. p53 and erbB-2 Are Not Associated in Matched Cases of Primary and Metastatic Ovarian Carcinomas

    Directory of Open Access Journals (Sweden)

    Cristina Rodríguez-Burford

    2003-01-01

    Full Text Available Ovarian cancer has a high mortality rate largely due to the limited number of ovarian carcinomas detected at an early stage. Understanding the molecular changes occurring during the progression of ovarian carcinoma would aid in the development of therapies that may inhibit or target metastasis. Primary and metastatic lesions from 54 and 40 patients with advanced ovarian carcinoma, respectively (including matched primary and metastatic lesions from 30 patients were evaluated for nuclear accumulation of p53 (clone BP53-12-1 and cytoplasmic and membranous immunostaining of p185 erbB-2 (clone 3B5 by immunohistochemistry. No differences in the immunostaining of p53 and p185erbB-2 (cytoplasm or membrane were observed between primary and metastatic lesions of the matched cases. Similarly, no differences in the proportion of positive cases of p53 between primary and metastatic lesions of the matched cases was observed. Thus, novel therapies that target p53 or p185erbB-2 can utilize specimens from either primary or metastatic lesions to characterize these targets prior to therapy. Spearman correlations between p53 and p185erbB-2 (cytoplasm or membrane immunohistochemistry scores were insignificant for the matched cases, all primary lesions, and all metastatic lesions. Also, no significant associations occurred between nuclear accumulation of p53 (positive versus negative and phenotypic expression of p185erbB-2 (cytoplasm or membrane immunostaining scores for the matched cases, all primary lesions, and all metastatic lesions. Thus, the nuclear accumulation of p53 and immunostaining of p185erbB-2 in the cytoplasm or on the cellular membranes are independent.

  16. Internal Quality Assurance Program for ERBB2 (HER2) Testing Improves the Selection of Breast Cancer Patients for Treatment with Trastuzumab.

    Science.gov (United States)

    Martin, Vittoria; Camponovo, Antonella; Ghisletta, Morena; Bongiovanni, Massimo; Mazzucchelli, Luca

    2012-01-01

    International guidelines for ERBB2 (HER2) testing procedures in breast cancer patients highlight the importance of external quality control. In contrast, internal quality assurance programs have been poorly defined, and their clinical significance has not yet been investigated. We developed a quality assurance scheme by performing HER2 FISH on 724 patients randomly selected out of 1996 patients with breast cancer presenting at our institute. We collected samples monthly for tissue microarray analysis and correlated HER2 gene status with IHC scores. The concordance was excellent (κ = 0.92, P internal assurance program improves patient selection and may lead to the definition of in-house tailored diagnostic algorithms different from those proposed in international guidelines.

  17. ErbB2-Driven Breast Cancer Cell Invasion Depends on a Complex Signaling Network Activating Myeloid Zinc Finger-1-Dependent Cathepsin B Expression

    DEFF Research Database (Denmark)

    Rafn, Bo; Nielsen, Christian Thomas Friberg; Andersen, Sofie Hagel

    2012-01-01

    signaling network activates the transcription of cathepsin B gene (CTSB) via myeloid zinc finger-1 transcription factor that binds to an ErbB2-responsive enhancer element in the first intron of CTSB. This work provides a model system for ErbB2-induced breast cancer cell invasiveness, reveals a signaling...

  18. Salivary Levels of ErbB2 and CEA in Oral Squamous Cell Carcinoma Patients.

    Science.gov (United States)

    Honarmand, Marieh Honarmand; Farhad-Mollashahi, Leila; Nakhaee, Alireza; Nehi, Masoume

    2016-01-01

    Oral squamous cell carcinoma (OSCC) is one of the ten most common causes of cancer death worldwide. Assessment of molecular changes can help detect and control lesions. The aim of this study was evaluation of salivary levels of ErbB2 and CEA in OSCC patients. In this case-control study, 27 OSCC patients and 26 healthy controls participated. After obtaining consent and filling out a questionnaire, unstimulated saliva samples were collected from people in the morning for measurement of the two markers using ELISA. Data were analyzed using Mann Whitney U test in SPSS 19 software with Ptumor marker in patients with OSCC must still be regarded as controversial and needs further studies to clarify any significance for early detection or screening. In contrast the salivary level of CEA may find application for early detection of patients.

  19. A novel mouse monoclonal antibody targeting ErbB2 suppresses breast cancer growth

    Energy Technology Data Exchange (ETDEWEB)

    Kawa, Seiji [Division of Oncology, Institute of Medical Science, University of Tokyo, Shirokanedai 4-6-1, Minato-ku, Tokyo 108-8639 (Japan); Matsushita, Hirohisa; Ohbayashi, Hirokazu [Department of Research and Development, Nichirei Biosciences Inc., Tokyo 104-8402 (Japan); Semba, Kentaro [Department of Life Science and Medical Bio-Science, School of Science and Engineering, Waseda University, Tokyo 169-8555 (Japan); Yamamoto, Tadashi, E-mail: tyamamot@ims.u-tokyo.ac.jp [Division of Oncology, Institute of Medical Science, University of Tokyo, Shirokanedai 4-6-1, Minato-ku, Tokyo 108-8639 (Japan)

    2009-07-03

    Overexpression of ErbB2 in breast cancer is associated with increased recurrence and worse prognosis. Accumulating evidences suggest that molecular targeted therapy is a promising anticancer strategy. In this study, we produced a novel anti-ErbB2 monoclonal antibody, 6G10, that recognized an epitope distinct from the trastuzumab binding site. 6G10 induced aggregation of BT474 breast cancer cells and inhibited proliferation of various breast cancer cell lines including BT474. A growth inhibition assay showed that 6G10 had EC{sub 50} values comparable to trastuzumab, indicating that the drugs have a similar level of potency. Furthermore, intraperitoneal administration of 6G10 completely inhibited the growth of xenografted tumors derived from BT474 and SK-BR-3 cells. These data suggested that 6G10 has great therapeutic potential and could be administered to patients alternatively, or synergistically, with trastuzumab.

  20. Copy Number Analysis of the DLX4 and ERBB2 Genes in South African Breast Cancer Patients.

    Science.gov (United States)

    Langa, Bridget C; Oliveira, Márcia M C; Pereira, Silma R F; Lupicki, Kamil; Marian, Catalin; Govender, Dhirendra; Panieri, Eugenio; Hiss, Donavon; Cavalli, Iglenir J; Abdul-Rasool, Sahar; Cavalli, Luciane R

    2015-01-01

    Breast cancer is one of the main causes of cancer death among South African women. Although several risk factors can be attributed to the observed high mortality rate, the biology of the tumors is not extensively investigated. Copy number gain of the DLX4 homeobox gene has been observed in breast cancer in association with poor prognosis and specific racial groups. Therefore, we aimed to assess the copy number and prognostic role of DLX4 in breast cancer from South African patients. Due to the co-location of ERBB2 and DLX4 in the 17q21 region, its copy number was also evaluated. Our results in the analysis of 66 cases demonstrated copy number gains of DLX4 and ERBB2 in 24.1 and 29.7% of the cases, respectively. Linear regression analysis showed no dependency between the copy number alterations in these genes. Although not significant, patients with DLX4 and ERBB2 gains presented a higher frequency of advanced-grade tumors. In addition, copy number alterations of these genes were not significantly differently observed in the 3 main racial groups of the Western Cape population: Colored, White, and Black. These findings indicate that gains of DLX4 and ERBB2 occur in South African breast cancer patients irrespectively of their race and factors known to influence prognosis. © 2015 S. Karger AG, Basel.

  1. A peptide conjugate of vitamin E succinate targets breast cancer cells with high erbB2 expression

    Czech Academy of Sciences Publication Activity Database

    Wang, X. F.; Birringer, M.; Dong, L.F.; Vepřek, Pavel; Low, P.; Swettenham, E.; Stantic, M.; Yuan, L. H.; Zobalová, Renata; Wu, K.; Ledvina, Miroslav; Ralph, S.J.; Neužil, Jiří

    2007-01-01

    Roč. 67, č. 7 (2007), s. 3337-3344 ISSN 0008-5472 R&D Projects: GA MZe QF3115 Institutional research plan: CEZ:AV0Z40550506; CEZ:AV0Z50520514 Keywords : vitamin e E * erbB2 * breast cancer Subject RIV: CC - Organic Chemistry Impact factor: 7.672, year: 2007

  2. A moderate elevation of circulating levels of IGF-I does not alter ErbB2 induced mammary tumorigenesis

    Directory of Open Access Journals (Sweden)

    Brown Powel H

    2011-08-01

    Full Text Available Abstract Background Epidemiological evidence suggests that moderately elevated levels of circulating insulin-like growth factor-I (IGF-I are associated with increased risk of breast cancer in women. How circulating IGF-I may promote breast cancer incidence is unknown, however, increased IGF-I signaling is linked to trastuzumab resistance in ErbB2 positive breast cancer. Few models have directly examined the effect of moderately high levels of circulating IGF-I on breast cancer initiation and progression. The purpose of this study was to assess the ability of circulating IGF-I to independently initiate mammary tumorigenesis and/or accelerate the progression of ErbB2 mediated mammary tumor growth. Methods We crossed heterozygous TTR-IGF-I mice with heterozygous MMTV-ErbB2 mice to generate 4 different genotypes: TTR-IGF-I/MMTV-ErbB2 (bigenic, TTR-IGF-I only, MMTV-ErbB2 only, and wild type (wt. Virgin females were palpated twice a week and harvested when tumors reached 1000 mm3. For study of normal development, blood and tissue were harvested at 4, 6 and 9 weeks of age in TTR-IGF-I and wt mice. Results TTR-IGF-I and TTR-IGF-I/ErbB2 bigenic mice showed a moderate 35% increase in circulating total IGF-I compared to ErbB2 and wt control mice. Elevation of circulating IGF-I had no effect upon pubertal mammary gland development. The transgenic increase in IGF-I alone wasn't sufficient to initiate mammary tumorigenesis. Elevated circulating IGF-I had no effect upon ErbB2-induced mammary tumorigenesis or metastasis, with median time to tumor formation being 30 wks and 33 wks in TTR-IGF-I/ErbB2 bigenic and ErbB2 mice respectively (p = 0.65. Levels of IGF-I in lysates from ErbB2/TTR-IGF-I tumors compared to ErbB2 was elevated in a similar manner to the circulating IGF-I, however, there was no effect on the rate of tumor growth (p = 0.23. There were no morphological differences in tumor type (solid adenocarcinomas between bigenic and ErbB2 mammary glands. Conclusion Using the first transgenic animal model to elevate circulating levels of IGF-I to those comparable to women at increased risk of breast cancer, we showed that moderately high levels of systemic IGF-I have no effect on pubertal mammary gland development, initiating mammary tumorigenesis or promoting ErbB2 driven mammary carcinogenesis. Our work suggests that ErbB2-induced mammary tumorigenesis is independent of the normal variation in circulating levels of IGF-I.

  3. Heregulin-β1-induced GPR30 upregulation promotes the migration and invasion potential of SkBr3 breast cancer cells via ErbB2/ErbB3-MAPK/ERK pathway.

    Science.gov (United States)

    Ruan, Shu-Qin; Wang, Zhan-Huai; Wang, Shan-Wei; Fu, Zhi-Xuan; Xu, Kan-Lun; Li, Dong-Bo; Zhang, Su-Zhan

    2012-04-06

    Estrogen receptor (ER)-negative breast cancer cells are probably more aggressive with larger metastatic potential than ER-positive cells. Loss of ER in recurrent breast cancer is associated with poor response to endocrine therapy. G protein-coupled receptor 30 (GPR30) is expressed in half of ER-negative breast cancers. Tumor cell-derived heregulin-β1 (HRG-β1) is also found mainly in ER-negative cancer. In SkBr3 breast cancer cells that lack ER but express GPR30, HRG-β1 upregulates mRNA and protein levels of GPR30 by promoting ErbB2-ErbB3 heterodimerization and activating the downstream MAPK-ERK signaling pathway. Moreover, GPR30 boosts HRG-β1-induced migration and invasion of SkBr3 cells after combinative treatment with E2, 4-hydroxy-tamoxifen or the specific GPR30 agonist G-1, which are blocked by the specific GPR30 antagonist G-15 or the transfection with the small interfering RNA for GPR30. The ErbB2 inhibitor AG825 and the MEK1/2 inhibitor U0126 also partly inhibit the enhanced migration and invasion. Therefore, HRG-β1-induced migration and invasion partly depend on the upregulation of GPR30 expression through activation of the ErbB2-ERK pathway in SkBr3 cells. The results of this study indicate that the crosstalk between GPR30 and HRGs signaling is important for endocrine therapy resistance and may provide a new therapeutic way to treat breast cancer. Copyright © 2012 Elsevier Inc. All rights reserved.

  4. Activation of EGFR/ERBB2 via pathways involving ERK1/2, P38 MAPK, AKT and FOXO enhances recovery of diabetic hearts from ischemia-reperfusion injury.

    Directory of Open Access Journals (Sweden)

    Saghir Akhtar

    Full Text Available This study characterized the effects of diabetes and/or ischemia on epidermal growth factor receptor, EGFR, and/or erbB2 signaling pathways on cardiac function. Isolated heart perfusion model of global ischemia was used to study the effect of chronic inhibition or acute activation of EGFR/erbB2 signaling on cardiac function in a rat model of type-1 diabetes. Induction of diabetes with streptozotocin impaired recovery of cardiac function (cardiac contractility and hemodynamics following 40 minutes of global ischemia in isolated hearts. Chronic treatment with AG825 or AG1478, selective inhibitors of erbB2 and EGFR respectively, did not affect hyperglycemia but led to an exacerbation whereas acute administration of the EGFR ligand, epidermal growth factor (EGF, led to an improvement in cardiac recovery in diabetic hearts. Diabetes led to attenuated dimerization and phosphorylation of cardiac erbB2 and EGFR receptors that was associated with reduced signaling via extracellular-signal-regulated kinase 1/2 (ERK1/2, p38 mitogen activated protein (MAP kinase and AKT (protein kinase B. Ischemia was also associated with reduced cardiac signaling via these molecules whereas EGF-treatment opposed diabetes and/or ischemia induced changes in ERK1/2, p38 MAP kinase, and AKT-FOXO signaling. Losartan treatment improved cardiac function in diabetes but also impaired EGFR phosphorylation in diabetic heart. Co-administration of EGF rescued Losartan-mediated reduction in EGFR phosphorylation and significantly improved cardiac recovery more than with either agent alone. EGFR/erbB2 signaling is an important cardiac survival pathway whose activation, particularly in diabetes, ischemia or following treatment with drugs that inhibit this cascade, significantly improves cardiac function. These findings may have clinical relevance particularly in the treatment of diabetes-induced cardiac dysfunction.

  5. The nonsteroidal anti-inflammatory drug tolfenamic acid inhibits BT474 and SKBR3 breast cancer cell and tumor growth by repressing erbB2 expression.

    Science.gov (United States)

    Liu, Xinyi; Abdelrahim, Maen; Abudayyeh, Ala; Lei, Ping; Safe, Stephen

    2009-05-01

    Tolfenamic acid (TA) is a nonsteroidal anti-inflammatory drug that inhibits pancreatic cancer cell and tumor growth through decreasing expression of specificity protein (Sp) transcription factors. TA also inhibits growth of erbB2-overexpressing BT474 and SKBR3 breast cancer cells; however, in contrast to pancreatic cancer cells, TA induced down-regulation of erbB2 but not Sp proteins. TA-induced erbB2 down-regulation was accompanied by decreased erbB2-dependent kinase activities, induction of p27, and decreased expression of cyclin D1. TA also decreased erbB2 mRNA expression and promoter activity, and this was due to decreased mRNA stability in BT474 cells and, in both cell lines, TA decreased expression of the YY1 and AP-2 transcription factors required for basal erbB2 expression. In addition, TA also inhibited tumor growth in athymic nude mice in which BT474 cells were injected into the mammary fat pad. TA represents a novel and promising new anticancer drug that targets erbB2 by decreasing transcription of this oncogene.

  6. Disruption of laminin-integrin-CD151-focal adhesion kinase axis sensitizes breast cancer cells to ErbB2 antagonists.

    Science.gov (United States)

    Yang, Xiuwei H; Flores, Ludmila M; Li, Qinglin; Zhou, Pengcheng; Xu, Fenghui; Krop, Ian E; Hemler, Martin E

    2010-03-15

    Resistance to anti-ErbB2 agents is a significant problem in the treatment of human ErbB2+ breast cancers. We show here that adhesion of human ErbB2+ breast cancer cells to basement membrane laminin-5 provides substantial resistance to trastuzumab and lapatinib, agents that respectively target the extracellular and kinase domains of ErbB2. Knockdown of laminin-binding integrins (alpha6beta4, alpha3beta1) or associated tetraspanin protein CD151 reversed laminin-5 resistance and sensitized ErbB2+ cells to trastuzumab and lapatinib. CD151 knockdown, together with trastuzumab treatment, inhibited ErbB2 activation and downstream signaling through Akt, Erk1/2, and focal adhesion kinase (FAK). Hence, ErbB2 function in mammary tumor cells is promoted by integrin-mediated adhesion to laminin-5, with strong support by CD151, leading to signaling through FAK. Consequently, removal or inhibition of any of these components (laminin-5, integrin, CD151, FAK) markedly sensitizes cells to anti-ErbB2 agents. These new insights should be useful when devising strategies for overcoming drug resistance in ErbB2+ cancers.

  7. Transcriptome analysis of basal and luminal tumor-initiating cells in ErbB2-driven breast cancer

    Directory of Open Access Journals (Sweden)

    Nicholas Borcherding

    2015-06-01

    Full Text Available Breast cancer is the leading cause of cancer-related mortality for females worldwide [1]. Improving early screening strategies and understanding the events that lead to tumor initiation have led to demonstrable improvements in clinical outcome. Our previous work revealed a variance in the tumorigenic capacity between different mammary epithelial cell populations in an MMTV-ErbB2 mouse model. In order to greater understand how different mammary epithelial cells influence the tumorigenic capacity in ErbB2-induced breast cancer, we transplanted different cell populations from pre-neoplastic MMTV-ErbB2 female mice into recipient mice for tumorigenic study. We found that different mammary epithelial cells bear different tumorigenic potentials even when induced by the same ErbB2 proto-oncogene. To understand the difference in tumors formed from different epithelial cells, we performed gene expression profiling using these tumors (GSE64487. Several genes were further validated using real-time reverse transcription polymerase chain reaction (RT-PCR. Here we provide further details on the experimental methods and microarray analysis. This data provides a resource to further understanding how different mammary cell populations can initiate ErbB2-driven tumors and the role of these cell populations as putative tumor-initiating cells (TICs.

  8. Detection of survivin, carcinoembryonic antigen and ErbB2 level in oral squamous cell carcinoma patients.

    Science.gov (United States)

    Li, Shu-Xia; Yang, Yan-Qi; Jin, Li-Jian; Cai, Zhi-Gang; Sun, Zheng

    2016-01-01

    The aim of this study was to detect the survivin, carcinoembryonic antigen (CEA) and ErbB2 in the saliva, serum and local tumor-exfoliated cells of oral squamous cell carcinoma (OSCC) patients, for providing reliable tumor markers for the early detection of oral malignant cancer. The saliva, serum, and local tumor-exfoliated cell samples of 26 OSCC patients without chemotherapy and 10 non-cancer patients were collected in Department of Oral and Maxillofacial Surgery, School of Stomatology, Peking University. The contents of survivin, CEA and ErbB2 using were detected usingenzyme-linked immunosorbent assay. The survivin and CEA levels in saliva and local tumor-exfoliated cells of OSCC patients were significantly higher than those in the non-cancer patients (P < 0.05), but there was no significant difference in the content of the above factors in the serum sample between two groups. There was no significant difference in the ErbB2 content in the saliva, serum or local tumor-exfoliated cells between two groups. Survivin and CEA levels are significantly increased in the saliva and local tumor-exfoliated cells in OSCC patients, and they can be used as reliable markers for the early detection of oral malignant cancer.

  9. Common ERBB2 polymorphisms and risk of breast cancer in a white British population: a case–control study

    International Nuclear Information System (INIS)

    Benusiglio, Patrick R; Ponder, Bruce AJ; Lesueur, Fabienne; Luccarini, Craig; Conroy, Donald M; Shah, Mitul; Easton, Douglas F; Day, Nick E; Dunning, Alison M; Pharoah, Paul D

    2005-01-01

    About two-thirds of the excess familial risk associated with breast cancer is still unaccounted for and may be explained by multiple weakly predisposing alleles. A gene thought to be involved in low-level predisposition to the disease is ERBB2 (HER2). This gene is involved in cell division, differentiation, and apoptosis and is frequently amplified in breast tumours. Its amplification correlates with poor prognosis. Moreover, the coding polymorphism I655V has previously been associated with an increased risk of breast cancer. We aimed to determine if common polymorphisms (frequency ≥ 5%) in ERBB2 were associated with breast cancer risk in a white British population. Five single-nucleotide polymorphisms (SNPs) were selected for study: SNP 1 near the promoter, SNP 2 in intron 1, SNP 3 in intron 4, SNP 4 in exon 17 (I655V), and SNP 5 in exon 27 (A1170P). We tested their association with breast cancer in a large case–control study (n = 2192 cases and 2257 controls). There were no differences in genotype frequencies between cases and controls for any of the SNPs examined. To investigate the possibility that a common polymorphism not included in our study might be involved in breast cancer predisposition, we also constructed multilocus haplotypes. Our set of SNPs generated all existing (n = 6) common haplotypes and no differences were seen in haplotype frequencies between cases and controls (P = 0.44). In our population, common ERBB2 polymorphisms are not involved in predisposition to breast cancer

  10. ErbB2-enhanced invasiveness of H-Ras MCF10A breast cells requires MMP-13 and uPA upregulation via p38 MAPK signaling.

    Science.gov (United States)

    Yong, Hae-Young; Kim, In-Young; Kim, Jong Suk; Moon, Aree

    2010-02-01

    Overexpression of ErbB2 has been frequently found in mammary carcinoma. We have previously shown that the aberrant activation of H-Ras induces human breast cell invasion and migration. The present study was aimed at investigating the effect of ErbB2 overexpression on H-Ras-induced breast cell invasion and to elucidate the underlying mechanisms. Herein, we show that overexpression of ErbB2 promotes invasive and migratory abilities of H-Ras-activated MCF10A human breast epithelial cells through upregulation of matrix metalloproteinase (MMP)-13 and urokinase-type plasminogen activator (uPA). We also demonstrate that the p38 MAPK is an important signaling molecule in the ErbB2-induced upregulation of MMP-13 and uPA and invasion/migration of H-Ras MCF10A cells overexpressing ErbB2. The present study elucidating the molecular mechanism underlying ErbB2-induced promotion of H-Ras MCF10A cell invasion may provide invaluable information for understanding breast cancer progression and establishing therapeutic interventions for breast cancer.

  11. Effect of spatial inhomogeneities on the membrane surface on receptor dimerization and signal initiation

    Directory of Open Access Journals (Sweden)

    Romica Kerketta

    2016-08-01

    Full Text Available Important signal transduction pathways originate on the plasma membrane, where microdomains may transiently entrap diffusing receptors. This results in a non-random distribution of receptors even in the resting state, which can be visualized as clusters by high resolution imaging methods. Here, we explore how spatial in-homogeneities in the plasma membrane might influence the dimerization and phosphorylation status of ErbB2 and ErbB3, two receptor tyrosine kinases that preferentially heterodimerize and are often co-expressed in cancer. This theoretical study is based upon spatial stochastic simulations of the two-dimensional membrane landscape, where variables include differential distributions and overlap of transient confinement zones (domains for the two receptor species. The in silico model is parameterized and validated using data from single particle tracking experiments. We report key differences in signaling output based on the degree of overlap between domains and the relative retention of receptors in such domains, expressed as escape probability. Results predict that a high overlap of domains, which favors transient co-confinement of both receptor species, will enhance the rate of hetero-interactions. Where domains do not overlap, simulations confirm expectations that homo-interactions are favored. Since ErbB3 is uniquely dependent on ErbB2 interactions for activation of its catalytic activity, variations in domain overlap or escape probability markedly alter the predicted patterns and time course of ErbB3 and ErbB2 phosphorylation. Taken together, these results implicate membrane domain organization as an important modulator of signal initiation, motivating the design of novel experimental approaches to measure these important parameters across a wider range of receptor systems.

  12. Internal Quality Assurance Program for ERBB2 (HER2 Testing Improves the Selection of Breast Cancer Patients for Treatment with Trastuzumab

    Directory of Open Access Journals (Sweden)

    Vittoria Martin

    2012-01-01

    Full Text Available International guidelines for ERBB2 (HER2 testing procedures in breast cancer patients highlight the importance of external quality control. In contrast, internal quality assurance programs have been poorly defined, and their clinical significance has not yet been investigated. We developed a quality assurance scheme by performing HER2 FISH on 724 patients randomly selected out of 1996 patients with breast cancer presenting at our institute. We collected samples monthly for tissue microarray analysis and correlated HER2 gene status with IHC scores. The concordance was excellent (=0.92, <0.0001. HER2 amplification characterized 25% of score 2+ but also 13% of score 1+, thus expanding the number of patients eligible for trastuzumab. Based on these findings, the FISH test is now recommended at our institution for score 1+ and 2+ patients. Adherence to internal assurance program improves patient selection and may lead to the definition of in-house tailored diagnostic algorithms different from those proposed in international guidelines.

  13. Metastatic Breast Cancer and Hormonal Receptor Status among a ...

    African Journals Online (AJOL)

    disease. Many studies show that metastatic lesions frequently lodge in bones, lung and liver. Tumour hormone receptor status correlates with site of metastatic lesions and survival among breast cancer patients. Objective: To determine the sites of metastatic breast lesions and how they relate to the hormonal receptor status.

  14. Effect of tetrahydrocurcumin on insulin receptor status in type 2 ...

    Indian Academy of Sciences (India)

    PRAKASH KUMAR G

    Effect of tetrahydrocurcumin on insulin receptor status in type 2 diabetic rats: studies on insulin binding to erythrocytes 63. J. Biosci. 33(1), March 2008. 1. Introduction. A number of recent studies have shown that human erythrocytes can be used as a cellular model for assessing the status of insulin receptors in diabetes ...

  15. Effect of tetrahydrocurcumin on insulin receptor status in type 2 ...

    Indian Academy of Sciences (India)

    PRAKASH KUMAR G

    the status of insulin receptors in diabetes (Pari et al 2004;. Ashokkumar et al 2006). ... [Murugan P, Pari L and Rao C A 2008 Effect of tetrahydrocurcumin on insulin receptor status in type 2 diabetic rats: studies on insulin binding to erythrocytes; J. .... animals were fed with a balanced commercial diet (Hindustan. Lever Ltd.

  16. Em08red, a dual functional antiproliferative emodin analogue, is a downregulator of ErbB2 expression and inducer of intracellular oxidative stress

    Directory of Open Access Journals (Sweden)

    Liang FP

    2015-03-01

    Full Text Available Fong-Pin Liang,1,* Jin-Cherng Lien,1,* Yu-Hua Wu,2 Chien-Shu Chen,2 Shin-Hun Juang1–3 1Graduate Institute of Pharmaceutical Chemistry, 2School of Pharmacy and Department of Pediatrics, Children’s Hospital, 3Department of Medical Research, China Medical University Hospital, Taichung, Taiwan *These authors contributed equally to this work Abstract: Expression of ErbB2 protein is inversely correlated with the prognosis in cancer patients. Consequently, strategies targeting ErbB2 remain an attractive option in treating several types of malignancies, including oral cancer. In addition, many studies have shown that emodin and emodin derivatives are able to inhibit growth of ErbB2-overexpressing tumor cells. In this study, a series of computer modeling-generated emodin analogues were synthesized and tested for their antiproliferative activity against oral cancer cell lines overexpressing ErbB2. Among these analogues, em08red (1,8-dihydroxy-9(10H-anthracenone demonstrated potent antiproliferative activity against all three tested ErbB2-overexpressing cell lines, ie, FaDu, HSC3, and OECM1. Treatment with em08red significantly downregulated activation of ErbB2 as well as the ErbB2 protein expression level in the tested cell lines and induced G2 arrest. Antiapoptosis protein (Bcl-xl and Bcl-2 expression levels were also downregulated, and active caspase-3 and caspase-9 was detected in cells after treatment with em08red. Moreover, treatment with em08red stimulated production of cytotoxic reactive oxygen species in treated cells, and this could be partially reversed by pretreatment with N-acetylcysteine. Overall, we demonstrated inhibition of ErbB2 function and induction of reactive oxygen species in tumor cells by em08red, which prevented proliferation of tumor cells and induced apoptotic cell death. Keywords: ErbB2, emodin, em08red, reactive oxygen species, structure-activity relationship 

  17. The negative cell cycle regulator, Tob (transducer of ErbB-2), is involved in motor skill learning

    International Nuclear Information System (INIS)

    Wang Xinming; Gao Xiang; Zhang Xuehan; Tu Yanyang; Jin Meilei; Zhao Guoping; Yu Lei; Jing Naihe; Li Baoming

    2006-01-01

    Tob (transducer of ErbB-2) is a negative cell cycle regulator with anti-proliferative activity in peripheral tissues. Our previous study identified Tob as a protein involved in hippocampus-dependent memory consolidation (M.L. Jin, X.M. Wang, Y.Y. Tu, X.H. Zhang, X. Gao, N. Guo, Z.Q. Xie, G.P. Zhao, N.H. Jing, B.M. Li, Y.Yu, The negative cell cycle regulator, Tob (Transducer of ErbB-2), is a multifunctional protein involved in hippocampus-dependent learning and memory, Neuroscience 131 (2005) 647-659). Here, we provide evidence that Tob in the central nervous system is engaged in acquisition of motor skill. Tob has a relatively high expression in the cerebellum. Tob expression is up-regulated in the cerebellum after rats receive training on a rotarod-running task. Rats infused with Tob antisense oligonucleotides into the 4th ventricle exhibit a severe deficit in running on a rotating rod or walking across a horizontally elevated beam

  18. Estrogen-Related Receptor Alpha (ERRa)-Coactivator Interactions as Targets for Discovery of New Anti-Breast Cancer Therapeutics

    National Research Council Canada - National Science Library

    Burgess, Richard R

    2006-01-01

    .... ERalpha-negative breast cancers do not respond to anti-estrogen treatment; instead, current therapeutics, such as Herceptin, have focused on the transmembrane tyrosine kinase receptor ErbB2 (HER2...

  19. NMDA and AMPA receptors: development and status epilepticus

    Czech Academy of Sciences Publication Activity Database

    Szczurowska, Ewa; Mareš, Pavel

    2013-01-01

    Roč. 62, Suppl.1 (2013), S21-S38 ISSN 0862-8408 Institutional support: RVO:67985823 Keywords : glutamate ionotropic receptors * ontogeny * status epilepticus Subject RIV: FH - Neurology Impact factor: 1.487, year: 2013

  20. Expression of merlin, NDRG2, ERBB2, and c-MYC in meningiomas: relationship with tumor grade and recurrence

    Directory of Open Access Journals (Sweden)

    B.R. Ongaratti

    2016-01-01

    Full Text Available Meningiomas are common, usually benign tumors of the central nervous system that have a high rate of post-surgical recurrence or regrowth. We determined expression of the proteins merlin, NDRG2, ERBB2, and c-MYC in meningiomas using immunohistochemistry and assessed relationships between protein expression and gender, age, tumor grade, and recurrence or regrowth. The study sample comprised 60 patients, (44 women and 16 men with a mean age of 53.2±12.7 years. Tumors were classified as grade I (n=48 or grades II and III (n=12. Expression of merlin, NDRG2, ERBB2, and c-MYC was not significantly different statistically with relation to gender, age, or meningioma recurrence or regrowth. Merlin was expressed in 100% of the cases. No statistically significant difference between tumor grade and recurrence or regrowth was identified. Statistically significant differences were identified between the mean age of patients with grade I (54.83±11.60 and grades II and III (46.58±15.08 meningiomas (P=0.043, between strong c-MYC expression and grades II and III (P<0.001, and between partial surgical resection and tumor recurrence or regrowth (P<0.001. These findings reveal the lower mean age among grades II and III meningioma patients than grade I patients, the influence of the protein merlin on tumorigenesis, the association of c-MYC with aggressive meningiomas, and that partial surgical resection is associated with tumor recurrence or regrowth.

  1. Vitamin E analogs trigger apoptosis in HER2/erbB2-overexpressing breast cancer cells by signaling via the mitochondrial pathway

    Czech Academy of Sciences Publication Activity Database

    Wang, X.-F.; Witting, P. K.; Salvatore, B.A.; Neužil, Jiří

    2005-01-01

    Roč. 326, č. 4 (2005), s. 282-289 ISSN 0006-291X Institutional research plan: CEZ:AV0Z5052915; CEZ:AV0Z50520514 Keywords : vitamin E analogs * apoptosis * ErbB2 Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.000, year: 2005

  2. Constitutively active ErbB2 regulates cisplatin-induced cell death in breast cancer cells via pro- and antiapoptotic mechanisms

    DEFF Research Database (Denmark)

    Sigurðsson, Haraldur H; Olesen, Christina Wilkens; Dybboe, Rie

    2015-01-01

    UNLABELLED: Despite the frequent expression of N-terminally truncated ErbB2 (ΔNErbB2/p95HER2) in breast cancer and its association with Herceptin resistance and poor prognosis, it remains poorly understood how ΔNErbB2 affects chemotherapy-induced cell death. Previously it was shown that ΔNErbB2...

  3. Prolyl isomerase Pin1 is highly expressed in Her2-positive breast cancer and regulates erbB2 protein stability

    Directory of Open Access Journals (Sweden)

    Lu Kun

    2008-12-01

    Full Text Available Abstract Overexpression of HER-2/Neu occurs in about 25–30% of breast cancer patients and is indicative of poor prognosis. While Her2/Neu overexpression is primarily a result of erbB2 amplification, it has recently been recognized that erbB2 levels are also regulated on the protein level. However, factors that regulate Her2/Neu protein stability are less well understood. The prolyl isomerase Pin1 catalyzes the isomerization of specific pSer/Thr-Pro motifs that have been phosphorylated in response to mitogenic signaling. We have previously reported that Pin1-catalyzed post-phosphorylational modification of signal transduction modulates the oncogenic pathways downstream from c-neu. The goal of this study was to examine the expression of prolyl isomerase Pin1 in human Her2+ breast cancer, and to study if Pin1 affects the expression of Her2/Neu itself. Methods Immunohistochemistry for Her2 and Pin1 were performed on two hundred twenty-three human breast cancers, with 59% of the specimen from primary cancers and 41% from metastatic sites. Pin1 inhibition was achieved using siRNA in Her2+ breast cancer cell lines, and its effects were studied using cell viability assays, immunoblotting and immunofluorescence. Results Sixty-four samples (28.7% stained positive for Her2 (IHC 3+, and 54% (122/223 of all breast cancers stained positive for Pin1. Of the Her2-positive cancers 40 (62.5% were also Pin1-positive, based on strong nuclear or nuclear and cytoplasmic staining. Inhibition of Pin1 via RNAi resulted in significant suppression of Her2-positive tumor cell growth in BT474, SKBR3 and AU565 cells. Pin1 inhibition greatly increased the sensitivity of Her2-positive breast cancer cells to the mTOR inhibitor Rapamycin, while it did not increase their sensitivity to Trastuzumab, suggesting that Pin1 might act on Her2 signaling. We found that Pin1 interacted with the protein complex that contains ubiquitinated erbB2 and that Pin1 inhibition accelerated erbB2 degradation, which could be prevented by treatments with the proteasome inhibitor ALLnL. Conclusion Pin1 is a novel regulator of erbB2 that modulates the ubiquitin-mediated degradation of erbB2. The overexpression of Pin1 in a majority of Her2-overexpressing breast cancer may contribute to maintain erbB2 levels. Pin1 inhibition alone and in conjunction with mTOR inhibition suppresses the growth of Her2+ breast cancer cells.

  4. ErbB2 regulates NHEJ repair pathway by affecting erbB1-triggered IR-induced Akt activity

    International Nuclear Information System (INIS)

    Toulany, Mahmoud; Peter Rodemann, H.

    2009-01-01

    We have already reported that erbBl-PI3K-AKT signaling is an important pathway in regulating radiation sensitivity and DNA double strand break repair of human tumor cells. In the present study using small interfering RNA and pharmacological inhibitors in non-small cell lung cancer cell lines we investigated the role of Aktl on radiation-induced DNA-PKcs activity and DNA-double strand break (DNA-DSB) repair. Likewise, the function of erbB2 as hetrodimerization partner of erbBl in radiation-induced Akt activity and regulation of DNA-dsb repair through DNA-PKcs was evaluated. In A549 and H460 transfected with AKTl-siRNA radiation-induced phosphorylation of DNA-PKcs the key enzyme regulating NHEJ repair pathway was markedly inhibited. In both cell lines downregulation of Aktl led to a significant enhancement of residual DNA-DSB, i.e. impaired DNA-DSB repair. Interestingly, in cells transfected with DNA-PKcs-siRNA a lack of effect of AKTl-siRNA on enhancement of residual DNA-DSBs was observed. This results indicate that Aktl regulates NHEJ repair in a DNA-PKcs dependent manner

  5. Mammary gland cancer in a colony of beagle dogs: Inheritance, and p53 ampersand erbB-2 expression

    International Nuclear Information System (INIS)

    Kelly, G.; Griffith, W.C.; Muggenburg, Tierney, L.A.; Lechner, J.F.; Hahn, F.F.

    1994-01-01

    One American woman in nine will be diagnosed with breast cancer in her lifetime. This somber statistic translates into 182,000 new diagnoses and 46,000 deaths per year. Efforts to decrease breast cancer mortality have focused on early detection and improved treatment. Such efforts would be facilitated by the identification of individuals predisposed to the disease. A family history of the disease can increase a woman's risk for developing breast cancer by two- to six-fold. Inheritance of this disease is consistent with at least one susceptibility locus on chromosome 17 (17q12-21) with incomplete penetrance. However, other mechanisms of inherited susceptibility also contribute to the high incidence of the disease. The purpose of the present study was to characterize familial pattern of mammary cancer development in the dog colony. In addition, the expression of the p53 tumor supressor gene and c-erbB2 (p185 erbB2 ) oncogene proteins, which are frequently altered in human breast cancer, were examined in dogs susceptible and resistant to mammary cancer

  6. Metastatic Breast Cancer and Hormonal Receptor Status among a ...

    African Journals Online (AJOL)

    Background: Breast cancer is the third commonest cancer in women in Uganda. The majority of breast cancer patients in Uganda present with advanced disease. Many studies show that metastatic lesions frequently lodge in bones, lung and liver. Tumour hormone receptor status correlates with site of metastatic lesions and ...

  7. Stiffness of the microenvironment upregulates ERBB2 expression in 3D cultures of MCF10A within the range of mammographic density.

    Science.gov (United States)

    Cheng, Qingsu; Bilgin, Cemal Cagatay; Fonteney, Gerald; Chang, Hang; Henderson, Matthew; Han, Ju; Parvin, Bahram

    2016-07-07

    The effects of the stiffness of the microenvironment on the molecular response of 3D colony organization, at the maximum level of mammographic density (MD), are investigated. Phenotypic profiling reveals that 3D colony formation is heterogeneous and increased stiffness of the microenvironment, within the range of the MD, correlates with the increased frequency of aberrant 3D colony formation. Further integrative analysis of the genome-wide transcriptome and phenotypic profiling hypothesizes overexpression of ERBB2 in the premalignant MCF10A cell lines at a stiffness value that corresponds to the collagen component at high mammographic density. Subsequently, ERBB2 overexpression has been validated in the same cell line. Similar experiments with a more genetically stable cell line of 184A1 also revealed an increased frequency of aberrant colony formation with the increased stiffness; however, 184A1 did not demonstrate overexpression of ERBB2 at the same stiffness value of the high MD. These results suggest that stiffness exacerbates premalignant cell line of MCF10A.

  8. Melatonin receptors: Current status, facts, and hypothesis

    International Nuclear Information System (INIS)

    Stankov, B.; Reiter, R.J.

    1990-01-01

    Great progress has been made in the identification of melatonin binding sites, commonly identified as melatonin receptors by many authors, in recent years. The bulk of these studies have investigated the sites using either autoradiographic and biochemical techniques with the majority of the experiments being done on the rat, Djungarian and Syrian hamster, and sheep, although human tissue has also been employed. Many of the studies have identified melatonin binding in the central nervous system with either tritium- or iodine-labelled ligands. The latter ligand seems to provide the most reproducible and consistent data. Of the central neural tissues examined, the suprachiasmatic nuclei are most frequently mentioned as a location for melatonin binding sites although binding seems to be widespread in the brain. The other tissue that has been prominently mentioned as a site for melatonin binding is the pars tuberalis of the anterior pituitary gland. There may be time-dependent variations in melatonin binding densities in both neural and pituitary gland tissue. Very few attempts have been made to identify melatonin binding outside of the central nervous system despite the widespread actions of melatonin. Preliminary experiments have been carried out on the intracellular second messengers which mediate the actions of melatonin

  9. tabAnti-HER2 (erbB-2) oncogene effects of phenolic compounds directly isolated from commercial Extra-Virgin Olive Oil (EVOO)

    International Nuclear Information System (INIS)

    Menendez, Javier A; Vazquez-Martin, Alejandro; Garcia-Villalba, Rocio; Carrasco-Pancorbo, Alegria; Oliveras-Ferraros, Cristina; Fernandez-Gutierrez, Alberto; Segura-Carretero, Antonio

    2008-01-01

    The effects of the olive oil-rich Mediterranean diet on breast cancer risk might be underestimated when HER2 (ERBB2) oncogene-positive and HER2-negative breast carcinomas are considered together. We here investigated the anti-HER2 effects of phenolic fractions directly extracted from Extra Virgin Olive Oil (EVOO) in cultured human breast cancer cell lines. Solid phase extraction followed by semi-preparative high-performance liquid chromatography (HPLC) was used to isolate phenolic fractions from commercial EVOO. Analytical capillary electrophoresis coupled to mass spectrometry was performed to check for the composition and to confirm the identity of the isolated fractions. EVOO polyphenolic fractions were tested on their tumoricidal ability against HER2-negative and HER2-positive breast cancer in vitro models using MTT, crystal violet staining, and Cell Death ELISA assays. The effects of EVOO polyphenolic fractions on the expression and activation status of HER2 oncoprotein were evaluated using HER2-specific ELISAs and immunoblotting procedures, respectively. Among the fractions mainly containing the single phenols hydroxytyrosol and tyrosol, the polyphenol acid elenolic acid, the lignans (+)-pinoresinol and 1-(+)-acetoxypinoresinol, and the secoiridoids deacetoxy oleuropein aglycone, ligstroside aglycone, and oleuropein aglycone, all the major EVOO polyphenols (i.e. secoiridoids and lignans) were found to induce strong tumoricidal effects within a micromolar range by selectively triggering high levels of apoptotic cell death in HER2-overexpressors. Small interfering RNA-induced depletion of HER2 protein and lapatinib-induced blockade of HER2 tyrosine kinase activity both significantly prevented EVOO polyphenols-induced cytotoxicity. EVOO polyphenols drastically depleted HER2 protein and reduced HER2 tyrosine autophosphorylation in a dose- and time-dependent manner. EVOO polyphenols-induced HER2 downregulation occurred regardless the molecular mechanism

  10. tabAnti-HER2 (erbB-2 oncogene effects of phenolic compounds directly isolated from commercial Extra-Virgin Olive Oil (EVOO

    Directory of Open Access Journals (Sweden)

    Carrasco-Pancorbo Alegria

    2008-12-01

    Full Text Available Abstract Background The effects of the olive oil-rich Mediterranean diet on breast cancer risk might be underestimated when HER2 (ERBB2 oncogene-positive and HER2-negative breast carcinomas are considered together. We here investigated the anti-HER2 effects of phenolic fractions directly extracted from Extra Virgin Olive Oil (EVOO in cultured human breast cancer cell lines. Methods Solid phase extraction followed by semi-preparative high-performance liquid chromatography (HPLC was used to isolate phenolic fractions from commercial EVOO. Analytical capillary electrophoresis coupled to mass spectrometry was performed to check for the composition and to confirm the identity of the isolated fractions. EVOO polyphenolic fractions were tested on their tumoricidal ability against HER2-negative and HER2-positive breast cancer in vitro models using MTT, crystal violet staining, and Cell Death ELISA assays. The effects of EVOO polyphenolic fractions on the expression and activation status of HER2 oncoprotein were evaluated using HER2-specific ELISAs and immunoblotting procedures, respectively. Results Among the fractions mainly containing the single phenols hydroxytyrosol and tyrosol, the polyphenol acid elenolic acid, the lignans (+-pinoresinol and 1-(+-acetoxypinoresinol, and the secoiridoids deacetoxy oleuropein aglycone, ligstroside aglycone, and oleuropein aglycone, all the major EVOO polyphenols (i.e. secoiridoids and lignans were found to induce strong tumoricidal effects within a micromolar range by selectively triggering high levels of apoptotic cell death in HER2-overexpressors. Small interfering RNA-induced depletion of HER2 protein and lapatinib-induced blockade of HER2 tyrosine kinase activity both significantly prevented EVOO polyphenols-induced cytotoxicity. EVOO polyphenols drastically depleted HER2 protein and reduced HER2 tyrosine autophosphorylation in a dose- and time-dependent manner. EVOO polyphenols-induced HER2 downregulation

  11. Assessment of staging, prognosis and mortality of colorectal cancer by tumor markers: receptor erbB-2 and cadherins

    Directory of Open Access Journals (Sweden)

    Jesus Eliane C.

    2005-01-01

    Full Text Available PURPOSE: To evaluate the prognostic significance and correlation with staging and degree of cell differentiation of the tumoral expression of the proteins c-erbB-2 and E-cadherin, in patients with colorectal adenocarcinoma. METHODS: The study included 117 patients with an average age of 63.1 years and an average follow-up duration of 28.1 months. The disease-free interval, survival, incidence of recurrence and specific mortality were evaluated. c-erbB-2 anti-oncoprotein antibodies (Dako were utilized via the streptavidin-biotin technique. Samples were considered to be positive for c-erbB-2 if 10% or more of the tumor cell membranes were stained.The anti-E-cadherin antibodies (Dako, evaluated this protein and is considered positive, if 50% or more of the cell membranes were stained. Statistical analysis was performed using Pearson's chi-squared test, Fisher's exact test, Kaplan-Meier's estimator, the log-rank test and Wilcoxon's test (Breslow version, setting the level of statistical significance at 5% (p<0.05. RESULTS: 52 of 108 patients studied for c-erbB-2 were positive (48,1%, 47 of 93 patients studied for E-cadherin were negative (50,5%. These data do not express any correlation with TNM (tumor, node and metastasis staging and the degree of cell differentiation or with the tumor recurrence rate. The disease-free interval among patients who were positive for c-erbB-2 and negative for E-cadherin was 68.0 months and did not differ from those with c-erbB-2 negative and E-cadherin positive ( 55.0 months - p = 0.5510. The average survival among patients positive for c-erbB-2 and negative for E-cadherin was 75 months without statistical significance difference with the other group ( 61 months - p = 0.5256. Specific mortality occurred in 20.0% of the cases and did not correlate with the expression of c-erbB-2 (p=0,446, E-cadherin (p=0,883. CONCLUSION: The tumoral expression of c-erbB-2 and E-cadherin did not demonstrate a correlation with the staging and degree of cell differentiation, and it did not present prognostic value regarding disease recurrence, disease-free interval, survival and specific mortality among patients with colorectal adenocarcinoma.

  12. ErbB2 and NFκB overexpression as predictors of chemoradiation resistance and putative targets to overcome resistance in muscle-invasive bladder cancer.

    Directory of Open Access Journals (Sweden)

    Fumitaka Koga

    Full Text Available Radical cystectomy for muscle-invasive bladder cancer (MIBC patients frequently impairs their quality of life (QOL due to urinary diversion. To improve their QOL, a bladder-sparing alternative strategy using chemoradiation has been developed. In bladder-sparing protocols, complete response (CR to induction chemoradiation is a prerequisite for bladder preservation and favorable survival. Thus predicting chemoradiation resistance and overcoming it would increase individual MIBC patients' chances of bladder preservation. The aim of this study is to investigate putative molecular targets for treatment aimed at improving chemoradiation response. Expression levels of erbB2, NFκB, p53, and survivin were evaluated immunohistochemically in pretreatment biopsy samples from 35 MIBC patients in whom chemoradiation sensitivity had been pathologically evaluated in cystectomy specimens, and associations of these expression levels with chemoradiation sensitivity and cancer-specific survival (CSS were investigated. Of the 35 patients, 11 (31% achieved pathological CR, while tumors in the remaining 24 patients (69% were chemoradiation-resistant. Multivariate analysis identified erbB2 and NFκB overexpression and hydronephrosis as significant and independent risk factors for chemoradiation resistance with respective relative risks of 11.8 (P = 0.014, 15.4 (P = 0.024 and 14.3 (P = 0.038. The chemoradiation resistance rate was 88.5% for tumors overexpressing erbB2 and/or NFκB, but only 11.1% for those negative for both (P <0.0001. The 5-year CSS rate was 74% overall. Through multivariate analysis, overexpression of erbB2 and/or NFκB was identified as an independent risk factor for bladder cancer death with marginal significance (hazard ratio 21.5, P = 0.056 along with chemoradiation resistance (P = 0.003 and hydronephrosis (P = 0.018. The 5-year CSS rate for the 11 patients achieving pathological CR was 100%, while that for the 24 with chemoradiation-resistant disease was 61% (P = 0.018. Thus, erbB2 and NFκB overexpression are relevant to chemoradiation resistance and are putative targets aimed at overcoming chemoradiation resistance in MIBC.

  13. Significance of ERBB2 Overexpression in Therapeutic Resistance and Cancer-Specific Survival in Muscle-Invasive Bladder Cancer Patients Treated With Chemoradiation-Based Selective Bladder-Sparing Approach

    International Nuclear Information System (INIS)

    Inoue, Masaharu; Koga, Fumitaka; Yoshida, Soichiro; Tamura, Tomoki; Fujii, Yasuhisa; Ito, Eisaku; Kihara, Kazunori

    2014-01-01

    Purpose: To investigate the associations of ERBB 2 overexpression with chemoradiation therapy (CRT) resistance and cancer-specific survival (CSS) in muscle-invasive bladder cancer (MIBC) patients treated with the CRT-based bladder-sparing protocol. Methods and Materials: From 1997 to 2012, 201 patients with cT2-4aN0M0 bladder cancer were treated with CRT (40 Gy with concurrent cisplatin) following transurethral resection of bladder tumor (TURBT). Basically, patients with tumors that showed good CRT response and were amenable to segmental resection underwent partial cystectomy (PC) with pelvic lymph node dissection for bladder preservation; otherwise, radical cystectomy (RC) was recommended. Included in this study were 119 patients in whom TURBT specimens were available for immunohistochemical analysis of ERBB 2 expression. Following CRT, 30 and 65 patients underwent PC or RC, respectively; the remaining 24 patients did not undergo cystectomy. Tumors were defined as CRT-resistant when patients did not achieve complete response after CRT. Associations of ERBB 2 overexpression with CRT resistance and CSS were evaluated. Results: CRT resistance was observed clinically in 56% (67 of 119 patients) and pathologically (in cystectomy specimens) in 55% (52 of 95 patients). ERBB 2 overexpression was observed in 45 patients (38%). On multivariate analysis, ERBB 2 overexpression was an independent predictor for CRT resistance clinically (odds ratio, 3.6; P=.002) and pathologically (odds ratio, 2.9; P=.031). ERBB 2 overexpression was associated with shorter CSS (5-year CSS rates, 56% vs 87% for the ERBB 2 overexpression group vs the others; P=.001). ERBB 2 overexpression was also an independent risk factor for bladder cancer death at all time points of our bladder-sparing protocol (pre-CRT, post-CRT, and post-cystectomy). Conclusions: ERBB 2 overexpression appears relevant to CRT resistance and unfavorable CSS in MIBC patients treated with the CRT-based bladder

  14. Significance of ERBB2 Overexpression in Therapeutic Resistance and Cancer-Specific Survival in Muscle-Invasive Bladder Cancer Patients Treated With Chemoradiation-Based Selective Bladder-Sparing Approach

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, Masaharu [Department of Urology, Tokyo Medical and Dental University, Graduate School, Tokyo (Japan); Koga, Fumitaka, E-mail: f-koga@cick.jp [Department of Urology, Tokyo Medical and Dental University, Graduate School, Tokyo (Japan); Yoshida, Soichiro [Department of Urology, Tokyo Medical and Dental University, Graduate School, Tokyo (Japan); Tamura, Tomoki [Department of Pathology, Tokyo Medical and Dental University, Graduate School, Tokyo (Japan); Fujii, Yasuhisa [Department of Urology, Tokyo Medical and Dental University, Graduate School, Tokyo (Japan); Ito, Eisaku [Department of Pathology, Tokyo Medical and Dental University, Graduate School, Tokyo (Japan); Kihara, Kazunori [Department of Urology, Tokyo Medical and Dental University, Graduate School, Tokyo (Japan)

    2014-10-01

    Purpose: To investigate the associations of ERBB 2 overexpression with chemoradiation therapy (CRT) resistance and cancer-specific survival (CSS) in muscle-invasive bladder cancer (MIBC) patients treated with the CRT-based bladder-sparing protocol. Methods and Materials: From 1997 to 2012, 201 patients with cT2-4aN0M0 bladder cancer were treated with CRT (40 Gy with concurrent cisplatin) following transurethral resection of bladder tumor (TURBT). Basically, patients with tumors that showed good CRT response and were amenable to segmental resection underwent partial cystectomy (PC) with pelvic lymph node dissection for bladder preservation; otherwise, radical cystectomy (RC) was recommended. Included in this study were 119 patients in whom TURBT specimens were available for immunohistochemical analysis of ERBB 2 expression. Following CRT, 30 and 65 patients underwent PC or RC, respectively; the remaining 24 patients did not undergo cystectomy. Tumors were defined as CRT-resistant when patients did not achieve complete response after CRT. Associations of ERBB 2 overexpression with CRT resistance and CSS were evaluated. Results: CRT resistance was observed clinically in 56% (67 of 119 patients) and pathologically (in cystectomy specimens) in 55% (52 of 95 patients). ERBB 2 overexpression was observed in 45 patients (38%). On multivariate analysis, ERBB 2 overexpression was an independent predictor for CRT resistance clinically (odds ratio, 3.6; P=.002) and pathologically (odds ratio, 2.9; P=.031). ERBB 2 overexpression was associated with shorter CSS (5-year CSS rates, 56% vs 87% for the ERBB 2 overexpression group vs the others; P=.001). ERBB 2 overexpression was also an independent risk factor for bladder cancer death at all time points of our bladder-sparing protocol (pre-CRT, post-CRT, and post-cystectomy). Conclusions: ERBB 2 overexpression appears relevant to CRT resistance and unfavorable CSS in MIBC patients treated with the CRT-based bladder

  15. Significance of ERBB2 overexpression in therapeutic resistance and cancer-specific survival in muscle-invasive bladder cancer patients treated with chemoradiation-based selective bladder-sparing approach.

    Science.gov (United States)

    Inoue, Masaharu; Koga, Fumitaka; Yoshida, Soichiro; Tamura, Tomoki; Fujii, Yasuhisa; Ito, Eisaku; Kihara, Kazunori

    2014-10-01

    To investigate the associations of ERBB 2 overexpression with chemoradiation therapy (CRT) resistance and cancer-specific survival (CSS) in muscle-invasive bladder cancer (MIBC) patients treated with the CRT-based bladder-sparing protocol. From 1997 to 2012, 201 patients with cT2-4aN0M0 bladder cancer were treated with CRT (40 Gy with concurrent cisplatin) following transurethral resection of bladder tumor (TURBT). Basically, patients with tumors that showed good CRT response and were amenable to segmental resection underwent partial cystectomy (PC) with pelvic lymph node dissection for bladder preservation; otherwise, radical cystectomy (RC) was recommended. Included in this study were 119 patients in whom TURBT specimens were available for immunohistochemical analysis of ERBB 2 expression. Following CRT, 30 and 65 patients underwent PC or RC, respectively; the remaining 24 patients did not undergo cystectomy. Tumors were defined as CRT-resistant when patients did not achieve complete response after CRT. Associations of ERBB 2 overexpression with CRT resistance and CSS were evaluated. CRT resistance was observed clinically in 56% (67 of 119 patients) and pathologically (in cystectomy specimens) in 55% (52 of 95 patients). ERBB 2 overexpression was observed in 45 patients (38%). On multivariate analysis, ERBB 2 overexpression was an independent predictor for CRT resistance clinically (odds ratio, 3.6; P=.002) and pathologically (odds ratio, 2.9; P=.031). ERBB 2 overexpression was associated with shorter CSS (5-year CSS rates, 56% vs 87% for the ERBB 2 overexpression group vs the others; P=.001). ERBB 2 overexpression was also an independent risk factor for bladder cancer death at all time points of our bladder-sparing protocol (pre-CRT, post-CRT, and post-cystectomy). ERBB 2 overexpression appears relevant to CRT resistance and unfavorable CSS in MIBC patients treated with the CRT-based bladder-sparing protocol. ERBB 2-targeting treatment may improve the outcomes

  16. Breast cancer receptor status assessment and clinicopathological association in Nigerian women: A retrospective analysis

    Directory of Open Access Journals (Sweden)

    Makanjuola SBL

    2014-08-01

    Full Text Available Background: Breast cancer markers are becoming increasingly important in breast cancer research due to their impact on prognosis, treatment and survival. The present retrospective study was carried out to quantify the proportion of estrogen (ER, progesterone (PR, and human epithelial receptor 2 (HER2 expressions and their association with tumour grade, age, and tumour size in breast cancer patients in Nigeria. Materials and methods: The paraffin embedded tissue sections were analysed for breast cancer markers using monoclonal antibody SP1 for ER and SP2 for PR and polyclonal antibody ErbB2 for HER2. Results: A total of 286 breast cancer paraffin wax tissue sections were analysed for ER, PR and HER2 expression. Of all the tissue samples examined, 20 (7% were ER-positive, 6 (2.1% were PR-positive, 11 (3.8% were HER2-positive whereas 248 (87% were triple-negative breast carcinoma. ER- and PR-positivity was associated with early grade I and II tumours (P 50mm (P < 0.0001. Conclusion: A small proportion of Nigerian women with breast cancer are ER/PR-positive which are associated with less aggressive, better prognosis and benefit from endocrine therapy. An even smaller proportion of patients with aggressive tumors were HER2-posivite but responsive to Herceptin treatment. Unfortunately, a very high proportion of cases were triple-negative which is associated with very aggressive tumours and no targeted treatment, which may explain the high mortality rates from breast cancer in Nigeria.

  17. Gene Expression Meta-Analysis identifies Cytokine Pathways and 5q Aberrations involved in Metastasis of ERBB2 Amplified and Basal Breast Cancer

    DEFF Research Database (Denmark)

    Thomassen, Mads; Tan, Qihua; Burton, Mark

    2013-01-01

    mechanisms, aside from the subtypes, were identified in a training set of 1,239 tumors and confirmed by survival analysis in two independent validation datasets from the same type of platform and consisting of very comparable node-negative patients that did not receive adjuvant medical therapy. The results...... show that high expression of 5q14 genes and low levels of TNFR2 pathway genes were associated with poor survival in basal-like cancers. Furthermore, low expression of 5q33 genes and interleukin-12 pathway genes were associated with poor outcome exclusively in ERBB2-like tumors. Conclusion...

  18. Cytologic assessment of estrogen receptor, progesterone receptor, and HER2 status in metastatic breast carcinoma.

    Science.gov (United States)

    Pareja, Fresia; Murray, Melissa P; Jean, Ryan Des; Konno, Fumiko; Friedlander, Maria; Lin, Oscar; Edelweiss, Marcia

    2017-01-01

    Discordance in the receptor status between primary breast carcinomas (PBC) and corresponding metastasis is well documented. Interrogation of the receptor status of metastatic breast carcinoma (MBC) in cytology material is common practice; however, its utility has not been thoroughly validated. We studied patients with MBC, and evaluated the concordance rates of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) between PBC surgical specimens and corresponding MBC cell blocks (CBs). We correlated the findings with clinicopathologic variables and with the fixation methods used. We searched for patients with MBC diagnosed on cytology from 2007 to 2009 and selected those with ER, PR and HER2 tested in both the PBC surgical specimens and the MBC CBs. We included CBs fixed in formalin and methanol based solution (CytoLyt®). All slides were reevaluated by cytopathologists. Clinical information was retrieved from the medical records. We studied 65 patients with PBC and MBC paired specimens. The concordance rates between PBC and MBC were 78.5%, 58.5% and 96.9%, for ER, PR and HER2, respectively. When discordant, PR status switched from positive (PBC) to negative (MBC) in most cases (23/27). The PR concordance rate was 45.2% for CBs fixed in formalin and 70.6% for those fixed with CytoLyt® (p=0.047). The ER, PR and HER2 concordance rates between the PBC and MBC CBs are similar to those reported in paired surgical specimens. PR status was the most prevalent discordance and was not accompanied by a switch in ER.

  19. Cytotoxicity of a natural anthraquinone (Aloin) against human breast cancer cell lines with and without ErbB-2: topoisomerase IIalpha coamplification.

    Science.gov (United States)

    Esmat, Amr Y; Tomasetto, Catherine; Rio, Marie-Christine

    2006-01-01

    In the present study the cytotoxic activity of aloin, a natural anthracycline from Aloe plant, is reported against two human breast cancer cell lines; without (MCF-7) and with (SKBR-3) erbB-2-topoIIalpha coamplification. MCF-7cell line was shown to be more sensitive to aloin than SKBR-3 demonstrated by MTT and clonogenic assays, from which IC50 and 50% ICF values are reported to be 60 microg/ml, respectively, in the former cell line and as high as 150 and 80 microg/ml, respectively, in the latter, which are still far below the maximum tolerated dose of the compound. The effect of aloin is suggested to be brought about by more than one mechanism depending on the dose level and tumor phenotype. This was demonstrated by flow cytometric analysis, fluorescence microscopy and western blot analysis, which revealed that aloin at higher concentrations caused a reduction in the proportion of cells undergoing mitosis by induction of apoptosis, inhibition of topo II alpha protein expression and downregulation of cyclin B1 protein expression in MCF-7 cell line, whereas erbB-2 protein expression was not affected. Topo IIalpha protein expression was mildly downregulated in SKBR-3 cell line at higher concentrations only.

  20. The Na+/H+ exchanger NHE1, but not the Na+, HCO3- cotransporter NBCn1, regulates motility of MCF7 breast cancer cells expressing constitutively active ErbB2

    DEFF Research Database (Denmark)

    Lauritzen, Gitte; Stock, Christian-Martin; Lemaire, Justine

    2012-01-01

    We and others have shown central roles of the Na(+)/H(+) exchanger NHE1 in cell motility. The aim of this study was to determine the roles of NHE1 and of the Na(+), HCO(3)(-) cotransporter NBCn1 in motility of serum-starved MCF-7 breast cancer cells expressing constitutively active ErbB2 (¿NErbB2...

  1. Comparing Neoadjuvant Nab-paclitaxel vs Paclitaxel Both Followed by Anthracycline Regimens in Women With ERBB2/HER2-Negative Breast Cancer-The Evaluating Treatment With Neoadjuvant Abraxane (ETNA) Trial: A Randomized Phase 3 Clinical Trial.

    Science.gov (United States)

    Gianni, Luca; Mansutti, Mauro; Anton, Antonio; Calvo, Lourdes; Bisagni, Giancarlo; Bermejo, Begoña; Semiglazov, Vladimir; Thill, Marc; Chacon, Jose Ignacio; Chan, Arlene; Morales, Serafin; Alvarez, Isabel; Plazaola, Arrate; Zambetti, Milvia; Redfern, Andrew D; Dittrich, Christian; Dent, Rebecca Alexandra; Magazzù, Domenico; De Fato, Raffaella; Valagussa, Pinuccia; Tusquets, Ignacio

    2018-03-01

    Studies of neoadjuvant chemotherapy regimens using anthracyclines followed by taxanes have reported a doubling of pathological complete remission (pCR) rates compared with anthracycline-based regimens alone. A reverse sequence did not reduce activity. Nab-paclitaxel is an albumin-bound nanoparticle of paclitaxel that allows for safe infusion without premedication, and its use led to a significantly higher rate of pCR in the GeparSepto trial. To determine whether nab-paclitaxel improves the outcomes of early and locally advanced human epidermal growth factor receptor 2 (ERBB2/HER2)-negative breast cancer compared with paclitaxel when delivered in a neoadjuvant setting. In this multicenter, open-label study, in collaboration with Grupo Español de Investigación en Cáncer de Mama (GEICAM) and Breast Cancer Research Center-Western Australia (BCRC-WA), patients with newly diagnosed and centrally confirmed ERBB2/HER2-negative breast cancer were recruited. Participants were randomly allocated to paclitaxel, 90 mg/m2 (349 patients), or nab-paclitaxel, 125 mg/m2 (346 patients). The 2 drugs were given on weeks 1, 2, and 3 followed by 1 week of rest for 4 cycles before 4 cycles of an anthracycline regimen per investigator choice. The primary end point was the rate of pCR, defined as absence of invasive cells in the breast and axillary nodes (ie, ypT0/is ypN0) at the time of surgery. A secondary end point was to assess tolerability and safety of the 2 regimens. From May 2013 to March 2015, 814 patients were registered to the study; 695 patients met central confirmation eligibility and were randomly allocated to receive either paclitaxel (349), or nab-paclitaxel (346) (median age, 50 years; range, 25-79 years). The intention-to-treat analysis of the primary end point pCR revealed that the improved pCR rate after nab-paclitaxel (22.5%) was not statistically significant compared with paclitaxel (18.6%; odds ratio [OR], 0.77; 95% CI, 0.52-1.13; P = .19). Overall, 38 of 335

  2. Polypeptide-based nanogels co-encapsulating a synergistic combination of doxorubicin with 17-AAG show potent anti-tumor activity in ErbB2-driven breast cancer models.

    Science.gov (United States)

    Desale, Swapnil S; Raja, Srikumar M; Kim, Jong Oh; Mohapatra, Bhopal; Soni, Kruti S; Luan, Haitao; Williams, Stetson H; Bielecki, Timothy A; Feng, Dan; Storck, Matthew; Band, Vimla; Cohen, Samuel M; Band, Hamid; Bronich, Tatiana K

    2015-06-28

    ErbB2-driven breast cancers constitute 20-25% of the cases diagnosed within the USA. The humanized anti-ErbB2 monoclonal antibody, Trastuzumab (Herceptin™; Genentech), with chemotherapy is the current standard of treatment. Novel agents and strategies continue to be explored, given the challenges posed by Trastuzumab-resistance development in most patients. The HSP90 inhibitor, 17-allylaminodemethoxygeldanamycin (17-AAG), which induces ErbB2 degradation and attenuates downstream oncogenic signaling, is one such agent that showed significant promise in early phase I and II clinical trials. Its low water solubility, potential toxicities and undesirable side effects observed in patients, partly due to the Cremophor-based formulation, have been discouraging factors in the advancement of this promising drug into clinical use. Encapsulation of 17-AAG into polymeric nanoparticle formulations, particularly in synergistic combination with conventional chemotherapeutics, represents an alternative approach to overcome these problems. Herein, we report an efficient co-encapsulation of 17-AAG and doxorubicin, a clinically well-established and effective modality in breast cancer treatment, into biodegradable and biocompatible polypeptide-based nanogels. Dual drug-loaded nanogels displayed potent cytotoxicity in a breast cancer cell panel and exerted selective synergistic anticancer activity against ErbB2-overexpressing breast cancer cell lines. Analysis of ErbB2 degradation confirmed efficient 17-AAG release from nanogels with activity comparable to free 17-AAG. Furthermore, nanogels containing both 17-AAG and doxorubicin exhibited superior antitumor efficacy in vivo in an ErbB2-driven xenograft model compared to the combination of free drugs. These studies demonstrate that polypeptide-based nanogels can serve as novel nanocarriers for encapsulating 17-AAG along with other chemotherapeutics, providing an opportunity to overcome solubility issues and thereby exploit its full potential as an anti-cancer agent. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Current Status of Poly(ADP-ribose Polymerase Inhibitors as Novel Therapeutic Agents for Triple-Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    David J. Hiller

    2012-01-01

    Full Text Available Triple-negative breast cancer (TNBC is an aggressive type of breast cancer that is clinically defined as lacking estrogen and progesterone receptors, as well as being ERBB2 (HER-2 negative. Without specific therapeutic targets, TNBC carries a worse prognosis than other types of breast cancer in the absence of therapy. Research has now further differentiated breast cancer into subtypes based on genetic expression patterns. One of these subtypes, basal-like, frequently overlaps with the clinical picture of TNBC. Additionally, both TNBC and basal-like breast cancer link to BRCA mutations. Recent pharmaceutical advances have created a class of drugs, poly(ADP-ribose polymerase (PARP inhibitors, which are showing potential to effectively treat these patients. The aim of this paper is to summarize the basis behind PARP inhibitors and update the current status of their development in clinical trials for the treatment of TNBC.

  4. Small Molecule Tyrosine Kinase Inhibitors of ErbB2/HER2/Neu in the Treatment of Aggressive Breast Cancer

    Directory of Open Access Journals (Sweden)

    Richard L. Schroeder

    2014-09-01

    Full Text Available The human epidermal growth factor receptor 2 (HER2 is a member of the erbB class of tyrosine kinase receptors. These proteins are normally expressed at the surface of healthy cells and play critical roles in the signal transduction cascade in a myriad of biochemical pathways responsible for cell growth and differentiation. However, it is widely known that amplification and subsequent overexpression of the HER2 encoding oncogene results in unregulated cell proliferation in an aggressive form of breast cancer known as HER2-positive breast cancer. Existing therapies such as trastuzumab (Herceptin® and lapatinib (Tyverb/Tykerb®, a monoclonal antibody inhibitor and a dual EGFR/HER2 kinase inhibitor, respectively, are currently used in the treatment of HER2-positive cancers, although issues with high recurrence and acquired resistance still remain. Small molecule tyrosine kinase inhibitors provide attractive therapeutic targets, as they are able to block cell signaling associated with many of the proposed mechanisms for HER2 resistance. In this regard we aim to present a review on the available HER2 tyrosine kinase inhibitors, as well as those currently in development. The use of tyrosine kinase inhibitors as sequential or combinatorial therapeutic strategies with other HER family inhibitors is also discussed.

  5. Machine learning approaches to decipher hormone and HER2 receptor status phenotypes in breast cancer.

    Science.gov (United States)

    Adabor, Emmanuel S; Acquaah-Mensah, George K

    2017-10-16

    Breast cancer prognosis and administration of therapies are aided by knowledge of hormonal and HER2 receptor status. Breast cancer lacking estrogen receptors, progesterone receptors and HER2 receptors are difficult to treat. Regarding large data repositories such as The Cancer Genome Atlas, available wet-lab methods for establishing the presence of these receptors do not always conclusively cover all available samples. To this end, we introduce median-supplement methods to identify hormonal and HER2 receptor status phenotypes of breast cancer patients using gene expression profiles. In these approaches, supplementary instances based on median patient gene expression are introduced to balance a training set from which we build simple models to identify the receptor expression status of patients. In addition, for the purpose of benchmarking, we examine major machine learning approaches that are also applicable to the problem of finding receptor status in breast cancer. We show that our methods are robust and have high sensitivity with extremely low false-positive rates compared with the well-established methods. A successful application of these methods will permit the simultaneous study of large collections of samples of breast cancer patients as well as save time and cost while standardizing interpretation of outcomes of such studies. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  6. Effect of tetrahydrocurcumin on insulin receptor status in type 2 ...

    Indian Academy of Sciences (India)

    Mean specific binding of insulin was significantly lowered in diabetic rats with a decrease in plasma insulin. This was due to a significant decrease in mean insulin receptors. Erythrocytes from diabetic rats showed a decreased ability for insulin–receptor binding when compared with THC-treated diabetic rats. Scatchard ...

  7. Engagement of immune effector cells by trastuzumab induces HER2/ERBB2 downregulation in cancer cells through STAT1 activation

    Science.gov (United States)

    2014-01-01

    Introduction Trastuzumab has been widely used for the treatment of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer for more than a decade. However, reports on the involvement of HER2 downregulation in trastuzumab’s mechanism of action are inconsistent. The aim of this study is to investigate if the dependence of trastuzumab-mediated cancer cell HER2 downregulation on immune effector cells represents a novel mechanism of action for trastuzumab. Methods HER2 expression was evaluated by Western blotting, flow cytometry, and real-time polymerase chain reaction (PCR) in cell lysates from co-cultures of multiple cancer cell lines with peripheral blood mononuclear cells (PBMCs) in the presence or absence of trastuzumab. The engagement of immune cells by trastuzumab through Fc gamma receptors (FcγRs) was tested using three trastuzumab variants with compromised or no Fc (fragment crystallizable) functions and FcγRs blocking experiments. The engagement of immune cells by trastuzumab in HER2 downregulation was also evaluated in in vivo mouse xenograft tumor models. Results HER2 downregulation of cancer cells by trastuzumab occurred only when trastuzumab was actively engaged with immune cells and cancer cells, as demonstrated consistently in co-cultures of cancer cell lines with PBMCs and in vivo mouse xenograft tumor models. We further demonstrated that HER2 downregulation in cancer cells by immune-cell-engaged trastuzumab was at the transcriptional level, not through the HER2 degradation pathway. Activation of signal transducer and activator of transcription 1 (STAT1) in cancer cells by the increased interferon gamma (IFN-γ) production in immune cells played an important role in downregulating HER2 in cancer cells upon engagement of immune cells by trastuzumab. Furthermore, HER2 downregulation in cancer cells induced by trastuzumab engagement of immune cells was correlated with the antibody’s antitumor efficacy in vivo. Conclusions This

  8. Current status and perspectives in peptide receptor radiation therapy.

    Science.gov (United States)

    Ansquer, Catherine; Kraeber-Bodéré, Françoise; Chatal, Jean François

    2009-01-01

    Regulatory peptide receptors are overexpressed in numerous human cancers. The specific receptor binding property of peptides can be exploited by their labelling with a radionuclide and their use as carriers to guide the radioactivity to the tissues expressing their specific receptors. During the past decade, radiolabelled receptor-binding peptides have emerged as an important class of radiopharmaceuticals for tumour diagnosis and therapy. The first and most successful imaging agents to date are somatostatin analogues which are routinely used for somatostatin receptor scintigraphy. Peptide receptor radionuclide therapy (PRRT) with (90)Y-DOTA-octreotide and (177)Lu-DOTA-octreotate in neuroendocrine tumours (NETs) results in symptomatic improvement, prolonged survival, and enhanced quality of life. The results in terms of tumour regression are very encouraging with few and mostly mild side effects when patients are carefully selected and kidney protective agents are given. Nevertheless much profit can be gained from improving the available receptor-targeting strategies and developing new strategies. In this review, the current state of clinical use of radiolabelled peptides for diagnosis and therapy of NETs is presented. In addition, potential directions for optimization and future developments are discussed. These include the optimization of peptide analogues or derivatives, increasing the access and binding on specific receptors on the tumour sites, increasing radiotoxicity profile and multimodality strategies. Other peptides such as minigastrin, glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), bombesin (BN)/gastrin-releasing peptide (GRP), substance P, neurotensin (NT), neuropeptide Y (NPY) and RGD peptides are promising for PRRT and currently under preclinical and clinical development.

  9. Insulin-receptors in diabetes and altered thyroidal status

    International Nuclear Information System (INIS)

    Chaujar, Meena; Subramanian, G.B.V.; Yadav, H.S.; Chauhan, U.P.S.

    1991-01-01

    Rats were made hypothyroid by treating with a single dose of 800 μCi of 131 I and hyperthyroid condition was created by administering 90 μg of thyroxine daily for 2 weeks. Diabetes was produced by administering single dose of alloxan monohydrate. Hypothyroid rats showed significant increase in 125 I-insulin binding with its liver plasma membrane receptors with respect to normal rats. In the case of hypothyroid diabetic rats such binding was greater as compared to hypothyroid rats without diabetes. Hyperthyroid rats with respect to normal control rats showed a decrease in 125 I-insulin binding to its liver plasma membrane receptors. When hyperthyroid rats were made diabetic, 125 I-insulin binding to its receptors was further decreased. The study infers that hyper-thyrodism further decreases insulin binding to its receptors which has already been decreased in diabetes. Hypothyroidism, on the other hand, improves upon the decreased insulin binding to its receptors in diabetes. (author). 16 refs., 6 figs., 2 tabs

  10. Reliable PCR quantitation of estrogen, progesterone and ERBB2 receptor mRNA from formalin-fixed, paraffin-embedded tissue is independent of prior macro-dissection

    DEFF Research Database (Denmark)

    Tramm, Trine; Hennig, Guido; Kyndi, Marianne

    2013-01-01

    Gene expression analysis on messenger RNA (mRNA) purified from formalin-fixed, paraffin-embedded tissue is increasingly used for research purposes. Tissue heterogeneity may question specificity and interpretation of results from mRNA isolated from a whole slide section, and thresholds for minimal...

  11. Microarray-Based Determination of Estrogen Receptor, Progesterone Receptor, and HER2 Receptor Status in Breast Cancer

    NARCIS (Netherlands)

    Roepman, Paul; Horlings, Hugo M.; Krijgsman, Oscar; Kok, Marleen; Bueno-de-Mesquita, Jolien M.; Bender, Richard; Linn, Sabine C.; Glas, Annuska M.; van de Vijver, Marc J.

    2009-01-01

    Purpose: The level of estrogen receptor (ER), progesterone receptor (PR), and HER2 aids in the determination of prognosis and treatment of breast cancer. Immunohistochemistry is currently the predominant method for assessment, but differences in methods and interpretation can substantially affect

  12. Anti-N-methyl-D-aspartate receptor encephalitis with favorable outcome despite prolonged status epilepticus

    OpenAIRE

    Finné Lenoir, Xavier; Sindic, Christian; Van Pesch, Vincent; El Sankari, Souraya; de Tourtchaninoff, Marianne; Denays, Roger; Hantson, Philippe

    2013-01-01

    BACKGROUND: To describe a case of auto-immune encephalitis in an adolescent with favorable outcome despite prolonged status epilepticus. METHODS: A 17 year old Asian man without previous medical history developed alteration of consciousness and partial seizures. The diagnosis of anti-N-methyl-D-aspartate receptor encephalitis was confirmed by the detection of specific antibodies in both cerebrospinal fluid and serum. RESULTS: The clinical course was complicated by prolonged status epilepticus...

  13. Vitamin D status, receptor gene BsmI (A/G) polymorphism and ...

    African Journals Online (AJOL)

    Vitamin D status, receptor gene BsmI (A/G) polymorphism and breast cancer in a group of Egyptian females. Rasha Rizk Elzehery, Azza A. Baiomy, Mohamed AbdEl-Fattah Hegazy, Rami Fares, Abdel-Hady El-Gilany, Refaat Hegazi ...

  14. Factors affecting estrogen receptor status in a multiracial Asian country : An analysis of 3557 cases

    NARCIS (Netherlands)

    Yip, C. H.; Pathy, N. Bhoo; Uiterwaal, C. S.; Taib, N. A.; Tan, G. H.; Mun, K. S.; Choo, W. Y.; Rhodes, A.

    Estrogen receptor (ER) positive rates in breast cancer may be influenced by grade, stage, age and race. This study reviews the ER positive rates over a 15-year period at the University Malaya Medical Centre, Kuala Lumpur, Malaysia. Data on ER status of 3557 patients from 1994 to 2008 was analyzed.

  15. Sex, social status, and CRF receptor densities in naked mole-rats.

    Science.gov (United States)

    Beery, Annaliese K; Bicks, Lucy; Mooney, Skyler J; Goodwin, Nastacia L; Holmes, Melissa M

    2016-02-01

    Naked mole-rats (Heterocephalus glaber) live in groups that are notable for their large size and caste structure, with breeding monopolized by a single female and a small number of males. Recent studies have demonstrated substantial differences between the brains of breeders and subordinates induced by changes in social standing. Corticotropin-releasing factor (CRF) receptors-which bind the hormone CRF as well as related peptides-are important regulators of stress and anxiety, and are emerging as factors affecting social behavior. We conducted autoradiographic analyses of CRF1 and CRF2 receptor binding densities in female and male naked mole-rats varying in breeding status. Both globally and in specific brain regions, CRF1 receptor densities varied with breeding status. CRF1 receptor densities were higher in subordinates across brain regions, and particularly in the piriform cortex and cortical amygdala. Sex differences were present in CRF2 receptor binding densities, as is the case in multiple vole species. CRF2 receptor densities were higher in females, both globally and in the cortical amygdala and lateral amygdalar nucleus. These results provide novel insights into the neurobiology of social hierarchy in naked mole-rats, and add to a growing body of work that links changes in the CRF system with social behavior. © 2015 Wiley Periodicals, Inc.

  16. Differences in breast cancer hormone receptor status in ethnic groups: a London population.

    Science.gov (United States)

    Jack, Ruth H; Davies, Elizabeth A; Renshaw, Christine; Tutt, Andrew; Grocock, Melanie J; Coupland, Victoria H; Møller, Henrik

    2013-02-01

    Triple negative breast cancer (TNBC) is associated with different ethnic groups in the United States (US), however this has not previously been examined in a population-based study within the United Kingdom (UK). Electronic pathology reports from the North East London Cancer Network (NELCN) on women diagnosed with breast cancer between 2005 and 2007 were collated. The statuses of oestrogen receptor, progesterone receptor and HER-2 were extracted. Women were classified as having TNBC if all three receptor statuses were negative, and as not having TNBC if at least one receptor was positive or borderline. Logistic regression was used to quantify the association between TNBC and ethnicity, adjusting for age, year of diagnosis and socioeconomic deprivation. Overall survival in different ethnic groups was examined using Cox regression, adjusting as appropriate for age, stage of disease, triple negative status, year of diagnosis, socioeconomic deprivation and recorded treatment. There were 2417 women resident in NELCN diagnosed with breast cancer between 2005 and 2007, and TNBC status was determined for 1228 (51%) women. Overall, of women who had their TNBC status determined, 128 (10%) were diagnosed with TNBC. Compared with White women, Black (odds ratio [OR]=2.81, p<0.001) and South Asian (OR=1.80, p=0.044) women with breast cancer were more likely to have TNBC. Black women had a worse age-adjusted survival than White women (hazard ratio [HR]=2.05, p<0.001). This was attenuated by further adjustment for stage of disease (1.52, p=0.032) and triple negative status (1.31, p=0.175). Better methods of early detection may need to be developed in addition to more effective systemic treatment in order to improve outcomes for women with TNBC. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. Steroid receptor status in breast cancer: the roles of radioreceptor assay and immunohistochemistry

    International Nuclear Information System (INIS)

    Myint Aye Mu; Ch'ong

    1997-01-01

    A total of 24 cases of female breast cancer were reviewed, typed and graded based on the WHO classification. The steroid receptors (oestrogen and progesterone receptors) status was assessed using radio-receptor assay (RRA) and immunohistochemical (IH) method. The data showed that there were 21 cases of infiltrating ductal carcinoma of the breast and 3 cases of medullary carcinoma. The age of the patients ranged from 36 to 71 years and 4 patients were post-menopausal. The oestrogen receptor (ER) and progesteronc receptor (PR) status were analyzed by radio-receptor assay using 'H-oestradiol and 3 H-ORG respectively, and also by IH using immunoperoxidase detection assay (DAKO LSAB 2 Kit. Peroxidase K 677). Primary antibodies used were also procured from Dako Corp. and these were mouse anti-human ER and rabbit anti-human PR antibodies. On RRA analysis, 22 (95.7%) cases showed ER positivity (i.e. >20 fmol/mg of cytosol protien), and the ER content ranged from 16.64 to 297.8 fmovmg of cytosol protein. All cases showed PR positivity, and PR content ranged from 20.56 to 364 fmoumg of cytosol protein. A significant positive correlation was found between the ER content and PR content of tumour tissues (r = 0.7132, p<0.003). No significant association was found between ER content and menopausal status or histological grade IH showed that 10 of 24 cases (41.67%) showed ER positivity of which 8 were also PR positive. PR status was negative in all ER negative tissues. A decreasing trend in ER positivity was observed with worsening in histological grade (67% positivity in Grade 1, 50% positivity in Grade 11, and 33% positivity in Grade 111). ER and PR positivity occurred more frequently in pre-menopausal women. The results of this study showed that the result derived from IH method were found to have association with grade of tumour and confirmed findings by other workers. These findings revealed that although the quantitative data from radio-receptor assay for estimation of

  18. Positron emission mammography: correlation of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status and 18F-FDG.

    Science.gov (United States)

    Wang, Carolyn L; MacDonald, Lawrence R; Rogers, James V; Aravkin, Aleksandr; Haseley, David R; Beatty, J David

    2011-08-01

    The study objective was to assess the correlation between (18)F-FDG uptake values on positron emission mammography (PEM), expressed as maximum uptake value and lesion-to-background ratio, and receptor status (i.e., estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2]), tumor histology, and tumor grade. We also evaluated for the correlation between maximum uptake value on PEM and maximum uptake value on a whole-body PET/CT. We retrospectively reviewed our database for patients with newly diagnosed breast cancer who were referred for PEM between June 2007 and September 2009. A subset of patients also underwent a whole-body PET/CT scan. The original pathology reports were reviewed to establish the histologic type, grade, and receptor status. The study involved 98 patients with 100 lesions. ER-negative tumors and PR-negative tumors had significantly higher mean lesion-to-background ratio than did their respective receptor-positive tumors (p = 0.02). Triple-negative tumors (i.e., ER-negative, PR-negative, and HER2-negative tumors) had statistically higher mean lesion-to-background ratio than did ER-positive PR-positive HER2-negative tumors (p = 0.04). Infiltrating ductal carcinomas had significantly higher PEM FDG uptake values than did infiltrating lobular carcinomas (p = 0.02-0.04). Breast tumors with higher histologic grade also had significantly higher PEM FDG uptake values than did those with lower grade (p = 0.03 and p PEM uptake values. This study shows a correlation between PEM FDG uptake values and the prognostic factors that have been shown to predict breast cancer survival.

  19. NBCn1 and NHE1 expression and activity in DeltaNErbB2 receptor-expressing MCF-7 breast cancer cells: contributions to pHi regulation and chemotherapy resistance

    DEFF Research Database (Denmark)

    Lauritzen, G; Jensen, M B F; Bødtkjer, Ebbe

    2010-01-01

    Altered pH-regulatory ion transport is characteristic of many cancers; however, the mechanisms and consequences are poorly understood. Here, we investigate how a truncated, constitutively active ErbB2 receptor (DeltaNErbB2) common in breast cancer impacts on the Na(+)/H(+)-exchanger NHE1 and the ...

  20. Role of ErbB2 mediated AKT and MAPK pathway in gall bladder cell proliferation induced by argemone oil and butter yellow. Argemone oil and butter yellow induced gall bladder cell proliferation.

    Science.gov (United States)

    Mishra, Vivek; Ansari, Kausar M; Khanna, Raj; Das, Mukul

    2012-06-01

    The effect of noncytotoxic doses of argemone oil (AO) and butter yellow (BY), the common adulterants in edible oil, on free radical generation and signaling pathway for cell proliferation in primary cells of gall bladder (GB) was undertaken. AO and BY showed no cytotoxicity at 0.1 μl/ml and 0.1 μg/ml concentration, respectively. AO caused significant increase in ROS after 30 min and RNS after 24 h in GB cells while no change was observed following BY treatment. Enhanced level of COX-2 was observed following AO (0.1 μl/ml) and BY (0.1 μg/ml) treatment to cells for 24 h. AO treatment caused phosphorylation of ErbB2, AKT, ERK, and JNK along with increased thymidine uptake indicating cell proliferation ability in GB cells. BY treatment also showed significant expression of these proteins with the exception of phosphorylated JNK. These results suggest that AO and BY have cell proliferative potential in GB cells following up-regulation of COX-2 and ErbB2; however, their downstream signaling molecules and free radical generation have differential response, indicating that the mechanism of proliferation is different for both compounds and may have relevance in gall bladder cancer.

  1. Prognostic effect of estrogen receptor status across age in primary breast cancer

    DEFF Research Database (Denmark)

    Bentzon, N.; During, M.; Rasmussen, B.B.

    2008-01-01

    Estrogen receptor (ER) status is considered as an important prognostic factor as well as a predictive factor for endocrine responsiveness in breast cancer. We analyzed the distribution of ER status across age and estimated variations in the prognostic impact of ER status related to patients' age...... and time since diagnosis. Overall, 26,944 patients with primary breast cancer diagnosed from 1989 to 2004 were included. The proportion of ER positive tumors increased over age from 51 to 82%. In multivariate analysis of overall survival, ER positive status was found to be a significantly positive...... prognostic factor over all age groups. This effect was limited to the first 5 years after diagnosis, RR: 2.08 (95% CI: 1.95-2.22, p women with ER negative tumors, RR of death: 0.89 (95% CI: 0.79-1.00, p = 0.049). Results were...

  2. Outcomes of Breast Cancer Patients With Triple Negative Receptor Status Treated With Accelerated Partial Breast Irradiation

    International Nuclear Information System (INIS)

    Wilkinson, J. Ben; Reid, Robert E.; Shaitelman, Simona F.; Chen, Peter Y.; Mitchell, Christine K.; Wallace, Michelle F.; Marvin, Kimberly S.; Grills, Inga S.; Margolis, Jeffrey M.; Vicini, Frank A.

    2011-01-01

    Purpose: Triple negative receptor status (TNRS) of patients undergoing breast-conserving therapy treated with whole-breast irradiation has been associated with increased distant metastasis and decreased disease-free and overall survival. This paper reports the outcomes of TNRS patients treated with accelerated partial breast irradiation (APBI). Methods and Materials: We studied 455 patients who received APBI at our institution, using interstitial, intracavitary, and three-dimensional conformal radiation therapy. TNRS was assigned if a patient tested negative for all three (ER [estrogen receptor], PR [progesterone receptor], and HER2/neu) receptors. Of 202 patients with all receptor results available, 20 patients were designated TNRS, and 182 patients had at least one receptor positive (RP). We analyzed ipsilateral breast tumor recurrence (IBTR), regional nodal failure (RNF), distant metastasis (DM), and overall survival (OS). Results: Mean follow-up was 4.1 years for the TNRS group and 5.1 years for the RP cohort (p = 0.11). TNRS patients had a higher histologic grade (59% TNRS vs. 13% RP; p 0.52). OS for the RP cohort was 93% at 5 years (p > 0.28). Conclusions: In our patient population, TNRS conferred a clinical outcome similar to that of patients with RP disease treated with APBI. Further investigation with larger patient populations and longer follow-up periods is warranted to confirm that APBI is a safe and effective treatment for patients with localized TNRS breast cancer.

  3. A Machine Learned Classifier That Uses Gene Expression Data to Accurately Predict Estrogen Receptor Status

    Science.gov (United States)

    Bastani, Meysam; Vos, Larissa; Asgarian, Nasimeh; Deschenes, Jean; Graham, Kathryn; Mackey, John; Greiner, Russell

    2013-01-01

    Background Selecting the appropriate treatment for breast cancer requires accurately determining the estrogen receptor (ER) status of the tumor. However, the standard for determining this status, immunohistochemical analysis of formalin-fixed paraffin embedded samples, suffers from numerous technical and reproducibility issues. Assessment of ER-status based on RNA expression can provide more objective, quantitative and reproducible test results. Methods To learn a parsimonious RNA-based classifier of hormone receptor status, we applied a machine learning tool to a training dataset of gene expression microarray data obtained from 176 frozen breast tumors, whose ER-status was determined by applying ASCO-CAP guidelines to standardized immunohistochemical testing of formalin fixed tumor. Results This produced a three-gene classifier that can predict the ER-status of a novel tumor, with a cross-validation accuracy of 93.17±2.44%. When applied to an independent validation set and to four other public databases, some on different platforms, this classifier obtained over 90% accuracy in each. In addition, we found that this prediction rule separated the patients' recurrence-free survival curves with a hazard ratio lower than the one based on the IHC analysis of ER-status. Conclusions Our efficient and parsimonious classifier lends itself to high throughput, highly accurate and low-cost RNA-based assessments of ER-status, suitable for routine high-throughput clinical use. This analytic method provides a proof-of-principle that may be applicable to developing effective RNA-based tests for other biomarkers and conditions. PMID:24312637

  4. A machine learned classifier that uses gene expression data to accurately predict estrogen receptor status.

    Directory of Open Access Journals (Sweden)

    Meysam Bastani

    Full Text Available BACKGROUND: Selecting the appropriate treatment for breast cancer requires accurately determining the estrogen receptor (ER status of the tumor. However, the standard for determining this status, immunohistochemical analysis of formalin-fixed paraffin embedded samples, suffers from numerous technical and reproducibility issues. Assessment of ER-status based on RNA expression can provide more objective, quantitative and reproducible test results. METHODS: To learn a parsimonious RNA-based classifier of hormone receptor status, we applied a machine learning tool to a training dataset of gene expression microarray data obtained from 176 frozen breast tumors, whose ER-status was determined by applying ASCO-CAP guidelines to standardized immunohistochemical testing of formalin fixed tumor. RESULTS: This produced a three-gene classifier that can predict the ER-status of a novel tumor, with a cross-validation accuracy of 93.17±2.44%. When applied to an independent validation set and to four other public databases, some on different platforms, this classifier obtained over 90% accuracy in each. In addition, we found that this prediction rule separated the patients' recurrence-free survival curves with a hazard ratio lower than the one based on the IHC analysis of ER-status. CONCLUSIONS: Our efficient and parsimonious classifier lends itself to high throughput, highly accurate and low-cost RNA-based assessments of ER-status, suitable for routine high-throughput clinical use. This analytic method provides a proof-of-principle that may be applicable to developing effective RNA-based tests for other biomarkers and conditions.

  5. Mammographic features of calcifications in DCIS: correlation with oestrogen receptor and human epidermal growth factor receptor 2 status

    Energy Technology Data Exchange (ETDEWEB)

    Bae, Min Sun; Moon, Woo Kyung; Chang, Jung Min; Cho, Nariya [Seoul National University College of Medicine, Department of Radiology, Seoul (Korea, Republic of); Park, So Yeon; Won, Jae-Kyung; Jeon, Yoon-Kyung; Park, In Ae [Seoul National University College of Medicine, Department of Pathology, Seoul (Korea, Republic of); Moon, Hyeong-Gon; Han, Wonshik [Seoul National University College of Medicine, Department of Surgery, Seoul (Korea, Republic of)

    2013-08-15

    This study investigated the correlation of oestrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status with the probability of malignancy (POM) of mammographic calcifications in ductal carcinoma in situ (DCIS). A total of 101 women (age range, 27-83 years) with pure DCIS that presented as mammographic calcifications were included. Three radiologists independently reviewed mammograms according to the BI-RADS lexicon and provided 100-point POM scores and a BI-RADS category. ER, HER2 and breast cancer subtypes were determined using immunohistochemistry (IHC) and fluorescence in situ hybridisation. Pairwise correlations between POM and IHC biomarker scores were calculated, and mammographic features were compared between breast cancer subtypes. HER2 level positively correlated with the POM score (P < 0.0001) and BI-RADS category (P < 0.0001), and ER level inversely correlated with the POM score (P < 0.013) and BI-RADS category (P < 0.010). Fine linear branching (P = 0.004) and segmental (P = 0.014) calcifications were significantly associated with HER2-positive cancers, and clustered calcifications were more frequently observed in ER-positive cancers (P = 0.014). HER2 status in DCIS correlated positively with the POM of mammographic calcifications, as determined by radiologists on the basis of the BI-RADS lexicon. (orig.)

  6. Breast cancer incidence by estrogen receptor status in Denmark from 1996 to 2007

    DEFF Research Database (Denmark)

    Bigaard, J; Stahlberg, C; Jensen, M-B

    2012-01-01

    During the past 50 years, breast cancer incidence has increased by 2-3 % annually. Despite many years of testing for estrogen receptors (ER), evidence is scarce on breast cancer incidence by ER status. The aim of this paper was to investigate the increase in breast cancer incidence by ER status....... Data were obtained from the clinical database of the Danish Breast Cancer Cooperative Group which holds nationwide data on diagnosis, including pathology, treatment, and follow-up on primary breast cancers since 1977. All Danish women...

  7. Estrogen-Receptor, Progesterone-Receptor and HER2 Status Determination in Invasive Breast Cancer. Concordance between Immuno-Histochemistry and MapQuant™ Microarray Based Assay.

    Directory of Open Access Journals (Sweden)

    D Mouttet

    Full Text Available Hormone receptor status and HER2 status are of critical interest in determining the prognosis of breast cancer patients. Their status is routinely assessed by immunohistochemistry (IHC. However, it is subject to intra-laboratory and inter-laboratory variability. The aim of our study was to compare the estrogen receptor, progesterone receptor and HER2 status as determined by the MapQuant™ test to the routine immuno-histochemical tests in early stage invasive breast cancer in a large comprehensive cancer center.We retrospectively studied 163 invasive early-stage breast carcinoma with standard IHC status. The genomic status was determined using the MapQuant™ test providing the genomic grade index.We found only 4 tumours out of 161 (2.5% with discrepant IHC and genomic results concerning ER status. The concordance rate between the two methods was 97.5% and the Cohen's Kappa coefficient was 0.89. Comparison between the MapQuant™ PR status and the PR IHC status gave more discrepancies. The concordance rate between the two methods was 91.4% and the Cohen's Kappa coefficient was 0.74. The HER2 MapQuant™ test was classified as « undetermined » in 2 out of 163 cases (1.2%. One HER2 IHC-negative tumour was found positive with a high HER2 MapQuant™ genomic score. The concordance rate between the two methods was 99.3% and the Cohen's Kappa coefficient was 0.86.Our results show that the MapQuant™ assay, based on mRNA expression assay, provides an objective and quantitative assessment of Estrogen receptor, Progesterone receptor and HER2 status in invasive breast cancer.

  8. Estrogen-Receptor, Progesterone-Receptor and HER2 Status Determination in Invasive Breast Cancer. Concordance between Immuno-Histochemistry and MapQuant™ Microarray Based Assay

    Science.gov (United States)

    Mouttet, D.; Laé, M.; Caly, M.; Gentien, D.; Carpentier, S.; Peyro-Saint-Paul, H.; Vincent-Salomon, A.; Rouzier, R.; Sigal-Zafrani, B.; Sastre-Garau, X.; Reyal, F.

    2016-01-01

    Background Hormone receptor status and HER2 status are of critical interest in determining the prognosis of breast cancer patients. Their status is routinely assessed by immunohistochemistry (IHC). However, it is subject to intra-laboratory and inter-laboratory variability. The aim of our study was to compare the estrogen receptor, progesterone receptor and HER2 status as determined by the MapQuant™ test to the routine immuno-histochemical tests in early stage invasive breast cancer in a large comprehensive cancer center. Patients and Methods We retrospectively studied 163 invasive early-stage breast carcinoma with standard IHC status. The genomic status was determined using the MapQuant™ test providing the genomic grade index. Results We found only 4 tumours out of 161 (2.5%) with discrepant IHC and genomic results concerning ER status. The concordance rate between the two methods was 97.5% and the Cohen’s Kappa coefficient was 0.89. Comparison between the MapQuant™ PR status and the PR IHC status gave more discrepancies. The concordance rate between the two methods was 91.4% and the Cohen’s Kappa coefficient was 0.74. The HER2 MapQuant™ test was classified as « undetermined » in 2 out of 163 cases (1.2%). One HER2 IHC-negative tumour was found positive with a high HER2 MapQuant™ genomic score. The concordance rate between the two methods was 99.3% and the Cohen’s Kappa coefficient was 0.86. Conclusion Our results show that the MapQuant™ assay, based on mRNA expression assay, provides an objective and quantitative assessment of Estrogen receptor, Progesterone receptor and HER2 status in invasive breast cancer. PMID:26829108

  9. Model-based global sensitivity analysis as applied to identification of anti-cancer drug targets and biomarkers of drug resistance in the ErbB2/3 network

    Science.gov (United States)

    Lebedeva, Galina; Sorokin, Anatoly; Faratian, Dana; Mullen, Peter; Goltsov, Alexey; Langdon, Simon P.; Harrison, David J.; Goryanin, Igor

    2012-01-01

    High levels of variability in cancer-related cellular signalling networks and a lack of parameter identifiability in large-scale network models hamper translation of the results of modelling studies into the process of anti-cancer drug development. Recently global sensitivity analysis (GSA) has been recognised as a useful technique, capable of addressing the uncertainty of the model parameters and generating valid predictions on parametric sensitivities. Here we propose a novel implementation of model-based GSA specially designed to explore how multi-parametric network perturbations affect signal propagation through cancer-related networks. We use area-under-the-curve for time course of changes in phosphorylation of proteins as a characteristic for sensitivity analysis and rank network parameters with regard to their impact on the level of key cancer-related outputs, separating strong inhibitory from stimulatory effects. This allows interpretation of the results in terms which can incorporate the effects of potential anti-cancer drugs on targets and the associated biological markers of cancer. To illustrate the method we applied it to an ErbB signalling network model and explored the sensitivity profile of its key model readout, phosphorylated Akt, in the absence and presence of the ErbB2 inhibitor pertuzumab. The method successfully identified the parameters associated with elevation or suppression of Akt phosphorylation in the ErbB2/3 network. From analysis and comparison of the sensitivity profiles of pAkt in the absence and presence of targeted drugs we derived predictions of drug targets, cancer-related biomarkers and generated hypotheses for combinatorial therapy. Several key predictions have been confirmed in experiments using human ovarian carcinoma cell lines. We also compared GSA-derived predictions with the results of local sensitivity analysis and discuss the applicability of both methods. We propose that the developed GSA procedure can serve as a refining tool in combinatorial anti-cancer drug discovery. PMID:22085636

  10. Nutritional factors, physical activity, and breast cancer by hormonal receptor status.

    Science.gov (United States)

    Rosato, Valentina; Bertuccio, Paola; Bosetti, Cristina; Negri, Eva; Edefonti, Valeria; Ferraroni, Monica; Decarli, Adriano; Talamini, Renato; Dal Maso, Luigino; Falcini, Fabio; Montella, Maurizio; Franceschi, Silvia; La Vecchia, Carlo

    2013-10-01

    To investigate the association between food and nutrient intake, occupational and leisure-time physical activity, and body mass index and breast cancer risk by estrogen receptor (ER) and progesterone receptor (PR) status. We analyzed data from a hospital-based case-control study conducted between 1991 and 1994 in Italy, including 1075 women with incident breast cancer and 1477 controls. The associations with breast cancer risk were similar according to ER status for all risk factors considered. In particular, significant reduced risk of ER- and ER+ breast cancers were observed for raw vegetables (multivariate odds ratio, OR, for high vs low consumption: 0.6 and 0.7, respectively) and for polyunsaturated fats (OR: 0.6 and 0.7, respectively). No significant heterogeneous risk estimates were observed for combinations of ER and PR status. Our study does not suggest major differences risk for various dietary and lifestyle factors according to ER and PR breast cancer subtypes. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Subjective social status predicts in vivo responsiveness of β-adrenergic receptors.

    Science.gov (United States)

    Euteneuer, Frank; Mills, Paul J; Rief, Winfried; Ziegler, Michael G; Dimsdale, Joel E

    2012-07-01

    Several poor health outcomes, including cardiovascular risk, have been associated with both subjective social status (SSS) and sympathetic overactivity. Because prolonged sympathetic overactivation down regulates beta adrenergic receptor (β-AR) function, reduced β-AR responsiveness is considered an indicator of sympathetic overactivity and a cardiovascular risk factor. Though prior research has focused on objective social status and β-AR function, no studies have examined the association between SSS and β-AR function. We aimed to learn whether SSS predicts the in vivo responsiveness of β-ARs. We assessed the chronotropic 25 dose (CD25), an in vivo marker of β-AR responsiveness, in 94 healthy participants. The MacArthur scales of subjective social status were used to assess SSS in the U.S.A. (SSS-USA) and in the local community (SSS-C). Objective social status was analyzed by calculating the Hollingshead two-factor index. β-AR responsiveness was reduced (as indicated by higher CD25 values) in participants with lower SSS-USA (p = .007) and lower SSS-C (p social status. Our results indicate that β-AR function may be an important component of the link between SSS and health.

  12. Dopamine D3 receptor status modulates sexual dimorphism in voluntary wheel running behavior in mice.

    Science.gov (United States)

    Klinker, Florian; Ko Hnemann, Kathrin; Paulus, Walter; Liebetanz, David

    2017-08-30

    Sexual dimorphism has been described in various aspects of physiological and pathophysiological processes involving dopaminergic signaling. This might account for the different disease characteristics in men and women in e.g. Parkinson's disease or ADHD. A better understanding might contribute to the future individualization of therapy. We examined spontaneous wheel running activity of male and female mice, homo- and heterozygote for dopamine D3 receptor deficiency (D3R -/- and D3R+/-), and compared them to wild type controls. We found higher wheel running activity in female mice than in their male littermates. D3-/- mice, irrespective of sex, were also hyperactive compared to both D3+/- and wild type animals. Hyperactivity of D3-/- female mice was pronounced during the first days of wheel running but then decreased while their male counterparts continued to be hyperactive. Physical activity was menstrual cycle-dependent. Activity fluctuations were also seen in D3 receptor knockout mice and are therefore presumably independent of D3 receptor activation. Our data underscore the complex interaction of dopaminergic signaling and gonadal hormones that leads to specific running behavior. Furthermore, we detected sex- and D3 receptor status-specific reactions during novel exposure to the running wheel. These findings suggest the need for adapting dopaminergic therapies to individual factors such as sex or even menstrual cycle to optimize therapeutic success. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Radioligands for PET studies of central benzodiazepine receptors and PK (peripheral benzodiazepine) binding sites -current status

    International Nuclear Information System (INIS)

    Pike, V.W.; Osman, S.; Shah, F.; Turton, D.R.; Waters, S.L.; Crouzel, C.; Nutt, D.J.

    1993-01-01

    The status of the radiochemical development and biological evaluation of radioligands for PET studies of central benzodiazepine (BZ) receptors and the so-called peripheral benzodiazepine binding sites, here discriminated and referred to as PK binding sites, is reviewed against current pharmacological knowledge, indicating those agents with present value and those with future potential. Practical recommendations are given for the preparation of two useful radioligands for PET studies, [N-methyl- 11 C]flumazenil for central BZ receptors, and [N-methyl- 11 C]PK 11195 for PK binding sites. Quality assurance and plasma metabolite analysis are also reviewed for these radioligands and practical recommendations are given on methodology for their performance. (Author)

  14. Prognostic factors in advanced breast cancer: Race and receptor status are significant after development of metastasis.

    Science.gov (United States)

    Ren, Zhiyong; Li, Yufeng; Shen, Tiansheng; Hameed, Omar; Siegal, Gene P; Wei, Shi

    2016-01-01

    Prognostic factors are well established in early-stage breast cancer (BC), but less well-defined in advanced disease. We analyzed 323 BC patients who had distant relapse during follow-up from 1997 to 2010 to determine the significant clinicopathologic factors predicting survival outcomes. By univariate analysis, race, tumor grade, estrogen and progesterone receptors (ER/PR) and HER2 status were significantly associated with overall survival (OS) and post-metastasis survival (PMS). Applying a Cox regression model revealed that all these factors remained significant for PMS, while race, tumor grade and HER2 were independent factors for OS. Tumor grade was the only significant factor for metastasis-free survival by univariate and multivariate analyses. Our findings demonstrated that being Caucasian, hormonal receptor positive (HR+) and HER2 positive (HER2+) were all associated with a decreased hazard of death and that patients with HR+/HER2+ tumors had superior outcomes to those with HR+/HER2- disease. Further, PR status held a prognostic value over ER, thus reflecting the biologic mechanism of the importance of the functional ER pathway and the heterogeneity in the response to endocrine therapy. These observations indicate that the patients' genetic makeup and the intrinsic nature of the tumor principally govern BC progression and prognosticate the long-term outcomes in advanced disease. Copyright © 2015 Elsevier GmbH. All rights reserved.

  15. Strong association of epidermal growth factor receptor status with breast cancer FDG uptake

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Joohee; Moon, Seung Hwan; Hyun, Seung Hyup; Cho, Young Seok; Choi, Joon Young; Kim, Byung-Tae; Lee, Kyung-Han [Sungkyunkwan University School of Medicine, Department of Nuclear Medicine, Samsung Medical Center, Seoul (Korea, Republic of); Lee, Eun Jeong [Seoul Medical Center, Department of Nuclear Medicine, Seoul (Korea, Republic of); Kim, Seokhwi [Sungkyunkwan University School of Medicine, Department of Pathology, Samsung Medical Center, Seoul (Korea, Republic of)

    2017-08-15

    Imaging tumor FDG uptake could complement breast cancer biomarkers of risk and treatment response. Although breast cancer FDG uptake is reputedly influenced by major biomarker states, the role of epidermal growth factor receptor (EGFR) expression remains largely unexplored. This is a retrospective study that included 499 patients with primary breast cancer at initial presentation. Tumor FDG uptake was measured on pretreatment PET/CT as maximum standardized uptake value (SUVmax), and biomarkers were assessed by immunohistochemistry of tumor tissue. Regression analysis was performed for predictors of high tumor FDG uptake (SUVmax ≥ 8.6). SUVmax was higher in ER- (36.5%; 11.2 ± 6.0 vs. 8.3 ± 5.3), PR- (42.3%; 10.9 ± 6.0 vs. 8.2 ± 5.2), and triple-negative tumors (19.8%; 12.0 ± 6.9 vs. 8.7 ± 5.2; all p < 0.0001). EGFR expression (28.5%) was more frequent in ER-, PR-, triple-negative, cytokeratin 5/6 (CK5/6) + and mutant P53 (mP53) + tumors (all p < 0.0001). EGFR+ was associated with higher SUVmax among all tumors (11.9 ± 6.0 vs. 8.3 ± 5.3), ER- tumors (p < 0.0001), PR- and + tumors (p < 0.0001 and 0.027), hormone receptor- and + tumors (p < 0.0001 and 0.004), human epidermal growth factor receptor 2 (HER2)- and + tumors (p < 0.0001 and 0.006), non-triple negative tumors (p < 0.0001), CK5/6- and + tumors (p = 0.021 and <0.0001), and mP53- and + tumors (p < 0.0001 and 0.008). Tumors had high FDG uptake in 73.2% of EGFR+ and 40.6% of EGFR- tumors. On regression analysis, significant multivariate predictors of high tumor FDG uptake were large size, EGFR+ and CK5/6+ for the entire subjects, and EGFR+ and CK5/6+ for ER- and hormone receptor negative subgroups. High FDG uptake was able to sub-stratify EGFR+ tumors that were more likely to be ER- and CK5/6+, and EGFR- tumors more likely to be mP53 +. Primary breast tumor FDG uptake is strongly influenced by EGFR status beyond that by other major biomarkers including hormone receptor and HER2 status, and EGFR

  16. The Role of Novel Substituted Diindolyl Methane Analogues in the Treatment of Triple-Negative and ErbB2-Positive Breast Cancer

    Science.gov (United States)

    2015-05-01

    DAX-1, an unusual orphan receptor at the crossroads of steroidogenic function and sexual differentiation, Mol. Endocrinol. 17 (2003) 1445–1453. [3] E...C.H. Park, M.S. Lim, Y.H. Rhee, S.H. Yi, B.K. Kim, J.W. Shim, Y.H. Kim, S.J. Jung , S. H. Lee, In vitro generation of mature dopamine neurons by

  17. Validation of a proxy for estrogen receptor status in breast cancer patients using dispensing data.

    Science.gov (United States)

    Srasuebkul, Preeyaporn; Dobbins, Timothy A; Pearson, Sallie-Anne

    2014-06-01

    To assess the performance of a proxy for estrogen receptor (ER) status in breast cancer patients using dispensing data. We derived our proxy using 167 patients. ER+ patients had evidence of at least one dispensing record for hormone therapy during the lookback period, irrespective of diagnosis date and ER- had no dispensing records for hormone therapy during the period. We validated the proxy against our gold standard, ER status from pathology reports or medical records. We assessed the proxy's performance using three lookback periods: 4.5 years, 2 years, 1 year. More than half of our cohort (62%) were >50 years, 54% had stage III/IV breast cancer at recruitment, (46%) were diagnosed with breast cancer in 2009 and 23% were diagnosed before 2006. Sensitivity and specificity were high for the 4.5 year lookback period (93%, 95% CI: 86-96%; and 95%: 83-99%), respectively) and remained high for the 2-year lookback period (91%: 84-95%; and 95%: 83-99%). Sensitivity decreased (83%: 75.2-89%) but specificity remained high (95%: 83-99%) using the 1-year lookback period and the period is long enough to allow sufficient time for hormone therapy to be dispensed. Our proxy accurately infers ER status in studies of breast cancer treatment based on secondary health data. The proxy is most robust with a minimum lookback period of 2 years. © 2012 Wiley Publishing Asia Pty Ltd.

  18. MET and PTEN gene copy numbers and Ki-67 protein expression associate with pathologic complete response in ERBB2-positive breast carcinoma patients treated with neoadjuvant trastuzumab-based therapy

    International Nuclear Information System (INIS)

    Calhoun, Benjamin C.; Portier, Bryce; Wang, Zhen; Minca, Eugen C.; Budd, G. Thomas; Lanigan, Christopher; Tubbs, Raymond R.; Morrison, Larry E.

    2016-01-01

    Pathologic complete response (pCR) after neoadjuvant chemotherapy for breast cancer is associated with improved prognosis in aggressive tumor subtypes, including ERBB2- positive tumors. Recent adoption of pCR as a surrogate endpoint for clinical trials in early stage breast cancer in the neoadjuvant setting highlights the need for biomarkers that, alone or in combination, help predict the likelihood of response to treatment. Biopsy specimens from 29 patients with invasive ductal carcinoma treated with trastuzumab-based therapy prior to definitive resection and pathologic staging were evaluated by dual color bright field in situ hybridization (dual ISH) using probes for MET, TOP2A, PTEN, and PIK3CA genes, each paired with centromeric probes to their respective chromosomes (chromosomes 7, 17, 10, and 3). Ki-67 expression was assessed by immunohistochemistry (IHC). Various parameters describing copy number alterations were evaluated for each gene and centromere probe to identify the optimal parameters for clinical relevance. Combinations of ISH parameters and IHC expression for Ki-67 were also evaluated. Of the four genes and their respective chromosomes evaluated by ISH, two gene copy number parameters provided statistically significant associations with pCR: MET gain or loss relative to chromosome 7 (AUC = 0.791, sensitivity = 92 % and specificity = 67 % at optimal cutoff, p = 0.0032) and gain of PTEN (AUC = 0.674, sensitivity = 38 % and specificity = 100 % at optimal cutoff, p = 0.039). Ki-67 expression was also found to associate significantly with pCR (AUC = 0.726, sensitivity = 100 % and specificity = 42 % at optimal cutoff, p = 0.0098). Combining gain or loss of MET relative to chromosome 7 with Ki-67 expression further improved the association with pCR (AUC = 0.847, sensitivity = 92 % and specificity = 83 % at optimal cutoffs, p = 0.0006). An immunogenotypic signature of low complexity comprising MET relative copy number and Ki-67 expression generated by dual

  19. Deep Learning Accurately Predicts Estrogen Receptor Status in Breast Cancer Metabolomics Data.

    Science.gov (United States)

    Alakwaa, Fadhl M; Chaudhary, Kumardeep; Garmire, Lana X

    2018-01-05

    Metabolomics holds the promise as a new technology to diagnose highly heterogeneous diseases. Conventionally, metabolomics data analysis for diagnosis is done using various statistical and machine learning based classification methods. However, it remains unknown if deep neural network, a class of increasingly popular machine learning methods, is suitable to classify metabolomics data. Here we use a cohort of 271 breast cancer tissues, 204 positive estrogen receptor (ER+), and 67 negative estrogen receptor (ER-) to test the accuracies of feed-forward networks, a deep learning (DL) framework, as well as six widely used machine learning models, namely random forest (RF), support vector machines (SVM), recursive partitioning and regression trees (RPART), linear discriminant analysis (LDA), prediction analysis for microarrays (PAM), and generalized boosted models (GBM). DL framework has the highest area under the curve (AUC) of 0.93 in classifying ER+/ER- patients, compared to the other six machine learning algorithms. Furthermore, the biological interpretation of the first hidden layer reveals eight commonly enriched significant metabolomics pathways (adjusted P-value machine learning methods. Among them, protein digestion and absorption and ATP-binding cassette (ABC) transporters pathways are also confirmed in integrated analysis between metabolomics and gene expression data in these samples. In summary, deep learning method shows advantages for metabolomics based breast cancer ER status classification, with both the highest prediction accuracy (AUC = 0.93) and better revelation of disease biology. We encourage the adoption of feed-forward networks based deep learning method in the metabolomics research community for classification.

  20. Coffee prevents early events in tamoxifen-treated breast cancer patients and modulates hormone receptor status.

    Science.gov (United States)

    Simonsson, Maria; Söderlind, Viktoria; Henningson, Maria; Hjertberg, Maria; Rose, Carsten; Ingvar, Christian; Jernström, Helena

    2013-05-01

    Whether coffee modulates response to endocrine therapy in breast cancer patients is currently unknown. The CYP1A2 and CYP2C8 enzymes contribute to tamoxifen and caffeine metabolism. The purpose was to investigate the impact of coffee consumption on tumor characteristics and risk for early events in relation to breast cancer treatment and CYP1A2 and CYP2C8 genotypes. Questionnaires regarding lifestyle were completed preoperatively by 634 patients in southern Sweden. CYP1A2*1F and CYP2C8*3 were genotyped. Clinical data and tumor characteristics were obtained from patients' charts, population registries, and pathology reports. Coffee consumption was categorized as low (0-1 cups/day), moderate (2-4 cups/day), or high (5+ cups/day). The proportion of estrogen receptor negative (ER-) tumors increased with increasing coffee consumption (p trend = 0.042). Moderate to high consumption was associated with lower frequency of discordant receptor status (ER + PgR-) OR 0.38 (0.23-0.63) compared to low consumption. Median follow-up time was 4.92 (IQR 3.01-6.42) years. Tamoxifen-treated patients with ER+ tumors (n = 310) who consumed two or more cups/day had significantly decreased risk for early events compared to patients with low consumption, adjusted HR 0.40 (0.19-0.83). Low consumption combined with at least one CYP1A2*1F C-allele (n = 35) or CYP2C8*3 (n = 13) was associated with a high risk for early events in tamoxifen-treated patients compared to other tamoxifen-treated patients, adjusted HRs 3.49 (1.54-7.91) and 6.15 (2.46-15.36), respectively. Moderate to high coffee consumption was associated with significantly decreased risk for early events in tamoxifen-treated patients and modified hormone receptor status. If confirmed, new recommendations regarding coffee consumption during tamoxifen treatment may be warranted.

  1. Prognostic impact of pregnancy after breast cancer according to estrogen receptor status

    DEFF Research Database (Denmark)

    Azim, Hatem A; Kroman, Niels; Paesmans, Marianne

    2013-01-01

    PURPOSE We questioned the impact of pregnancy on disease-free survival (DFS) in women with history of breast cancer (BC) according to estrogen receptor (ER) status. PATIENTS AND METHODS A multicenter, retrospective cohort study in which patients who became pregnant any time after BC were matched (1....... The primary objective was DFS in patients with ER-positive BC. DFS in the ER-negative cohort, whole population, and overall survival (OS) were secondary objectives. Subgroup analyses included DFS according to pregnancy outcome and BC-pregnancy interval. With a two-sided α = 5% and β = 20%, 645 ER.......91; 95% CI, 0.67 to 1.24, P = .55) or the ER-negative (HR = 0.75; 95% CI, 0.51 to 1.08, P = .12) cohorts. However, the pregnant group had better OS (HR = 0.72; 95% CI, 0.54 to 0.97, P = .03), with no interaction according to ER status (P = .11). Pregnancy outcome and BC-pregnancy interval did not seem...

  2. Gene expression signature of estrogen receptor α status in breast cancer

    Directory of Open Access Journals (Sweden)

    Baggerly Keith

    2005-03-01

    Full Text Available Abstract Background Estrogens are known to regulate the proliferation of breast cancer cells and to modify their phenotypic properties. Identification of estrogen-regulated genes in human breast tumors is an essential step toward understanding the molecular mechanisms of estrogen action in cancer. To this end we generated and compared the Serial Analysis of Gene Expression (SAGE profiles of 26 human breast carcinomas based on their estrogen receptor α (ER status. Thus, producing a breast cancer SAGE database of almost 2.5 million tags, representing over 50,000 transcripts. Results We identified 520 transcripts differentially expressed between ERα-positive (+ and ERα-negative (- primary breast tumors (Fold change ≥ 2; p Estrogen Responsive Elements (EREs distributed on the promoter regions of 163 out of the 473 up-modulated genes in ERα (+ breast tumors. In brief, we observed predominantly up-regulation of cell growth related genes, DNA binding and transcription factor activity related genes based on Gene Ontology (GO biological functional annotation. GO terms over-representation analysis showed a statistically significant enrichment of various transcript families including: metal ion binding related transcripts (p = 0.011, calcium ion binding related transcripts (p = 0.033 and steroid hormone receptor activity related transcripts (p = 0.031. SAGE data associated with ERα status was compared with reported information from breast cancer DNA microarrays studies. A significant proportion of ERα associated gene expression changes was validated by this cross-platform comparison. However, our SAGE study also identified novel sets of genes as highly expressed in ERα (+ invasive breast tumors not previously reported. These observations were further validated in an independent set of human breast tumors by means of real time RT-PCR. Conclusion The integration of the breast cancer comparative transcriptome analysis based on ERα status coupled to

  3. Short-term breast cancer survival in relation to ethnicity, stage, grade and receptor status: national cohort study in England.

    Science.gov (United States)

    Møller, Henrik; Henson, Katherine; Lüchtenborg, Margreet; Broggio, John; Charman, Jackie; Coupland, Victoria H; Davies, Elizabeth; Jack, Ruth H; Sullivan, Richard; Vedsted, Peter; Horgan, Kieran; Pearce, Neil; Purushotham, Arnie

    2016-11-22

    In the re-organisation of cancer registration in England in 2012, a high priority was given to the recording of cancer stage and other prognostic clinical data items. We extracted 86 852 breast cancer records for women resident in England and diagnosed during 2012-2013. Information on age, ethnicity, socio-economic status, comorbidity, tumour stage, grade, morphology and oestrogen, progesterone and HER2 receptor status was included. The two-year cumulative risk of death from any cause was estimated with the Kaplan-Meier method, and univariate and multivariate Cox proportional hazards regressions were used to estimate hazard ratios (HR) and their 95% confidence intervals (95% CI). The follow-up ended on 31 December 2014. The completeness of registration for prognostic variables was generally high (around 80% or higher), but it was low for progesterone receptor status (41%). Women with negative receptor status for each of the oestrogen, progesterone and HER2 receptors (triple-negative cancers) had an adjusted HR for death of 2.00 (95%CI 1.84-2.17). Black women had an age-adjusted HR of 1.77 (1.48-2.13) compared with White women. The excess mortality of Black women with breast cancer has contributions from socio-economic factors, stage distribution and tumour biology. The study illustrates the richness of detail in the national cancer registration data. This allows for analysis of cancer outcomes at a high level of resolution, and may form the basis for risk stratification.

  4. Transactivation of ErbB receptors by leptin in the cardiovascular system: mechanisms, consequences and target for therapy.

    Science.gov (United States)

    Bełtowski, Jerzy; Jazmroz-Wiśniewska, Anna

    2014-01-01

    Many experimental and clinical studies have demonstrated that elevated leptin concentration in patients with obesity/metabolic syndrome contributes to the pathogenesis of cardiovascular disorders including arterial hypertension, atherosclerosis, restenosis after coronary angioplasty and myocardial hypertrophy. Receptor tyrosine kinases belonging to the ErbB family, especially ErbB1 (epidermal growth factor receptor) and ErbB2 are abundantly expressed in the blood vessels and the heart. EGFR is activated not only by its multiple peptide ligands but also by many other factors including angiotensin II, endothelin-1, norepinephrine, thrombin and prorenin; the phenomenon referred to as "transactivation". Augmented EGFR signaling contributes to abnormalities of vascular tone and renal sodium handling as well as vascular remodeling and myocardial hypertrophy through various intracellular mechanisms, in particular extracellular signal-regulated kinases (ERK) and phosphoinositide 3-kinase (PI3K). Recent experimental studies indicate that chronically elevated leptin transactivates the EGFR through the mechanisms requiring reactive oxygen species and cytosolic tyrosine kinase, c-Src. In addition, hyperleptinemia increases ErbB2 activity in the arterial wall. Stimulation of EGFR and ErbB2 downstream signaling pathways such as ERK and PI3K in the vascular wall and the kidney may contribute to the increase in vascular tone, enhanced tubular sodium reabsorption as well as vascular and renal lesions in hyperleptinemic obese subjects.

  5. Optical redox ratio differentiates breast cancer cell lines based on estrogen receptor status.

    Science.gov (United States)

    Ostrander, Julie Hanson; McMahon, Christine M; Lem, Siya; Millon, Stacy R; Brown, J Quincy; Seewaldt, Victoria L; Ramanujam, Nimmi

    2010-06-01

    Autofluorescence spectroscopy is a powerful imaging technique that exploits endogenous fluorophores. The endogenous fluorophores NADH and flavin adenine dinucleotide (FAD) are two of the principal electron donors and acceptors in cellular metabolism, respectively. The optical oxidation-reduction (redox) ratio is a measure of cellular metabolism and can be determined by the ratio of NADH/FAD. We hypothesized that there would be a significant difference in the optical redox ratio of normal mammary epithelial cells compared with breast tumor cell lines and that estrogen receptor (ER)-positive cells would have a higher redox ratio than ER-negative cells. To test our hypothesis, the optical redox ratio was determined by collecting the fluorescence emission for NADH and FAD via confocal microscopy. We observed a statistically significant increase in the optical redox ratio of cancer compared with normal cell lines (P < 0.05). Additionally, we observed a statistically significant increase in the optical redox ratio of ER(+) breast cancer cell lines. The level of ESR1 expression, determined by real-time PCR, directly correlated with the optical redox ratio (Pearson's correlation coefficient = 0.8122, P = 0.0024). Furthermore, treatment with tamoxifen and ICI 182,870 statistically decreased the optical redox ratio of only ER(+) breast cancer cell lines. The results of this study raise the important possibility that fluorescence spectroscopy can be used to identify subtypes of breast cancer based on receptor status, monitor response to therapy, or potentially predict response to therapy. This source of optical contrast could be a potentially useful tool for drug screening in preclinical models. Copyright 2010 AACR.

  6. Risk of second breast cancers after lobular carcinoma in situ according to hormone receptor status.

    Directory of Open Access Journals (Sweden)

    Kai Mao

    Full Text Available Although subsequent breast cancer risk after primary lobular carcinoma in situ (LCIS has been studied intensively, whether the risk of second breast cancer after first LCIS varies with hormone receptor (HR status of primary tumor remains unclear.We identified 10,304 women with primary pure unilateral LCIS between 1998 and 2007 from the Surveillance, Epidemiology and End Results (SEER 18 Registries. Kaplan-Meier estimates of 5 or 10-year probabilities of second ipsilateral breast cancers (IBCs and contralateral breast cancers (CBCs were calculated. Multivariable Cox proportional model was performed to identify impact of HR status of primary LCIS, and other demographic, clinicopathologic or treatment characteristics on risk of second IBCs or CBCs.Of the 10,304 women with primary LCIS included in this study, 9949 (96.5% patients had HR+ tumors, and 355 (3.5% had HR- tumors. Multivariable-adjusted analyses showed that although there was no difference in risk of total second IBCs between women with HR+ and HR- LCIS (P = 0.152, patients with HR+ LCIS had a statistically lower risk of second invasive IBCs compared to those with HR- LCIS (hazard ratio 0.356, 95% CI 0.141-0.899, P = 0.029. Women with primary HR+ LCIS had lower risks of both second total and invasive CBCs compared to those with HR- LCIS (total CBCs: hazard ratio 0.340, 95% CI 0.228-0.509, P<0.001; invasive CBCs: hazard ratio 0.172, 95% CI 0.108-0.274, P<0.001. Additionally, black women had a 2-fold risk of developing subsequent total IBCs than white women (P = 0.028.This population-based study demonstrated that the risk of second breast cancers was significantly increased in women with HR- first LCIS compared to those with HR+ LCIS. These findings warrant intensive surveillance for second breast cancers in HR- LCIS survivors.

  7. Serum transferrin receptor and zinc protoporphyrin as indicators of iron status in African children.

    Science.gov (United States)

    Zimmermann, Michael B; Molinari, Luciano; Staubli-Asobayire, Franziska; Hess, Sonja Y; Chaouki, Noureddine; Adou, Pierre; Hurrell, Richard F

    2005-03-01

    Although transferrin receptor (TfR) and zinc protoporphyrin (ZnPP) are often used to define iron status in school-age children in developing countries, the diagnostic cutoffs for this age group are uncertain. The objective was to determine the sensitivity and specificity of TfR and ZnPP in predicting iron deficiency in black and white children in Africa. Hemoglobin, C-reactive protein (CRP), serum ferritin (SF), TfR, and ZnPP were measured in children in Côte d'Ivoire and Morocco. We excluded children with elevated CRP and then used receiver operating characteristic (ROC) curves to evaluate TfR and ZnPP alone and in combination in screening for iron deficiency, defined as an SF concentration ZnPP were limited by considerable overlap between iron-sufficient, nonanemic children and those with IDA. On the basis of ROC curves, we identified diagnostic cutoffs for TfR and ZnPP that achieved specificities and sensitivities of approximately 60-80%. Separate cutoffs for Côte d'Ivoire and Morocco gave the best performance; the cutoffs for both TfR and ZnPP were higher in Côte d'Ivoire. Moreover, a comparison of nonanemic, iron-sufficient subjects showed that Ivorian children had significantly higher TfR and ZnPP concentrations than did Moroccan children (P ZnPP, based on ROC curve analyses, may improve the performance of these indexes in defining iron status in children. Significant ethnic differences in TfR and ZnPP suggest that separate cutoffs may be needed for black and white children.

  8. Risk of second breast cancer according to estrogen receptor status and family history.

    Science.gov (United States)

    Bouchardy, Christine; Benhamou, Simone; Fioretta, Gérald; Verkooijen, Helena M; Chappuis, Pierre O; Neyroud-Caspar, Isabelle; Castiglione, Monica; Vinh-Hung, Vincent; Vlastos, Georges; Rapiti, Elisabetta

    2011-05-01

    A recent study reported an increased risk of contralateral estrogen-negative breast cancer after a first primary estrogen-negative breast cancer. Our study aims to confirm this result and to evaluate how the risk of second breast cancer occurrence is affected by family history of breast cancer and anti-estrogen treatment. We included all 4,152 women diagnosed with breast cancer between 1995 and 2007, using data from the population-based Geneva Cancer Registry. We compared the incidence of second breast cancer among patients according to estrogen receptor (ER) status with that expected in the general population by age-period Standardized Incidence Ratios (SIRs). Among the cohort, 63 women developed second breast cancer. Patients with ER-positive first tumors had a decreased risk of second breast cancer occurrence (SIR: 0.67, 95% CI: 0.48-0.90), whereas patients with ER-negative primary tumors had an increased risk (SIR: 1.98, 95% CI: 1.19-3.09) limited to ER-negative second tumors (SIR: 7.94, 95% CI: 3.81-14.60). Patients with positive family history had a tenfold (SIR: 9.74, 95% CI: 3.57-21.12) higher risk of ER-negative second tumor which increased to nearly 50-fold (SIR: 46.18, 95% CI: 12.58-118.22) when the first tumor was ER-negative. Treatment with anti-estrogen decreased the risk of second ER-positive tumors but not ER-negative tumors. The risk of second ER-negative breast cancer is very high after a first ER-negative tumor, in particular among women with strong family history. Surveillance and prevention of second cancer occurrence should consider both ER status of the first tumor and family history.

  9. Pattern of brain metastatic disease according to HER-2 and ER receptor status in breast cancer patients.

    Science.gov (United States)

    Lekanidi, K; Evans, A L; Shah, J; Jaspan, T; Baker, L; Evans, A J

    2013-10-01

    To document the type, location, extent, and complications of brain metastases in patients with breast cancer and identify associations with oestrogen receptor (ER) negative and human epidermal growth factor receptor 2 (HER-2) receptor expression. Breast cancer patients with known brain metastases were included in this retrospective study, if cross-sectional imaging of the brain [computed tomography (CT)] was available to review and HER-2 and ER status was known. Two neuroradiologists, who were blinded to the receptor status, separately and for each patient, documented on a proforma the location, number, and dimensions of the deposits and the presence or absence of hydrocephalus. Adjudication was sought where there was discrepancy between the two reports. ER status, HER-2 receptor status, and patient age were also documented. The results were analysed using two-sided Fisher's exact tests with Lancaster's mid-P correction and associations were sought between the tumour characteristics and the pattern of brain disease. Sixty patients were included in the study. There was an association between young age (brain stem metastases [11 of 18 (61%) versus three of 26 (11.5%); p = 0.035], more frequent occurrence of hydrocephalus [7 of 12 (36.8%) versus three of 26 (11.5%); p = 0.049], and a higher incidence of occipital metastases [12 of 18 (66.7%) versus eight of 26 (30.8%); p = 0.029]. ER-negative HER-2-positive women are more likely to present with a larger number of lesions, more brain stem/occipital metastases, and hydrocephalus, which may predispose them to unfavourable outcomes following treatment. Copyright © 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

  10. Iron status of Filipino infants and preschoolers using plasma ferritin and transferrin receptor levels.

    Science.gov (United States)

    Kuizon, M D; Madriaga, J R; Desnacido, J A; Cheong, R L; Perlas, L A

    1996-06-01

    Iron status of 1,861 Filipino infants and preschoolers was evaluated by measurements of plasma ferritin (PF), transferrin receptor (TR) and hemoglobin (Hb). One group of subjects (Group I) consisted of all anemic subjects together with a systematic subsample from the Fourth National Nutrition Survey-Biochemical Phase. Results showed that depleted iron stores based on PF ( 8.5 mg/l) was present in higher proportion (80.0% and 73.7% for infants and preschoolers) which was comparable to the proportion of anemia (80.3%). In a subgroup of subjects from the Country Program for Children IV (Group 2) elevated TR was present in 61.4% of infants and 46.5% of preschoolers. A lower proportion of depleted iron stores of 22.7% in infants and 15.2% in preschoolers was observed. Correlation test showed that there was a closer relationship between Hb and TR (r = -0.42) than Hb and PF (r = 0.20) even if PF was expected to give a higher proportion of values below normal. The occurrence of anemia in the presence of elevated TR without any decrease in PF values suggest that the diagnostic ability of PF could be limited in the presence of infection. Therefore, future studies should include biochemical tests such as C-reactive proteins (CRP) to determine the extent of association between anemia and infection.

  11. Dietary fiber intake and risk of breast cancer by menopausal and estrogen receptor status.

    Science.gov (United States)

    Li, Qian; Holford, Theodore R; Zhang, Yawei; Boyle, Peter; Mayne, Susan T; Dai, Min; Zheng, Tongzhang

    2013-02-01

    Evaluate the hypothesis that relation of breast cancer associated with dietary fiber intakes varies by type of fiber, menopausal, and the tumor's hormone receptor status. A case-control study of female breast cancer was conducted in Connecticut. A total of 557 incident breast cancer cases and 536 age frequency-matched controls were included in the analysis. Information on dietary intakes was collected through in-person interviews with a semi-quantitative food frequency questionnaire and was converted into nutrient intakes. Odds ratios and 95% confidence intervals were estimated by unconditional logistic regression. Among pre-menopausal women, higher intake of soluble fiber (highest versus lowest quartile of intake) was associated with a significantly reduced risk of breast cancer (OR = 0.38, 95% CI, 0.15-0.97, P (trend) = 0.08). When further restricted to pre-menopausal women with ER(-) tumors, the adjusted OR for the highest quartile of intake was 0.15 (95% CI, 0.03-0.69, P (trend) = 0.02) for soluble fiber intake. Among post-menopausal women, no reduced risk of breast cancer was observed for either soluble or insoluble fiber intakes or among ER(+) or ER(-) tumor groups. The results from this study show that dietary soluble fiber intake is associated with a significantly reduced risk of ER(-) breast cancer among pre-menopausal women. Additional studies with larger sample size are needed to confirm these results.

  12. Region-specific associations between sex, social status, and oxytocin receptor density in the brains of eusocial rodents.

    Science.gov (United States)

    Mooney, S J; Coen, C W; Holmes, M M; Beery, A K

    2015-09-10

    Naturally occurring variations in neuropeptide receptor distributions in the brain contribute to numerous mammalian social behaviors. In naked mole-rats, which live in large social groups and exhibit remarkable reproductive skew, colony-related social behaviors vary with reproductive status. Here we examined whether variation in social status is associated with variations in the location and/or density of oxytocin binding in this species. Autoradiography was performed to assess forebrain oxytocin receptor (OTR) densities in breeding and non-breeding naked mole-rats of both sexes. Overall, males exhibited higher OTR binding in the medial amygdala in comparison to females. While there were no main effects of reproductive status in any region, a sex difference in OTR binding in the nucleus accumbens was mediated by status. Specifically, breeding males tended to have more OTR binding than breeding females in the nucleus accumbens, while no sex difference was observed in subordinates. These effects suggest that oxytocin may act in a sex- and region-specific way that corresponds to reproductive status and associated social behaviors. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  13. Insulin use, hormone receptor status and hematopoietic cytokines׳ circulation in women with diabetes mellitus and breast cancer

    Directory of Open Access Journals (Sweden)

    Zachary A.P. Wintrob

    2017-04-01

    The data presented here is among the first to show a relationship between pre-existing use of injectable insulin in women diagnosed with breast cancer and type 2 diabetes mellitus, hematopoietic cytokine profiles at time of breast cancer diagnosis, and subsequent cancer outcomes. A Pearson correlation analysis evaluating the relationship between G-CSF, GM-CSF, and IL-7 stratified by insulin use, controls, as well as by estrogen and progesterone receptor status is also provided.

  14. Initial estimation of correlation between estrogen receptor status and histopathology, and also some selected prognostic factors in breast cancer patients

    International Nuclear Information System (INIS)

    Cwikla, J.; Badowski, J.; Shafie, D.; Gugala, K.; Koziorowski, M.

    1996-01-01

    The goal of this study was to assess the correlation between estrogen receptor (ER) status and histopathology findings, likewise to assess some selected prognostic factors in patients with breast cancer. The study was carried out on 126 patients with breast cancer. ER concentration was estimated by the standard biochemical assay (DCC-dextran-coated charcoal assay). The correlation between established risk factors like: lymph node status; age menopausal status and ER status were analysed.The ER yielded in 61% positive results. The mean value of ER in invasive ductal carcinoma was 43.9 fmol/mg protein and the mean value of ER in invasive lobular carcinoma 51.4 fmol/mg protein. The significant statistics negative correlation between ER status of pre-menopausal patients with ductal breast carcinoma and regional lymph nodes involvement was found. There was no difference between ER status and histological type of the cancer. No correlation was found between ER status and age of patients. (author)

  15. Upregulation of epidermal growth factor receptor 4 in oral leukoplakia

    Science.gov (United States)

    Kobayashi, Hiroshi; Kumagai, Kenichi; Gotoh, Akito; Eguchi, Takanori; Yamada, Hiroyuki; Hamada, Yoshiki; Suzuki, Satsuki; Suzuki, Ryuji

    2013-01-01

    In the present study, we investigate the expression profile of the epidermal growth factor receptor family, which comprises EGFR/ErbB1, HER2/ErbB2, HER3/ErbB3 and HER4/ErbB4 in oral leukoplakia (LP). The expression of four epidermal growth factor receptor (EGFR) family genes and their ligands were measured in LP tissues from 14 patients and compared with levels in 10 patients with oral lichen planus (OLP) and normal oral mucosa (NOM) from 14 healthy donors by real-time polymerase chain reaction (PCR) and immunohistochemistry. Synchronous mRNA coexpression of ErbB1, ErbB2, ErbB3 and ErbB4 was detected in LP lesions. Out of the receptors, only ErbB4 mRNA and protein was more highly expressed in LP compared with NOM tissues. These were strongly expressed by epithelial keratinocytes in LP lesions, as shown by immunohistochemistry. Regarding the ligands, the mRNA of Neuregulin2 and 4 were more highly expressed in OLP compared with NOM tissues. Therefore, enhanced ErbB4 on the keratinocytes and synchronous modulation of EGFR family genes may contribute to the pathogenesis and carcinogenesis of LP. PMID:23492901

  16. Estrogen receptor status in primary breast cancer: iodine 123-labeled cis-11beta-methoxy-17alpha-iodovinyl estradiol scintigraphy

    NARCIS (Netherlands)

    Bennink, R. J.; Rijks, L. J.; van Tienhoven, G.; Noorduyn, L. A.; Janssen, A. G.; Sloof, G. W.

    2001-01-01

    PURPOSE: To determine the sensitivity of iodine 123 ((123)I)-labeled cis-11beta-methoxy-17alpha-iodovinyl estradiol (Z-MIVE) scintigraphy for the detection of estrogen receptors in patients with primary breast carcinoma. MATERIALS AND METHODS: In 22 patients, estrogen receptor status was assessed

  17. Prognostic factors and status of hormone receptors and angiogenic factors in uterine carcinosarcoma.

    Science.gov (United States)

    Etoh, Tomomaro; Nakai, Hidekatsu

    2014-03-01

    To determine novel prognostic factors and treatment modalities for uterine carcinosarcoma (UCS). We performed immunohistochemical staining of estrogen receptor (ER)-α, ER-β, progesterone receptor, gonadotropin-releasing hormone receptor, vascular endothelial growth factor (VEGF), platelet-derived endothelial cell growth factor (PD-ECGF) and platelet-derived growth factor receptor (PDGFR)-β in a clinicopathological study of 15 UCS patients. No significant differences were found between the sarcomatous and carcinomatous components with respect to expression of ER-α, ER-β and progesterone receptor. However, VEGF was significantly more frequently expressed in the carcinomatous component, while PD-ECGF and PDGFR-β were significantly more frequently expressed in the sarcomatous component. Only one patient showed gonadotropin-releasing hormone receptor expression in the sarcomatous component. Moreover, ER-β expression in resected specimens, increased serum levels of carbohydrate antigen (CA)-125 and C-reactive protein (CRP), and thrombocytosis were determined as significant UCS prognostic factors. Combination of anti-VEGF therapy and anti-PD-ECGF or anti-PDGFR-β therapy would be expected in advanced or recurrent UCS. Furthermore, careful monitoring for early detection of recurrence should be performed when UCS patients showed preoperative increase in serum CA-125 levels, CRP and platelet counts, and ER-β expression in biopsied or surgically resected specimens. © 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.

  18. Risk Reduction of Breast Cancer by Childbirth, Breastfeeding, and Their Interaction in Korean Women: Heterogeneous Effects Across Menopausal Status, Hormone Receptor Status, and Pathological Subtypes

    Directory of Open Access Journals (Sweden)

    Seok Hun Jeong

    2017-11-01

    Full Text Available Objectives The purpose of this study was to examine the associations of childbirth, breastfeeding, and their interaction with breast cancer (BC risk reduction, and to evaluate the heterogeneity in the BC risk reduction effects of these factors by menopause, hormone receptor (HR status, and pathological subtype. Methods BC patients aged 40+ from the Korean Breast Cancer Registry in 2004-2012 and controls from the Health Examinee cohort participants were included in this study after 1:1 matching (12 889 pairs by age and enrollment year. BC risk according to childbirth, breastfeeding, and their interaction was calculated in logistic regression models using odds ratios (ORs and 95% confidence intervals (CIs. Results BC risk decreased with childbirth (3+ childbirths relative to 1 childbirth: OR, 0.66; 95% CI, 0.56 to 0.78 and OR, 0.80; 95% CI, 0.68 to 0.95 in postmenopausal and premenopausal women, respectively; and the degree of risk reduction by the number of children was heterogeneous according to menopausal status (p-heterogeneity=0.04, HR status (p-heterogeneity<0.001, and pathological subtype (p-heterogeneity<0.001; whereas breastfeeding for 1-12 months showed a heterogeneous association with BC risk according to menopausal status, with risk reduction only in premenopausal women (p-heterogeneity<0.05. The combination of 2 more childbirths and breastfeeding for ≥13 months had a much stronger BC risk reduction of 49% (OR, 0.51; 95% CI, 0.45 to 0.58. Conclusions This study suggests that the combination of longer breastfeeding and more childbirths reduces BC risk more strongly, and that women who experience both 2 or more childbirths and breastfeed for ≥13 months can reduce their BC risk by about 50%.

  19. Evaluation of functional erythropoietin receptor status in skeletal muscle in vivo

    DEFF Research Database (Denmark)

    Christensen, Britt; Lundby, Carsten; Jessen, Niels

    2012-01-01

    Background: Erythropoietin receptors have been identified in human skeletal muscle tissue, but downstream signal transduction has not been investigated. We therefore studied in vivo effects of systemic erythropoietin exposure in human skeletal muscle. Methodology/Principal Findings: The protocols...... involved 1) acute effects of a single bolus injection of erythropoietin followed by consecutive muscle biopsies for 1-10 hours, and 2) a separate study with prolonged administration for 16 days with biopsies obtained before and after. The presence of erythropoietin receptors in muscle tissue as well...... as activation of Epo signalling pathways (STAT5, MAPK, Akt, IKK) were analysed by western blotting. Changes in muscle protein profiles after prolonged erythropoietin treatment were evaluated by 2D gel-electrophoresis and mass spectrometry. The presence of the erythropoietin receptor in skeletal muscle...

  20. Clinicopathologic Characteristics of Oestrogen Receptor-Positive/Progesterone Receptor-Negative/Her2-Negative Breast Cancer According to a Novel Definition of Negative Progesterone Receptor Status: A Large Population-Based Study from China.

    Directory of Open Access Journals (Sweden)

    An-qi Li

    Full Text Available A lack of progesterone receptor (PgR expression in oestrogen receptor-positive (ER+ tumours is associated with worse survival. PgR status is usually defined as positive or negative using 1% positive nuclei as a cut-off point. In this study, we aimed to assess the clinicopathologic characteristics of ER+/PgR-/HER2- tumours by comparing them with ER+/PgR+/HER2- tumours using a PgR cut-off point of 20% as a divisive criterion.We analysed 1,522 patients with primary breast cancer who had undergone surgery at the Cancer Center of Fudan University between 2012 and 2014. Age, grade, tumour size, lymph node status and lymphovascular invasion were assessed. Multinomial logistic regression, linear regression and chi-square test models were applied to assess associations between ER, PR and clinical features.ER+/PgR-/HER2- tumours showed poorer clinicopathologic characteristics relative to ER+/PgR+/HER2- tumours using a PgR threshold of 20% instead of 1%. The clinicopathologic characteristics did not differ between tumours with purely negative PgR expression and tumours with a PgR percentage ranging from 1% to 19%. The prognostic significance of PR expression appeared more pronounced in patients under a high Ki-67 status than those under a low Ki-67 status.Based on these findings, we propose the use of a novel threshold of 20% to define PgR status. Nevertheless, the impact of this new criterion on patient management and clinical treatment requires additional study.

  1. Performance comparison of machine learning methods for prognosis of hormone receptor status in breast cancer tissue samples.

    Science.gov (United States)

    Kalinli, Adem; Sarikoc, Fatih; Akgun, Hulya; Ozturk, Figen

    2013-06-01

    We examined the classification and prognostic scoring performances of several computer methods on different feature sets to obtain objective and reproducible analysis of estrogen receptor status in breast cancer tissue samples. Radial basis function network, k-nearest neighborhood search, support vector machines, naive bayes, functional trees, and k-means clustering algorithm were applied to the test datasets. Several features were employed and the classification accuracies of each method for these features were examined. The assessment results of the methods on test images were also experimentally compared with those of two experts. According to the results of our experimental work, a combination of functional trees and the naive bayes classifier gave the best prognostic scores indicating very good kappa agreement values (κ=0.899 and κ=0.949, p<0.001) with the experts. This combination also gave the best dichotomization rate (96.3%) for assessment of estrogen receptor status. Wavelet color features provided better classification accuracy than Laws texture energy and co-occurrence matrix features. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  2. "Light switch" mental status changes and irritable insomnia are two particularly salient features of anti-NMDA receptor antibody encephalitis.

    Science.gov (United States)

    DeSena, Allen D; Greenberg, Benjamin M; Graves, Donna

    2014-07-01

    Anti-N-methyl-D-aspartate antibody encephalitis is becoming increasingly recognized as a cause of acute and subacute encephalopathy in both adults and children. The typical features of this disorder include some degree of encephalopathy, seizures, and often a movement disorder component. However, there is wide variability in its presentation, and diagnosis based on clinical features alone is often delayed. We report a series of four of 12 patients observed at our children's hospital between 2011 and 2013 that we chose as particularly representative examples of two distinct clinical features. In these individuals with anti-N-methyl-D-aspartate receptor antibody encephalitis, we note a very rapid on-off state between responsiveness and nonresponsiveness and/or insomnia accompanied by extreme irritability. We describe the abrupt mental status shift as "light switch" because the patients can awaken in seconds from a completely nonresponsive state. The insomnia noted in our patients was also impressive and often present early in the patients' courses. Light switch mental status changes and irritable insomnia are important early features of anti-N-methyl-D-aspartate receptor antibody encephalitis that can signal the presence of this disorder. The exact pathophysiology of these two symptoms has not been fully elucidated, and we feel that presence of one or both of these symptoms early in the disease course should prompt immediate concern for this disorder. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. The combined status of estrogen receptor (ER) and epidermal growth factor (EGFR) predicts a poor outcome in primary breast cancer

    International Nuclear Information System (INIS)

    Artagaveytia, N.; Román, E.; Alonso, I.; Sabini, G.; Garófalo, E.

    2004-01-01

    The aim of this study was to investigate retrospectively the presence of ER, PR, Db Receptor and Epidermal Growth Factor (EGFR) in 678 patients carrying primary breast cancer, its correlation with clinic pathological parameters and evolution. the determination of ER, PR and EGFR was performed by Scatchard biochemical technique, based cutoff 10 fmoles / mg of protein. The RE-b detection performed by RT-PCR from total RNA, using the GAPDH gene as a control. Statistical analyzes were applied the Chi2 tests, Spearman and Kruskal-Wallis. The disease-free survival (SVLE) and survival overall (SVG) were analyzed using Kaplan Meier / Log Rank Test and analysis Cox regression. Median follow-up was 28 months (range 1-218 months). sixty Four percent of the patients were post-menopausal and 83% occurred in stages Early disease (I-II, pTNM UICC). The receptor positivity was 68%, 47%, 23% and 58% for ER, PR, EGFR and ER-b-mRNA, respectively. A correlation was found positive between the content of ER and PR (p = 1.10-5) and negative between these receptors and EGFR (n = 359, p = 0.014 and p = 0.018, respectively). We observed a trend to increased expression ER-b when ER, PR or both receptors were negative comparable to that observed with EGFR. Also, a gradual decrease in the content of ER and PR was observed with the progression to more advanced stages (p = 0.04 and p = 0.03). Of a total of 501 evaluable patients 23% relapsed and 12% died. ER positivity was associated with a greater SVLE and SVG 24 and 60 months follow up (p = 0.06). A major impact did the RE content, levels less than 45 fmol / mg protein were associated with disease recurrence (p = 0.03 and p = 0.006 for 24 and 60 months). Although less significant EGFR status influenced SVLE and SVG. In particular, the presence of EGFR in ER + group affected the evolution tripling relapses and deaths (p = 0.058). The presence of ER-b also had a negative impact on this patient group. In Cox regression analysis, N + and T> 2cm

  4. Interleukin-1 receptor is a target for adjunctive control of diazepam-refractory status epilepticus in mice.

    Science.gov (United States)

    Xu, Zheng-Hao; Wang, Yi; Tao, An-Feng; Yu, Jie; Wang, Xiao-Yu; Zu, Yun-Yun; Zhang, Shi-Hong; Chen, Zhong

    2016-07-22

    Proinflammatory cytokine interleukin-1 beta (IL-1β) may accumulate in the brain during status epilepticus, but whether it contributes to the progressive refractoriness of SE remains unclear. By using a kainic acid-induced SE mice model, we tested whether pharmacological blockade or knock-out of interleukin-1 receptor type 1 (IL-1R1) could influence the diazepam-refractory phenomenon of prolonged SE. We confirmed diazepam failed to terminate prolonged SE (allowed to continue for 40min before diazepam administration). The expression level of IL-1β in the hippocampus during prolonged SE was significantly higher than that of baseline. Interestingly, prolonged SE was not diazepam-refractory in IL-1R1 knock-out mice. Moreover, administration of interleukin-1 receptor antagonist (IL-1RA) combined with diazepam terminated established prolonged SE, while IL-1RA alone is not capable to terminate prolonged SE. On the contrary, administration of recombinant human IL-1β weakens the efficacy of diazepam by prolonging its latency to terminate non-prolonged SE. Thus, the present study provides direct evidence that accumulated IL-1β contributed to the diazepam refractoriness of prolonged SE, and suggests that interleukin-1 receptor is a target for adjunctive control of diazepam-refractory SE. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  5. Intake of whole grain products and risk of breast cancer by hormone receptor status and histology among postmenopausal women.

    Science.gov (United States)

    Egeberg, Rikke; Olsen, Anja; Loft, Steffen; Christensen, Jane; Johnsen, Nina Føns; Overvad, Kim; Tjønneland, Anne

    2009-02-01

    No clear relationship between whole grain products and risk of breast cancer has been established. In a large prospective cohort study, we investigated the association between intake of whole grain products and risk of breast cancer by tumour receptor status [oestrogen receptor (ER) and progesterone receptor (PR)] and tumour histology (ductal/lobular). It was further investigated whether the association differed by use of hormone replacement therapy (HRT). The study included 25,278 postmenopausal women participating in the Danish Diet, Cancer and Health cohort study (1993-1997). During a mean follow-up time of 9.6 years, 978 breast cancer cases were diagnosed. Associations between intake of whole grain products and the breast cancer rate were analysed using Cox's regression model. A higher intake of whole grain products was not associated with a lower risk of breast cancer. Per an increment in intake of total whole grain products of 50 g per day the adjusted incidence rate ratio (95% confidence interval) was 1.01 (0.96-1.07). Intake of rye bread, oatmeal and whole grain bread was not associated with breast cancer risk. No association was observed between the intake of total or specific whole grain products and the risk of developing ER+, ER-, PR+, PR-, combined ER/PR status, ductal or lobular breast cancer. Furthermore, there was no interaction between intake of whole grain products and use of HRT on risk of breast cancer. In conclusion, intake of whole grain products was not associated with risk of breast cancer in a cohort of Danish postmenopausal women. Copyright (c) 2008 Wiley-Liss, Inc.

  6. Estrogen receptor-alpha distribution in the human hypothalamus in relation to sex and endocrine status

    NARCIS (Netherlands)

    Kruijver, Frank P. M.; Balesar, Rawien; Espila, Ana M.; Unmehopa, Unga A.; Swaab, Dick F.

    2002-01-01

    The present study reports the first systematic rostrocaudal distribution of estrogen receptor-a immunoreactivity (ERalpha-ir) in the human hypothalamus and its adjacent areas in young adults. Postmortem material taken from 10 subjects (five male and five female), between 20 and 39 years of age, was

  7. Evaluation of functional erythropoietin receptor status in skeletal muscle in vivo

    DEFF Research Database (Denmark)

    Christensen, Britt; Lundby, Carsten; Jessen, Niels

    2012-01-01

    as activation of Epo signalling pathways (STAT5, MAPK, Akt, IKK) were analysed by western blotting. Changes in muscle protein profiles after prolonged erythropoietin treatment were evaluated by 2D gel-electrophoresis and mass spectrometry. The presence of the erythropoietin receptor in skeletal muscle...

  8. Vitamin D status, receptor gene BsmI (A/G) polymorphism and ...

    African Journals Online (AJOL)

    Rasha Rizk Elzehery

    d Abbott Nutrition Reserch and Development, Columbus, OH, USA. a r t i c l e i n f o. Article history: Received 19 October 2016. Accepted 20 November 2016. Available online 5 December 2016. Keywords: 25 Hydroxy vitamin D. Vitamin D receptor (VDR). Breast cancer risk. Polymorphisms. Genotype. a b s t r a c t.

  9. Polymorphisms in the gene encoding bovine interleukin-10 receptor alpha are associated with Mycobacterium avium ssp. paratuberculosis infection status

    Directory of Open Access Journals (Sweden)

    Kelton David F

    2010-04-01

    Full Text Available Abstract Background Johne's disease is a chronic inflammatory bowel disease (IBD of ruminants caused by Mycobacterium avium ssp. paratuberculosis (MAP. Since this pathogen has been implicated in the pathogenesis of human IBDs, the goal of this study was to assess whether single nucleotide polymorphism (SNPs in several well-known candidate genes for human IBD are associated with susceptibility to MAP infection in dairy cattle. Methods The bovine candidate genes, interleukin-10 (IL10, IL10 receptor alpha/beta (IL10RA/B, transforming growth factor beta 1 (TGFB1, TGFB receptor class I/II (TGFBR1/2, and natural resistance-associated macrophage protein 1 (SLC11A1 were sequenced for SNP discovery using pooled DNA samples, and the identified SNPs were genotyped in a case-control association study comprised of 242 MAP negative and 204 MAP positive Holstein dairy cattle. Logistic regression was used to determine the association of SNPs and reconstructed haplotypes with MAP infection status. Results A total of 13 SNPs were identified. Four SNPs in IL10RA (984G > A, 1098C > T, 1269T > C, and 1302A > G were tightly linked, and showed a strong additive and dominance relationship with MAP infection status. Haplotypes AGC and AAT, containing the SNPs IL10RA 633C > A, 984G > A and 1185C > T, were associated with an elevated and reduced likelihood of positive diagnosis by serum ELISA, respectively. Conclusions SNPs in IL10RA are associated with MAP infection status in dairy cattle. The functional significance of these SNPs warrants further investigation.

  10. Effects of Constant Flickering Light on Refractive Status, 5-HT and 5-HT2A Receptor in Guinea Pigs.

    Science.gov (United States)

    Li, Bing; Luo, Xiumei; Li, Tao; Zheng, Changyue; Ji, Shunmei; Ma, Yuanyuan; Zhang, Shuangshuang; Zhou, Xiaodong

    2016-01-01

    To investigate the effects of constant flickering light on refractive development, the role of serotonin (i.e.5-hydroxytryptamine, 5-HT)and 5-HT2A receptor in myopia induced by flickering light in guinea pigs. Forty-five guinea pigs were randomly divided into three groups: control, form deprivation myopia (FDM) and flickering light induced myopia (FLM) groups(n = 15 for each group). The right eyes of the FDM group were covered with semitransparent hemispherical plastic shells serving as eye diffusers. Guinea pigs in FLM group were raised with illumination of a duty cycle of 50% at a flash frequency of 0.5Hz. The refractive status, axial length (AL), corneal radius of curvature(CRC) were measured by streak retinoscope, A-scan ultrasonography and keratometer, respectively. Ultramicroscopy images were taken by electron microscopy. The concentrations of 5-HTin the retina, vitreous body and retinal pigment epithelium (RPE) were assessed by high performance liquid chromatography, the retinal 5-HT2A receptor expression was evaluated by immunohistofluorescence and western blot. The refraction of FDM and FLM eyes became myopic from some time point (the 4th week and the 6th week, respectively) in the course of the experiment, which was indicated by significantly decreased refraction and longer AL when compared with the controls (pguinea pigs. 5-HT and 5-HT2A receptor increased both in form deprivation myopia and flickering light induced myopia, indicating that 5-HT possibly involved in myopic development via binding to5-HT2A receptor.

  11. [Hormone replacement Up-to-date. Selective androgen receptor modulators (SARMs). Current status and their future].

    Science.gov (United States)

    Tsukamoto, Taiji; Kato, Ryuichi; Kobayashi, Koh

    2007-09-01

    Selective androgen receptor modulators (SARMs) with tissue or organ-specificity are expected for their development. Indeed, they will be widely applied for patients with late onset of hypodonadism and those with prostate cancer who have hormone treatment-induced osteoporosis. SARMs having anabolic action on the bone or muscle but no or weak androgenic action on the prostate will be welcomed in the clinical setting.

  12. Effects of LiCl/pilocarpine-induced status epilepticus on rat brain mu and benzodiazepine receptor binding: Regional and ontogenetic studies

    Czech Academy of Sciences Publication Activity Database

    Rocha, L.; Suchomelová, Lucie; Mareš, Pavel; Kubová, Hana

    2007-01-01

    Roč. 1181, - (2007), s. 104-117 ISSN 0006-8993 R&D Projects: GA MŠk(CZ) LC554; GA ČR GA304/05/2582 Grant - others: CONACyT (MX) 45943-M Institutional research plan: CEZ:AV0Z50110509 Keywords : benzodiazepine receptor * µ receptor binding * status epilepticus Subject RIV: ED - Physiology Impact factor: 2.218, year: 2007

  13. Current status of muscarinic M1 and M4 receptors as drug targets for neurodegenerative diseases.

    Science.gov (United States)

    Felder, Christian C; Goldsmith, Paul J; Jackson, Kimberley; Sanger, Helen E; Evans, David A; Mogg, Adrian J; Broad, Lisa M

    2018-01-25

    The cholinergic signalling system has been an attractive pathway to seek targets for modulation of arousal, cognition, and attention which are compromised in neurodegenerative and neuropsychiatric diseases. The acetylcholine muscarinic receptor M1 and M4 subtypes which are highly expressed in the central nervous system, in cortex, hippocampus and striatum, key areas of cognitive and neuropsychiatric control, have received particular attention. Historical muscarinic drug development yielded first generation agonists with modest selectivity for these two receptor targets over M2 and M3 receptors, the major peripheral sub-types hypothesised to underlie the dose-limiting clinical side effects. More recent compound screening and medicinal chemistry optimization of orthosteric and allosteric agonists, and positive allosteric modulators binding to sites distinct from the highly homologous acetylcholine binding pocket have yielded a collection of highly selective tool compounds for preclinical validation studies. Several M1 selective ligands have progressed to early clinical development and in time will hopefully lead to useful therapeutics for treating symptoms of Alzheimer's disease and related disorders. Copyright © 2018. Published by Elsevier Ltd.

  14. Role of ErbB receptors in cancer cell migration and invasion

    Directory of Open Access Journals (Sweden)

    Aline eAppert-Collin

    2015-11-01

    Full Text Available Growth factors mediate their diverse biologic responses (regulation of cellular proliferation, differentiation, migration and survival by binding to and activating cell-surface receptors with intrinsic protein kinase activity named Receptor Tyrosine Kinases (RTKs. About 60 RTKs have been identified and can be classified into more than 16 different receptor families. Their activity is normally tightly controlled and regulated. Overexpression of RTK proteins or functional alterations caused by mutations in the corresponding genes or abnormal stimulation by autocrine growth factor loops contribute to constitutive RTK signaling, resulting in alterations in the physiological activities of cells. The ErbB receptor family of RTKs comprises four distinct receptors: the EGFR (also known as ErbB1/HER1, ErbB2 (neu, HER2, ErbB3 (HER3 and ErbB4 (HER4. ErbB family members are often overexpressed, amplified, or mutated in many forms of cancer, making them important therapeutic targets. EGFR has been found to be amplified in gliomas and non-small-cell lung carcinoma while ErbB2 amplifications are seen in breast, ovarian, bladder, non-small-cell lung carcinoma, as well as several other tumor types. Several data have shown that ErbB receptor family and its downstream pathway regulate epithelial-mesenchymal transition, migration, and tumor invasion by modulating extracellular matrix components. Recent findings indicate that extracellular matrix components such as matrikines bind specifically to EGF receptor and promote cell invasion. In this review, we will present an in-depth overview of the structure, mechanisms, cell signaling, and functions of ErbB family receptors in cell adhesion and migration. Furthermore, we will describe in a last part the new strategies developed in anti-cancer therapy to inhibit ErbB family receptor activation.

  15. Adjuvant Trastuzumab in HER2-Positive Early Breast Cancer by Age and Hormone Receptor Status: A Cost-Utility Analysis.

    Directory of Open Access Journals (Sweden)

    William Leung

    2016-08-01

    Full Text Available The anti-human epidermal growth factor receptor 2 (HER2 monoclonal antibody trastuzumab improves outcomes in patients with node-positive HER2+ early breast cancer. Given trastuzumab's high cost, we aimed to estimate its cost-effectiveness by heterogeneity in age and estrogen receptor (ER and progesterone receptor (PR status, which has previously been unexplored, to assist prioritisation.A cost-utility analysis was performed using a Markov macro-simulation model, with a lifetime horizon, comparing a 12-mo regimen of trastuzumab with chemotherapy alone using the latest (2014 effectiveness measures from landmark randomised trials. A New Zealand (NZ health system perspective was adopted, employing high-quality national administrative data. Incremental quality-adjusted life-years for trastuzumab versus chemotherapy alone are two times higher (2.33 times for the age group 50-54 y; 95% CI 2.29-2.37 for the worst prognosis (ER-/PR- subtype compared to the best prognosis (ER+/PR+ subtype, causing incremental cost-effectiveness ratios (ICERs for the former to be less than half those of the latter for the age groups from 25-29 to 90-94 y (0.44 times for the age group 50-54 y; 95% CI 0.43-0.45. If we were to strictly apply an arbitrary cost-effectiveness threshold equal to the NZ gross domestic product per capita (2011 purchasing power parity [PPP]-adjusted: US$30,300; €23,700; £21,200, our study suggests that trastuzumab (2011 PPP-adjusted US$45,400/€35,900/£21,900 for 1 y at formulary prices may not be cost-effective for ER+ (which are 61% of all node-positive HER2+ early breast cancer patients but cost-effective for ER-/PR- subtypes (37% of all cases to age 69 y. Market entry of trastuzumab biosimilars will likely reduce the ICER to below this threshold for premenopausal ER+/PR- cancer but not for ER+/PR+ cancer. Sensitivity analysis using the best-case effectiveness measure for ER+ cancer had the same result. A key limitation was a lack of

  16. Immunohistochemical analysis of aldehyde dehydrogenase isoforms and their association with estrogen-receptor status and disease progression in breast cancer

    Directory of Open Access Journals (Sweden)

    Opdenaker LM

    2014-12-01

    Full Text Available Lynn M Opdenaker,1,2 Kimberly M Arnold,1,3 Ryan T Pohlig,3,4 Jayasree S Padmanabhan,1 Daniel C Flynn,1,3 Jennifer Sims-Mourtada1–3 1Center for Translational Cancer Research, Helen F Graham Cancer Center, Christiana Care Health Services, Inc., Newark, Delaware, USA; 2Department of Biological Sciences, 3Department of Medical Laboratory Sciences, 4Biostatistics Core Facility, University of Delaware, Newark, Delaware, USA Abstract: In many types of tumors, especially breast tumors, aldehyde dehydrogenase (ALDH activity has been used to identify cancer stem-like cells within the tumor. The presence and quantity of these cells are believed to predict the response of tumors to chemotherapy. Therefore, identification and eradication of these cells would be necessary to cure the patient. However, there are 19 different ALDH isoforms that could contribute to the enzyme activity. ALDH1A1 and ALDH1A3 are among the isoforms mostly responsible for the increased ALDH activity observed in these stem-like cells, although the main isoforms vary in different tissues and tumor types. In the study reported here, we attempted to determine if ALDH1A1 or ALDH1A3, specifically, correlate with tumor stage, grade, and hormone-receptor status in breast-cancer patients. While there was no significant correlation between ALDH1A1 and any of the parameters tested, we were able to identify a positive correlation between ALDH1A3 and tumor stage in triple-negative cancers. In addition, ALDH1A3 was negatively correlated with estrogen-receptor status. Our data suggest that ALDH1A3 could be utilized as a marker to identify stem-like cells within triple-negative tumors. Keywords: breast tumor, ALDH, ALDH1A1, ALDH1A3, stem-like cells, triple-negative cancer

  17. Fighting experience alters brain androgen receptor expression dependent on testosterone status

    Science.gov (United States)

    Li, Cheng-Yu; Earley, Ryan L.; Huang, Shu-Ping; Hsu, Yuying

    2014-01-01

    Contest decisions are influenced by the outcomes of recent fights (winner–loser effects). Steroid hormones and serotonin are closely associated with aggression and therefore probably also play important roles in mediating winner–loser effects. In mangrove rivulus fish, Kryptolebias marmoratus, individuals with higher testosterone (T), 11-ketotestosterone and cortisol levels are more capable of winning, but titres of these hormones do not directly mediate winner–loser effects. In this study, we investigated the effects of winning/losing experiences on brain expression levels of the receptor genes for androgen (AR), oestrogen α/β (ERα/β), glucocorticoid (GR) and serotonin (5-HT1AR). The effect of contest experience on AR gene expression depended on T levels: repeated losses decreased, whereas repeated wins increased AR gene expression in individuals with low T but not in individuals with medium or high T levels. These results lend strong support for AR being involved in mediating winner–loser effects, which, in previous studies, were more detectable in individuals with lower T. Furthermore, the expression levels of ERα/β, 5-HT1AR and GR genes were higher in individuals that initiated contests against larger opponents than in those that did not. Overall, contest experience, underlying endocrine state and hormone and serotonin receptor expression patterns interacted to modulate contest decisions jointly. PMID:25320171

  18. Sch proteins are localized on endoplasmic reticulum membranes and are redistributed after tyrosine kinase receptor activation

    DEFF Research Database (Denmark)

    Lotti, L V; Lanfrancone, L; Migliaccio, E

    1996-01-01

    The intracellular localization of Shc proteins was analyzed by immunofluorescence and immunoelectron microscopy in normal cells and cells expressing the epidermal growth factor receptor or the EGFR/erbB2 chimera. In unstimulated cells, the immunolabeling was localized in the central perinuclear...... and endocytic structures, such as coated pits and endosomes, and with the peripheral cytosol. Receptor activation in cells expressing phosphorylation-defective mutants of Shc and erbB-2 kinase showed that receptor autophosphorylation, but not Shc phosphorylation, is required for redistribution of Shc proteins....... The rough endoplasmic reticulum localization of Shc proteins in unstimulated cells and their massive recruitment to the plasma membrane, endocytic structures, and peripheral cytosol following receptor tyrosine kinase activation could account for multiple putative functions of the adaptor protein....

  19. Epidermal growth factor receptor gene status by fluorescence in situ hybridization in malignant, atypical, and benign hidradenomas.

    Science.gov (United States)

    Piris, Adriano; Scopsi, Lucio; Clemente, Claudio; Cetti Serbelloni, Federica; Mihm, Martin C; Hoang, Mai P

    2010-08-01

    Epidermal growth factor receptor (EGFR) protein overexpression and gene amplification are important prognostic factors in various tumors and EGFR inhibitors are now available as promising chemotherapeutic agents. There is little information in the literature regarding the EGFR protein and gene status in hidradenocarcinomas which has an aggressive biologic course characterized by repeated local recurrences and systemic metastasis. We have previously reported EGFR protein overexpression in malignant, atypical, and benign hidradenomas and would like to further evaluate their gene status by fluorescence in situ hybridization. Fluorescence in situ hybridization by 2-color probe Vysis LSI EGFR SpectrumOrange/CEP 7 SpectrumGreen Probe (Abbott Molecular) and EGFR immunostain (H11, Dakocytomation) were performed in 15 malignant, 15 atypical, and 7 benign hidradenomas. High polysomy and low trisomy was noted in 1 and 4 hidradenocarcinoma, respectively; however, EGFR overexpression was seen only in 1 low trisomy case. Disomy is noted in the remaining 29 cases (9 hidradenocarcinomas, 15 atypical hidradenomas, and 5 benign hidradenomas). EGFR overexpression was seen in 3/12 (25%) malignant hidradenomas, 7/15 (47%) atypical hidradenomas, and 3/5 (60%) benign hidradenomas; none of these cases demonstrated EGFR gene amplification. Polysomy/trisomy is more frequently seen in hidradenocarcinoma than atypical and benign hidradenomas. The role of EGFR inhibitor therapy in hidradenocarcinoma cases with protein overexpression remains unclear. Lack of correlation between the protein expression and polysomy/gene amplification suggests that molecular mechanisms other than gene amplification play a role in EGFR overexpression in malignant, atypical, and benign hidradenomas.

  20. Prognostic effect of estrogen receptor status across age in primary breast cancer

    DEFF Research Database (Denmark)

    Bentzon, Niels; Düring, Maria; Rasmussen, Birgitte Bruun

    2008-01-01

    unchanged in patients who did not receive adjuvant systemic therapy (n = 6,272). Thus, positive ER status does not confer a negative impact on survival in young women as has been previously reported. The inferior prognosis for ER negative patients during the first 5 years after diagnosis changes...... into a slightly superior residual prognosis compared to ER positive patients independent of use of adjuvant systemic therapy. This may have an impact on future designing of guidelines for adjuvant endocrine therapy beyond 5 years....

  1. Effect of the endocannabinoid receptor agonist Win-55 212-2 on early electrographic changes in a post-status model of epileptogenesis

    NARCIS (Netherlands)

    Suleymanova, E.M.; Blik, V.; Rijn, C.M. van; Vinogradova, L.V.

    2015-01-01

    Purpose: This study was performed to investigate whether stimulation of endocannabinoid system early after status epilepticus (SE) could prevent or modify the subsequent epileptogenesis. We studied the effect of an agonist of endocannabinoid receptors, WIN-55 212-2, on electrographic features during

  2. Social status and sex independently influence androgen receptor expression in the eusocial naked mole-rat brain.

    Science.gov (United States)

    Holmes, Melissa M; Goldman, Bruce D; Forger, Nancy G

    2008-08-01

    Naked mole-rats (Heterocephalus glaber) are eusocial rodents that live in large subterranean colonies including a single breeding female and 1-3 breeding males; all other members of the colony, known as subordinates, are reproductively suppressed. We recently found that naked mole-rats lack many of the sex differences in the brain and spinal cord commonly found in other rodents. Instead, neural morphology is influenced by breeding status, such that breeders, regardless of sex, have more neurons than subordinates in the ventromedial nucleus of the hypothalamus (VMH), and larger overall volumes of the bed nucleus of the stria terminalis (BST), paraventricular nucleus (PVN) and medial amygdala (MeA). To begin to understand how breeding status influences brain morphology, we examined the distribution of androgen receptor (AR) immunoreactivity in gonadally intact breeders and subordinates of both sexes. All animals had AR+ nuclei in many of the same regions positive for AR in other mammals, including the VMH, BST, PVN, MeA, and the ventral portion of the premammillary nucleus (PMv). We also observed diffuse labeling throughout the preoptic area, demonstrating that distribution of the AR protein in presumptive reproductive brain nuclei is well-conserved, even in a species that exhibits remarkably little sexual dimorphism. In contrast to other rodents, however, naked mole-rats lacked AR+ nuclei in the suprachiasmatic nucleus and hippocampus. Males had more AR+ nuclei in the MeA, VMH, and PMv than did females. Surprisingly, breeders had significantly fewer AR+ nuclei than subordinates in all brain regions examined (VMH, BST, PVN, MeA, and PMv). Thus, social status is strongly correlated with AR immunoreactivity in this eusocial species.

  3. Modeling ERBB receptor-regulated G1/S transition to find novel targets for de novo trastuzumab resistance

    Directory of Open Access Journals (Sweden)

    Thieffry Denis

    2009-01-01

    Full Text Available Abstract Background In breast cancer, overexpression of the transmembrane tyrosine kinase ERBB2 is an adverse prognostic marker, and occurs in almost 30% of the patients. For therapeutic intervention, ERBB2 is targeted by monoclonal antibody trastuzumab in adjuvant settings; however, de novo resistance to this antibody is still a serious issue, requiring the identification of additional targets to overcome resistance. In this study, we have combined computational simulations, experimental testing of simulation results, and finally reverse engineering of a protein interaction network to define potential therapeutic strategies for de novo trastuzumab resistant breast cancer. Results First, we employed Boolean logic to model regulatory interactions and simulated single and multiple protein loss-of-functions. Then, our simulation results were tested experimentally by producing single and double knockdowns of the network components and measuring their effects on G1/S transition during cell cycle progression. Combinatorial targeting of ERBB2 and EGFR did not affect the response to trastuzumab in de novo resistant cells, which might be due to decoupling of receptor activation and cell cycle progression. Furthermore, examination of c-MYC in resistant as well as in sensitive cell lines, using a specific chemical inhibitor of c-MYC (alone or in combination with trastuzumab, demonstrated that both trastuzumab sensitive and resistant cells responded to c-MYC perturbation. Conclusion In this study, we connected ERBB signaling with G1/S transition of the cell cycle via two major cell signaling pathways and two key transcription factors, to model an interaction network that allows for the identification of novel targets in the treatment of trastuzumab resistant breast cancer. Applying this new strategy, we found that, in contrast to trastuzumab sensitive breast cancer cells, combinatorial targeting of ERBB receptors or of key signaling intermediates does not

  4. Zinc presence in invasive ductal carcinoma of the breast and its correlation with oestrogen receptor status

    International Nuclear Information System (INIS)

    Farquharson, M J; Al-Ebraheem, A; Geraki, K; Leek, R; Jubb, A; Harris, A L

    2009-01-01

    Zinc is known to play an important role in many cellular processes, and the levels of zinc are controlled by specific transporters from the ZIP (SLC39A) influx transporter group and the ZnT (SLC30A) efflux transporter group. The distribution of zinc was measured in 59 samples of invasive ductal carcinoma of breast using synchrotron radiation micro probe x-ray fluorescence facilities. The samples were formalin fixed paraffin embedded tissue micro arrays (TMAs) enabling a high throughput of samples and allowing us to correlate the distribution of trace metals with tumour cell distribution and, for the first time, important biological variables. The samples were divided into two classes, 34 oestrogen receptor positive (ER+ve) and 25 oestrogen receptor negative (ER-ve) based on quantitative immunohistochemistry assessment. The overall levels of zinc (i.e. in tumour and surrounding tissue) in the ER+ve samples were on average 60% higher than those in the ER-ve samples. The zinc levels were higher in the ER+ve tumour areas compared to the ER-ve tumour areas with the mean levels in the ER+ve samples being approximately 80% higher than the mean ER-ve levels. However, the non-tumour tissue regions of the samples contained on average the same levels of zinc in both types of breast cancers. The relative levels of zinc in tumour areas of the tissue were compared with levels in areas of non-tumour surrounding tissue. There was a significant increase in zinc in the tumour regions of the ER+ve samples compared to the surrounding regions (P < 0.001) and a non-significant increase in the ER-ve samples. When comparing the increase in zinc in the tumour regions expressed as a percentage of the surrounding non-tumour tissue zinc level in the same sample, a significant difference between the ER+ve and ER-ve samples was found (P < 0.01).

  5. receptores

    Directory of Open Access Journals (Sweden)

    Salete Regina Daronco Benetti

    2006-01-01

    Full Text Available Se trata de un estudio etnográfico, que tuvo lo objetivo de interpretar el sistema de conocimiento y del significado atribuidos a la sangre referente a la transfusión sanguínea por los donadores y receptores de un banco de sangre. Para la colecta de las informaciones se observaron los participantes y la entrevista etnográfica se realizó el análisis de dominio, taxonómicos y temáticos. Los dominios culturales fueron: la sangre es vida: fuente de vida y alimento valioso; creencias religiosas: fuentes simbólicas de apoyos; donación sanguínea: un gesto colaborador que exige cuidarse, gratifica y trae felicidad; donación sanguínea: fuente simbólica de inseguridad; estar enfermo es una condición para realizar transfusión sanguínea; transfusión sanguínea: esperanza de vida; Creencias populares: transfusión sanguínea como riesgo para la salud; donadores de sangre: personas benditas; donar y recibir sangre: como significado de felicidad. Temática: “líquido precioso que origina, sostiene, modifica la vida, provoca miedo e inseguridad”.

  6. Epidermal Growth Factor Receptor and K-RAS status in two cohorts of squamous cell carcinomas

    International Nuclear Information System (INIS)

    Van Damme, Nancy; Pauwels, Patrick; Peeters, Marc; Deron, Philippe; Van Roy, Nadine; Demetter, Pieter; Bols, Alain; Dorpe, Jo Van; Baert, Filip; Van Laethem, Jean-Luc; Speleman, Franki

    2010-01-01

    With the availability of effective anti-EGFR therapies for various solid malignancies, such as non-cell small lung cancer, colorectal cancer and squamous cell carcinoma of the head and neck, the knowledge of EGFR and K-RAS status becomes clinically important. The aim of this study was to analyse EGFR expression, EGFR gene copy number and EGFR and K-RAS mutations in two cohorts of squamous cell carcinomas, specifically anal canal and tonsil carcinomas. Formalin fixed, paraffin-embedded tissues from anal and tonsil carcinoma were used. EGFR protein expression and EGFR gene copy number were analysed by means of immunohistochemistry and fluorescence in situ hybridisation. The somatic status of the EGFR gene was investigated by PCR using primers specific for exons 18 through 21. For the K-RAS gene, PCR was performed using exon 2 specific primers. EGFR immunoreactivity was present in 36/43 (83.7%) of anal canal and in 20/24 (83.3%) of tonsil squamous cell carcinomas. EGFR amplification was absent in anal canal tumours (0/23), but could be identified in 4 of 24 tonsil tumours. From 38 anal canal specimens, 26 specimens were successfully analysed for exon 18, 30 for exon 19, 34 for exon 20 and 30 for exon 21. No EGFR mutations were found in the investigated samples. Thirty samples were sequenced for K-RAS exon 2 and no mutation was identified. From 24 tonsil specimens, 22 were successfully analysed for exon 18 and all 24 specimens for exon 19, 20 and 21. No EGFR mutations were found. Twenty-two samples were sequenced for K-RAS exon 2 and one mutation c.53C > A was identified. EGFR mutations were absent from squamous cell carcinoma of the anus and tonsils, but EGFR protein expression was detected in the majority of the cases. EGFR amplification was seen in tonsil but not in anal canal carcinomas. In our investigated panel, only one mutation in the K-RAS gene of a tonsil squamous cell carcinoma was identified. This indicates that EGFR and K-RAS mutation analysis is not

  7. Hepatitis C Virus Activates a Neuregulin-Driven Circuit to Modify Surface Expression of Growth Factor Receptors of the ErbB Family.

    Directory of Open Access Journals (Sweden)

    Sabine Stindt

    Full Text Available Recently, the epidermal growth factor (EGF receptor (EGFR, a member of the ErbB receptor family, and its down-stream signalling have been identified as co-factors for HCV entry and replication. Since EGFR also functions as a heterodimer with other ErbB receptor family members, the subject of the present study was to investigate a possible viral interference with these cellular components. By using genotype 1b replicon cells as well as an infection-based system we found that while transcript and protein levels of EGFR and ErbB2 were up-regulated or unaffected, respectively, HCV induced a substantial reduction of ErbB3 and ErbB4 expression. Down-regulation of ErbB3 expression by HCV involves specificity protein (Sp1-mediated induction of Neuregulin (NRG1 expression as well as activation of Akt. Consistently, at transcript level disruption of ErbB3 expression by HCV can be prevented by knockdown of NRG1 or Sp1 expression, whereas reconstitution of ErbB3 protein levels requires inhibition of HCV-induced NRG1 expression and of Akt activity. Interestingly, the NRG1-mediated suppression of ErbB3 expression by HCV results in an enhanced expression of EGFR and ErbB2 on the cell surface, which can be mimicked by siRNA-mediated knockdown of ErbB3 expression. These data delineate a novel mechanism enabling HCV to sway the composition of the ErbB family members on the surface of its host cell by an NRG1-driven circuit and unravels a yet unknown cross-regulation between ErbB3 and the two other family members ErbB2 and EGFR. The shift of the receptor surface expression of the ErbB family towards enhanced expression of ErbB2 and EGFR triggered by HCV was found to promote viral RNA replication and infectivity. This suggests that HCV rearranges expression of ErbB family members to adapt the cellular environment to its requirements.

  8. Juvenile idiopathic arthritis patients and their skeletal status: possible role of vitamin D receptor gene polymorphism.

    Science.gov (United States)

    Kostik, M M; Smirnov, A M; Demin, G S; Scheplyagina, L A; Larionova, V I

    2014-01-01

    We evaluated bone mineralization and metabolism changes related to vitamin D receptor (VDR) polymorphic genotypes in children with juvenile idiopathic arthritis. One hundred and ninety eight children (82 boys and 116 girls) were included in our study. Bone mineral density (BMD) was measured by lumbar spine DXA. Osteocalcin, CTX, parathyroid hormone, total and ionized calcium, inorganic phosphate, total alkaline phosphatase activity was utilized for assessment of bone metabolism. Molecular testing: TaqI (rs731236) and Cdx2 (rs11568820) polymorphisms of VDR were detected by RFLP. No differences in TaqI and Cdx2 haplotypes, genotypes and alleles distribution related with normal and low BMD (Zscore 90th percentile) had the highest frequency of allele A-contained genotypes (GA+AA) of Cdx2 VDR (p = 0.009). Girls with TT TaqI VDR, who never been treated by glucocorticoides had lower BMD-Zscore than C allele carriers (TT = -0.94SD [IQR: -2.1;-0.5], TC+CC = -0.62SD [IQR: -1.26;0.39], p = 0.03). Girls with Tanner I with TT had higher total and ionized Ca level than carriers of C allele (Ca: TT = 2.43 ± 0.15 mmol/l, TC+CC = 2.28 ± 0.2 mmol/l, p = 0.024; Ca(2+): TT = 1.15 ± 0.08 mmol/l, TC+CC = 1.06 ± 0.13 mmol/l, p = 0.026). Presence of TT genotype negatively correlated with BMD-Zscore (r = -0.28, p = 0.04), and positively with frequency of LBMD (r = 0.3, p = 0.037). Boy with GG Cdx2 genotype had lower total Ca (GG = 2.3 ± 0.17 mmol/l, GA+AA = 2.43 ± 0.17 mmol/l, p = 0.004) compare with carriers of A allele. Pubertal boys (Tanner IV-V) with GG had higher CTX (GG = 1.75 ± 0.11 ng/ml, GA+AA = 1.06 ± 0.07 ng/ml, p = 0.04. TT genotype of TaqI and GG genotype of Cdx2 VDR is a negative factor impact bone mineralization metabolism and linear growth.

  9. Estrogen receptor targeted contrast agents for molecular magnetic resonance imaging of breast cancer hormonal status

    Directory of Open Access Journals (Sweden)

    Adi ePais

    2016-04-01

    Full Text Available The estrogen receptor α (ER is over expressed in most breast cancers and its level serves as a major prognostic factor. It is important to develop quantitative molecular imaging methods that specifically detect ER in vivo and assess its function throughout the entire primary breast cancer, as well as in metastatic breast cancer lesions. This study presents the biochemical and molecular features, as well as the magnetic resonance imaging effects of two novel ER- targeted contrast agents (CAs based on pyridine-tetra-acetate-Gd(III chelate conjugated to 17β-estradiol (EPTA-Gd or to tamoxifen (TPTA-Gd. The experiments were conducted in solution, in human breast cancer cells and in severe combined immunodeficient mice implanted with transfected ER-positive and ER-negative MDA-MB-231 human breast cancer xenografts. Binding studies with ER in solution and in human breast cancer cells indicated affinities in the micromolar range of both CAs. Biochemical and molecular studies in breast cancer cell cultures showed that both CAs exhibit estrogen like agonistic activity, enhancing cell proliferation, as well as up-regulating cMyc oncogene and down-regulating ER expression levels. The MRI longitudinal relaxivity was significantly augmented by EPTA-Gd in ER-positive cells as compared to ER-negative cells. Dynamic contrast enhanced studies with EPTA-Gd in vivo indicated specific augmentation of the MRI water signal in the ER-positive versus ER-negative xenografts, confirming EPTA-Gd specific interaction with ER. In contrast, TPTA-Gd did not show increased enhancement in ER-positive tumors and did not appear to interact in vivo with the tumors’ ER. However, TPTA-Gd was found to interact strongly with muscle tissue, enhancing muscle signal intensity in a mechanism independent of the presence of ER. The specificity of EPTA-Gd interaction with ER in vivo was further verified by acute and chronic competition with tamoxifen. The chronic tamoxifen treatment also

  10. Weight gain in hormone receptor-positive (HR+) early-stage breast cancer: is it menopausal status or something else?

    Science.gov (United States)

    Nyrop, Kirsten A; Deal, Allison M; Lee, Jordan T; Muss, Hyman B; Choi, Seul Ki; Wheless, Amy; Carey, Lisa A; Shachar, Shlomit S

    2018-01-01

    This study investigates weight trajectories in pre- versus postmenopausal breast cancer (BC) survivors diagnosed with hormone receptor-positive tumors, with a specific focus on discerning menopausal status and type of endocrine treatment (ET) as risk factors for weight gain during ET. We conducted a retrospective review of electronic medical records. Descriptive statistics and Chi-squared and t tests were used to compare pre- and postmenopausal women. Chi-squared tests and ANOVA were used for within-group associations between patient characteristics and weight trajectories. Log-binomial regression models were used to estimate relative risk for weight gain. The final sample was 32% premenopausal (n = 140) and 68% postmenopausal (n = 298). Relative risk (RR) for weight gain during ET was highest in women who were premenopausal (RR = 1.29, 1.03-1.52) and had Stage 3 BC (RR = 2.12, 1.59-2.82), mastectomy (RR = 1.49, 1.19-1.88), axillary node dissection (RR = 1.39, 1.11-1.73), and chemotherapy (RR = 1.80, 1.37-2.36). For each kg of weight gained between BC diagnosis and start of ET, and for each additional year of age, RR of gaining weight during ET decreased (RR = 0.98, 0.97-0.99, and RR = 0.99, 0.98-0.99, respectively). Menopausal status and type of ET were not significant predictors of weight gain. In multivariable analysis, only weight loss between BC diagnosis and start of ET was significant. The association of weight loss prior to ET and subsequent substantial weight gain during ET warrants further investigation.

  11. Association between lifetime exposure to passive smoking and risk of breast cancer subtypes defined by hormone receptor status among non-smoking Caucasian women.

    Directory of Open Access Journals (Sweden)

    Loreta Strumylaite

    Full Text Available Tobacco smoking is inconsistently associated with breast cancer. Although some studies suggest that breast cancer risk is related to passive smoking, little is known about the association with breast cancer by tumor hormone receptor status. We aimed to explore the association between lifetime passive smoking and risk of breast cancer subtypes defined by estrogen receptor and progesterone receptor status among non-smoking Caucasian women. A hospital-based case-control study was performed in 585 cases and 1170 controls aged 28-90 years. Information on lifetime passive smoking and other factors was collected via a self-administered questionnaire. Logistic regression was used for analyses restricted to the 449 cases and 930 controls who had never smoked actively. All statistical tests were two-sided. Adjusted odds ratio of breast cancer was 1.01 (95% confidence interval (CI: 0.72-1.41 in women who experienced exposure to passive smoking at work, 1.88 (95% CI: 1.38-2.55 in women who had exposure at home, and 2.80 (95% CI: 1.84-4.25 in women who were exposed at home and at work, all compared with never exposed regularly. Increased risk was associated with longer exposure: women exposed ≤ 20 years and > 20 years had 1.27 (95% CI: 0.97-1.66 and 2.64 (95% CI: 1.87-3.74 times higher risk of breast cancer compared with never exposed (Ptrend 0.05. There was evidence of interaction between passive smoking intensity and menopausal status in both overall group (P = 0.02 and hormone receptor-positive breast cancer group (P < 0.05. In Caucasian women, lifetime exposure to passive smoking is associated with the risk of breast cancer independent of tumor hormone receptor status with the strongest association in postmenopausal women.

  12. Classical-type invasive lobular carcinoma with HER2 overexpression: clinical, histologic, and hormone receptor characteristics.

    Science.gov (United States)

    Yu, Jing; Dabbs, David J; Shuai, Yongli; Niemeier, Leo A; Bhargava, Rohit

    2011-07-01

    The majority of invasive lobular carcinomas (ILCs) express estrogen receptor (ER) and progesterone receptor (PR) but lack ERBB2 (HER2) amplification. HER2 overexpression is traditionally considered to occur in the pleomorphic variant of ILCs. We describe 12 cases of classical-type ILCs with HER2 overexpression in a 3-year period. All tumors displayed the characteristic morphologic features of classical ILC with uniform cells and discohesive growth patterns. The lobular phenotype was confirmed by the absence of E-cadherin staining. Multiple variables regarding clinical, histologic, and hormone receptor characteristics of tumors were evaluated and compared with a set of HER2- classical ILCs. The study identified 2 main pathologic features associated with HER2 overexpression in classical type ILC: histiocytoid morphologic features and absence of PR expression. ER is still expressed in HER2+ classical ILCs, although the level of expression is significantly reduced compared with the HER2- cases. The implications of the findings are discussed.

  13. Interaction between body mass index and hormone-receptor status as a prognostic factor in lymph-node-positive breast cancer.

    Directory of Open Access Journals (Sweden)

    Il Yong Chung

    Full Text Available The aim of this study was to determine the relationship between the body mass index (BMI at a breast cancer diagnosis and various factors including the hormone-receptor, menopause, and lymph-node status, and identify if there is a specific patient subgroup for which the BMI has an effect on the breast cancer prognosis. We retrospectively analyzed the data of 8,742 patients with non-metastatic invasive breast cancer from the research database of Asan Medical Center. The overall survival (OS and breast-cancer-specific survival (BCSS outcomes were compared among BMI groups using the Kaplan-Meier method and Cox proportional-hazards regression models with an interaction term. There was a significant interaction between BMI and hormone-receptor status for the OS (P = 0.029, and BCSS (P = 0.013 in lymph-node-positive breast cancers. Obesity in hormone-receptor-positive breast cancer showed a poorer OS (adjusted hazard ratio [HR] = 1.51, 95% confidence interval [CI] = 0.92 to 2.48 and significantly poorer BCSS (HR = 1.80, 95% CI = 1.08 to 2.99. In contrast, a high BMI in hormone-receptor-negative breast cancer revealed a better OS (HR = 0.44, 95% CI = 0.16 to 1.19 and BCSS (HR = 0.53, 95% CI = 0.19 to 1.44. Being underweight (BMI < 18.50 kg/m2 with hormone-receptor-negative breast cancer was associated with a significantly worse OS (HR = 1.98, 95% CI = 1.00-3.95 and BCSS (HR = 2.24, 95% CI = 1.12-4.47. There was no significant interaction found between the BMI and hormone-receptor status in the lymph-node-negative setting, and BMI did not interact with the menopause status in any subgroup. In conclusion, BMI interacts with the hormone-receptor status in a lymph-node-positive setting, thereby playing a role in the prognosis of breast cancer.

  14. EGF receptor inhibitors increase ErbB3 mRNA and protein levels in breast cancer cells

    DEFF Research Database (Denmark)

    Grøvdal, Lene Melsæther; Kim, Jiyoung; Holst, Mikkel Roland

    2012-01-01

    The potential benefits of drugs directly targeting the ErbB receptors for cancer therapy have led to an extensive development within this field. However, the clinical effects of ErbB receptor-targeting drugs in cancer treatment are limited due to a high frequency of resistance. It has been reported...... that, when inhibiting the epidermal growth factor receptor (EGFR) with the tyrosine kinase inhibitor gefitinib, increased activation of ErbB3 via MET, or by re-localization of ErbB3 mediates cell survival. Here we show further evidence that members of the ErbB receptor family facilitate resistance...... to EGFR inhibitor treatment in ErbB2 overexpressing breast cancer cells. We found that gefitinib treatment increased ErbB3 expression, both at protein and mRNA levels. ErbB3 expression was upregulated not only by gefitinib but also by a panel of different EGFR inhibitors, suggesting that inhibition...

  15. P2X7 receptor-mediated PARP1 activity regulates astroglial death in the rat hippocampus following status epilepticus

    Directory of Open Access Journals (Sweden)

    Ji Yang eKim

    2015-09-01

    Full Text Available Poly(ADP-ribose polymerase-1 (PARP1 plays a regulatory role in apoptosis, necrosis, and other cellular processes after injury. Recently, we revealed that PARP1 regulates the differential neuronal/astroglial responses to pilocarpine-induced status epilepticus (SE in the distinct brain regions. In addition, P2X7 receptor (P2X7R, an ATP-gated ion channel, activation accelerates astroglial apoptosis, while it attenuates clasmatodendrosis (lysosome-derived autophagic astroglial death. Therefore, we investigated whether P2X7R regulates regional specific astroglial PARP1 expression/activation in response to SE. In the present study, P2X7R activation exacerbates SE-induced astroglial apoptosis, while P2X7R inhibition attenuates it accompanied by increasing PARP1 activity in the molecular layer of the dentate gyrus following SE. In the CA1 region, however, P2X7R inhibition deteriorates SE-induced clasmatodendrosis via PARP1 activation following SE. Taken together, our findings suggest that P2X7R function may affect SE-induced astroglial death by regulating PARP1 activation/expression in regional-specific manner. Therefore, the selective modulation of P2X7R-mediated PARP1 functions may be a considerable strategy for controls in various types of cell deaths.

  16. Night work and breast cancer risk defined by human epidermal growth factor receptor-2 (HER2) and hormone receptor status: A population-based case-control study in France.

    Science.gov (United States)

    Cordina-Duverger, Emilie; Koudou, Yves; Truong, Thérèse; Arveux, Patrick; Kerbrat, Pierre; Menegaux, Florence; Guénel, Pascal

    Night work has been associated with risk of breast cancer but this association needs to be confirmed. Because breast cancer is an etiologically heterogeneous disease, we explored the association of night work with breast cancer subtypes defined by tumor status (positive of negative) for estrogen-receptor (ER), progesterone-receptor (PR) and human epidermal growth factor-receptor 2 (HER2). Using the data from a case-control study in France including 975 cases and 1317 controls, we found that the odds ratios for ER+, PR+ or HER2+ breast cancers subtypes were significantly elevated, while no association with night shift work was observed for ER, PR or HER2-negative tumors. After stratification by menopausal status, the associations of night work with receptor-positive breast tumor subtypes were clearly seen in premenopausal women (odds ratios 2.04, 1.98 and 2.80, respectively) but did not appear in postmenopausal women. This study provides evidence that working at night may increase risk of ER, PR and HER2-positive subtypes of breast cancer particularly among premenopausal women.

  17. Cerebral 5-HT2A receptor and serotonin transporter binding in humans are not affected by the val66met BDNF polymorphism status or blood BDNF levels

    DEFF Research Database (Denmark)

    Klein, Anders Bue; Trajkovska, Viktorija; Erritzoe, David

    2010-01-01

    Recent studies have proposed an interrelation between the brain-derived neurotrophic factor (BDNF) val66met polymorphism and the serotonin system. In this study, we investigated whether the BDNF val66met polymorphism or blood BDNF levels are associated with cerebral 5-hydroxytryptamine 2A (5-HT(2A......)) receptor or serotonin transporter (SERT) binding in healthy subjects. No statistically significant differences in 5-HT(2A) receptor or SERT binding were found between the val/val and met carriers, nor were blood BDNF values associated with SERT binding or 5-HT(2A) receptor binding. In conclusion, val66met...... BDNF polymorphism status is not associated with changes in the serotonergic system. Moreover, BDNF levels in blood do not correlate with either 5-HT(2A) or SERT binding....

  18. Diffusion Profiling via a Histogram Approach Distinguishes Low-grade from High-grade Meningiomas, Can Reflect the Respective Proliferative Potential and Progesterone Receptor Status.

    Science.gov (United States)

    Gihr, Georg Alexander; Horvath-Rizea, Diana; Garnov, Nikita; Kohlhof-Meinecke, Patricia; Ganslandt, Oliver; Henkes, Hans; Meyer, Hans Jonas; Hoffmann, Karl-Titus; Surov, Alexey; Schob, Stefan

    2018-02-01

    Presurgical grading, estimation of growth kinetics, and other prognostic factors are becoming increasingly important for selecting the best therapeutic approach for meningioma patients. Diffusion-weighted imaging (DWI) provides microstructural information and reflects tumor biology. A novel DWI approach, histogram profiling of apparent diffusion coefficient (ADC) volumes, provides more distinct information than conventional DWI. Therefore, our study investigated whether ADC histogram profiling distinguishes low-grade from high-grade lesions and reflects Ki-67 expression and progesterone receptor status. Pretreatment ADC volumes of 37 meningioma patients (28 low-grade, 9 high-grade) were used for histogram profiling. WHO grade, Ki-67 expression, and progesterone receptor status were evaluated. Comparative and correlative statistics investigating the association between histogram profiling and neuropathology were performed. The entire ADC profile (p10, p25, p75, p90, mean, median) was significantly lower in high-grade versus low-grade meningiomas. The lower percentiles, mean, and modus showed significant correlations with Ki-67 expression. Skewness and entropy of the ADC volumes were significantly associated with progesterone receptor status and Ki-67 expression. ROC analysis revealed entropy to be the most accurate parameter distinguishing low-grade from high-grade meningiomas. ADC histogram profiling provides a distinct set of parameters, which help differentiate low-grade versus high-grade meningiomas. Also, histogram metrics correlate significantly with histological surrogates of the respective proliferative potential. More specifically, entropy revealed to be the most promising imaging biomarker for presurgical grading. Both, entropy and skewness were significantly associated with progesterone receptor status and Ki-67 expression and therefore should be investigated further as predictors for prognostically relevant tumor biological features. Since absolute ADC

  19. Dual surrogate markers for rapid prediction of epidermal growth factor receptor mutation status in advanced adenocarcinoma of the lung: A novel approach in resource-limited setting

    OpenAIRE

    K S Udupa; R Rajendranath; T G Sagar; S Sundersingh; T Joseph

    2015-01-01

    Introduction: Tyrosine kinase inhibitors have revolutionized the treatment of metastatic lung cancer in patients with epidermal growth factor receptor (EGFR) mutations. Amplified refractory mutation system (ARMS)-reverse transcription-polymerase chain reaction (RT-PCR), the current standard for detecting EGFR mutation status is time-consuming and highly expensive. Consequently any surrogate test which are cheaper, faster and as accurate as the PCR method will help in early diagnosis and manag...

  20. Depression, inflammation, and epidermal growth factor receptor (EGFR) status in metastatic non-small cell lung cancer: A pilot study.

    Science.gov (United States)

    Jacobs, Jamie M; Traeger, Lara; Eusebio, Justin; Simon, Naomi M; Sequist, Lecia V; Greer, Joseph A; Temel, Jennifer S; Pirl, William F

    2017-08-01

    Patients with stage IV non-small cell lung cancer (NSCLC) have high risk for depressive symptoms and major depressive disorder (MDD); however, those with epidermal growth factor receptor (EGFR) mutations may have decreased risk. The biological underpinning of this relationship is unknown. We examined differences in depression severity and MDD in patients with newly diagnosed stage IV NSCLC based on EGFR mutation status, and examined proinflammatory cytokines and growth factors known to play a role in cancer progression and depression. Fifty-five patients with newly diagnosed stage IV NSCLC completed self-report and clinician-administered depression assessments prior to receiving results of tumor genotyping. We measured serum levels of circulating biological markers of inflammation: IL-1β, IL-6, TGF-α, and TNF-α. We examined differences in depression severity, MDD, and inflammatory biomarkers in patients with and without EGFR mutations. Patients with EGFR mutations (n=10) had lower depression severity (t[43]=2.38, p=0.03) than those without EGFR mutations (n=38) and fewer patients with EGFR mutations had concurrent MDD (2.08%) relative to those without mutations (27.08%). Patients with MDD had higher levels of TNF-α than those without MDD (t[40]=2.95, p=0.005). Those with EGFR mutations exhibited higher levels of TNF-α relative to those without EGFR mutations (t[35]=2.17, p=0.04). Patients with stage IV NSCLC harboring an EGFR mutation exhibited elevated proinflammatory marker TNF-α, yet had lower depression severity than patients without EGFR mutations. More work is warranted to examine the interaction between tumor genotyping and inflammatory cytokines in the context of depression. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Human epidermal growth factor receptor 2 status of gastric cancer patients in Asia: results from a large, multicountry study.

    Science.gov (United States)

    Pathmanathan, Nirmala; Geng, Jing-Shu; Li, Wencai; Nie, Xiu; Veloso, Januario; Wang, John; Hill, Julie; Mccloud, Philip; Bilous, Michael

    2017-06-01

    Current estimates of the human epidermal growth factor receptor 2 (HER2)-positivity rate in gastric cancer vary widely in the literature, and there are limited data from countries in Asia. The primary aim of this study was to conduct a clinical audit of laboratories across seven countries in Asia to determine the incidence of HER2-positive gastric cancer in this region. Pathologists were asked to collect data on patient gender, age, cancer site, specimen type, tumor spread, type and grade, HER2 test results, including protein and/or gene copy enumeration, and final HER2 status on consecutive gastric cancer cases tested for HER2 in their laboratory over a 2-year period. HER2 results from 5,301 gastric cancers were submitted by 50 laboratories. The overall HER2-positivity rate was 9.7% which, after the exclusion of China, increased to 18.1%. The rate between countries ranged from 0% to 23.1%, and from 0% to 50.0% between laboratories. An equivocal HER2 result was recorded in 19.5% of cases. Despite the lack of centralized testing to confirm the accuracy of HER2 diagnoses, the incidence of HER2-positive gastric cancer observed here was comparable to that reported in the literature. Nevertheless, rates were highly variable between countries and laboratories, which suggests a lack of HER2 testing expertise in gastric cancer. Given that the mortality rates for gastric cancer in Eastern Asia are the highest in the world, efforts should focus on improving HER2 testing expertise in the region so that patients receive the appropriate treatment early in their disease. © 2016 The Authors. Asia-Pacific Journal of Clinical Oncology Published by John Wiley & Sons Australia, Ltd.

  2. [Correlation between the methylation status of Runx3 gene and positive expression of estrogen receptor in breast cancer].

    Science.gov (United States)

    Yan, Zhantao; Gao, Shan; Wu, Xia; Liu, Hui

    2015-04-01

    To investigate the relationship between hypermethylation of Runx3 gene promoter and estrogen receptor (ER) and the implications of Runx3 gene promoter hypermethylation in ER positive breast cancer. Western blot and RT-PCR were used to detect the protein and mRNA expression of Runx3 gene in breast cancer cell lines (MCF7 and SKBR3) and normal breast epithelium cell line (MCF10A). Immunohistochemical SP method was used to detect the expression of ER and Runx3 proteins in 113 tissue samples of breast cancer. Moreover, methylation specific PCR was used to detect RUN3 promoter methylation in cell lines MCF7, SKBR3, MCF10A and 113 tissue samples of breast cancer. Of the 3 cell lines, Runx3 protein and mRNA were detectable in MCF10A, but were absent in MCF7 and SKBR3. MCF7 had a high methylation status at Runx3 promoter, in contrast, MCF10A and SKBR3 showed unmethylated RUN3 promoter. Among the 113 cases of breast cancer, 68 cases were ER positive and 45 were negative. The positive rates of Runx3 protein expression in ER positive and negative tumors were 26.5% (18/68) and 66.7% (30/45), respectively (P<0.05). Runx3 promoter hypermethylation was seen in 82.4% (56/68) of ER positive breast cancer cases and 22.2% (10/45) of ER negative ones (P<0.05). Among 68 cases of ER positive cases, Runx3 promoter hypermethylation was positively correlated with the clinical tumor stage (OR=5.84, P<0.05). Runx3 gene promoter hypermethylation is present mainly in the ER positive breast cancers. Testing of Runx3 promoter methylation may provide additional reference for clinical stage and prognosis of breast cancer patients, especially in those with ER positive tumors.

  3. Epidermal growth factor receptor mutation status in cell-free DNA supernatant of bronchial washings and brushings.

    Science.gov (United States)

    Kawahara, Akihiko; Fukumitsu, Chihiro; Taira, Tomoki; Abe, Hideyuki; Takase, Yorihiko; Murata, Kazuya; Yamaguchi, Tomohiko; Azuma, Koichi; Ishii, Hidenobu; Takamori, Shinzo; Akiba, Jun; Hoshino, Tomoaki; Kage, Masayoshi

    2015-10-01

    The aim of the current study was to examine whether it would be possible to detect epidermal growth factor receptor (EGFR) mutations in cytology cell-free DNA (ccfDNA) from the supernatant fluids of bronchial cytology samples. This study investigated cell damage via immunostaining with a cleaved caspase 3 antibody and the quantity of cell-free DNA in supernatant fluid from 2 cancer cell lines, and the EGFR mutation status was evaluated via polymerase chain reaction (PCR) analysis. EGFR mutations were also evaluated via PCR analysis in 74 clinical samples of ccfDNA from bronchial washing samples with physiological saline or from bronchial brushing liquid-based cytology samples with CytoRich Red. The quantity and fragmentation of cell-free DNA in the supernatant fluid and the cell damage and cleaved caspase 3 expression in the sediment gradually increased in a time-dependent manner in the cell lines. In the 74 clinical samples, the quantity of ccfDNA extracted from the supernatant was adequate to perform the PCR assay, whereas the quality of ccfDNA in physiological saline was often decreased. The detection of EGFR mutations with ccfDNA showed a sensitivity of 88.0%, a specificity of 100%, a positive predictive value of 100%, a negative predictive value of 89.7%, and an accuracy of 94.1% in samples with malignant or atypical cells. These results suggest that activating EGFR mutations can be detected with ccfDNA extracted from the supernatant fluid of liquid-based samples via a PCR assay. This could be a rapid and sensitive method for achieving a parallel diagnosis by both morphology and DNA analysis in non-small cell lung cancer patients. © 2015 American Cancer Society.

  4. Breast cancer histology and receptor status characterization in Asian Indian and Pakistani women in the U.S. - a SEER analysis

    International Nuclear Information System (INIS)

    Kakarala, Madhuri; Rozek, Laura; Cote, Michele; Liyanage, Samadhi; Brenner, Dean E

    2010-01-01

    Recent reports suggest increase in estrogen receptor (ER), progesterone receptor (PR) negative breast cancer yet little is known about histology or receptor status of breast cancer in Indian/Pakistani women.in the U.S. We examined the United States National Cancer Institute's Surveillance Epidemiology and End Results (SEER) Cancer program to assess: a) frequency of breast cancer by age, b) histologic subtypes, c) receptor status of breast cancer and, d) survival in Indians/Pakistanis compared to Caucasians. There were 360,933 breast cancer cases diagnosed 1988-2006. Chi-Square analyses and Cox proportional hazards models, to estimate relative risks for breast cancer mortality after adjusting for confounders, were performed using Statistical Analysis Software 9.2. Among Asian Indian/Pakistani breast cancer patients, 16.2% were < 40 yrs. old compared to 6.23% in Caucasians (p < 0.0001). Asian Indian women had more invasive ductal carcinoma (69.1 vs. 65.7%, p < 0.0001), inflammatory cancer (1.4% vs. 0.8, p < 0.0001) and less invasive lobular carcinoma (4.2% vs. 8.1%, p < 0.0001) than Caucasians. Asian Indian/Pakistani women had more ER/PR negative breast cancer (30.6% vs. 21.8%, p = 0.0095) than Caucasians. Adjusting for stage at diagnosis, age, tumor grade, nodal status, and histology, Asian Indian/Pakistani women's survival was similar to Caucasians, while African Americans' was worse. Asian Indian/Pakistani women have higher frequency of breast cancer (particularly in age < 40), ER/PR negative invasive ductal and inflammatory cancer than Caucasians

  5. Physical activity and risk of breast cancer overall and by hormone receptor status: the European prospective investigation into cancer and nutrition.

    Science.gov (United States)

    Steindorf, Karen; Ritte, Rebecca; Eomois, Piia-Piret; Lukanova, Annekatrin; Tjonneland, Anne; Johnsen, Nina Føns; Overvad, Kim; Østergaard, Jane Nautrup; Clavel-Chapelon, Françoise; Fournier, Agnès; Dossus, Laure; Teucher, Birgit; Rohrmann, Sabine; Boeing, Heiner; Wientzek, Angelika; Trichopoulou, Antonia; Karapetyan, Tina; Trichopoulos, Dimitrios; Masala, Giovanna; Berrino, Franco; Mattiello, Amalia; Tumino, Rosario; Ricceri, Fulvio; Quirós, J Ramón; Travier, Noémie; Sánchez, María-José; Navarro, Carmen; Ardanaz, Eva; Amiano, Pilar; Bueno-de-Mesquita, H B As; van Duijnhoven, Franzel; Monninkhof, Evelyn; May, Anne M; Khaw, Kay-Tee; Wareham, Nick; Key, Tim J; Travis, Ruth C; Borch, Kristin Benjaminsen; Sund, Malin; Andersson, Anne; Fedirko, Veronika; Rinaldi, Sabina; Romieu, Isabelle; Wahrendorf, Jürgen; Riboli, Elio; Kaaks, Rudolf

    2013-04-01

    Physical activity is associated with reduced risks of invasive breast cancer. However, whether this holds true for breast cancer subtypes defined by the estrogen receptor (ER) and the progesterone receptor (PR) status is controversial. The study included 257,805 women from the multinational EPIC-cohort study with detailed information on occupational, recreational and household physical activity and important cofactors assessed at baseline. During 11.6 years of median follow-up, 8,034 incident invasive breast cancer cases were identified. Data on ER, PR and combined ER/PR expression were available for 6,007 (67.6%), 4,814 (54.2%) and 4,798 (53.9%) cases, respectively. Adjusted hazard ratios (HR) were estimated by proportional hazards models. Breast cancer risk was inversely associated with moderate and high levels of total physical activity (HR = 0.92, 95% confidence interval (CI): 0.86-0.99, HR = 0.87, 95%-CI: 0.79-0.97, respectively; p-trend = 0.002), compared to the lowest quartile. Among women diagnosed with breast cancer after age 50, the largest risk reduction was found with highest activity (HR = 0.86, 95%-CI: 0.77-0.97), whereas for cancers diagnosed before age 50 strongest associations were found for moderate total physical activity (HR = 0.78, 95%-CI: 0.64-0.94). Analyses by hormone receptor status suggested differential associations for total physical activity (p-heterogeneity = 0.04), with a somewhat stronger inverse relationship for ER+/PR+ breast tumors, primarily driven by PR+ tumors (p-heterogeneity breast cancer risk. Heterogeneities by receptor status indicate hormone-related mechanisms. Copyright © 2012 UICC.

  6. The erbB3- and IGF-1 receptor-initiated signaling pathways exhibit distinct effects on lapatinib sensitivity against trastuzumab-resistant breast cancer cells.

    Science.gov (United States)

    Lyu, Hui; Yang, Xiao He; Edgerton, Susan M; Thor, Ann D; Wu, Xiaoying; He, Zhimin; Liu, Bolin

    2016-01-19

    Both erbB3 and IGF-1 receptor (IGF-1R) have been shown to play an important role in trastuzumab resistance. However, it remains unclear whether erbB3- and IGF-1R-initiated signaling pathways possess distinct effects on the sensitivity of lapatinib, a dual tyrosine kinase inhibitor against both EGFR and erbB2, in trastuzumab-resistant breast cancer. Here, we show that the trastuzumab-resistant SKBR3-pool2 and BT474-HR20 breast cancer sublines, as compared the parental SKBR3 and BT474 cells, respectively, exhibit refractoriness to lapatinib. Knockdown of erbB3 inhibited Akt in SKBR3-pool2 and BT474-HR20 cells, significantly increased lapatinib efficacy, and dramatically re-sensitized the cells to lapatinib-induced apoptosis. In contrast, specific knockdown of IGF-1R did not alter the cells' responsiveness to lapatinib. While the levels of phosphorylated Src (P-Src) were reduced upon IGF-1R downregulation, the P-Akt levels remained unchanged. Furthermore, a specific inhibitor of Akt, but not Src, significantly enhanced lapatinib-mediated anti-proliferative/anti-survival effects on SKBR3-pool2 and BT474-HR20 cells. These data indicate that erbB3 signaling is critical for both trastuzumab and lapatinib resistances mainly through the PI-3K/Akt pathway, whereas IGF-1R-initiated Src activation results in trastuzumab resistance without affecting lapatinib sensitivity. Our findings may facilitate the development of precision therapeutic regimens for erbB2-positive breast cancer patients who become resistant to erbB2-targeted therapy.

  7. Differential ontogenetic exposure to obesogenic environment induces hyperproliferative status and nuclear receptors imbalance in the rat prostate at adulthood.

    Science.gov (United States)

    Pytlowanciv, Eloísa Zanin; Pinto-Fochi, Maria Etelvina; Reame, Vanessa; Gobbo, Marina Guimarães; Ribeiro, Daniele Lisboa; Taboga, Sebastião Roberto; Góes, Rejane Maira

    2016-05-01

    Experimental data indicate that high-fat diet (HFD) may alter proliferative activity and prostate health. However, the consequences of HFD exposure during different periods of ontogenetic development on prostate histophysiology remain to be elucidated. Herein, we compare the influence of obesogenic environment (OE) due to maternal obesity and HFD at different periods of life on proliferative activity and nuclear receptors frequency in the rat ventral prostate and a possible relationship with metabolic and hormonal alterations. Male Wistar rats (19 weeks old), treated with balanced chow (Control group-C; 3% high-fat, 3.5 Kcal/g), were compared with those exposed to HFD (20% high-fat, 4.9 kcal/g) during gestation (G-maternal obesity), gestation and lactation (GL), from post-weaning to adulthood (WA), from lactation to adulthood (LA) and from gestation to adulthood (GA). After the experimental period, the ventral prostate lobes were removed and analyzed with different methods. Metabolic data indicated that G and GL rats became insulin resistant and WA, LA, and GA became insulin resistant and obese. There was a strong inverse correlation between serum testosterone (∼133% lower) and leptin levels (∼467% higher) in WA, LA, and GA groups. Estrogen serum levels increased in GA, and insulin levels increased in all groups, especially in WA (64.8×). OE-groups exhibited prostatic hypertrophy, since prostate weight increased ∼40% in G, GL, LA, and GA and 31% in WA. As indicated by immunohistochemistry, all HFD-groups except G exhibited an increase in epithelial cell proliferation (PCNA-positive) and a decrease in frequency of AR- and ERβ-positive epithelial cells; there was also an increment of ERα-positive stromal cells in comparison with control. Cells containing PPARγ increased in both epithelium and stroma of all OE groups and those expressing LXRα decreased, particularly in groups OE-exposed during gestation (G, GL and GA). OE leads to prostate hypertrophy

  8. Dietary fiber intake and risk of breast cancer defined by estrogen and progesterone receptor status: the Japan Public Health Center-based Prospective Study.

    Science.gov (United States)

    Narita, Saki; Inoue, Manami; Saito, Eiko; Abe, Sarah K; Sawada, Norie; Ishihara, Junko; Iwasaki, Motoki; Yamaji, Taiki; Shimazu, Taichi; Sasazuki, Shizuka; Shibuya, Kenji; Tsugane, Shoichiro

    2017-06-01

    Epidemiological studies have suggested a protective effect of dietary fiber intake on breast cancer risk while the results have been inconsistent. Our study aimed to investigate the association between dietary fiber intake and breast cancer risk and to explore whether this association is modified by reproductive factors and hormone receptor status of the tumor. A total of 44,444 women aged 45 to 74 years from the Japan Public Health Center-based Prospective Study were included in analyses. Dietary intake assessment was performed using a validated 138-item food frequency questionnaire (FFQ). Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer incidence were calculated by multivariate Cox proportional hazards regression models. During 624,423 person-years of follow-up period, 681 breast cancer cases were identified. After adjusting for major confounders for breast cancer risk, inverse trends were observed but statistically non-significant. Extremely high intake of fiber was associated with decreased risk of breast cancer but this should be interpreted with caution due to limited statistical power. In stratified analyses by menopausal and hormone receptor status, null associations were observed except for ER-PR- status. Our findings suggest that extreme high fiber intake may be associated with decreased risk of breast cancer but the level of dietary fiber intake among Japanese population might not be sufficient to examine the association between dietary fiber intake and breast cancer risk.

  9. Prolactin modulates phosphorylation, signaling and trafficking of epidermal growth factor receptor in human T47D breast cancer cells.

    Science.gov (United States)

    Huang, Y; Li, X; Jiang, J; Frank, S J

    2006-12-07

    Prolactin (PRL) is a polypeptide hormone produced by the anterior pituitary gland and other sites that acts both systemically and locally to cause lactation and other biological effects by interacting with the PRL receptor, a Janus kinase (JAK)2-coupled cytokine receptor family member, and activating downstream signal pathways. Recent evidence suggests PRL is a player in the pathogenesis and progression of breast cancer. Epidermal growth factor (EGF) also has effects on breast tissue, working through its receptors, epidermal growth factor receptor (EGFR) and ErbB-2 (c-neu, HER2), both intrinsic tyrosine kinase growth factor receptors. EGFR promotes pubertal breast ductal morphogenesis in mice, and both EGFR and ErbB-2 are relevant in pathogenesis and behavior of breast and other human cancers. Previous studies showed that PRL and EGF synergize to enhance motility in the human breast cancer cell line, T47D. In this study, we explored crosstalk between the PRL and EGF signaling pathways in T47D cells, with an ultimate aim of understanding how these two important factors might work together in vivo to affect breast cancer behavior. Both PRL and EGF caused robust signaling in T47D cells; PRL acutely activated JAK2, signal transducer and activator of transcription-5 (STAT5), and extracellular signal-regulated kinase-1 and -2 (ERK1 and ERK2), whereas EGF caused EGFR activation and consequent src homology collagen (SHC) activation and ERK activation. Notably, PRL also caused phosphorylation of the EGFR and ErbB-2 at sites detected by PTP101, an antibody that recognizes threonine phosphorylation at consensus motifs for ERK-induced phosphorylation. PRL-induced PTP101-reactive phosphorylation was prevented by pretreatment with PD98059, an ERK pathway inhibitor. Furthermore, PRL synergized with EGF in activating SHC and ERK and transactivating a luciferase reporter driven by c-fos gene enhancer elements, suggesting that PRL allowed markedly enhanced EGF signaling. This was

  10. ANALYSIS OF ASSOCIATIONS OF VEGF-A GENE POLYMORPHISM AT POSITIONS 2578A/C AND +936C/T WITH DIFFERENT RECEPTOR STATUS IN BREAST CANCER PATIENTS

    Directory of Open Access Journals (Sweden)

    A. V. Shevchenko

    2013-01-01

    Full Text Available The study of functional polymorphism of the VEGF-A gene at positions –2578 in the promoter region and +936 in the 3`untranslated region in breast cancer patients with different receptor status of the tumor was undertaken to identify markers associated with risk of breast cancer. DNA samples from 292 women with breast cancer were analyzed. The genotyping of С–2578A and C+936T VEG-FA polymorphisms was performed using the method of restriction analysis of amplification products. The distributions of VEGF-A genotypes in patients having estrogen and progesterone receptors in tumor tissues were investigated and genotypes associated with risk of breast cancer recurrences were detected.

  11. Serotonin 5-HT(2A) receptor antagonists in the treatment of insomnia: present status and future prospects.

    Science.gov (United States)

    Monti, J M

    2010-03-01

    Benzodiazepine (BZD) and non-BZD hypnotics improve sleep induction and sleep maintenance. BZD induces a further reduction of slow wave sleep (SWS) and rapid eye movement (REM) sleep, whereas SWS and REM values remain decreased during non-BZD administration. There is evidence indicating that the nonselective serotonin 5-HT(2A/2C) receptor antagonists, ritanserin, ketanserin, seganserin and ICI-169369, the selective 5-HT(2A) receptor antagonist eplivanserin and the 5-HT(2A) receptor inverse agonist pimavanserin, increase SWS in subjects with normal sleep. In addition, it has been shown that prior administration of ritanserin prevents the nitrazepam-induced suppression of SWS in normal subjects. Of note, ritanserin also induced an increase of SWS in poor sleepers, patients with chronic primary insomnia and psychiatric patients with a generalized anxiety disorder or a mood disorder. The 5-HT(2A) receptor inverse agonist APD-125 gave rise to a similar effect in patients with chronic primary insomnia. Thus, presently available evidence tends to indicate that the association of a 5-HT(2A) receptor antagonist or a 5-HT(2A) receptor inverse agonist with a BZD or a non-BZD hypnotic could be a valid alternative to normalize SWS in patients with primary or comorbid insomnia. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

  12. Risk of Breast Cancer in Relation to Combined Effects of Hormone Therapy, Body Mass Index, and Alcohol Use, by Hormone-receptor Status

    DEFF Research Database (Denmark)

    Hvidtfeldt, Ulla Arthur; Tjonneland, Anne; Keiding, Niels

    2015-01-01

    BACKGROUND: Alcohol consumption, increased body mass index (BMI), and hormone therapy are risk factors for postmenopausal breast cancer, but their combined effects are not well understood. Because hormone therapy is effective for the relief of menopausal symptoms, the identification of "high......-risk" users is important for therapeutic reasons. We investigated interactions between hormone therapy use and alcohol-use/high BMI status in relation to invasive breast cancer risk, both overall and according to estrogen receptor (ER) status. METHODS: Two Danish prospective cohorts were pooled, including 30......,938 person-years of follow-up, 1579 women developed invasive breast cancer. Among nonusers of hormone therapy, the risk of breast cancer was slightly increased with overweight/obesity and increasing alcohol consumption. Compared with normal-weight nonusers, the risk of breast cancer was higher in hormone...

  13. GWAS in the SIGNAL/PHARE clinical cohort restricts the association between the FGFR2 locus and estrogen receptor status to HER2-negative breast cancer patients

    Science.gov (United States)

    Cox, David G.; Curtit, Elsa; Romieu, Gilles; Fumoleau, Pierre; Rios, Maria; Bonnefoi, Hervé; Bachelot, Thomas; Soulié, Patrick; Jouannaud, Christelle; Bourgeois, Hugues; Petit, Thierry; Tennevet, Isabelle; Assouline, David; Mathieu, Marie-Christine; Jacquin, Jean-Philippe; Lavau-Denes, Sandrine; Darut-Jouve, Ariane; Ferrero, Jean-Marc; Tarpin, Carole; Lévy, Christelle; Delecroix, Valérie; Trillet-Lenoir, Véronique; Cojocarasu, Oana; Meunier, Jérôme; Pierga, Jean-Yves; Faure-Mercier, Céline; Blanché, Hélène; Sahbatou, Mourad; Boland, Anne; Bacq, Delphine; Besse, Céline; Deleuze, Jean-François; Pauporté, Iris; Thomas, Gilles; Pivot, Xavier

    2016-01-01

    Genetic polymorphisms are associated with breast cancer risk. Clinical and epidemiological observations suggest that clinical characteristics of breast cancer, such as estrogen receptor or HER2 status, are also influenced by hereditary factors. To identify genetic variants associated with pathological characteristics of breast cancer patients, a Genome Wide Association Study was performed in a cohort of 9365 women from the French nationwide SIGNAL/PHARE studies (NCT00381901/RECF1098). Strong association between the FGFR2 locus and ER status of breast cancer patients was observed (ER-positive n=6211, ER-negative n=2516; rs3135718 OR=1.34 p=5.46×10−12). This association was limited to patients with HER2-negative tumors (ER-positive n=4267, ER-negative n=1185; rs3135724 OR=1.85 p=1.16×10−11). The FGFR2 locus is known to be associated with breast cancer risk. This study provides sound evidence for an association between variants in the FGFR2 locus and ER status among breast cancer patients, particularly among patients with HER2-negative disease. This refinement of the association between FGFR2 variants and ER-status to HER2-negative disease provides novel insight to potential biological and clinical influence of genetic polymorphisms on breast tumors. PMID:27764800

  14. Nutritional status in the era of target therapy: poor nutrition is a prognostic factor in non-small cell lung cancer with activating epidermal growth factor receptor mutations.

    Science.gov (United States)

    Park, Sehhoon; Park, Seongyeol; Lee, Se-Hoon; Suh, Beomseok; Keam, Bhumsuk; Kim, Tae Min; Kim, Dong-Wan; Kim, Young Whan; Heo, Dae Seog

    2016-11-01

    Pretreatment nutritional status is an important prognostic factor in patients treated with conventional cytotoxic chemotherapy. In the era of target therapies, its value is overlooked and has not been investigated. The aim of our study is to evaluate the value of nutritional status in targeted therapy. A total of 2012 patients with non-small cell lung cancer (NSCLC) were reviewed and 630 patients with activating epidermal growth factor receptor (EGFR) mutation treated with EGFR tyrosine kinase inhibitor (TKI) were enrolled for the final analysis. Anemia, body mass index (BMI), and prognostic nutritional index (PNI) were considered as nutritional factors. Hazard ratio (HR), progression-free survival (PFS) and overall survival (OS) for each group were calculated by Cox proportional analysis. In addition, scores were applied for each category and the sum of scores was used for survival analysis. In univariable analysis, anemia (HR, 1.29; p = 0.015), BMI lower than 18.5 (HR, 1.98; p = 0.002), and PNI lower than 45 (HR, 1.57; p nutritional status is a prognostic marker in NSCLC patients treated with EGFR TKI. Hence, baseline nutritional status should be more carefully evaluated and adequate nutrition should be supplied to these patients.

  15. Technical validation of an RT-qPCR in vitro diagnostic test system for the determination of breast cancer molecular subtypes by quantification of ERBB2, ESR1, PGR and MKI67 mRNA levels from formalin-fixed paraffin-embedded breast tumor specimens.

    Science.gov (United States)

    Laible, Mark; Schlombs, Kornelia; Kaiser, Katharina; Veltrup, Elke; Herlein, Stefanie; Lakis, Sotiris; Stöhr, Robert; Eidt, Sebastian; Hartmann, Arndt; Wirtz, Ralph M; Sahin, Ugur

    2016-07-07

    MammaTyper is a novel CE-marked in vitro diagnostic RT-qPCR assay which assigns routinely processed breast cancer specimens into the molecular subtypes Luminal A-like, Luminal B-like (HER2 positive or negative), HER2 positive (non-luminal) and Triple negative (ductal) according to the mRNA expression of ERBB2, ESR1, PGR and MKI67 and the St Gallen consensus surrogate clinical definition. Until now and regarding formalin-fixed, paraffin-embedded material (FFPE), this has been a task mostly accomplished by immunohistochemistry (IHC). However the discrepancy rates of IHC for the four breast cancer biomarkers are frequently under debate, especially for Ki-67 which carries the highest degree of inter- and even intra-observer variability. Herein we describe a series of studies in FFPE specimens which aim to fully validate the analytical performance of the MammaTyper assay, including the site to site reproducibility of the individual marker measurements. Tumor RNA was extracted with the novel RNXtract RNA extraction kit. Synthetic RNA was used to assess the sensitivity of the RNXtract kit. DNA and RNA specific qPCR assays were used so as to determine analyte specificity of RNXtract. For the assessment of limit of blank, limit of detection, analytical measurement range and PCR efficiency of the MammaTyper kit serial dilutions of samples were used. Analytical precision studies of MammaTyper were built around two different real time PCR platforms and involved breast tumor samples belonging to different subtypes analyzed across multiple sites and under various stipulated conditions. The MammaTyper assay robustness was tested against RNA input variations, alternative extraction methods and tumor cell content. Individual assays were linear up to at least 32.33 and 33.56 Cqs (quantification cycles) for the two qPCR platforms tested. PCR efficiency ranged from 99 to 109 %. In qPCR platform 1, estimates for assay specific inter-site standard deviations (SD) were between 0.14 and

  16. Technical validation of an RT-qPCR in vitro diagnostic test system for the determination of breast cancer molecular subtypes by quantification of ERBB2, ESR1, PGR and MKI67 mRNA levels from formalin-fixed paraffin-embedded breast tumor specimens

    International Nuclear Information System (INIS)

    Laible, Mark; Schlombs, Kornelia; Kaiser, Katharina; Veltrup, Elke; Herlein, Stefanie; Lakis, Sotiris; Stöhr, Robert; Eidt, Sebastian; Hartmann, Arndt; Wirtz, Ralph M.; Sahin, Ugur

    2016-01-01

    MammaTyper is a novel CE-marked in vitro diagnostic RT-qPCR assay which assigns routinely processed breast cancer specimens into the molecular subtypes Luminal A-like, Luminal B-like (HER2 positive or negative), HER2 positive (non-luminal) and Triple negative (ductal) according to the mRNA expression of ERBB2, ESR1, PGR and MKI67 and the St Gallen consensus surrogate clinical definition. Until now and regarding formalin-fixed, paraffin-embedded material (FFPE), this has been a task mostly accomplished by immunohistochemistry (IHC). However the discrepancy rates of IHC for the four breast cancer biomarkers are frequently under debate, especially for Ki-67 which carries the highest degree of inter- and even intra-observer variability. Herein we describe a series of studies in FFPE specimens which aim to fully validate the analytical performance of the MammaTyper assay, including the site to site reproducibility of the individual marker measurements. Tumor RNA was extracted with the novel RNXtract RNA extraction kit. Synthetic RNA was used to assess the sensitivity of the RNXtract kit. DNA and RNA specific qPCR assays were used so as to determine analyte specificity of RNXtract. For the assessment of limit of blank, limit of detection, analytical measurement range and PCR efficiency of the MammaTyper kit serial dilutions of samples were used. Analytical precision studies of MammaTyper were built around two different real time PCR platforms and involved breast tumor samples belonging to different subtypes analyzed across multiple sites and under various stipulated conditions. The MammaTyper assay robustness was tested against RNA input variations, alternative extraction methods and tumor cell content. Individual assays were linear up to at least 32.33 and 33.56 Cqs (quantification cycles) for the two qPCR platforms tested. PCR efficiency ranged from 99 to 109 %. In qPCR platform 1, estimates for assay specific inter-site standard deviations (SD) were between 0.14 and 0

  17. Use of imputed population-based cancer registry data as a method of accounting for missing information: application to estrogen receptor status for breast cancer.

    Science.gov (United States)

    Howlader, Nadia; Noone, Anne-Michelle; Yu, Mandi; Cronin, Kathleen A

    2012-08-15

    The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program provides a rich source of data stratified according to tumor biomarkers that play an important role in cancer surveillance research. These data are useful for analyzing trends in cancer incidence and survival. These tumor markers, however, are often prone to missing observations. To address the problem of missing data, the authors employed sequential regression multivariate imputation for breast cancer variables, with a particular focus on estrogen receptor status, using data from 13 SEER registries covering the period 1992-2007. In this paper, they present an approach to accounting for missing information through the creation of imputed data sets that can be analyzed using existing software (e.g., SEER*Stat) developed for analyzing cancer registry data. Bias in age-adjusted trends in female breast cancer incidence is shown graphically before and after imputation of estrogen receptor status, stratified by age and race. The imputed data set will be made available in SEER*Stat (http://seer.cancer.gov/analysis/index.html) to facilitate accurate estimation of breast cancer incidence trends. To ensure that the imputed data set is used correctly, the authors provide detailed, step-by-step instructions for conducting analyses. This is the first time that a nationally representative, population-based cancer registry data set has been imputed and made available to researchers for conducting a variety of analyses of breast cancer incidence trends.

  18. Somatostatin receptors subtypes 2 and 5, dopamine receptor type 2 expression and gsp status as predictors of octreotide LAR responsiveness in acromegaly.

    Science.gov (United States)

    Vieira Neto, Leonardo; Taboada, Giselle Fernandes; Gadelha, Mônica Roberto

    2008-11-01

    We present two acromegalic patients in which clinical and molecular data are discussed in regard to their ability to predict long term octreotide LAR therapy response. Patient 1: female, 36 years old at diagnosis. Basal GH and IGF-I at diagnosis were 133 ng/mL and 181% above the upper limit of reference values (ULRV), respectively. Growth hormone during acute test with subcutaneous octreotide decreased from 133 to 13 ng/mL. Patient started on primary octreotide LAR therapy (20mg q28 days) and achieved biochemical parameters of disease control after 6 months. Molecular analysis of tumor fragments: gsp +; quantitative analysis of SSTR (somatostatin receptor) and DR (dopamine receptor) mRNA - SSTR2 23954; SSTR5 2407; DR2 total 17016 copies. Patient 2: male, 38 years old at diagnosis. Basal GH and IGF-I at diagnosis were 120 ng/mL and 114% ULRV, respectively. Patient underwent non-curative trans-sphenoidal surgery. Post-operative GH and IGF-I were 112 ng/mL and 137% ULRV, respectively. Growth hormone during acute test with subcutaneous octreotide decreased from 112 to 7 ng/mL. Octreotide LAR therapy (20 mg q28 days) was then initiated. After 6 months of treatment, patient did not attain biochemical control of disease and displayed increased tumor volume. Molecular analysis of tumor fragments: gsp not done; quantitative analysis of SSTR and DR mRNA - SSTR2 416; SSTR5 3767; DR2 total 3439 copies. In conclusion, these two cases illustrate how laboratory data can be conflicting as predictors of octreotide LAR responsiveness and how molecular analysis of tumor fragments can help explain different behaviors in clinically similar patients.

  19. The M1 Muscarinic Receptor Antagonist VU0255035 Delays the Development of Status Epilepticus after Organophosphate Exposure and Prevents Hyperexcitability in the Basolateral Amygdala

    Science.gov (United States)

    Miller, Steven L.; Aroniadou-Anderjaska, Vassiliki; Pidoplichko, Volodymyr I.; Figueiredo, Taiza H.; Apland, James P.; Krishnan, Jishnu K. S.

    2017-01-01

    Exposure to organophosphorus toxins induces seizures that progress to status epilepticus (SE), which can cause brain damage or death. Seizures are generated by hyperstimulation of muscarinic receptors, subsequent to inhibition of acetylcholinesterase; this is followed by glutamatergic hyperactivity, which sustains and reinforces seizure activity. It has been unclear which muscarinic receptor subtypes are involved in seizure initiation and the development of SE in the early phases after exposure. Here, we show that pretreatment of rats with the selective M1 receptor antagonist, VU0255035 [N-(3-oxo-3-(4-(pyridine-4-yl)piperazin-1-yl)propyl)-benzo[c][1,2,5]thiadiazole-4 sulfonamide], significantly suppressed seizure severity and prevented the development of SE for about 40 minutes after exposure to paraoxon or soman, suggesting an important role of the M1 receptor in the early phases of seizure generation. In addition, in in vitro brain slices of the basolateral amygdala (a brain region that plays a key role in seizure initiation after nerve agent exposure), VU0255035 blocked the effects produced by bath application of paraoxon—namely, a brief barrage of spontaneous inhibitory postsynaptic currents, followed by a significant increase in the ratio of the total charge transferred by spontaneous excitatory postsynaptic currents over that of the inhibitory postsynaptic currents. Furthermore, paraoxon enhanced the hyperpolarization-activated cation current Ih in basolateral amygdala principal cells, which could be one of the mechanisms underlying the increased glutamatergic activity, an effect that was also blocked in the presence of VU0255035. Thus, selective M1 antagonists may be an efficacious pretreatment in contexts in which there is risk for exposure to organophosphates, as these antagonists will delay the development of SE long enough for medical assistance to arrive. PMID:27799295

  20. Combined Effects of Circulating Levels of 25-Hydroxyvitamin D and Th1 and Th2 Cytokines on Breast Cancer Estrogen Receptor Status

    Energy Technology Data Exchange (ETDEWEB)

    Yao, Song, E-mail: song.yao@roswellpark.org; Hong, Chi-Chen; McCann, Susan E.; Zirpoli, Gary; Quan, Lei; Gong, Zhihong [Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263 (United States); Johnson, Candace S. [Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263 (United States); Trump, Donald L. [Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263 (United States); Ambrosone, Christine B. [Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263 (United States)

    2014-01-27

    Vitamin D has been recognized for its immune-modulating properties. We have previously found that levels of 25OHD, and cytokines including IL5, IFNα2, and TNFα, are also associated with estrogen receptor (ER) negative breast cancer in younger women. Thus, we hypothesized that there may be interactions between vitamin D and the immune system in influencing breast cancer ER status, which was tested in 490 women with incident breast cancer. There was no correlation of the levels of 25OHD with any cytokine, and their associations with tumor ER negative status were independent of each other. However, premenopausal women with low 25OHD and high TNFα levels had the highest likelihood of having ER negative cancer (odds ratio [OR] = 7.32, 95% confidence interval [CI] = 2.44−21.98), with evidence of synergy between the two (relative excess risk due to interaction [RERI] = 5.46, p for additive interaction = 0.14, and p for multiplicative interaction = 0.09). There were similar synergistic associations between 25OHD and IL5, and several IFNα2 to Th2 cytokine ratios. This is the first study to provide evidence of interactions between vitamin D and the immune system in relation to breast cancer ER status, which may inform combinational use of vitamin D and anti-inflammatory drugs for cancer prevention and therapy.

  1. Combined effects of circulating levels of 25-hydroxyvitamin d and Th1 and th2 cytokines on breast cancer estrogen receptor status.

    Science.gov (United States)

    Yao, Song; Hong, Chi-Chen; McCann, Susan E; Zirpoli, Gary; Quan, Lei; Gong, Zhihong; Johnson, Candace S; Trump, Donald L; Ambrosone, Christine B

    2014-01-27

    Vitamin D has been recognized for its immune-modulating properties. We have previously found that levels of 25OHD, and cytokines including IL5, IFNα2, and TNFα, are also associated with estrogen receptor (ER) negative breast cancer in younger women. Thus, we hypothesized that there may be interactions between vitamin D and the immune system in influencing breast cancer ER status, which was tested in 490 women with incident breast cancer. There was no correlation of the levels of 25OHD with any cytokine, and their associations with tumor ER negative status were independent of each other. However, premenopausal women with low 25OHD and high TNFα levels had the highest likelihood of having ER negative cancer (odds ratio [OR] = 7.32, 95% confidence interval [CI] = 2.44-21.98), with evidence of synergy between the two (relative excess risk due to interaction [RERI] = 5.46, p for additive interaction = 0.14, and p for multiplicative interaction = 0.09). There were similar synergistic associations between 25OHD and IL5, and several IFNα2 to Th2 cytokine ratios. This is the first study to provide evidence of interactions between vitamin D and the immune system in relation to breast cancer ER status, which may inform combinational use of vitamin D and anti-inflammatory drugs for cancer prevention and therapy.

  2. Combined Effects of Circulating Levels of 25-Hydroxyvitamin D and Th1 and Th2 Cytokines on Breast Cancer Estrogen Receptor Status

    Directory of Open Access Journals (Sweden)

    Song Yao

    2014-01-01

    Full Text Available Vitamin D has been recognized for its immune-modulating properties. We have previously found that levels of 25OHD, and cytokines including IL5, IFNα2, and TNFα, are also associated with estrogen receptor (ER negative breast cancer in younger women. Thus, we hypothesized that there may be interactions between vitamin D and the immune system in influencing breast cancer ER status, which was tested in 490 women with incident breast cancer. There was no correlation of the levels of 25OHD with any cytokine, and their associations with tumor ER negative status were independent of each other. However, premenopausal women with low 25OHD and high TNFα levels had the highest likelihood of having ER negative cancer (odds ratio [OR] = 7.32, 95% confidence interval [CI] = 2.44−21.98, with evidence of synergy between the two (relative excess risk due to interaction [RERI] = 5.46, p for additive interaction = 0.14, and p for multiplicative interaction = 0.09. There were similar synergistic associations between 25OHD and IL5, and several IFNα2 to Th2 cytokine ratios. This is the first study to provide evidence of interactions between vitamin D and the immune system in relation to breast cancer ER status, which may inform combinational use of vitamin D and anti-inflammatory drugs for cancer prevention and therapy.

  3. Mortality risk of black women and white women with invasive breast cancer by hormone receptors, HER2, and p53 status

    International Nuclear Information System (INIS)

    Ma, Huiyan; Folger, Suzanne G; Simon, Michael S; Sullivan-Halley, Jane; Press, Michael F; Bernstein, Leslie; Lu, Yani; Malone, Kathleen E; Marchbanks, Polly A; Deapen, Dennis M; Spirtas, Robert; Burkman, Ronald T; Strom, Brian L; McDonald, Jill A

    2013-01-01

    Black women are more likely than white women to have an aggressive subtype of breast cancer that is associated with higher mortality and this may contribute to the observed black-white difference in mortality. However, few studies have investigated the black-white disparity in mortality risk stratified by breast cancer subtype, defined by estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status. Furthermore, it is not known whether additional consideration of p53 protein status influences black-white differences in mortality risk observed when considering subtypes defined by ER, PR and HER2 status. Four biomarkers were assessed by immunohistochemistry in paraffin-embedded breast tumor tissue from 1,204 (523 black, 681 white) women with invasive breast cancer, aged 35–64 years at diagnosis, who accrued a median of 10 years’ follow-up. Multivariable Cox proportional hazards regression models were fit to assess subtype-specific black-white differences in mortality risk. No black-white differences in mortality risk were observed for women with triple negative (ER-negative [ER-], PR-, and HER2-) subtype. However, older (50–64 years) black women had greater overall mortality risk than older white women if they had been diagnosed with luminal A (ER-positive [ER+] or PR+ plus HER2-) breast cancer (all-cause hazard ratio, HR, 1.88; 95% confidence interval, CI, 1.18 to 2.99; breast cancer-specific HR, 1.51; 95% CI, 0.83 to 2.74). This black-white difference among older women was further confined to those with luminal A/p53- tumors (all-cause HR, 2.22; 95% CI, 1.30 to 3.79; breast cancer-specific HR, 1.89; 95% CI, 0.93 to 3.86). Tests for homogeneity of race-specific HRs comparing luminal A to triple negative subtype and luminal A/p53- to luminal A/p53+ subtype did not achieve statistical significance, although statistical power was limited. Our findings suggest that the subtype-specific black-white difference in

  4. Novel Drugs that Target ErbB2

    Science.gov (United States)

    2012-05-01

    drugs including curcumin , arsenic trioxide, non-steroidal anti-inflammatory drugs, and triterpenoids such as celastrol, 2-cyano-1,12-dioxooleana-1,9...and tumors. These include curcumin , arsenic trioxide, tolfenamic acid and structurally related nonsteroidal anti-inflammatory drugs, BA, and...Jutooru I, Chintharlapalli S, Papineni S, Smith R, 3rd, Li X, et al. Curcumin decreases specificity protein expression in bladder cancer cells

  5. Intake of whole grain products and risk of breast cancer by hormone receptor status and histology among postmenopausal women

    DEFF Research Database (Denmark)

    Egeberg, Rikke; Olsen, Anja; Loft, Steffen

    2009-01-01

    ) and progesterone receptor (PR)] and tumour histology (ductal/lobular). It was further investigated whether the association differed by use of hormone replacement therapy (HRT). The study included 25,278 postmenopausal women participating in the Danish Diet, Cancer and Health cohort study (1993-1997). During a mean...... follow-up time of 9.6 years, 978 breast cancer cases were diagnosed. Associations between intake of whole grain products and the breast cancer rate were analysed using Cox's regression model. A higher intake of whole grain products was not associated with a lower risk of breast cancer. Per an increment...

  6. Glycoprotein CD44 expression in normal, hyperplasic and neoplastic endometrium. An immunohistochemical study including correlations with p53, steroid receptor status and proliferative indices (PCNA, MIB1).

    Science.gov (United States)

    Zagorianakou, N; Ioachim, E; Mitselou, A; Kitsou, E; Zagorianakou, P; Stefanaki, S; Makrydimas, G; Agnantis, N J

    2003-01-01

    We have studied by immunohistochemistry the presence and localization of CD44, estrogen and progesterone receptors, p53 and proliferative associated indices (MIB1, PCNA) in archival endometrial tissue, in order to determine their diagnostic and prognostic value as well as the possible correlations between them. We examined 186 samples of endometrial tissue (100 endometrial carcinomas of endometrioid type, 40 cases of hyperplasia and 46 of normal endometrium). Patient records were examined for FIGO stage, grade, and depth of myometrial invasion, histology, and lympho-vascular space invasion. Strong membranous immunostaining (> 10% of neoplastic cells) was observed in 45% of the carcinomas. A statistically significant correlation was found in the expression of protein in stromal cells, when compared with epithelial cells (p failed to show any statistical correlation with tumor grade or with vessel invasion. The expression of the protein was lower in FIGO Stage II compared with Stage I (p = 0.03). A positive relation of CD44 expression with progesterone receptor status (p = 0.02) was detected. CD44 expression was also positively associated with the proliferation associated with the proliferative index MIB1 (p = 0.001). CD44 is closely related to the secretory phase of the normal menstrual cycle and its expression is decreased in hyperplasia (simple or complex with or without atypia) and in cancer cases. These observations suggest that decreased CD44 expression might be functionally involved in the multiple mechanisms of the development and progression of endometrial lesions.

  7. Organochlorine exposures influence on breast cancer risk and survival according to estrogen receptor status: a Danish cohort-nested case-control study

    Directory of Open Access Journals (Sweden)

    Rank Fritz

    2001-07-01

    Full Text Available Abstract Background The relationship between breast cancer and organochlorine exposure is controversial and complex. As estrogen receptor positive and negative breast cancer may represent different entities of the disease, this study was undertaken to evaluate organochlorines influence on breast cancer risk and survival according to receptor status. Methods The background material stems from the Copenhagen City Heart Study (Denmark 1976-78. The breast cancer risk was investigated in a cohort nested case-control design including 161 cases and twice as many breast cancer free controls. The cases served as a cohort in the survival analysis. Serum organochlorine concentrations were determined by gaschromotography. Results The observed increased breast cancer risk associated with exposure to dieldrin derived from women who developed an estrogen receptor negative (ERN tumor (Odds ratio [OR] I vs. IV quartile, 7.6, 95% confidence interval [95% CI] 1.4-46.1, p-value for linear trend 0.01. Tumors in women with the highest dieldrin serum level were larger and more often spread at the time of diagnosis than ERP tumors. The risk of dying was for the remaining evaluated compounds higher among patients with ERP breast cancer when compared to those with ERN. In the highest quartile of polychlorinated biphenyls (ΣPCB it was more than 2-fold increased (Relative risk [RR] I vs. IV quartile, 2.5, 95% CI 1.1-5.7, but no dose-response relation was apparent. Conclusion The results do not suggest that exposure to potential estrogenic organochlorines leads to development of an ERP breast cancer. A possible adverse effect on prognosis of hormone-responsive breast cancers needs to be clarified.

  8. Organochlorine exposures influence on breast cancer risk and survival according to estrogen receptor status: a Danish cohort-nested case-control study

    International Nuclear Information System (INIS)

    Høyer, Annette P; Jørgensen, Torben; Rank, Fritz; Grandjean, Philippe

    2001-01-01

    The relationship between breast cancer and organochlorine exposure is controversial and complex. As estrogen receptor positive and negative breast cancer may represent different entities of the disease, this study was undertaken to evaluate organochlorines influence on breast cancer risk and survival according to receptor status. The background material stems from the Copenhagen City Heart Study (Denmark 1976-78). The breast cancer risk was investigated in a cohort nested case-control design including 161 cases and twice as many breast cancer free controls. The cases served as a cohort in the survival analysis. Serum organochlorine concentrations were determined by gaschromotography. The observed increased breast cancer risk associated with exposure to dieldrin derived from women who developed an estrogen receptor negative (ERN) tumor (Odds ratio [OR] I vs. IV quartile, 7.6, 95% confidence interval [95% CI] 1.4-46.1, p-value for linear trend 0.01). Tumors in women with the highest dieldrin serum level were larger and more often spread at the time of diagnosis than ERP tumors. The risk of dying was for the remaining evaluated compounds higher among patients with ERP breast cancer when compared to those with ERN. In the highest quartile of polychlorinated biphenyls (ΣPCB) it was more than 2-fold increased (Relative risk [RR] I vs. IV quartile, 2.5, 95% CI 1.1-5.7), but no dose-response relation was apparent. The results do not suggest that exposure to potential estrogenic organochlorines leads to development of an ERP breast cancer. A possible adverse effect on prognosis of hormone-responsive breast cancers needs to be clarified

  9. Alcohol consumption, body mass index and breast cancer risk by hormone receptor status: Women’ Lifestyle and Health Study

    International Nuclear Information System (INIS)

    Shin, Aesun; Sandin, Sven; Lof, Marie; Margolis, Karen L.; Kim, Kyeezu; Couto, Elisabeth; Adami, Hans Olov; Weiderpass, Elisabete

    2015-01-01

    We aimed to estimate the effect of alcohol consumption on breast cancer risk and to test whether overweight and obesity modifies this association. We included in the analysis 45,233 women enrolled in the Swedish Women’s Lifestyle and Health study between 1991 and 1992. Participants were followed for occurrence of breast cancer and death until December 2009. Poisson regression models were used, and analyses were done for overall breast cancer and for estrogen receptor positive or negative (ER+, ER-) and progesterone receptor positive and negative (PR+, PR-) tumors separately. A total of 1,385 breast cancer cases were ascertained during the follow-up period. Overall, we found no statistically significant association between alcohol intake and breast cancer risk after adjustment for confounding, with an estimated relative risk (RR) of 1.01 (95 % CI: 0.98–1.04) for an increment in alcohol consumption of 5 g/day. A statistically significant elevated breast cancer risk associated with higher alcohol consumption was found only among women with BMI ≤25 (RR 1.03, 95 % CI 1.0–1.05 per 5 g/day increase). An increase in breast cancer risk with higher alcohol consumption was found for breast cancers in women with a BMI ≤25 kg/m 2

  10. The under-appreciated promiscuity of the epidermal growth factor receptor family.

    Directory of Open Access Journals (Sweden)

    Sean P Kennedy

    2016-08-01

    Full Text Available Each member of the epidermal growth factor receptor (EGFR family plays a key role in normal development, homeostasis and a variety of pathophysiological conditions, most notably in cancer. According to the prevailing dogma, these four receptor tyrosine kinases (RTKs; EGFR, ERBB2, ERBB3 and ERBB4 function exclusively through the formation of homodimers and heterodimers within the EGFR family. These combinatorial receptor interactions are known to generate increased interactome diversity and therefore influence signalling output, subcellular localization and function of the heterodimer. This molecular plasticity is also thought to play a role in the development of resistance towards targeted cancer therapies aimed at these known oncogenes. Interestingly, many studies now challenge this dogma and suggest that the potential for EGFR family receptors to interact with more distantly related RTKs is much greater than currently appreciated. Here we discuss how the promiscuity of these oncogenic receptors may lead to the formation of many unexpected receptor pairings and the significant implications for the efficiency of many targeted cancer therapies.

  11. Signal transduction of Helicobacter pylori during interaction with host cell protein receptors of epithelial and immune cells

    Science.gov (United States)

    Pachathundikandi, Suneesh Kumar; Tegtmeyer, Nicole; Backert, Steffen

    2013-01-01

    Helicobacter pylori infections can induce pathologies ranging from chronic gastritis, peptic ulceration to gastric cancer. Bacterial isolates harbor numerous well-known adhesins, vacuolating cytotoxin VacA, protease HtrA, urease, peptidoglycan, and type IV secretion systems (T4SS). It appears that H. pylori targets more than 40 known host protein receptors on epithelial or immune cells. A series of T4SS components such as CagL, CagI, CagY, and CagA can bind to the integrin α5β1 receptor. Other targeted membrane-based receptors include the integrins αvβ3, αvβ5, and β2 (CD18), RPTP-α/β, GP130, E-cadherin, fibronectin, laminin, CD46, CD74, ICAM1/LFA1, T-cell receptor, Toll-like receptors, and receptor tyrosine kinases EGFR, ErbB2, ErbB3, and c-Met. In addition, H. pylori is able to activate the intracellular receptors NOD1, NOD2, and NLRP3 with important roles in innate immunity. Here we review the interplay of various bacterial factors with host protein receptors. The contribution of these interactions to signal transduction and pathogenesis is discussed. PMID:24280762

  12. UDP-glucuronosyltransferase and sulfotransferase polymorphisms, sex hormone concentrations, and tumor receptor status in breast cancer patients

    International Nuclear Information System (INIS)

    Sparks, Rachel; Yuan, Xiaopu; Lin, Ming Gang; McVarish, Lynda; Aiello, Erin J; McTiernan, Anne; Ulrich, Cornelia M; Bigler, Jeannette; Tworoger, Shelley S; Yasui, Yutaka; Rajan, Kumar B; Porter, Peggy; Stanczyk, Frank Z; Ballard-Barbash, Rachel

    2004-01-01

    UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes are involved in removing sex hormones from circulation. Polymorphic variation in five UGT and SULT genes – UGT1A1 ((TA) 6 /(TA) 7 ), UGT2B4 (Asp 458 Glu), UGT2B7 (His 268 Tyr), UGT2B15 (Asp 85 Tyr), and SULT1A1 (Arg 213 His) – may be associated with circulating sex hormone concentrations, or the risk of an estrogen receptor-negative (ER - ) or progesterone receptor-negative (PR - ) tumor. Logistic regression analysis was used to estimate the odds ratios of an ER - or PR - tumor associated with polymorphisms in the genes listed above for 163 breast cancer patients from a population-based cohort study of women in western Washington. Adjusted geometric mean estradiol, estrone, and testosterone concentrations were calculated within each UGT and SULT genotype for a subpopulation of postmenopausal breast cancer patients not on hormone therapy 2–3 years after diagnosis (n = 89). The variant allele of UGT1A1 was associated with reduced risk of an ER - tumor (P for trend = 0.03), and variants of UGT2B15 and SULT1A1 were associated with non-statistically significant risk reductions. There was some indication that plasma estradiol and testosterone concentrations varied by UGT2B15 and SULT1A1 genotypes; women with the UGT2B15 Asp/Tyr and Tyr/Tyr genotypes had higher concentrations of estradiol than women with the Asp/Asp genotype (P = 0.004). Compared with women with the SULT1A1 Arg/Arg and Arg/His genotypes, women with the His/His genotype had elevated concentrations of testosterone (P = 0.003). The risk of ER - breast cancer tumors may vary by UGT or SULT genotype. Further, plasma estradiol and testosterone concentrations in breast cancer patients may differ depending on some UGT and SULT genotypes

  13. Customized chemotherapy based on epidermal growth factor receptor mutation status for elderly patients with advanced non-small-cell lung cancer: a phase II trial

    International Nuclear Information System (INIS)

    Fujita, Shiro; Mio, Tadashi; Katakami, Nobuyuki; Masago, Katsuhiro; Yoshioka, Hiroshige; Tomii, Keisuke; Kaneda, Toshihiko; Hirabayashi, Masataka; Kunimasa, Kei; Morizane, Toshio

    2012-01-01

    Elderly patients are more vulnerable to toxicity from chemotherapy. Activating epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) are associated with enhanced response to EGFR tyrosine-kinase inhibitors. We studied patients with advanced NSCLC for whom treatment was customized based on EGFR mutation status. We screened 57 chemotherapy-naïve patients with histologically or cytologically confirmed NSCLC, stage IIIB or IV, aged 70 years or older, and with an Eastern Cooperative Oncology Group performance status 0 or 1, for EGFR exon 19 codon 746–750 deletion and exon 21 L858R mutation. Twenty-two patients with EGFR mutations received gefitinib; 32 patients without mutations received vinorelbine or gemcitabine. The primary endpoint was the response rate. The response rate was 45.5% (95% confidence interval [CI]: 24.4%, 67.8%) in patients with EGFR mutations and 18.8% (95% CI: 7.2%, 36.4%) in patients without EGFR mutations. The median overall survival was 27.9 months (95%CI: 24.4 months, undeterminable months) in patients with EGFR mutations and 14.9 months (95%CI: 11.0 months, 22.4 months) in patients without EGFR mutations. In the gefitinib group, grade 3/4 hepatic dysfunction and dermatitis occurred in 23% and 5% of patients, respectively. In patients treated with vinorelbine or gemcitabine, the most common grade 3 or 4 adverse events were neutropenia (47%; four had febrile neutropenia), anemia (13%), and anorexia (9%). No treatment-related deaths occurred. Treatment customization based on EGFR mutation status deserves consideration, particularly for elderly patients who often cannot receive second-line chemotherapy due to poor organ function or comorbidities. This trial is registered at University hospital Medical Information Network-clinical trial registration (http://www.umin.ac.jp/ctr/index/htm) with the registration identification number C000000436

  14. Dual surrogate markers for rapid prediction of epidermal growth factor receptor mutation status in advanced adenocarcinoma of the lung: A novel approach in resource-limited setting.

    Science.gov (United States)

    Udupa, K S; Rajendranath, R; Sagar, T G; Sundersingh, S; Joseph, T

    2015-01-01

    Tyrosine kinase inhibitors have revolutionized the treatment of metastatic lung cancer in patients with epidermal growth factor receptor (EGFR) mutations. Amplified refractory mutation system (ARMS)-reverse transcription-polymerase chain reaction (RT-PCR), the current standard for detecting EGFR mutation status is time-consuming and highly expensive. Consequently any surrogate test which are cheaper, faster and as accurate as the PCR method will help in early diagnosis and management of patients with lung cancer, especially in resource-limited settings. Eighty-five patients, all of South Indian origin, with adenocarcinoma of lung, registered between October 2009 and January 2013, were evaluated for EGFR mutation status by using scorpion probe based ARMS RT-PCR method. Immunohistochemical (IHC) was performed using the phosphorylated AKT (P-AKT) and thyroid transcription factor-1 (TTF-1) on above patient's sample, and the results were compared with EGFR mutation tests. EGFR mutation was positive in 34 of 85 patients (40%). P-AKT and TTF-1 were positive in 50 (58.8%) and 68 (80%) patients respectively. Both P-AKT and TTF-1 had statistically significant correlation with EGFR mutation status. Positive and negative predictive value of P-AKT in diagnosing EGFR mutation was 58% and 85.5% and that for TTF-1 was 48.5% and 94.1%, respectively. The problem of low positive predictive value can partly be overcome by testing P-AKT and TTF-1 simultaneously. P-AKT and TTF-1 using IHC had statistically significant correlation with EGFR mutation with high negative predictive value. In the case of urgency of starting treatment, EGFR mutation testing may be avoided in those patients who are negative for these IHC markers and can be started on chemotherapy.

  15. Parity and breastfeeding among African-American women: differential effects on breast cancer risk by estrogen receptor status in the Women's Circle of Health Study.

    Science.gov (United States)

    Ambrosone, Christine B; Zirpoli, Gary; Ruszczyk, Melanie; Shankar, Jyoti; Hong, Chi-Chen; McIlwain, Demetra; Roberts, Michelle; Yao, Song; McCann, Susan E; Ciupak, Gregory; Hwang, Helena; Khoury, Thaer; Jandorf, Lina; Bovbjerg, Dana H; Pawlish, Karen; Bandera, Elisa V

    2014-02-01

    It has long been held that parity reduces risk of breast cancer. However, accumulating evidence indicates that the effects of parity, as well as breastfeeding, may vary according to estrogen receptor (ER) status. We evaluated these associations in a case-control study among African-American women in New York City and New Jersey. In the Women's Circle of Health Study, including 786 African-American women with breast cancer and 1,015 controls, data on reproductive histories were collected from in-person interviews, with tumor characteristics abstracted from pathology reports. We calculated number of live births and months breastfeeding for each child, and examined each in relation to breast cancer by ER status, and for triple-negative (TN) breast cancer. Although associations were not statistically significant, having children was associated with reduced risk of ER+ breast cancer [odds ratio (OR) 0.82, 95 % confidence interval (CI) 0.58-1.16], but increased risk of ER- tumors, with associations most pronounced for TN breast cancer (OR 1.81, 95 % CI 0.93-3.51). Breastfeeding gave no additional benefit for ER+ cancer, but reduced the risk of ER- disease associated with parity. Accumulating data from a number of studies, as well as our own in African-American women, indicate that the effects of parity and breastfeeding differ by ER status. African-American women are more likely to have children and not to breastfeed, and to have ER- and TN breast cancer. It is possible that breastfeeding in this population could reduce risk of more aggressive breast cancers.

  16. The role of quantitative estrogen receptor status in predicting tumor response at surgery in breast cancer patients treated with neoadjuvant chemotherapy.

    Science.gov (United States)

    Raphael, Jacques; Gandhi, Sonal; Li, Nim; Lu, Fang-I; Trudeau, Maureen

    2017-07-01

    Estrogen receptor (ER) negative (-) breast cancer (BC) patients have better tumor response rates than ER-positive (+) patients after neoadjuvant chemotherapy (NCT). We conducted a retrospective review using the institutional database "Biomatrix" to assess the value of quantitative ER status in predicting tumor response at surgery and to identify potential predictors of survival outcomes. Univariate followed by multivariable regression analyses were conducted to assess the association between quantitative ER and tumor response assessed as tumor size reduction and pathologic complete response (pCR). Predictors of recurrence-free survival (RFS) were identified using a cox proportional hazards model (CPH). A log-rank test was used to compare RFS between groups if a significant predictor was identified. 304 patients were included with a median follow-up of 43.3 months (Q1-Q3 28.7-61.1) and a mean age of 49.7 years (SD 10.9). Quantitative ER was inversely associated with tumor size reduction and pCR (OR 0.99, 95% CI 0.99-1.00, p = 0.027 and 0.98 95% CI 0.97-0.99, p Quantitative ER status is inversely associated with tumor response in BC patients treated with NCT. A cut-off of 60 and 80% predicts best the association with tumor size reduction and pCR, respectively. Therefore, patients with an ER status higher than the cut-off might benefit from a neoadjuvant endocrine therapy approach. Patients with pCR had better survival outcomes independently of their tumor phenotype. Further prospective studies are needed to validate the clinical utility of quantitative ER as a predictive marker of tumor response.

  17. Anti-N-Methyl-d-Aspartate Receptor Encephalitis as an Unusual Cause of Altered Mental Status in the Emergency Department.

    Science.gov (United States)

    Weaver, Michael; Griffey, Richard T

    2016-08-01

    Anti-N-methyl-d-aspartate (NMDA) receptor autoimmune encephalitis is a newly identified form of encephalitis whose incidence is on the rise. Awareness of this condition and symptom recognition are key to early diagnosis and prompt treatment, which may alter the course of the disease. A 35-year-old woman presented to our Emergency Department (ED) with lethargy, bizarre behavior, agitation, confusion, memory deficits, and word-finding difficulties. Her symptoms and evaluation were potentially consistent with a primary psychiatric disorder, but the absence of frank psychosis and presence of neurologic features related to memory and cognition prompted other considerations. In the ED we performed a lumbar puncture, and in addition to routine studies, ordered anti-NMDAR antibody screening. The screening studies returned positive, leading to treatment with glucocorticoids and intravenous immune globulin and resulting in improvement to near baseline function. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although anti-NMDAR encephalitis is relatively uncommon, reports of this previously unrecognized condition are increasing, with an unclear true incidence of disease. Emergency providers should consider this diagnosis in their differential for patients presenting with new neuropsychiatric symptoms, particularly in young women. Prompt treatment leads to near complete neurologic recovery in 75% of patients, whereas delays in diagnosis and treatment may be associated with worse outcomes including death. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Rapid phospho-turnover by receptor tyrosine kinases impacts downstream signaling and drug binding.

    Science.gov (United States)

    Kleiman, Laura B; Maiwald, Thomas; Conzelmann, Holger; Lauffenburger, Douglas A; Sorger, Peter K

    2011-09-02

    Epidermal growth factor receptors (ErbB1-4) are oncogenic receptor tyrosine kinases (RTKs) that regulate diverse cellular processes. In this study, we combine measurement and mathematical modeling to quantify phospho-turnover at ErbB receptors in human cells and to determine the consequences for signaling and drug binding. We find that phosphotyrosine residues on ErbB1 have half-lives of a few seconds and therefore turn over 100-1000 times in the course of a typical immediate-early response to ligand. Rapid phospho-turnover is also observed for EGF-activated ErbB2 and ErbB3, unrelated RTKs, and multiple intracellular adaptor proteins and signaling kinases. Thus, the complexes formed on the cytoplasmic tail of active receptors and the downstream signaling kinases they control are highly dynamic and antagonized by potent phosphatases. We develop a kinetic scheme for binding of anti-ErbB1 drugs to receptors and show that rapid phospho-turnover significantly impacts their mechanisms of action. Copyright © 2011 Elsevier Inc. All rights reserved.

  19. Inhibition of the prostaglandin E2 receptor EP2 prevents status epilepticus-induced deficits in the novel object recognition task in rats

    Science.gov (United States)

    Rojas, Asheebo; Ganesh, Thota; Manji, Zahra; O’neill, Theon; Dingledine, Raymond

    2016-01-01

    Survivors of exposure to an organophosphorus nerve agent may develop a number of complications including long-term cognitive deficits (Miyaki et al., 2005; Nishiwaki et al., 2001). We recently demonstrated that inhibition of the prostaglandin E2 receptor, EP2, attenuates neuroinflammation and neurodegeneration caused by status epilepticus (SE) induced by the soman analog, diisopropylfluorophosphate (DFP), which manifest within hours to days of the initial insult. Here, we tested the hypothesis that DFP exposure leads to a loss of cognitive function in rats that is blocked by early, transient EP2 inhibition. Adult male Sprague-Dawley rats were administered vehicle or the competitive EP2 antagonist, TG6-10-1, (ip) at various times relative to DFP-induced SE. DFP administration resulted in prolonged seizure activity as demonstrated by cortical electroencephalography (EEG). A single intraperitoneal injection of TG6-10-1 or vehicle 1 h prior to DFP did not alter the development of seizures, the latency to SE or the duration of SE. Rats administered six injections of TG6-10-1 starting 90 min after the onset of DFP-induced SE could discriminate between a novel and familiar object 6–12 weeks after SE, unlike vehicle treated rats which showed no preference for the novel object. By contrast, behavioral changes in the light-dark box and open field assays were not affected by TG6-10-1. Delayed mortality after DFP was also unaffected by TG6-10-1. Thus, selective inhibition of the EP2 receptor may prevent SE-induced memory impairment in rats caused by exposure to a high dose of DFP. PMID:27477533

  20. Identification of gene transcript signatures predictive for estrogen receptor and lymph node status using a stepwise forward selection artificial neural network modelling approach.

    Science.gov (United States)

    Lancashire, Lee J; Rees, Robert C; Ball, Graham R

    2008-06-01

    The advent of microarrays has attracted considerable interest from biologists due to the potential for high throughput analysis of hundreds of thousands of gene transcripts. Subsequent analysis of the data may identify specific features which correspond to characteristics of interest within the population, for example, analysis of gene expression profiles in cancer patients to identify molecular signatures corresponding with prognostic outcome. These high throughput technologies have resulted in an unprecedented rate of data generation, often of high complexity, highlighting the need for novel data analysis methodologies that will cope with data of this nature. Stepwise methods using artificial neural networks (ANNs) have been developed to identify an optimal subset of predictive gene transcripts from highly dimensional microarray data. Here these methods have been applied to a gene microarray dataset to identify and validate gene signatures corresponding with estrogen receptor and lymph node status in breast cancer. Many gene transcripts were identified whose expression could differentiate patients to very high accuracies based upon firstly whether they were positive or negative for estrogen receptor, and secondly whether metastasis to the axillary lymph node had occurred. A number of these genes had been previously reported to have a role in cancer. Significantly fewer genes were used compared to other previous studies. The models using the optimal gene subsets were internally validated using an extensive random sample cross-validation procedure and externally validated using a follow up dataset from a different cohort of patients on a newer array chip containing the same and additional probe sets. Here, the models retained high accuracies, emphasising the potential power of this approach in analysing complex systems. These findings show how the proposed method allows for the rapid analysis and subsequent detailed interrogation of gene expression signatures to

  1. Neuroimmune interactions in Sjögren's syndrome: relationship of exocrine gland dysfunction with autoantibodies to muscarinic acetylcholine receptor-3 and mental health status parameters.

    Science.gov (United States)

    Deák, Magdolna; Szvetnik, Attila; Balog, Attila; Sohár, Nicolette; Varga, Renáta; Pokorny, Gyula; Tóth, Gábor; Kiss, Mária; Kovács, László

    2013-01-01

    Antimuscarinic acetylcholine receptor-3 (m3AChR) autoantibodies have been described in primary Sjögren's syndrome (pSS). The aim of this study was to compare various methods for their detection and to assess the contributions of anti-m3AChR and other immunological and psychosocial factors to the pathomechanism of secondary SS (sSS). Sixty-five rheumatoid arthritis (RA) patients, 103 systemic lupus erythematosus (SLE) patients, 76 pSS patients and 50 controls were compared. Three immunodominant epitopes of m3AChR were synthesized and used in ELISA. Two extracellular epitopes were also prepared in fusion with glutathione-S-transferase and one in conjugation with bovine serum albumin. Mental health status was assessed with the 36-item Short-Form Health Survey and Functional Assessment of Chronic Illness Therapy fatigue scale. Correlations were evaluated between glandular function and anti-m3AChR positivities and specificities, features of SLE and RA, and mental health parameters. Fourteen RA and 27 SLE patients had sSS. The autoantibody levels to all epitopes of m3AChR were significantly higher in pSS and SLE patients than in the controls. The fusion protein forms discriminated RA from pSS and SLE; furthermore, the YNIP fusion protein also distinguished pSS from SLE. The prevalence and the mean levels of all autoantibodies did not differ statistically between sicca and non-sicca SLE or RA patients. Glandular dysfunction correlated with higher age in SLE and RA and an impaired health-related quality of life in SLE. The second and third extracellular loops of m3AChR are antigenic in pSS. Immunoassays with antigens as fusion peptides demonstrate the best performance. Sicca SLE patients have worse mental health status. Anti-m3AChR antibodies represent a peculiar example of neuroimmune interactions. Copyright © 2012 S. Karger AG, Basel.

  2. Whole-body vibration improves the anti-inflammatory status in elderly subjects through toll-like receptor 2 and 4 signaling pathways.

    Science.gov (United States)

    Rodriguez-Miguelez, Paula; Fernandez-Gonzalo, Rodrigo; Collado, Pilar S; Almar, Mar; Martinez-Florez, Susana; de Paz, José A; González-Gallego, Javier; Cuevas, María J

    2015-09-01

    Regular physical exercise has anti-inflammatory effects in elderly subjects. Yet, the inflammatory responses after whole body vibration (WBV) training, a popular exercise paradigm for the elderly, remain to be elucidated. This study assessed the effects of WBV training on the inflammatory response associated with toll-like receptors (TLRs) signaling pathways. Twenty-eight subjects were randomized to a training group (TG) or a control group (CG). TG followed an 8-week WBV training program. Blood samples were obtained before and after the training period in both groups. Peripheral blood mononuclear cells were isolated, and mRNA and protein levels of makers involved in the TLR2/TLR4 myeloid differentiation primary response gen 88 (MyD88) and TIR domain-containing adaptor inducing interferon (TRIF)-dependent pathways were analyzed. Plasma TNFα and C-reactive protein levels were also assessed. The WBV program reduced protein expression of TLR2, TLR4, MyD88, p65, TRIF and heat shock protein (HSP) 60, while HSP70 content increased. IL-10 mRNA level and protein concentration were upregulated, and TNFα protein content decreased, after WBV training. Plasma concentration of C-reactive protein and TNFα decreased in the TG. The current data suggest WBV may improve the anti-inflammatory status of elderly subjects through an attenuation of MyD88- and TRIF-dependent TLRs signaling pathways. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  3. Human NK cells maintain licensing status and are subject to killer immunoglobulin-like receptor (KIR) and KIR-ligand inhibition following ex vivo expansion.

    Science.gov (United States)

    Wang, Wei; Erbe, Amy K; Alderson, Kory A; Phillips, Emily; Gallenberger, Mikayla; Gan, Jacek; Campana, Dario; Hank, Jacquelyn A; Sondel, Paul M

    2016-09-01

    Infusion of allogeneic NK cells is a potential immunotherapy for both hematopoietic malignancies and solid tumors. Interactions between killer immunoglobulin-like receptors (KIR) on human NK cells and KIR-ligands on tumor cells influence the magnitude of NK function. To obtain sufficient numbers of activated NK cells for infusion, one potent method uses cells from the K562 human erythroleukemia line that have been transfected to express activating 41BB ligand (41BBL) and membrane-bound interleukin 15 (mbIL15). The functional importance of KIRs on ex vivo expanded NK cells has not been studied in detail. We found that after a 12-day co-culture with K562-mbIL15-41BBL cells, expanded NK cells maintained inhibition specificity and prior in vivo licensing status determined by KIR/KIR-ligand interactions. Addition of an anti-CD20 antibody (rituximab) induced NK-mediated antibody-dependent cellular cytotoxicity and augmented killing of CD20+ target cells. However, partial inhibition induced by KIR/KIR-ligand interactions persisted. Finally, we found that extended co-cultures of NK cells with stimulatory cells transduced to express various KIR-ligands modified both the inhibitory and activating KIR repertoires of the expanded NK cell product. These studies demonstrate that the licensing interactions known to occur during NK ontogeny also influence NK cell function following NK expansion ex vivo with HLA-null stimulatory cells.

  4. Association of suboptimal health status with psychosocial stress, plasma cortisol and mRNA expression of glucocorticoid receptor α/β in lymphocyte.

    Science.gov (United States)

    Yan, Yu-Xiang; Dong, Jing; Liu, You-Qin; Zhang, Jie; Song, Man-Shu; He, Yan; Wang, Wei

    2015-01-01

    Suboptimal health status (SHS) has become a new public health challenge in China. This study investigated whether high SHS is associated with psychosocial stress, changes in cortisol level and/or glucocorticoid receptor (GR) isoform expression. Three-hundred eighty-six workers employed in three companies in Beijing were recruited. The SHS score was derived from data collection in the SHS questionnaire (SHSQ-25). The short standard version of the Copenhagen Psychosocial Questionnaire (COPSOQ) was used to assess job-related psychosocial stress. The mean value of the five scales of COPSOQ and distribution of plasma cortisol and mRNA expression of GRα/GRβ between the high level of SHS group and the low level of SHS group were compared using a general linear model procedure. Multiple linear regression analysis was used to analyze the effect of psychosocial stress on SHS. We identified three factors that were predictive of SHS, including "demands at work", "interpersonal relations and leadership" and "insecurity at work". Significantly higher levels of plasma cortisol and GRβ/GRα mRNA ratio were observed among the high SHS group. High level of SHS is associated with decreased mRNA expression of GRα. This study confirmed the association between chronic psychosocial stress and SHS, indicating that improving the psychosocial work environment may reduce SHS and then prevent chronic diseases effectively.

  5. Variable number of tandem repeat polymorphisms of the interleukin-1 receptor antagonist gene IL-1RN: a novel association with the athlete status

    Directory of Open Access Journals (Sweden)

    Ryckman Kelli K

    2010-02-01

    Full Text Available Abstract Background The interleukin-1 (IL-1 family of cytokines is involved in the inflammatory and repair reactions of skeletal muscle during and after exercise. Specifically, plasma levels of the IL-1 receptor antagonist (IL-1ra increase dramatically after intense exercise, and accumulating evidence points to an effect of genetic polymorphisms on athletic phenotypes. Therefore, the IL-1 family cytokine genes are plausible candidate genes for athleticism. We explored whether IL-1 polymorphisms are associated with athlete status in European subjects. Methods Genomic DNA was obtained from 205 (53 professional and 152 competitive non-professional Italian athletes and 458 non-athlete controls. Two diallelic polymorphisms in the IL-1β gene (IL-1B at -511 and +3954 positions, and a variable number tandem repeats (VNTR in intron 2 of the IL-1ra gene (IL-1RN were assessed. Results We found a 2-fold higher frequency of the IL-1RN 1/2 genotype in athletes compared to non-athlete controls (OR = 1.93, 95% CI = 1.37-2.74, 41.0% vs. 26.4%, and a lower frequency of the 1/1 genotype (OR = 0.55, 95% CI = 0.40-0.77, 43.9% vs. 58.5%. Frequency of the IL-1RN 2/2 genotype did not differ between groups. No significant differences between athletes and controls were found for either -511 or +3954 IL-1B polymorphisms. However, the haplotype (-511C-(+3954T-(VNTR2 was 3-fold more frequent in athletes than in non-athletes (OR = 3.02, 95% CI = 1.16-7.87. Interestingly, the IL-1RN 1/2 genotype was more frequent in professional than in non-professional athletes (OR = 1.92, 95% CI = 1.02-3.61, 52.8% vs. 36.8%. Conclusions Our study found that variants at the IL-1ra gene associate with athletic status. This confirms the crucial role that cytokine IL-1ra plays in human physical exercise. The VNTR IL-1RN polymorphism may have implications for muscle health, performance, and/or recovery capacities. Further studies are needed to assess these specific issues. As VNTR IL-1RN

  6. Chimeric Antigen Receptor-Engineered NK-92 Cells: An Off-the-Shelf Cellular Therapeutic for Targeted Elimination of Cancer Cells and Induction of Protective Antitumor Immunity

    Directory of Open Access Journals (Sweden)

    Congcong Zhang

    2017-05-01

    Full Text Available Significant progress has been made in recent years toward realizing the potential of natural killer (NK cells for cancer immunotherapy. NK cells can respond rapidly to transformed and stressed cells and have the intrinsic potential to extravasate and reach their targets in almost all body tissues. In addition to donor-derived primary NK cells, also the established NK cell line NK-92 is being developed for adoptive immunotherapy, and general safety of infusion of irradiated NK-92 cells has been established in phase I clinical trials with clinical responses observed in some of the cancer patients treated. To enhance their therapeutic utility, NK-92 cells have been modified to express chimeric antigen receptors (CARs composed of a tumor-specific single chain fragment variable antibody fragment fused via hinge and transmembrane regions to intracellular signaling moieties such as CD3ζ or composite signaling domains containing a costimulatory protein together with CD3ζ. CAR-mediated activation of NK cells then bypasses inhibitory signals and overcomes NK resistance of tumor cells. In contrast to primary NK cells, CAR-engineered NK-92 cell lines suitable for clinical development can be established from molecularly and functionally well-characterized single cell clones following good manufacturing practice-compliant procedures. In preclinical in vitro and in vivo models, potent antitumor activity of NK-92 variants targeted to differentiation antigens expressed by hematologic malignancies, and overexpressed or mutated self-antigens associated with solid tumors has been found, encouraging further development of CAR-engineered NK-92 cells. Importantly, in syngeneic mouse tumor models, induction of endogenous antitumor immunity after treatment with CAR-expressing NK-92 cells has been demonstrated, resulting in cures and long-lasting immunological memory protecting against tumor rechallenge at distant sites. Here, we summarize the current status and future

  7. Chimeric Antigen Receptor-Engineered NK-92 Cells: An Off-the-Shelf Cellular Therapeutic for Targeted Elimination of Cancer Cells and Induction of Protective Antitumor Immunity.

    Science.gov (United States)

    Zhang, Congcong; Oberoi, Pranav; Oelsner, Sarah; Waldmann, Anja; Lindner, Aline; Tonn, Torsten; Wels, Winfried S

    2017-01-01

    Significant progress has been made in recent years toward realizing the potential of natural killer (NK) cells for cancer immunotherapy. NK cells can respond rapidly to transformed and stressed cells and have the intrinsic potential to extravasate and reach their targets in almost all body tissues. In addition to donor-derived primary NK cells, also the established NK cell line NK-92 is being developed for adoptive immunotherapy, and general safety of infusion of irradiated NK-92 cells has been established in phase I clinical trials with clinical responses observed in some of the cancer patients treated. To enhance their therapeutic utility, NK-92 cells have been modified to express chimeric antigen receptors (CARs) composed of a tumor-specific single chain fragment variable antibody fragment fused via hinge and transmembrane regions to intracellular signaling moieties such as CD3ζ or composite signaling domains containing a costimulatory protein together with CD3ζ. CAR-mediated activation of NK cells then bypasses inhibitory signals and overcomes NK resistance of tumor cells. In contrast to primary NK cells, CAR-engineered NK-92 cell lines suitable for clinical development can be established from molecularly and functionally well-characterized single cell clones following good manufacturing practice-compliant procedures. In preclinical in vitro and in vivo models, potent antitumor activity of NK-92 variants targeted to differentiation antigens expressed by hematologic malignancies, and overexpressed or mutated self-antigens associated with solid tumors has been found, encouraging further development of CAR-engineered NK-92 cells. Importantly, in syngeneic mouse tumor models, induction of endogenous antitumor immunity after treatment with CAR-expressing NK-92 cells has been demonstrated, resulting in cures and long-lasting immunological memory protecting against tumor rechallenge at distant sites. Here, we summarize the current status and future prospects of CAR

  8. Association analyses for dopamine receptor gene polymorphisms and weight status in a longitudinal analysis in obese children before and after lifestyle intervention.

    Science.gov (United States)

    Roth, Christian L; Hinney, Anke; Schur, Ellen A; Elfers, Clinton T; Reinehr, Thomas

    2013-11-27

    Dopamine receptors are involved in midbrain reward circuit activation. Polymorphisms in two dopamine receptor genes, DRD2 and DRD4, have been associated with altered perception of food reward and weight gain. The objective of this study was to determine whether the same risk alleles were associated with overweight/obesity and with lower reduction of overweight after a 1-year lifestyle intervention. In a longitudinal study the association of polymorphisms in DRD2 (rs18000497, risk allele: T, formerly A1 allele at the TaqI A1 polymorphism) and DRD4 (variable number of tandem repeats (VNTR); 48 bp repeat in exon III; risk alleles: 7 repeats or longer: 7R+) was tested on weight loss success following a 1-year lifestyle childhood obesity intervention (OBELDICKS). An additional exploratory cross-sectional case-control study was performed to compare the same DRD polymorphisms in these overweight/obese children and adolescents versus lean adult controls. Subjects were 423 obese and 28 overweight children participating in lifestyle intervention (203 males), age median 12.0 (interquartile range 10.0-13.7) years, body mass index - standard deviation score (BMI-SDS) 2.4 ± 0.5; 583 lean adults (232 males); age median 25.3 (interquartile range 22.5-26.8) years, BMI 19.1 ± 1.9 kg/m2. BMI, BMI-SDS and skinfold thickness measures were assessed at baseline and after 1 year; genotyping was performed for DRD2 risk variant rs1800497 and DRD4 exon III VNTR. The DRD2 genotype had a nominal effect on success in the weight loss intervention. The weakest BMI-SDS reduction was in children homozygous for two rs1800497 T-alleles (n = 11) compared to the combined group with zero (n = 308) or one (n = 132) rs1800497 T-allele (-0.08 ± 0.36 vs. -0.28 ± 0.34; p DRD4 VNTR alleles and genotypes and success in the weight loss intervention. No associations of the risk alleles of the DRD2 and DRD4 polymorphisms and obesity were observed in the cross-sectional part of

  9. Initial estimation of correlation between estrogen receptor status and histopathology, and also some selected prognostic factors in breast cancer patients; Wstepna ocena zaleznosci miedzy stezeniem receptora estrogenow a obrazem histopatologicznym oraz wybranymi wskaznikami rokowniczymi u chorych na raka sutka

    Energy Technology Data Exchange (ETDEWEB)

    Cwikla, J.; Badowski, J.; Shafie, D.; Gugala, K.; Koziorowski, M. [Wojewodzki Szpital Zespolony, Olsztyn (Poland)

    1996-12-31

    The goal of this study was to assess the correlation between estrogen receptor (ER) status and histopathology findings, likewise to assess some selected prognostic factors in patients with breast cancer. The study was carried out on 126 patients with breast cancer. ER concentration was estimated by the standard biochemical assay (DCC-dextran-coated charcoal assay). The correlation between established risk factors like: lymph node status; age menopausal status and ER status were analysed.The ER yielded in 61% positive results. The mean value of ER in invasive ductal carcinoma was 43.9 fmol/mg protein and the mean value of ER in invasive lobular carcinoma 51.4 fmol/mg protein. The significant statistics negative correlation between ER status of pre-menopausal patients with ductal breast carcinoma and regional lymph nodes involvement was found. There was no difference between ER status and histological type of the cancer. No correlation was found between ER status and age of patients. (author) 32 refs, 2 figs, 2 tabs

  10. DCE-MRI texture analysis with tumor subregion partitioning for predicting Ki-67 status of estrogen receptor-positive breast cancers

    KAUST Repository

    Fan, Ming

    2017-12-08

    Breast tumor heterogeneity is related to risk factors that lead to worse prognosis, yet such heterogeneity has not been well studied.To predict the Ki-67 status of estrogen receptor (ER)-positive breast cancer patients via analysis of tumor heterogeneity with subgroup identification based on patterns of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).Retrospective study.Seventy-seven breast cancer patients with ER-positive breast cancer were investigated, of whom 51 had low Ki-67 expression.T1 -weighted 3.0T DCE-MR images.Each tumor was partitioned into multiple subregions using three methods based on patterns of dynamic enhancement: 1) time to peak (TTP), 2) peak enhancement rate (PER), and 3) kinetic pattern clustering (KPC). In each tumor subregion, 18 texture features were computed.Univariate and multivariate logistic regression analyses were performed using a leave-one-out-based cross-validation (LOOCV) method. The partitioning results were compared with the same feature extraction methods across the whole tumor.In the univariate analysis, the best-performing feature was the texture statistic of sum variance in the tumor subregion with early TTP for differentiating between patients with high and low Ki-67 expression (area under the receiver operating characteristic curves, AUC = 0.748). Multivariate analysis showed that features from the tumor subregion associated with early TTP yielded the highest performance (AUC = 0.807) among the subregions for predicting the Ki-67 status. Among all regions, the tumor area with high PER at a precontrast MR image achieved the highest performance (AUC = 0.722), while the subregion that exhibited the highest overall enhancement rate based on KPC had an AUC of 0.731. These three models based on intratumoral texture analysis significantly (P < 0.01) outperformed the model using features from the whole tumor (AUC = 0.59).Texture analysis of intratumoral heterogeneity has the potential to serve as a valuable

  11. Metrics for monitoring cancer inequities: residential segregation, the Index of Concentration at the Extremes (ICE), and breast cancer estrogen receptor status (USA, 1992-2012).

    Science.gov (United States)

    Krieger, Nancy; Singh, Nakul; Waterman, Pamela D

    2016-09-01

    To address the paucity of evidence on residential segregation and cancer, we explored their relationship using a new metric: the Index of Concentration at the Extremes (ICE). We focused on breast cancer estrogen receptor (ER) status, a biomarker associated with survival and, etiologically, with social and economic privilege. We obtained data from the 13 registry group of US Surveillance, Epidemiology, and End Results (SEER) program for 1992-2012 on all women aged 25-84 who were diagnosed with primary invasive breast cancer (n = 516,382). We appended to each case's record her annual county median household income quintile and the quintile for her annual county value for ICE measures for income (≤20th vs. ≥80th household income quintile), race/ethnicity (black vs. white), and income plus race/ethnicity (low-income black vs. high-income white). The odds of being ER+ versus ER- were estimated in relation to the county-level income and ICE measures, adjusting for relevant covariates. Women in the most privileged versus deprived county quintile for household income and for all three ICE measures had a 1.1- to 1.3-fold increased odds (95 % confidence intervals excluding 1) of having an ER+ tumor. These results were robust to adjustment for age at diagnosis, cancer registry, tumor characteristics (tumor stage, size, histology, grade), and race/ethnicity. A focus on segregation offers news possibilities for understanding how inequitable group relations contribute to cancer inequities. The utility of employing the ICE for monitoring cancer inequities should be investigated in relation to other cancer outcomes.

  12. Molecular subclassification determined by human papillomavirus and epidermal growth factor receptor status is associated with the prognosis of oropharyngeal squamous cell carcinoma.

    Science.gov (United States)

    Nakano, Takafumi; Yamamoto, Hidetaka; Nakashima, Torahiko; Nishijima, Toshimitsu; Satoh, Masanobu; Hatanaka, Yui; Shiratsuchi, Hideki; Yasumatsu, Ryuji; Toh, Satoshi; Komune, Shizuo; Oda, Yoshinao

    2016-04-01

    Human papillomavirus (HPV) infection is an indicator of good response to chemoradiotherapy in oropharyngeal squamous cell carcinoma (OPSCC), and epidermal growth factor receptor (EGFR) is a molecular-therapeutic target in head and neck squamous cell carcinoma. Here we investigated the prevalence and prognostic significance of HPV infection and EGFR alteration in OPSCC. We analyzed the presence of high-risk HPV using in situ hybridization, protein expressions of p16 and EGFR using immunohistochemistry, and the EGFR gene copy number gain using chromogenic in situ hybridization (CISH) in 105 cases of OPSCC. The biopsy specimens before chemoradiotherapy were used for these analyses. HPV infection and p16 protein overexpression were detected in 53.3% and 52.4% of the OPSCCs, and each factor was associated with better overall survival (P = .0026 and P = .0026) and nonkeratinizing histology (P = .0002 and P = .0004), respectively. EGFR gene copy number gain (high polysomy or amplification) was detected in 12.4% of the OPSCCs and was correlated with EGFR protein overexpression (P = .0667) and worse overall survival (P CISH positive) were mutually exclusive. The HPV-negative/EGFR CISH-positive OPSCCs had significantly worse overall survival than did the HPV-positive/EGFR CISH-negative OPSCCs and HPV-negative/EGFR CISH-negative OPSCCs (P CISH-negative OPSCCs had favorable prognosis irrespective of HPV infection. Our results suggest that EGFR gene copy number gain-positive tumors represent an HPV-negative, aggressive subgroup of OPSCCs. The molecular subclassification of OPSCCs based on HPV infection and EGFR status may serve as important information for appropriate therapeutic strategy. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Inhibition of P2X7 Receptor Ameliorates Nuclear Factor-Kappa B Mediated Neuroinflammation Induced by Status Epilepticus in Rat Hippocampus.

    Science.gov (United States)

    Huang, Cheng; Chi, Xiao-Sa; Li, Rui; Hu, Xin; Xu, Hai-Xia; Li, Jin-Mei; Zhou, Dong

    2017-10-01

    P2X7 receptor (P2X7R) has been reported participating in neuroinflammation in multiple neurological diseases. We explored the role of P2X7R in a rat status epilepticus (SE) model induced by coriaria lactone (CL) and its association with neuroinflammation. Thirty minutes after intracerebroventricular infusion with P2X7R antagonists Brilliant blue G (BBG), A-438079, A-740003, or agonists 2',3'-O-(4-benzoylbenzoyl)-adenosine 5'-triphosphate (BzATP), SE was induced by intramuscular injection of CL in Sprague-Dawley rats. Seizures severity was recorded according to the Racine scale and Morris water maze test was performed. P2X7R expression was measured by western blotting. Immunohistochemical staining was performed to assess pro-inflammation cytokines expression, neuronal loss, and astrocyte activation. The results showed P2X7R level began to increase at 1 day, peaked at 2 days, and gradually decreased to baseline by 2 weeks in rat hippocampus after SE. P2X7R activation induced NF-κB phosphorylation, along with increased IL-1β and IL-6 expression. Pretreatment with P2X7R antagonists ameliorated SE-induced neuroinflammation, neuronal damage, and astroglial and microglial activation to variable extent. In addition, these antagonists ameliorated seizure severity and improved cognitive function. These findings suggest P2X7R activation plays a critical role in epileptogenesis via regulation of neuroinflammation and blocking P2X7R may be a novel therapeutic strategy for epilepsy.

  14. Imaging characteristics of stage I non-small cell lung cancer on CT and FDG-PER; Relationship with epidermal growth factor receptor protein expression status and survival

    International Nuclear Information System (INIS)

    Lee, Youkyung; Lee, Hyun Ju; Kim, Young Tae; Kang, Chang Hyun; Goo, Jin Mo; Park, Chang Min; Paeng, Jin Chul; Chung, Doo Hyun; Jeon, Yoon Kyung

    2013-01-01

    To identify CT and FDG-PET features associated with epidermal growth factor receptor (EGFR) protein overexpression, and to evaluate whether imaging features and EGFR-overexpression can help predict clinical outcome. In 214 patients (M : F = 129 : 85; mean age, 63.2) who underwent curative resection of stage I non-small cell lung cancer, EGFR protein expression status was determined through immunohistochemical analysis. Imaging characteristics on CT and FDG-PET was assessed in relation to EGFR-overexpression. Imaging features and EGFR-overexpression were also evaluated for clinical outcome by using the Cox proportional hazards model. EGFR-overexpression was found in 51 patients (23.8%). It was significantly more frequent in tumors with an SUVmax > 5.0 (p 2.43 cm (p 5.0 (OR, 3.113; 95% CI, 1.375-7.049; p = 0.006) and diameter > 2.43 cm (OR, 2.799; 95% CI, 1.285-6.095; p = 0.010) were independent predictors of EGFR overexpression. Multivariate analysis showed that SUVmax > 4.0 (hazard ratio, 10.660; 95% CI, 1.370-82.966; p = 0.024), and the presence of cavitation within a tumor (hazard ratio, 3.122; 95% CI, 1.143-8.532; p = 0.026) were factors associated with poor prognosis. EGFR-overexpression is associated with high SUVmax, large tumor diameter, and small GGO proportion. CT and FDG-PET findings, which are closely related to EGFR overexpression, can be valuable in the prediction of clinical outcome.

  15. Antitumoral actions of the anti-obesity drug orlistat (XenicalTM) in breast cancer cells: blockade of cell cycle progression, promotion of apoptotic cell death and PEA3-mediated transcriptional repression of Her2/neu (erbB-2) oncogene.

    Science.gov (United States)

    Menendez, J A; Vellon, L; Lupu, R

    2005-08-01

    Orlistat (Xenicaltrade mark), a US Food and Drug Administration (FDA)-approved drug for bodyweight loss, has recently been demonstrated to exhibit antitumor properties towards prostate cancer cells by virtue of its ability to block the lipogenic activity of fatty acid synthase (FAS). FAS (oncogenic antigen-519) is up-regulated in about 50% of breast cancers, is an indicator of poor prognosis, and has recently been functionally associated with the Her2/neu (erbB-2) oncogene. We assessed the antitumoral effects of orlistat against the human breast cancer cell line SK-Br3, an in vitro paradigm of FAS and Her2/neu overexpression in breast cancer. Cell cycle analyses revealed that micromolar concentrations of orlistat induced, in a time- and dose-dependent manner, significant changes in the distribution of cell populations including a complete loss of G2-M phase, S-phase accumulation and a concomitant increase in the emerging sub-G1 (apoptotic) cells. Poly (ADP-ribose) polymerase (PARP) cleavage, an early event required for cells committed to apoptosis, was more predominant in orlistat-treated G1 phase cells. When we characterized signaling molecules participating in the cellular events following orlistat-induced inhibition of FAS activity and preceded inhibition of breast cancer cell proliferation, a dramatic down-regulation of Her2/neu-coded p185(Her2/neu) oncoprotein was found in orlistat-treated SK-Br3 cells (>90% reduction). Interestingly, a significant accumulation of the DNA-binding protein PEA3, a member of the Ets transcription factor family that specifically targets a PEA3-binding motif present on the Her2/neu gene promoter and down-regulates its activity, was observed in orlistat-treated SK-Br3 cells. When a Luciferase reporter gene driven by the Her2/neu promoter was transiently transfected in SK-Br3 cells, orlistat exposure was found to dramatically repress the promoter activity of Her2/neu gene, whereas a Her2/neu promoter bearing a mutated binding DNA sequence was not subject to negative regulation by orlistat, thus demonstrating that the intact PEA3 binding site on the Her2/neu promoter is required for the orlistat-induced transcriptional repression of Her2/neu overexpression. RNA interference (RNAi)-mediated silencing of FAS gene expression similarly repressed Her2/neu gene expression in a PEA3-dependent manner, thus ruling out a role for non-FAS orlistat-mediated effects. When the combination of orlistat and the anti-Her2/neu antibody trastuzumab (Herceptintrade mark) in either concurrent (orlistat + trastuzumab) or sequential (orlistat --> trastuzumab; trastuzumab --> orlistat) schedules was tested for synergism, addition or antagonism using the combination index (CI) method of Chou-Talalay, co-exposure of orlistat and trastuzumab demonstrated strong synergistic effects (CI10-90 = 0.110-0.847), whereas sequential exposure to orlistat followed by trastuzumab (CI10-90 = 0.380-1.210) and trastuzumab followed by orlistat (CI10-90 = 0.605-1.278) mainly showed additive or antagonistic interactions. Indeed, orlistat-induced FAS inhibition synergistically promoted apoptotic cell death when concurrently combined with trastuzumab as determined by an ELISA for histone-associated DNA fragments. Importantly, the degree of FAS expression in a panel of human breast cancer cell lines was predictive of sensitivity to orlistat-induced anti-proliferative effects as determined by a MTT-based characterization of metabolically viable breast cancer cells. Moreover, hypersensitivity to orlistat-induced cytotoxicity was observed in MCF-7 breast cancer cells engineered to overexpress Her2/neu (MCF-7/Her2-18 cells), which exhibit a significant up-regulation of FAS expression and activity. These findings reveal that the development of more potent and/or bioavailable orlistat's variants targeting the lipogenic activity of FAS may open a novel therapeutic avenue for treating Her2/neu-overexpressing breast carcinomas.

  16. Effect of Exposure to 900 MHz GSM Mobile Phone Radiofrequency Radiation on Estrogen Receptor Methylation Status in Colon Cells of Male Sprague Dawley Rats

    Directory of Open Access Journals (Sweden)

    Mokarram P.

    2017-03-01

    Full Text Available Background: Over the past several years, the rapidly increasing use of mobile phones has raised global concerns about the biological effects of exposure to radiofrequency (RF radiation. Numerous studies have shown that exposure to electromagnetic fields (EMFs can be associated with effects on the nervous, endocrine, immune, cardiovascular, hematopoietic and ocular systems. In spite of genetic diversity, the onset and progression of cancer can be controlled by epigenetic mechanisms such as gene promoter methylation. There are extensive studies on the epigenetic changes of the tumor suppressor genes as well as the identification of methylation biomarkers in colorectal cancer. Some studies have revealed that genetic changes can be induced by exposure to RF radiation. However, whether or not RF radiation is capable of inducing epigenetic alteration has not been clarified yet. To date, no study has been conducted on the effect of radiation on epigenetic alterations in colorectal cancer (CRC. Several studies have also shown that methylation of estrogen receptor α (ERα, MYOD, MGMT, SFRP2 and P16 play an important role in CRC. It can be hypothesized that RF exposure can be a reason for the high incidence of CRC in Iran. This study aimed to investigate whether epigenetic pattern of ERα is susceptible to RF radiation and if RF radiation can induce radioadaptive response as epigenetic changes after receiving the challenge dose (γ-ray. Material and Method: 40 male Sprague-Dawley rats were divided into 4 equal groups (Group I: exposure to RF radiation of a GSM cell phone for 4 hours and sacrificed after 24 hours; Group II: RF exposure for 4 hours, exposure to Co-60 gamma radiation (3 Gy after 24 hours and sacrificed after 72 hrs; Group III: only 3Gy gamma radiation; Group 4: control group. DNA from colon tissues was extracted to evaluate the methylation status by methylation specific PCR. Results: Our finding showed that exposure to GSM cell phone RF

  17. Stable, Nonviral Expression of Mutated Tumor Neoantigen-specific T-cell Receptors Using the Sleeping Beauty Transposon/Transposase System

    Science.gov (United States)

    Deniger, Drew C; Pasetto, Anna; Tran, Eric; Parkhurst, Maria R; Cohen, Cyrille J; Robbins, Paul F; Cooper, Laurence JN; Rosenberg, Steven A

    2016-01-01

    Neoantigens unique to each patient's tumor can be recognized by autologous T cells through their T-cell receptor (TCR) but the low frequency and/or terminal differentiation of mutation-specific T cells in tumors can limit their utility as adoptive T-cell therapies. Transfer of TCR genes into younger T cells from peripheral blood with a high proliferative potential could obviate this problem. We generated a rapid, cost-effective strategy to genetically engineer cancer patient T cells with TCRs using the clinical Sleeping Beauty transposon/transposase system. Patient-specific TCRs reactive against HLA-A*0201-restriced neoantigens AHNAKS2580F or ERBB2H473Y or the HLA-DQB*0601-restricted neoantigen ERBB2IPE805G were assembled with murine constant chains and cloned into Sleeping Beauty transposons. Patient peripheral blood lymphocytes were coelectroporated with SB11 transposase and Sleeping Beauty transposon, and transposed T cells were enriched by sorting on murine TCRβ (mTCRβ) expression. Rapid expansion of mTCRβ+ T cells with irradiated allogeneic peripheral blood lymphocytes feeders, OKT3, interleukin-2 (IL-2), IL-15, and IL-21 resulted in a preponderance of effector (CD27−CD45RA−) and less-differentiated (CD27+CD45RA+) T cells. Transposed T cells specifically mounted a polyfunctional response against cognate mutated neoantigens and tumor cell lines. Thus, Sleeping Beauty transposition of mutation-specific TCRs can facilitate the use of personalized T-cell therapy targeting unique neoantigens. PMID:26945006

  18. Clinical Significance of ErbB Receptor Family in Urothelial Carcinoma of the Bladder: A Systematic Review and Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Yuh-Shyan Tsai

    2012-01-01

    Full Text Available The prognostic importance of examining ErbB receptor family expression in human bladder cancer remains uncertain. Using published evidence, we examined the clinical value and the updated results of clinical trials targeting ErbB receptor family members. Twenty-seven articles from 65 references related to ErbB receptor expression assessment in bladder cancer were reviewed. The estimates included the association significance, hazard ratios, and 95% confidence intervals (CIs from actuarial curves and survival analyses. A meta-analysis was done on those reports using univariate log-rank tests or a Cox-regression model. The methods of analysis and study subjects chosen varied widely among studies. The overall risks of disease progression for patients with EGFR or ErbB2 overexpression were 4.5 (95% CI: 2.5–8.4 and 1.1 (95% CI: 0.6–1.9, and the risks of mortality were 3.0 (95% CI: 1.6–5.9 and 1.1 (95% CI: 1.0–1.2, respectively. However, the significance of coexpression patterns of the ErbB receptor family remains controversial. None of six clinical trials yielded convincing results for blockading ErbB receptor signaling in urothelial carcinoma. The results of this analysis suggest that assessing co-expression patterns of the ErbB family may provide better prognostic information for bladder cancer patients.

  19. Mechanism for activation of mutated epidermal growth factor receptors in lung cancer.

    Science.gov (United States)

    Red Brewer, Monica; Yun, Cai-Hong; Lai, Darson; Lemmon, Mark A; Eck, Michael J; Pao, William

    2013-09-17

    The initiation of epidermal growth factor receptor (EGFR) kinase activity proceeds via an asymmetric dimerization mechanism in which a "donor" tyrosine kinase domain (TKD) contacts an "acceptor" TKD, leading to its activation. In the context of a ligand-induced dimer, identical wild-type EGFR TKDs are thought to assume the donor or acceptor roles in a random manner. Here, we present biochemical reconstitution data demonstrating that activated EGFR mutants found in lung cancer preferentially assume the acceptor role when coexpressed with WT EGFR. Mutated EGFRs show enhanced association with WT EGFR, leading to hyperphosphorylation of the WT counterpart. Mutated EGFRs also hyperphosphorylate the related erythroblastic leukemia viral oncogene (ErbB) family member, ErbB-2, in a similar manner. This directional "superacceptor activity" is particularly pronounced in the drug-resistant L834R/T766M mutant. A 4-Å crystal structure of this mutant in the active conformation reveals an asymmetric dimer interface that is essentially the same as that in WT EGFR. Asymmetric dimer formation induces an allosteric conformational change in the acceptor subunit. Thus, superacceptor activity likely arises simply from a lower energetic cost associated with this conformational change in the mutant EGFR compared with WT, rather than from any structural alteration that impairs the donor role of the mutant. Collectively, these findings define a previously unrecognized mode of mutant-specific intermolecular regulation for ErbB receptors, knowledge of which could potentially be exploited for therapeutic benefit.

  20. Breast Cancer and Risk Factors Among African-American Women Aged 20-54: A Case-Control Study According to Estrogen Receptor Status

    National Research Council Canada - National Science Library

    Zhu, Kangmin

    1999-01-01

    ...) status among African-American women. During the period of the project, we established collaborations with the Tennessee Cancer Reporting System, hospitals in the study areas, and basic science researchers...

  1. Sex differences in androgen receptors of the human mamillary bodies are related to endocrine status rather than to sexual orientation or transsexuality

    NARCIS (Netherlands)

    Kruijver, F. P.; Fernández-Guasti, A.; Fodor, M.; Kraan, E. M.; Swaab, D. F.

    2001-01-01

    In a previous study we found androgen receptor (AR) sex differences in several regions throughout the human hypothalamus. Generally, men had stronger nuclear AR immunoreactivity (AR-ir) than women. The strongest nuclear labeling was found in the caudal hypothalamus in the mamillary body complex

  2. Expression of vitamin D receptor and vitamin D status in patients with oral neoplasms and effect of vitamin D supplementation on quality of life in advanced cancer treatment

    Directory of Open Access Journals (Sweden)

    Akshay Anand

    2017-06-01

    Full Text Available Aim of the study: Vitamin D receptor (VDR expression and serum vitamin D scores in oral premalignant lesions and oral cancer have not been widely analyzed. The role of vitamin D supplementation in advanced oral cancer for improving quality of life (QOL is also a matter of research. Material and methods: Vitamin D receptor expression and vitamin D scores were analyzed in normal oral mucosa (n = 95, leukoplakia (n = 23 and oral cancer (n = 87. 45 patients with advanced oral cancer subjected to chemoradiation were evaluated for the effect of vitamin D supplementation on most observable QOL parameters such as oral mucositis, swallowing performance and overall QOL. Results: Vitamin D receptor expression was increased in oral neoplastic lesions. Vitamin D scores were significantly lower in cases compared to healthy controls (p = 0.002. Vitamin D supplementation significantly reduced the therapy-related toxicities in advanced cancer, thus reducing morbidity and improving QOL. Conclusions : Vitamin D receptor expression is increased in premalignant lesions and oral cancer. Vitamin D insufficiency and deficiency are prevalent in patients with oral neoplastic lesions. Vitamin D supplementation has a role in reducing treatment-related toxicities, especially in advanced cancer.

  3. Insulin receptors

    International Nuclear Information System (INIS)

    Kahn, C.R.; Harrison, L.C.

    1988-01-01

    This book contains the proceedings on insulin receptors. Part A: Methods for the study of structure and function. Topics covered include: Method for purification and labeling of insulin receptors, the insulin receptor kinase, and insulin receptors on special tissues

  4. The Role of Nuclear Receptor Coactivators in Recurrent Prostate Cancer

    Science.gov (United States)

    2006-02-01

    phosphate- buffered saline containing the protease inhibitors 0.02 mg/ml pancreas extract, 0.005 mg/ml Pronase, 0.0005 mg/ml thermolysin , 0.003 mg/ml...mediated through MAP kinase signaling pathways. The response was blocked by IRESSA and GW2016, inhibitors of ErbB1 and ErbB2. EGF signaling increased...the HER1 (ErbB1) and HER2 (ErbB2) inhibitor GW572016 (lapatinib) to a greater extent than the HER1 (ErbB1) specific inhibitor ZD1839 (gefitinib

  5. Modulation of insulin-like growth factor-1 receptor and its signaling network for the treatment of cancer: current status and future perspectives

    Directory of Open Access Journals (Sweden)

    Meizhong Jin

    2013-04-01

    Full Text Available Based on over three decades of pre-clinical data, insulin-like growth factor-1 receptor (IGF-1R signaling has gained recognition as a promoter of tumorogenesis, driving cell survival and proliferation in multiple human cancers. As a result, IGF-1R has been pursued as a target for cancer treatment. Early pioneering efforts targeting IGF-1R focused on highly selective monoclonal antibodies, with multiple agents advancing to clinical trials. However, despite some initial promising results, recent clinical disclosures have been less encouraging. Moreover, recent studies have revealed that IGF-1R participates in a dynamic and complex signaling network, interacting with additional targets and pathways thereof through various crosstalk and compensatory signaling mechanisms. Such mechanisms of bypass signaling help to shed some light on the decreased effectiveness of selective IGF- 1R targeted therapies (e.g. monoclonal antibodies and suggest that targeting multiple nodes within this signaling network might be necessary to produce a more effective therapeutic response. Additionally, such findings have led to the development of small molecule IGF-1R inhibitors which also co-inhibit additional targets such as insulin receptor and epidermal growth factor receptor. Such findings have helped to guide the design rationale of numerous drug combinations that are currently being evaluated in clinical trials.

  6. Development of a Novel Test System for Screening Antagonists of ErbB Receptors in Breast Cancer

    National Research Council Canada - National Science Library

    Blau, Helen

    2004-01-01

    The focus of this project was to design a system for screening chemical compounds that would inhibit the dimerization of the EGFR family members ErbB2 and ErbB3 using beta-galactosidase complementation...

  7. Development of a Novel Test System for Screening for Antagonists of ErbB5 Receptors in Breast Cancer

    National Research Council Canada - National Science Library

    Blau, Helen

    2003-01-01

    The focus of this project was to design a system for screening chemical compounds that would inhibit the dimerization of the EGFR family members ErbB2 and ErbB3 using beta-galactosidase complementation...

  8. Development of novel epidermal growth receptor-based radiopharmaceuticals: Imaging agents for breast cancer

    International Nuclear Information System (INIS)

    Van Brocklin, Henry F.

    2001-01-01

    The goal of this research was to develop epidermal growth factor receptor (EGFR) nuclear medicine breast cancer imaging agents. Our approach was to synthesize small molecule inhibitors of the EGFR tyrosine kinase (tk) suitable for labeling with single photon or positron-emitting radioisotopes and evaluate the imaging potential of these new molecules.We have synthesized and fully characterized 22 quinazoline compounds. All compounds inhibit EGFR tk phosphorylation activity in the nanomolar range. All compounds tested exhibited specificity for the EGFR tk versus the ErbB2 and ErbB4 tyrosine kinases. A radiometric binding assay using an iodine-125 labeled quinazoline was developed to determine the affinity of the quinazolines for the EGFR tk ATP binding site. The affinities ranged from 0.4-51 nM. The octanol/water partition coefficients (Log P; lipophilicity) of the new compounds ranged from 2.2-5.5. Six compounds have been labeled with fluorine-18. Biodistribution in EGFR overexpressing tumor bearing mice demonstrated tumor uptake but highlighted delivery and metabolism issues. The 2-fluoro quinazoline was not metabolized in an in vitro hepatocyte study. From this work a breadth of agent characteristics was created establishing the foundation for future research toward the optimal EGFR imaging agent

  9. β-catenin-independent WNT signaling and Ki67 in contrast to the estrogen receptor status are prognostic and associated with poor prognosis in breast cancer liver metastases.

    Science.gov (United States)

    Bleckmann, Annalen; Conradi, Lena-Christin; Menck, Kerstin; Schmick, Nadine Annette; Schubert, Antonia; Rietkötter, Eva; Arackal, Jetcy; Middel, Peter; Schambony, Alexandra; Liersch, Torsten; Homayounfar, Kia; Beißbarth, Tim; Klemm, Florian; Binder, Claudia; Pukrop, Tobias

    2016-04-01

    Liver metastasis development in breast cancer patients is common and confers a poor prognosis. So far, the prognostic significance of surgical resection and clinical relevance of biomarker analysis in metastatic tissue have barely been investigated. We previously demonstrated an impact of WNT signaling in breast cancer brain metastasis. This study aimed to investigate the value of established prognostic markers and WNT signaling components in liver metastases. Overall N = 34 breast cancer liver metastases (with matched primaries in 19/34 cases) were included in this retrospective study. Primaries and metastatic samples were analyzed for their expression of the estrogen (ER) and progesterone receptor, HER-2, Ki67, and various WNT signaling-components by immunohistochemistry. Furthermore, β-catenin-dependent and -independent WNT scores were generated and analyzed for their prognostic value. Additionally, the influence of the alternative WNT receptor ROR on signaling and invasiveness was analyzed in vitro. ER positivity (HR 0.09, 95 % CI 0.01-0.56) and high Ki67 (HR 3.68, 95 % CI 1.12-12.06) in the primaries had prognostic impact. However, only Ki67 remained prognostic in the metastatic tissue (HR 2.46, 95 % CI 1.11-5.44). Additionally, the β-catenin-independent WNT score correlated with reduced overall survival only in the metastasized situation (HR 2.19, 95 % CI 1.02-4.69, p = 0.0391). This is in line with the in vitro results of the alternative WNT receptors ROR1 and ROR2, which foster invasion. In breast cancer, the value of prognostic markers established in primary tumors cannot directly be translated to metastases. Our results revealed β-catenin-independent WNT signaling to be associated with poor prognosis in patients with breast cancer liver metastasis.

  10. miR-205-5p-mediated downregulation of ErbB/HER receptors in breast cancer stem cells results in targeted therapy resistance.

    Science.gov (United States)

    De Cola, A; Volpe, S; Budani, M C; Ferracin, M; Lattanzio, R; Turdo, A; D'Agostino, D; Capone, E; Stassi, G; Todaro, M; Di Ilio, C; Sala, G; Piantelli, M; Negrini, M; Veronese, A; De Laurenzi, V

    2015-07-16

    The ErbB tyrosine kinase receptor family has been shown to have an important role in tumorigenesis, and the expression of its receptor members is frequently deregulated in many types of solid tumors. Various drugs targeting these receptors have been approved for cancer treatment. Particularly, in breast cancer, anti-Her2/EGFR molecules represent the standard therapy for Her2-positive malignancies. However, in a number of cases, the tumor relapses or progresses thus suggesting that not all cancer cells have been targeted. One possibility is that a subset of cells capable of regenerating the tumor, such as cancer stem cells (CSCs), may not respond to these therapeutic agents. Accumulating evidences indicate that miR-205-5p is significantly downregulated in breast tumors compared with normal breast tissue and acts as a tumor suppressor directly targeting oncogenes such as Zeb1 and ErbB3. In this study, we report that miR-205-5p is highly expressed in BCSCs and represses directly ERBB2 and indirectly EGFR leading to resistance to targeted therapy. Furthermore, we show that miR-205-5p directly regulates the expression of p63 which is in turn involved in the EGFR expression suggesting a miR-205/p63/EGFR regulation.

  11. Influence of early life status epilepticus on the developmental expression profile of the GluA2 subunit of AMPA receptors

    Czech Academy of Sciences Publication Activity Database

    Szczurowska, Ewa; Ergang, Peter; Kubová, Hana; Druga, Rastislav; Salaj, M.; Mareš, Pavel

    2016-01-01

    Roč. 283, Part A (2016), s. 97-109 ISSN 0014-4886 R&D Projects: GA ČR(CZ) GA15-16605S; GA ČR(CZ) GBP304/12/G069 Institutional support: RVO:67985823 Keywords : development * pilocarpine * status epilepticus * LiCl * AMPA * GluA2 * subunit * expression * GRIA2A Subject RIV: FH - Neurology Impact factor: 4.706, year: 2016

  12. A population-based study of Kurdish breast cancer in northern Iraq: Hormone receptor and HER2 status. A comparison with Arabic women and United States SEER data

    Directory of Open Access Journals (Sweden)

    Runnak Majid A

    2012-06-01

    Full Text Available Abstract Background Hormone receptor (HR and HER2 expression predict the therapeutic response and prognosis of breast cancer. In the Middle-East, breast cancer is diagnosed at a young age, and Arabic women are reported to have a low frequency of HR positive tumors. This study investigates HR and HER2 expression among Kurdish and Arabic women. Methods During 2008–2010, the Sulaimaniyah Directorate of Health records identified 514 Sulaimaniyah Kurdish women, 227 Kurdish women of other Governates, and 83 Arabic women with a first diagnosis of breast cancer. The breast cancers of 432 women had immunohistochemistry (IHC performed for estrogen and progesterone receptors (ER and PR and HER2. Age specific and age standardized incidence rates were calculated for Sulaimaniyah Kurds. Results were compared with Egypt and with United States (US SEER data. Results The median patient age was 46 years and 60.4% were  Conclusions Compared to the US, low age standardized and age specific breast cancer incidence rates were found in Kurdish women; nevertheless, the proportional expression of HR and HER2 for both Kurds and Arabs was comparable to that of US white women. The great majority of the breast cancer was ER+/HER2- and should respond to anti-estrogen therapy.

  13. Association of the Genetic Polymorphisms in Transcription Factor 7-Like 2 and Peroxisome Proliferator-Activated Receptors- γ 2 with Type 2 Diabetes Mellitus and is Interaction with Obesity Status in Emirati Population.

    Science.gov (United States)

    Al-Safar, Habiba; Hassoun, Ahmed; Almazrouei, Shaikha; Kamal, Wala; Afandi, Bachar; Rais, Naushad

    2015-01-01

    Transcription factor 7-like 2 gene (TCF7L2) and peroxisome proliferator-activated receptors-γ2 (PPAR-γ2) have a profound effect on the incidence of type 2 diabetes mellitus (T2DM) and had previously been found to be associated with T2DM risk in various ppopulations. However, studies in the Arab population are inconsistent. We conducted a case control study to confirm the association of variants rs10885409 of TCF7L2 and Pro12Ala (rs1801282) of PPAR-γ2 with risk of T2DM and related complications in Emirati population of Arab origin. We also investigated the interaction of these associations with obesity status. DNA was extracted from the saliva samples of 272 T2DM patients and 216 nondiabetic Emiratis. Genotyping for rs10885409 (TCF7L2) and rs1801282 (PPAR-γ2 P12A) variants was accomplished with a TaqMan assay. The subgroups were constituted according to obesity status. In the nonobese group, the rs10885409 C allele in the recessive model was significantly associated with the incidence of T2DM (OR 1.975 [95% CI 1.127-3.461], P = 0.017), but this association was not observed in the obese group or when BMI was not considered. PPAR-γ2 risk allele Pro12 frequency (0.96) was similar in the groups tested and more than 90% population was homozygous for this allele. Our case-control study is the first of its kind in Emiratis which establishes TCF7L2 rs10885409 C allele as a T2DM risk factor in Emiratis and this association is modulated by obesity status. We also confirmed that Pro12Ala mutation in PPAR-γ2 is not associated with T2DM risk in this population.

  14. The effect of radio- and chemotherapy on the hormonal status of breast cancer patients taking account of the level of receptors in tumor

    International Nuclear Information System (INIS)

    Bassalyk, L.S.; Koposova, T.L.; Murav'eva, N.I.; Gershtejn, E.S.; Smirnova, K.D.; Kuz'mina, Z.V.

    1986-01-01

    A study was made of the content of the steroid and peptide hormones in the blood of 115 patients with Stage 3 a, b, c breast cancer (54 patients at the reproductive age and 61 in the menopause) before treatment and during radio- and chemotherapy. Data on the concentration of the steroid hormones in the patients' blood were compared with the presence of the respective receptors in tumor. Before treatment a significant rise of the estradiol concentration was noted in the blood of the menopause patients, that of prolactin both in the menopause patients and in the patients with preserved menstruation. A raised testosterone concentration was also noted in the patients with preserved menstruation. After radiotherapy the blood prolactin level, particularly in the patients with preserved menstruation, increased more than 2-fold. There was no correlation between the levels of the steroid and peptide hormones during therapy and its efficasy. The prolactin level can be used as a criterion of efficasy of antytumor therapy, its stable rise in operated patients during therapy being an unfavourable prognostic sign

  15. Low or undetectable TPO receptor expression in malignant tissue and cell lines derived from breast, lung, and ovarian tumors

    Directory of Open Access Journals (Sweden)

    Erickson-Miller Connie L

    2012-09-01

    Full Text Available Abstract Background Numerous efficacious chemotherapy regimens may cause thrombocytopenia. Thrombopoietin receptor (TPO-R agonists, such as eltrombopag, represent a novel approach for the treatment of chemotherapy-induced thrombocytopenia. The TPO-R MPL is expressed on megakaryocytes and megakaryocyte precursors, although little is known about its expression on other tissues. Methods Breast, lung, and ovarian tumor samples were analyzed for MPL expression by microarray and/or quantitative reverse transcription-polymerase chain reaction (qRT-PCR, and for TPO-R protein expression by immunohistochemistry (IHC. Cell line proliferation assays were used to analyze the in vitro effect of eltrombopag on breast, lung, and ovarian tumor cell proliferation. The lung carcinoma cell lines were also analyzed for TPO-R protein expression by Western blot. Results MPL mRNA was not detectable in 118 breast tumors and was detectable at only very low levels in 48% of 29 lung tumors studied by microarray analysis. By qRT-PCR, low but detectable levels of MPL mRNA were detectable in some normal (14-43% and malignant (3-17% breast, lung, and ovarian tissues. A comparison of MPL to EPOR, ERBB2, and IGF1R mRNA demonstrates that MPL mRNA levels were far lower than those of EPOR and ERBB2 mRNA in the same tissues. IHC analysis showed negligible TPO-R protein expression in tumor tissues, confirming mRNA analysis. Culture of breast, lung, and ovarian carcinoma cell lines showed no increase, and in fact, showed a decrease in proliferation following incubation with eltrombopag. Western blot analyses revealed no detectable TPO-R protein expression in the lung carcinoma cell lines. Conclusions Multiple analyses of breast, lung, and ovarian tumor samples and/or cell lines show no evidence of MPL mRNA or TPO-R protein expression. Eltrombopag does not stimulate growth of breast, lung, or ovarian tumor cell lines at doses likely to exert their actions on megakaryocytes and

  16. Low or undetectable TPO receptor expression in malignant tissue and cell lines derived from breast, lung, and ovarian tumors.

    Science.gov (United States)

    Erickson-Miller, Connie L; Pillarisetti, Kodandaram; Kirchner, Jennifer; Figueroa, David J; Ottesen, Lone; Martin, Anne-Marie; Liu, Yuan; Kamel, Yasser Mostafa; Messam, Conrad

    2012-09-11

    Numerous efficacious chemotherapy regimens may cause thrombocytopenia. Thrombopoietin receptor (TPO-R) agonists, such as eltrombopag, represent a novel approach for the treatment of chemotherapy-induced thrombocytopenia. The TPO-R MPL is expressed on megakaryocytes and megakaryocyte precursors, although little is known about its expression on other tissues. Breast, lung, and ovarian tumor samples were analyzed for MPL expression by microarray and/or quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and for TPO-R protein expression by immunohistochemistry (IHC). Cell line proliferation assays were used to analyze the in vitro effect of eltrombopag on breast, lung, and ovarian tumor cell proliferation. The lung carcinoma cell lines were also analyzed for TPO-R protein expression by Western blot. MPL mRNA was not detectable in 118 breast tumors and was detectable at only very low levels in 48% of 29 lung tumors studied by microarray analysis. By qRT-PCR, low but detectable levels of MPL mRNA were detectable in some normal (14-43%) and malignant (3-17%) breast, lung, and ovarian tissues. A comparison of MPL to EPOR, ERBB2, and IGF1R mRNA demonstrates that MPL mRNA levels were far lower than those of EPOR and ERBB2 mRNA in the same tissues. IHC analysis showed negligible TPO-R protein expression in tumor tissues, confirming mRNA analysis. Culture of breast, lung, and ovarian carcinoma cell lines showed no increase, and in fact, showed a decrease in proliferation following incubation with eltrombopag. Western blot analyses revealed no detectable TPO-R protein expression in the lung carcinoma cell lines. Multiple analyses of breast, lung, and ovarian tumor samples and/or cell lines show no evidence of MPL mRNA or TPO-R protein expression. Eltrombopag does not stimulate growth of breast, lung, or ovarian tumor cell lines at doses likely to exert their actions on megakaryocytes and megakaryocyte precursors.

  17. Single nucleotide variants in metastasis-related genes are associated with breast cancer risk, by lymph node involvement and estrogen receptor status, in women with European and African ancestry.

    Science.gov (United States)

    Roberts, Michelle R; Sucheston-Campbell, Lara E; Zirpoli, Gary R; Higgins, Michael; Freudenheim, Jo L; Bandera, Elisa V; Ambrosone, Christine B; Yao, Song

    2017-03-01

    Single nucleotide polymorphisms (SNPs) in pathways influencing lymph node (LN) metastasis and estrogen receptor (ER) status in breast cancer may partially explain inter-patient variability in prognosis. We examined 154 SNPs in 12 metastasis-related genes for associations with breast cancer risk, stratified by LN and ER status, in European-American (EA) and African-American (AA) women. Two-thousand six hundred and seventy-one women enrolled in the Women's Circle of Health Study were genotyped. Pathway analyses were conducted using the adaptive rank truncated product (ARTP) method, with p ARTP  ≤ 0.10 as significant. Multi-allelic risk scores were created for the ARTP-significant gene(s). Single-SNP and risk score associations were modeled using logistic regression, with false discovery rate (FDR) P-value adjustment. Although single-SNP associations were not significant at p FDR  women, significant ARTP gene-level associations included CDH1 with LN+ (p ARTP  = 0.10; multi-allelic OR = 1.13, 95%CI 1.07-1.19, p FDR  = 0.0003) and SIPA1 with ER- breast cancer (p ARTP  = 0.10; multi-allelic OR = 1.16, 95%CI 1.02-1.31, p FDR  = 0.03). In EA women, MTA2 was associated with overall breast cancer risk (p ARTP  = 0.004), regardless of ER status, and with LN- disease (p ARTP  = 0.01). Also significant were SATB1 in ER- (p ARTP  = 0.03; multi-allelic OR = 1.12, 95%CI 1.05-1.20, p FDR  = 0.003) and KISS1 in LN- (p ARTP  = 0.10; multi-allelic OR = 1.18, 95%CI 1.08-1.29, p FDR  = 0.002) analyses. Among LN+ cases, significant ARTP associations were observed for SNAI1, CD82, NME1, and CTNNB1 (multi-allelic OR = 1.09, 95%CI 1.04-1.14, p FDR  = 0.001). Our findings suggest that variants in several metastasis genes may affect breast cancer risk by LN or ER status, although verification in larger studies is required. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  18. Differences in sNPF receptor-expressing neurons in brains of fire ant (Solenopsis invicta Buren worker subcastes: indicators for division of labor and nutritional status?

    Directory of Open Access Journals (Sweden)

    Paula Castillo

    Full Text Available In the red imported fire ant, Solenopsis invicta Buren, the neuronal and molecular mechanisms related to worker division of labor are poorly understood. Workers from different subcastes (major, medium and minors perform different tasks, which are loosely associated with their size. We hypothesized that the short neuropeptide F (sNPF signaling system (NPY-like could be involved in mechanisms of worker division of labor and sensing or responding to colony nutritional requirements. Thus, we investigated the expression of the short neuropeptide F receptor (sNPFR in the brain and subesophageal ganglion (SEG of workers from colonies with and without brood. Across worker subcastes a total of 9 clusters of immunoreactive sNPFR cells were localized in the brain and the subesophageal ganglion (SEG; some of these cells were similar to those observed previously in the queen. Worker brain sNPFR cell clusters were found in the protocerebrum near mushroom bodies, in the central complex and in the lateral horn. Other sNPFR immunoreactive cells were found at the edge of the antennal lobes. Across subcastes, we observed both a constant and a differential pattern of sNPFR clusters, with a higher number of sNPFR cells found in minor than in major workers. Those sNPFR cells detected in all worker subcastes appear to be involved in olfaction or SEG functions. The differential expression of clusters in subcastes suggests that sNPFR signaling is involved in regulating behaviors associated with specific subcastes and thus, division of labor. Some sNPFR cells appear to be involved in nutrient sensing and/or brood care, feeding behavior and locomotion. In colonies without brood, workers showed a lower cluster number, and an overall reduced sNPFR signal. Our results suggest the sNPF signaling system is a candidate for the neurobiological control of worker division of labor and sensing brood presence, perhaps correlating with protein requirements and availability.

  19. Epidermal Growth Factor Receptor Status in Circulating Tumor Cells as a Predictive Biomarker of Sensitivity in Castration-Resistant Prostate Cancer Patients Treated with Docetaxel Chemotherapy

    Directory of Open Access Journals (Sweden)

    Takatsugu Okegawa

    2016-11-01

    Full Text Available Objective: We examined whether epidermal growth factor receptor (EGFR expression in circulating tumor cells (CTCs can be used to predict survival in a population of bone-metastatic castration-resistant prostate cancer (mCRPC patients treated with docetaxel chemotherapy. Methods: All patients with mCRPC who had experienced treatment failure with androgen-deprivation therapy and had received docetaxel chemotherapy were eligible. CTCs and EGFR expression in CTCs were enumerated with the CellSearch System in whole blood. This system is a semi-automated system that detects and enriches epithelial cells from whole blood using an EpCAM antibody-based immunomagnetic capture. In addition, the EGFR-positive CTCs were assessed using CellSearch® Tumor Phenotyping Reagent EGFR. Results: The median CTC count at baseline before starting trial treatment was eight CTCs per 7.5 mL of blood (range 0–184. There were 37 patients (61.7% who had ≥5 CTCs, with median overall survival of 11.5 months compared with 20.0 months for 23 patients (38.3% with <5 CTCs (p < 0.001. A total of 15 patients (40.5%, 15/37 with five or more CTCs were subjected to automated immunofluorescence staining and cell sorting for EGFR protein. Patients with EGFR-positive CTCs had a shorter overall survival (OS (5.5 months than patients with EGFR-negative CTCs (20.0 months. CTCs, EGFR-positive CTCs, and alkaline phosphatase (ALP were independent predictors of overall survival time (p = 0.002, p < 0.001, and p = 0.017, respectively. Conclusion: CTCs may be an independent predictor of OS in CRPC treated with docetaxel chemotherapy. The EGFR expression detected in CTCs was important for assessing the response to chemotherapy and predicting disease outcome.

  20. Recurrence and mortality according to Estrogen Receptor status for breast cancer patients undergoing conservative surgery. Ipsilateral breast tumour recurrence dynamics provides clues for tumour biology within the residual breast

    International Nuclear Information System (INIS)

    Demicheli, Romano; Ardoino, Ilaria; Boracchi, Patrizia; Coradini, Danila; Agresti, Roberto; Ferraris, Cristina; Gennaro, Massimiliano; Hrushesky, William JM; Biganzoli, Elia

    2010-01-01

    the study was designed to determine how tumour hormone receptor status affects the subsequent pattern over time (dynamics) of breast cancer recurrence and death following conservative primary breast cancer resection. Time span from primary resection until both first recurrence and death were considered among 2825 patients undergoing conservative surgery with or without breast radiotherapy. The hazard rates for ipsilateral breast tumour recurrence (IBTR), distant metastasis (DM) and mortality throughout 10 years of follow-up were assessed. DM dynamics displays the same bimodal pattern (first early peak at about 24 months, second late peak at the sixth-seventh year) for both estrogen receptor (ER) positive (P) and negative (N) tumours and for all local treatments and metastatic sites. The hazard rates for IBTR maintain the bimodal pattern for ERP and ERN tumours; however, each IBTR recurrence peak for ERP tumours is delayed in comparison to the corresponding timing of recurrence peaks for ERN tumours. Mortality dynamics is markedly different for ERP and ERN tumours with more early deaths among patients with ERN than among patients with ERP primary tumours. DM dynamics is not influenced by the extent of conservative primary tumour resection and is similar for both ER phenotypes across different metastatic sites, suggesting similar mechanisms for tumour development at distant sites despite apparently different microenvironments. The IBTR risk peak delay observed in ERP tumours is an exception to the common recurrence risk rhythm. This suggests that the microenvironment within the residual breast tissue may enforce more stringent constraints upon ERP breast tumour cell growth than other tissues, prolonging the latency of IBTR. This local environment is, however, apparently less constraining to ERN cells, as IBTR dynamics is similar to the corresponding recurrence dynamics among other distant tissues

  1. A Shift from Nuclear to Cytoplasmic Breast Cancer Metastasis Suppressor 1 Expression Is Associated with Highly Proliferative Estrogen Receptor-Negative Breast Cancers

    Science.gov (United States)

    Frolova, Natalya; Edmonds, Mick D.; Bodenstine, Thomas M.; Seitz, Robert; Johnson, Martin R.; Feng, Rui; Welch, Danny R.; Frost, Andra R.

    2009-01-01

    Background/Aims To determine breast cancer metastasis suppressor 1 (BRMS1) expression in breast cancers and the efficacy of BRMS1 as a prognostic indicator, BRMS1 expression was assessed in two sets of breast cancer tissues. Methods Epithelial cells from 36 frozen samples of breast cancers and corresponding normal breast were collected by laser capture microdissection and assessed for BRMS1 by quantitative RT-PCR and immunohistochemistry. BRMS1 was also evaluated by immunohistochemistry in a tissue microarray of 209 breast cancers and correlated with indicators of prognosis [estrogen receptor (ER), progesterone receptor (PR), ErbB2, p53, p27Kip1, Bcl2 and Ki-67]. Results BRMS1 mRNA and protein were higher in 94 and 81%, respectively, of breast cancers than in corresponding normal epithelium. BRMS1 localization was predominantly nuclear, but 60–70% of cancers also exhibited cytoplasmic immunostaining. Breast cancers with lower nuclear than cytoplasmic BRMS1 (nuclear score – cytoplasmic score ≤0; 11% of cancers) had lower ER, lower PR and higher Ki-67 expression. There was also a trend toward poorer overall survival in this group of cancers, but this was only of borderline significance (p = 0.073). In Cox proportional hazards models, loss of nuclear BRMS1 was not a significant predictor of overall survival. Conclusions Loss of nuclear BRMS1 was associated with ER-negative cancers and a high rate of proliferation, but was not an independent indicator of prognosis. PMID:19609101

  2. Epidermal growth factor receptor (EGFR mutation status and Rad51 determine the response of glioblastoma (GBM to multimodality therapy with cetuximab, temozolomide and radiation

    Directory of Open Access Journals (Sweden)

    Phyllis Rachelle Wachsberger

    2013-02-01

    Full Text Available Purpose: EGFR amplification and mutation (i.e., EGFRvIII are found in 40% of primary GBM tumors and are believed to contribute to tumor development and therapeutic resistance. This study was designed to investigate how EGFR mutational status modulates response to multimodality treatment with cetuximab, an anti-EGFR inhibitor, the chemotherapeutic agent, temozolamide (TMZ and radiation therapy (RT Methods and Materials: In vitro and in vivo experiments were performed on two isogenic U87 GBM cell lines: one overexpressing wildtype EGFR (U87wtEGFR and the other overexpressing EGFRvIII (U87EGFRvIII. Results: Xenografts harboring EGFRvIII were more sensitive to TMZ alone and TMZ in combination with RT and/or cetuximab than xenografts expressing wtEGFR. In vitro experiments demonstrated that U87EGFRvIII-expressing tumors appear to harbor defective DNA homologous recombination repair in the form of Rad51 processing, Conclusions: The difference in sensitivity between EGFR-expressing and EGFRvIII-expressing tumors to combined modality treatment may help in the future tailoring of GBM therapy to subsets of patients expressing more or less of the EGFR mutant.

  3. Sex differences in androgen receptors of the human mamillary bodies are related to endocrine status rather than to sexual orientation or transsexuality.

    Science.gov (United States)

    Kruijver, F P; Fernández-Guasti, A; Fodor, M; Kraan, E M; Swaab, D F

    2001-02-01

    In a previous study we found androgen receptor (AR) sex differences in several regions throughout the human hypothalamus. Generally, men had stronger nuclear AR immunoreactivity (AR-ir) than women. The strongest nuclear labeling was found in the caudal hypothalamus in the mamillary body complex (MBC), which is known to be involved in aspects of cognition and sexual behavior. The present study was carried out to investigate whether the sex difference in AR-ir of the MBC is related to sexual orientation or gender identity (i.e. the feeling of being male or female) or to circulating levels of androgens, as nuclear AR-ir is known to be up-regulated by androgens. Therefore, we studied the MBC in postmortem brain material from the following groups: young heterosexual men, young homosexual men, aged heterosexual castrated and noncastrated men, castrated and noncastrated transsexuals, young heterosexual women, and a young virilized woman. Nuclear AR-ir did not differ significantly between heterosexual and homosexual men, but was significantly stronger than that in women. A female-like pattern of AR-ir (i.e. no to weak nuclear staining) was observed in 26- to 53-yr-old castrated male-to-female transsexuals and in old castrated and noncastrated men, 67--87 yr of age. In analogy with animal studies showing strong activational effects of androgens on nuclear AR-ir, the present data suggest that nuclear AR-ir in the human MBC is dependent on the presence or absence of circulating levels of androgen. The group data were, moreover, supported by the fact that a male-like AR-ir (i.e. intense nuclear AR-ir) was found in a 36-yr-old bisexual noncastrated male-to-female transsexual and in a heterosexual virilized woman, 46 yr of age, with high levels of circulating testosterone. In conclusion, the sexually dimorphic AR-ir in the MBC seemed to be clearly related to circulating levels of androgens and not to sexual orientation or gender identity. The functional implications of these

  4. Phosphorylated and sumoylation-deficient progesterone receptors drive proliferative gene signatures during breast cancer progression

    Science.gov (United States)

    2012-01-01

    remodeling. PR SUMOylation blocks these events, suggesting that SUMO modification of PR prevents interactions with mediators of early chromatin remodeling at 'closed' enhancer regions. SUMO-deficient (phospho-Ser294) PR gene signatures are significantly associated with human epidermal growth factor 2 (ERBB2)-positive luminal breast tumors and predictive of early metastasis and shortened survival. Treatment with antiprogestin or MEK inhibitor abrogated expression of SUMO-sensitive PR target-genes and inhibited proliferation in BT-474 (estrogen receptor (ER)+/PR+/ERBB2+) breast cancer cells. Conclusions We conclude that reversible PR SUMOylation/deSUMOylation profoundly alters target gene selection in breast cancer cells. Phosphorylation-induced PR deSUMOylation favors a permissive chromatin environment via recruitment of CBP and MLL2. Patients whose ER+/PR+ tumors are driven by hyperactive (that is, derepressed) phospho-PRs may benefit from endocrine (antiestrogen) therapies that contain an antiprogestin. PMID:22697792

  5. Bone Status in a Patient with Insulin-Like Growth Factor-1 Receptor Deletion Syndrome: Bone Quality and Structure Evaluation Using Dual-Energy X-Ray Absorptiometry, Peripheral Quantitative Computed Tomography, and Quantitative Ultrasonography.

    Science.gov (United States)

    Pelosi, Paola; Lapi, Elisabetta; Cavalli, Loredana; Verrotti, Alberto; Pantaleo, Marilena; de Martino, Maurizio; Stagi, Stefano

    2017-01-01

    Haploinsufficiency of the insulin-like growth factor ( IGF )-1 receptor ( IGF1R ) gene is a rare, probably under-diagnosed, cause of short stature. However, the effects of IGF1R haploinsufficiency on glucose metabolism, bone status, and metabolism have rarely been investigated. We report the case of a patient referred to our center at the age of 18 months for short stature, failure to thrive, and Silver-Russell-like phenotype. Genetic analysis did not show hypomethylation of the 11p15.5 region or uniparental disomy of chromosome 7. Growth hormone (GH) stimulation tests revealed GH deficiency, whereas IGF-1 was 248 ng/mL. r-hGH treatment showed only a slight improvement (from -4.4 to -3.5 SDS). At 10 years of age, the child was re-evaluated: CGH-array identified a heterozygous de novo 4.92 Mb deletion in 15q26.2, including the IGF1R gene. Dual-energy X-ray absorptiometry showed a normal bone mineral density z -score, while peripheral quantitative computed tomography revealed reduced cortical and increased trabecular elements. A phalangeal bone quantitative ultrasonography showed significantly reduced amplitude-dependent speed of sound and bone transmission time values. The changes in bone architecture, quality, and metabolism in heterozygous IGF1R deletion patients, support the hypothesis that IGF-1 can be a key factor in bone modeling and accrual.

  6. Significant Effect of Anti-tyrosine Kinase Inhibitor (Gefitinib) on Overall Survival of the Glioblastoma Multiforme Patients in the Backdrop of Mutational Status of Epidermal Growth Factor Receptor and PTEN Genes

    Science.gov (United States)

    Arif, Sajad Hussain; Pandith, Arshad Ahmad; Tabasum, Rehana; Ramzan, Altaf Umar; Singh, Sarabjeet; Siddiqi, Mushtaq Ahmad; Bhat, Abdul Rashid

    2018-01-01

    Introduction: We aimed to assess the effect of anti-tyrosine kinase inhibitors (TKIs) (gefitinib) in overall survival (OS) of the glioblastoma multiforme (GBM) patients in the backdrop of mutational status of epidermal growth factor receptor (EGFR) and PTEN genes. Materials and Methods: All the patients subjected to resection or biopsies were put on gefitinib, and radiotherapy was delivered as per the hospital protocol. EGFR and PTEN mutational spectrum was performed by single-strand conformation polymorphism followed by DNA sequencing. Results: In total, 50% GBM tumors had mutation either in EGFR or PTEN. Median progression-free survival (PFS) and OS observed in patients with EGFR +ve/PTEN −ve were significantly favorable (P < 0.05) which aggregated to 9(7, 11) months and 20 (16, 24) months, respectively, than 6 (4, 8) months and 13 (7, 19) months in patients with PTEN +ve/EGFR −ve. Patients positive for both EGFR/PTEN had lower disease-free survival and OS of 6 and 9 months as compared to 6 (5, 7) and 14 (12, 24) months for those negative for both EGFR/PTEN. Conclusions: We conclude that EGFR gene alterations with wild-type PTEN are associated with significantly better PFS and OS in patients treated with anti-TKIs (gefitinib). Combined EGFR and PTEN gene mutation is associated with significantly poor response to gefitinib in terms of median OS. PMID:29492119

  7. Significant Effect of Anti-tyrosine Kinase Inhibitor (Gefitinib) on Overall Survival of the Glioblastoma Multiforme Patients in the Backdrop of Mutational Status of Epidermal Growth Factor Receptor and PTEN Genes.

    Science.gov (United States)

    Arif, Sajad Hussain; Pandith, Arshad Ahmad; Tabasum, Rehana; Ramzan, Altaf Umar; Singh, Sarabjeet; Siddiqi, Mushtaq Ahmad; Bhat, Abdul Rashid

    2018-01-01

    We aimed to assess the effect of anti-tyrosine kinase inhibitors (TKIs) (gefitinib) in overall survival (OS) of the glioblastoma multiforme (GBM) patients in the backdrop of mutational status of epidermal growth factor receptor ( EGFR ) and PTEN genes. All the patients subjected to resection or biopsies were put on gefitinib, and radiotherapy was delivered as per the hospital protocol. EGFR and PTEN mutational spectrum was performed by single-strand conformation polymorphism followed by DNA sequencing. In total, 50% GBM tumors had mutation either in EGFR or PTEN . Median progression-free survival (PFS) and OS observed in patients with EGFR +ve/ PTEN -ve were significantly favorable ( P PTEN +ve/ EGFR -ve. Patients positive for both EGFR / PTEN had lower disease-free survival and OS of 6 and 9 months as compared to 6 (5, 7) and 14 (12, 24) months for those negative for both EGFR / PTEN . We conclude that EGFR gene alterations with wild-type PTEN are associated with significantly better PFS and OS in patients treated with anti-TKIs (gefitinib). Combined EGFR and PTEN gene mutation is associated with significantly poor response to gefitinib in terms of median OS.

  8. Bone Status in a Patient with Insulin-Like Growth Factor-1 Receptor Deletion Syndrome: Bone Quality and Structure Evaluation Using Dual-Energy X-Ray Absorptiometry, Peripheral Quantitative Computed Tomography, and Quantitative Ultrasonography

    Directory of Open Access Journals (Sweden)

    Paola Pelosi

    2017-09-01

    Full Text Available Haploinsufficiency of the insulin-like growth factor (IGF-1 receptor (IGF1R gene is a rare, probably under-diagnosed, cause of short stature. However, the effects of IGF1R haploinsufficiency on glucose metabolism, bone status, and metabolism have rarely been investigated. We report the case of a patient referred to our center at the age of 18 months for short stature, failure to thrive, and Silver–Russell-like phenotype. Genetic analysis did not show hypomethylation of the 11p15.5 region or uniparental disomy of chromosome 7. Growth hormone (GH stimulation tests revealed GH deficiency, whereas IGF-1 was 248 ng/mL. r-hGH treatment showed only a slight improvement (from −4.4 to −3.5 SDS. At 10 years of age, the child was re-evaluated: CGH-array identified a heterozygous de novo 4.92 Mb deletion in 15q26.2, including the IGF1R gene. Dual-energy X-ray absorptiometry showed a normal bone mineral density z-score, while peripheral quantitative computed tomography revealed reduced cortical and increased trabecular elements. A phalangeal bone quantitative ultrasonography showed significantly reduced amplitude-dependent speed of sound and bone transmission time values. The changes in bone architecture, quality, and metabolism in heterozygous IGF1R deletion patients, support the hypothesis that IGF-1 can be a key factor in bone modeling and accrual.

  9. Effects of radiation on the epidermal growth factor receptor pathway in the heart.

    Science.gov (United States)

    Sridharan, Vijayalakshmi; Sharma, Sunil K; Moros, Eduardo G; Corry, Peter M; Tripathi, Preeti; Lieblong, Benjamin J; Guha, Chandan; Hauer-Jensen, Martin; Boerma, Marjan

    2013-07-01

    Radiation-induced heart disease (RIHD) is a serious side-effect of thoracic radiotherapy. The epidermal growth factor receptor (EGFR) pathway is essential for the function and survival of cardiomyocytes. Hence, agents that target the EGFR pathway are cardiotoxic. Tocotrienols protect from radiation injury, but may also enhance the therapeutic effects of EGFR pathway inhibitors in cancer treatment. This study investigated the effects of local irradiation on the EGFR pathway in the heart and tests whether tocotrienols may modify radiation-induced changes in this pathway. Male Sprague-Dawley rats received image-guided localized heart irradiation with 21 Gy. Twenty four hours before irradiation, rats received a single dose of tocotrienol-enriched formulation or vehicle by oral gavage. At time points from 2 h to 9 months after irradiation, left ventricular expression of EGFR pathway mediators was studied. Irradiation caused a decrease in the expression of epidermal growth factor (EGF) and neuregulin-1 (Nrg-1) mRNA from 6 h up to 10 weeks, followed by an upregulation of these ligands and the receptor erythroblastic leukemia viral oncogene homolog (ErbB)4 at 6 months. In addition, the upregulation of Nrg-1 was statistically significant up to 9 months after irradiation. A long-term upregulation of ErbB2 protein did not coincide with changes in transcription or post-translational interaction with the chaperone heat shock protein 90 (HSP90). Pretreatment with tocotrienols prevented radiation-induced changes at 2 weeks. Local heart irradiation causes long-term changes in the EGFR pathway. Studies have to address how radiation may interact with cardiotoxic effects of EGFR inhibitors.

  10. Somatostatin receptors

    DEFF Research Database (Denmark)

    Møller, Lars Neisig; Stidsen, Carsten Enggaard; Hartmann, Bolette

    2003-01-01

    therefore been acknowledged to be a third endogenous ligand at SRIF receptors. This review goes through mechanisms of signal transduction, pharmacology, and anatomical distribution of SRIF receptors. Structurally, SRIF receptors belong to the superfamily of G protein-coupled (GPC) receptors, sharing....... The generation of knock-out (KO) mice, intended as a means to define the contributions made by individual receptor subtypes, necessarily marks but an approximation. Furthermore, we must now take into account the stunning complexity of receptor co-operation indicated by the observation of receptor homo......-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype...

  11. Adenosine receptor neurobiology: overview.

    Science.gov (United States)

    Chen, Jiang-Fan; Lee, Chien-fei; Chern, Yijuang

    2014-01-01

    Adenosine is a naturally occurring nucleoside that is distributed ubiquitously throughout the body as a metabolic intermediary. In the brain, adenosine functions as an important upstream neuromodulator of a broad spectrum of neurotransmitters, receptors, and signaling pathways. By acting through four G-protein-coupled receptors, adenosine contributes critically to homeostasis and neuromodulatory control of a variety of normal and abnormal brain functions, ranging from synaptic plasticity, to cognition, to sleep, to motor activity to neuroinflammation, and cell death. This review begun with an overview of the gene and genome structure and the expression pattern of adenosine receptors (ARs). We feature several new developments over the past decade in our understanding of AR functions in the brain, with special focus on the identification and characterization of canonical and noncanonical signaling pathways of ARs. We provide an update on functional insights from complementary genetic-knockout and pharmacological studies on the AR control of various brain functions. We also highlight several novel and recent developments of AR neurobiology, including (i) recent breakthrough in high resolution of three-dimension structure of adenosine A2A receptors (A2ARs) in several functional status, (ii) receptor-receptor heterodimerization, (iii) AR function in glial cells, and (iv) the druggability of AR. We concluded the review with the contention that these new developments extend and strengthen the support for A1 and A2ARs in brain as therapeutic targets for neurologic and psychiatric diseases. © 2014 Elsevier Inc. All rights reserved.

  12. Genistein inhibits the proliferation of human HER2-positive cancer cells by downregulating HER2 receptor

    Directory of Open Access Journals (Sweden)

    Guodong Shen

    2013-07-01

    Full Text Available Functional Foods in Health and Disease 2013; 3(7:291-299Research Article Open AccessGenistein inhibits the proliferation of human HER2-positive cancer cells by downregulating HER2 receptorGuodong Shen, Haiying Yu, Geng Bian, Min Gao, Lingqing Liu, Min Cheng, Gan Shen, Shilian HuGeriatrics Department, Gerontology Institute, Anhui Provincial Hospital; Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei 230001, ChinaCorresponding Author: Shilian Hu, Department of Geriatrics, Anhui Provincial Hospital, No. 17 Lujiang Road, Hefei 230001, China Submission date: June 9, 2013; Acceptance date: July 19, 2013; Publication date: July 20, 2013ABSTRACTBackground: It was well studied that HER2/ErbB2/p185 overexpression in human malignant cancers correlates with poor prognosis and chemo-resistance. Meanwhile, Genistein (4,5,7-trihydroxyisoflavone, a major isoflavone component of soybeans and other leguminous plants, has been shown to exhibit a potent anti-proliferative effect on some sex hormone dependent cancers. Objective: The effects of genistein on the proliferation of human HER2-overexpressing breast and ovarian cancer cell lines were investigated, and the action mechanism was explored.Methods: Western blotting, fluorescence-activated cell sorting (FACS and immunofluorescence methods, cell proliferation assay kit from Promega and cell apoptosis assay kit from Biolegend were used. The dose- or time-response relationship of genistein were observed on the HER2-negative breast cancer cell line MCF-7 or HER2-positive breast cancer cell lines BT-474 and MCF-7/Her2 derived from MCF-7, and ovarian cancer cell line SKOV-3.Results: The addition of genistein ranged from 1-10g/ml in the medium for 48 hours had a marked inhibition on the proliferation of HER2-positive cancer cell lines MCF-7/Her2, BT-474 and SKOV-3, compared with tamoxifen and DMSO control (P<0.01, and a dose-dependent response was presented. However, genistein

  13. Somatostatin receptors

    DEFF Research Database (Denmark)

    Møller, Lars Neisig; Stidsen, Carsten Enggaard; Hartmann, Bolette

    2003-01-01

    therefore been acknowledged to be a third endogenous ligand at SRIF receptors. This review goes through mechanisms of signal transduction, pharmacology, and anatomical distribution of SRIF receptors. Structurally, SRIF receptors belong to the superfamily of G protein-coupled (GPC) receptors, sharing......- and heterodimerisation, let alone oligomerisation. Theoretically, this phenomenon adds a novel series of functional megareceptors/super-receptors, with varied pharmacological profiles, to the catalogue of monomeric receptor subtypes isolated and cloned in the past. SRIF analogues include both peptides and non......-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype...

  14. Treatment pattern by hormone receptors and HER2 status in patients with metastatic breast cancer in the UK, Germany, France, Spain and Italy (EU-5): results from a physician survey.

    Science.gov (United States)

    DeKoven, Mitch; Bonthapally, Vijayveer; Jiao, Xiaolong; Ganguli, Arijit; Pathak, Prathamesh; Lee, Won Chan; Ray, Saurabh

    2012-09-01

    The differences in country-specific treatment patterns across Europe for metastatic breast cancer (mBC) patients have not been extensively studied. This study compared the treatment choices in aggregate, as well as by biomarker status, between various lines of therapy in clinical practice in the EU-5 countries among newly diagnosed mBC patients. The IMS LifeLink™ Oncology Analyzer database, based on surveys of practicing oncologists, was used to identify mBC patients aged ≥21 years. In this database, sample-level data are projected to national-level estimates for each country using a sample projection technique. The prevalence of hormone receptors (71-74%) is quite similar across different countries, while HER2 overexpression varies from 22 (France) to 34% (Italy); chemotherapy combined with HER2-targeted medicine was the mainstay of treatment for HER2(+) patients. The use of HER2-targeted medicine and bevacizumab greatly varied: while they were most frequently used in France, they were least frequently used in the UK. Fewer treatment options existed for triple-negative patients and patients with HER2(+) disease following trastuzumab treatment. Chemotherapy was the treatment choice for triple-negative patients, as these patients do not respond to hormonal therapy and HER2-targeted medicine. This study found that, while a trastuzumab-based regimen is the preferred option for treating HER2(+) mBC patients in the EU-5, variations in this personalized medicine approach exist between different EU-5 countries. However, fewer treatment options exist for triple-negative and HER2(+) patients after trastuzumab treatment, highlighting the unmet need for these patient subgroups.

  15. LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling

    NARCIS (Netherlands)

    J. Chang (Jufang); M.M. Nicolau (Monica); T.R. Cox (Thomas); D. Wetterskog (Daniel); J.W.M. Martens (John); H. E Barker (Holly); J.T. Erler (Janine)

    2013-01-01

    textabstractIntroduction: Lysyl oxidase-like 2 (LOXL2) is a matrix-remodeling enzyme that has been shown to play a key role in invasion and metastasis of breast carcinoma cells. However, very little is known about its role in normal tissue homeostasis. Here, we investigated the effects of LOXL2

  16. LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling

    DEFF Research Database (Denmark)

    Chang, Joan; Nicolau, Monica; Cox, Thomas R

    2013-01-01

    Lysyl oxidase-like 2 (LOXL2) is a matrix remodeling enzyme that has been shown to play a key role in invasion and metastasis of breast carcinoma cells. However, very little is known about its role in normal tissue homeostasis. Here, we investigate the effects of LOXL2 expression in normal mammary...

  17. Erbb2 Is Required for Cardiac Atrial Electrical Activity during Development

    Czech Academy of Sciences Publication Activity Database

    Tenin, G.; Clowes, Ch.; Wolton, K.; Krejčí, Eliška; Wright, J. A.; Lovell, S. C.; Sedmera, David; Hentges, K. E.

    2014-01-01

    Roč. 9, č. 9 (2014), e107041 E-ISSN 1932-6203 R&D Projects: GA ČR(CZ) GA13-12412S; GA ČR(CZ) GAP302/11/1308 Institutional support: RVO:67985823 Keywords : mouse * embryo * atrium * conduction * optical mapping * ENU mutagenesis Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 3.234, year: 2014

  18. Role of Stat3 and ErbB2 in Breast Cancer

    Science.gov (United States)

    2013-12-01

    leads to loss of G(1) control and immortalization . Genes Dev 14: 3037-3050, 2000. 12 Klinghoffer RA, Sachsenmaier C, Cooper JA and Soriano P: Src family...are a subfamily of the Ras superfamily which are highly conserved from lower eucaryotes to plants and mammals [7]. They differ from other members of the

  19. ERbB2 Trafficking and Signaling in Human Vestibular Schwannomas

    Science.gov (United States)

    2011-10-01

    anti-actin (1:5,000 Ab-5; BD Biosciences, Mississauga, ON, Canada), and antiYNF-2/schwannomin/merlin (1:10,000, sc- 331; Santa Cruz Biotechnology...Santa Cruz , CA, USA). All blots were washed and then treated with either goat antimouse or goat antirabbit horseradish peroxidaseYconjugated antibody at...Neuregulin-1 proteins in rat brain and trans- fected cells are localized to lipid rafts. J Neurochem 2001;77: 1Y12. 20. Stickney JT, Bacon WC, Rojas M

  20. Role of Stat3 and ErbB2 in Breast Cancer

    Science.gov (United States)

    2011-10-01

    human papilloma viruses 16 and 18 have been implicated in the development of epithelial malignancies, especially cancer of the uterine cervix and other... Cancer Institute, Queen’s University, Botterell Hall, Rm. 713, Kingston, Ontario, Canada K7L 3N6 b Université Bordeaux 1, Centre de Recherche Paul Pascal...demonstrated in breast and other cancers , while a constitutively active form of Stat3, Stat3C, is able to transform cultured cells3 , further pointing to an

  1. The Effects of Bisphenol A (BPA) on ErbB2 Positive Breast Cancer

    Science.gov (United States)

    2010-11-01

    canned fruits, vegetables, and meat products, condensed and infant milk, canned sodas and juice, cardboard milk and juice containers, plastic food... xenobiotics impact preadolescents and onset of puberty or menarche is uncertain, given the paucity of longitudinal studies. Perinatal exposure to 250...Lamartiniere CA SC, Clark J, Tilson HA, Lucier GW. Organizational effects of hormonally-active xenobiotics on postnatal development. Dayton, Ohio: U.S

  2. Redirected Primary Human Chimeric Antigen Receptor Natural Killer Cells As an “Off-the-Shelf Immunotherapy” for Improvement in Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Olaf Oberschmidt

    2017-06-01

    Full Text Available Primary human natural killer (NK cells recognize and subsequently eliminate virus infected cells, tumor cells, or other aberrant cells. However, cancer cells are able to develop tumor immune escape mechanisms to undermine this immune control. To overcome this obstacle, NK cells can be genetically modified to express chimeric antigen receptors (CARs in order to improve specific recognition of cancer surface markers (e.g., CD19, CD20, and ErbB2. After target recognition, intracellular CAR domain signaling (CD3ζ, CD28, 4-1BB, and 2B4 leads to activation of PI3K or DNAX proteins (DAP10, DAP12 and finally to enhanced cytotoxicity, proliferation, and/or interferon γ release. This mini-review summarizes both the first preclinical trials with CAR-engineered primary human NK cells and the translational implications for “off-the-shelf immunotherapy” in cancer treatment. Signal transduction in NK cells as well as optimization of CAR signaling will be described, becoming more and more a focal point of interest in addition to redirected T cells. Finally, strategies to overcome off-target effects will be discussed in order to improve future clinical trials and to avoid attacking healthy tissues.

  3. Receptor Status and Associated Clinico- Histopathological ...

    African Journals Online (AJOL)

    7. 6. 6. 32. 28. *Other cancers included cancer cervix (5) cancer oesophagus (4) hepatocellular cancer (2) cancer colon (2). †missing values 75 ... Table 3: Distribution of clinical- histopathological characteristics associated with triple negative breast cancer. Clinico-histopathological. Characteristics. Triple.

  4. Maintenance of Epithelial Stem Cells by Cbl Proteins

    Science.gov (United States)

    2012-09-01

    Sarkisian CJ, Portocarrero CP, Sterner CJ, et al. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell. 2005;8:197–209...ErbB2 protein levels, patient selection typically involves assessment of the ErbB2 status by fluorescent or chromogenic in situ hybridization (FISH/CISH

  5. Collagen Type I Selectively Activates Ectodomain Shedding of the Discoidin Domain Receptor 1: Involvement of Src Tyrosine Kinase

    Science.gov (United States)

    Slack, Barbara E.; Siniaia, Marina S.; Blusztajn, Jan K.

    2008-01-01

    The discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that is highly expressed in breast carcinoma cells. Upon binding to collagen, DDR1 undergoes autophosphorylation followed by limited proteolysis to generate a tyrosine phosphorylated C-terminal fragment (CTF). Although it was postulated that this fragment is formed as a result of shedding of the N-terminal ectodomain, collagen-dependent release of the DDR1 extracellular domain has not been demonstrated. We now report that, in conjunction with CTF formation, collagen type I stimulates concentration-dependent, saturable shedding of the DDR1 ectodomain from two carcinoma cell lines, and from transfected cells. In contrast, collagen did not promote cleavage of other transmembrane proteins including the amyloid precursor protein (APP), ErbB2, and E-cadherin. Collagen-dependent tyrosine phosphorylation and proteolysis of DDR1 in carcinoma cells were reduced by a pharmacologic Src inhibitor. Moreover, expression of a dominant negative Src mutant protein in human embryonic kidney cells inhibited collagen-dependent phosphorylation and shedding of co-transfected DDR1. The hydroxamate-based metalloproteinase inhibitor TAPI-1 (tumor necrosis factor-α protease inhibitor-1), and tissue inhibitor of metalloproteinase (TIMP)-3, also blocked collagen-evoked DDR1 shedding, but did not reduce levels of the phosphorylated CTF. Neither shedding nor CTF formation were affected by the γ-secretase inhibitor, L-685,458. The results demonstrate that collagen-evoked ectodomain cleavage of DDR1 is mediated in part by Src-dependent activation or recruitment of a matrix- or disintegrin metalloproteinase, and that CTF formation can occur independently of ectodomain shedding. Delayed shedding of the DDR1 ectodomain may represent a mechanism that limits DDR1-dependent cell adhesion and migration on collagen matrices. PMID:16440311

  6. Molecular imaging of estrogen receptors

    NARCIS (Netherlands)

    van Kruchten, Michel

    2015-01-01

    For patients with estrogen receptor (ER) positive breast cancer, endocrine therapy plays a major role in both the adjuvant and palliative setting. For adequate treatment decision-making it is crucial to obtain up-to-date information on the ER-status of the tumor(s), since ER-expression is the sole

  7. Hormone receptor expression in male breast cancers | Akosa ...

    African Journals Online (AJOL)

    Male breast cancers are rare but have been found in higher proportions in Black Africans. Prognostic factors for breast cancers include tumour size, grade and stage, and hormone receptor status. The hormone receptor status is an invaluable guide in the use of adjuvant endocrine therapy, but none of the reports available ...

  8. The combination of Ki67, histological grade and estrogen receptor status identifies a low-risk group among 1,854 chemo-naïve women with N0/N1 primary breast cancer

    DEFF Research Database (Denmark)

    Strand, Carina; Bak, Martin; Borgquist, Signe

    2013-01-01

    The aim was to confirm a previously defined prognostic index, combining a proliferation marker, histological grade, and estrogen receptor (ER) in different subsets of primary N0/N1 chemo-naïve breast cancer patients.......The aim was to confirm a previously defined prognostic index, combining a proliferation marker, histological grade, and estrogen receptor (ER) in different subsets of primary N0/N1 chemo-naïve breast cancer patients....

  9. Status epilepticus

    NARCIS (Netherlands)

    Hensiek, AE; Absalom, Anthony

    2006-01-01

    Status epilepticus is defined as epileptic activity that continues for more than 30 minutes as a single seizure or as recurrent seizures without inter-ictal return of consciousness. The seizure activity is usually classified as partial or generalized. Although status epilepticus is an uncommon

  10. Characterization of MCF mammary epithelial cells overexpressing the Arylhydrocarbon receptor (AhR)

    International Nuclear Information System (INIS)

    Wong, Patrick S; Li, Wen; Vogel, Christoph F; Matsumura, Fumio

    2009-01-01

    Recent reports indicate the existence of breast cancer cells expressing very high levels of the Arylhydrocarbon receptor (AhR), a ubiquitous intracellular receptor best known for mediating toxic action of dioxin and related pollutants. Positive correlation between the degree of AhR overexpression and states of increasing transformation of mammary epithelial cells appears to occur in the absence of any exogenous AhR ligands. These observations have raised many questions such as why and how AhR is overexpressed in breast cancer and its physiological roles in the progression to advanced carcinogenic transformation. To address those questions, we hypothesized that AhR overexpression occurs in cells experiencing deficiencies in normally required estrogen receptor (ER) signaling, and the basic role of AhR in such cases is to guide the affected cells to develop orchestrated cellular changes aimed at substituting the normal functions of ER. At the same time, the AhR serves as the mediator of the cell survival program in the absence of ER signaling. We subjected two lines of Michigan Cancer Foundation (MCF) mammary epithelial cells to 3 different types ER interacting agents for a number of passages and followed the changes in the expression of AhR mRNA. The resulting sublines were analyzed for phenotypical changes and unique molecular characteristics. MCF10AT1 cells continuously exposed to 17-beta-estradiol (E2) developed sub-lines that show AhR overexpression with the characteristic phenotype of increased proliferation, and distinct resistance to apoptosis. When these chemically selected cell lines were treated with a specific AhR antagonist, 3-methoxy-4-nitroflavone (MNF), both of the above abnormal cellular characteristics disappeared, indicating the pivotal role of AhR in expressing those cellular phenotypes. The most prominent molecular characteristics of these AhR overexpressing MCF cells were found to be overexpression of ErbB2 and COX-2. Furthermore, we could

  11. Glutamate receptors

    DEFF Research Database (Denmark)

    Kristensen, Anders S; Geballe, Matthew T; Snyder, James P

    2006-01-01

    Fast excitatory synaptic transmission in the CNS relies almost entirely on the neurotransmitter glutamate and its family of ion channel receptors. An appreciation of the coupling between agonist binding and channel opening has advanced rapidly during the past five years, largely as a result of ne...

  12. Stock Status

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — These data inform the public of the most recent stock status for all stocks (FSSI and non-FSSI) in the fishery management unit contained in a fishery managment plan....

  13. STATUS REPORT

    Indian Academy of Sciences (India)

    First page Back Continue Last page Graphics. STATUS REPORT. Raman scattering observed – 90, 135, 180 degrees and back scattering. Traditionally specific angle dependence to learn about polarization response. Learn molecular information from the surface or materials just below the surface (upto 12 mm depth) ...

  14. Compliance status

    International Nuclear Information System (INIS)

    Black, D.G.

    1995-01-01

    This section of the 1994 Hanford Site Environmental Report summarizes the activities conducted to ensure that the Hanford Site is in compliance with federal environmental protection statutes and related Washington State and local environmental protection regulations and the status of Hanford's compliance with these requirements. Environmental permits required under the environmental protection regulations are discussed under the applicable statute

  15. New factors influencing G protein coupled receptors' system functions

    African Journals Online (AJOL)

    New factors such as the G protein coupled receptor (GPCR) surrounding's chemical environment, cell membrane constituents, the existent gap junction, endogenous receptor affinity status and animal species have been shown to influence the GPCR physiology and variations of those factors can modify the functions of the ...

  16. G1 cell cycle arrest due to the inhibition of erbB family receptor tyrosine kinases does not require the retinoblastoma protein

    International Nuclear Information System (INIS)

    Gonzales, Andrea J.; Fry, David W.

    2005-01-01

    The erbB receptor family (EGFr, erbB-2, erbB-3, and erbB-4) consists of transmembrane glycoproteins that transduce extracellular signals to the nucleus when activated. erbB family members are widely expressed in epithelial, mesenchymal, and neuronal cells and contribute to the proliferation, differentiation, migration, and survival of these cell types. The present study evaluates the effects of erbB family signaling on cell cycle progression and the role that pRB plays in regulating this process. ErbB family RTK activity was inhibited by PD 158780 in the breast epithelial cell line MCF10A. PD 158780 (0.5 μM) inhibited EGF-stimulated and heregulin-stimulated autophosphorylation and caused a G1 cell cycle arrest within 24 h, which correlated with hypophosporylation of pRB. MCF10A cells lacking functional pRB retained the ability to arrest in G1 when treated with PD 158780. Both cell lines showed induction of p27 KIP1 protein when treated with PD 158780 and increased association of p27 KIP1 with cyclin E-CDK2. Furthermore, CDK2 kinase activity was dramatically inhibited with drug treatment. Changes in other pRB family members were noted with drug treatment, namely a decrease in p107 and an increase in p130. These findings show that the G1 arrest induced through inhibition of erbB family RTK activity does not require functional pRB

  17. Multi-institutional Oncogenic Driver Mutation Analysis in Lung Adenocarcinoma: The Lung Cancer Mutation Consortium Experience.

    Science.gov (United States)

    Sholl, Lynette M; Aisner, Dara L; Varella-Garcia, Marileila; Berry, Lynne D; Dias-Santagata, Dora; Wistuba, Ignacio I; Chen, Heidi; Fujimoto, Junya; Kugler, Kelly; Franklin, Wilbur A; Iafrate, A John; Ladanyi, Marc; Kris, Mark G; Johnson, Bruce E; Bunn, Paul A; Minna, John D; Kwiatkowski, David J

    2015-05-01

    Molecular genetic analyses of lung adenocarcinoma have recently become standard of care for treatment selection. The Lung Cancer Mutation Consortium was formed to enable collaborative multi-institutional analyses of 10 potential oncogenic driver mutations. Technical aspects of testing and clinicopathologic correlations are presented. Mutation testing in at least one of the eight genes (epidermal growth factor receptor [EGFR], KRAS, ERBB2, AKT1, BRAF, MEK1, NRAS, and PIK3CA) using SNaPshot, mass spectrometry, Sanger sequencing+/- peptide nucleic acid and/or sizing assays, along with anaplastic lymphoma kinase (ALK) and/or MET fluorescence in situ hybridization, were performed in six labs on 1007 patients from 14 institutions. In all, 1007 specimens had mutation analysis performed, and 733 specimens had all 10 genes analyzed. Mutation identification rates did not vary by analytic method. Biopsy and cytology specimens were inadequate for testing in 26% and 35% of cases compared with 5% of surgical specimens. Among the 1007 cases with mutation analysis performed, EGFR, KRAS, ALK, and ERBB2 alterations were detected in 22%, 25%, 8.5%, and 2.4% of cases, respectively. EGFR mutations were highly associated with female sex, Asian race, and never-smoking status; and less strongly associated with stage IV disease, presence of bone metastases, and absence of adrenal metastases. ALK rearrangements were strongly associated with never-smoking status and more weakly associated with presence of liver metastases. ERBB2 mutations were strongly associated with Asian race and never-smoking status. Two mutations were seen in 2.7% of samples, all but one of which involved one or more of PIK3CA, ALK, or MET. Multi-institutional molecular analysis across multiple platforms, sample types, and institutions can yield consistent results and novel clinicopathological observations.

  18. Evaluation of Human Epidermal Growth Factor Receptor 2 (HER2) Gene Status in Human Breast Cancer Formalin-Fixed Paraffin-Embedded (FFPE) Tissue Specimens by Fluorescence In Situ Hybridization (FISH).

    Science.gov (United States)

    Hwang, Harry C; Gown, Allen M

    2016-01-01

    Current standard of care requires that HER2 gene testing be performed on all newly diagnosed invasive breast cancers in order to determine eligibility for anti-HER2 antibody therapy and should be performed in accordance with current ASCO-CAP guidelines (Hammond et al., J Clin Oncol 29(15):e458, 2011; Wolff et al., J Clin Oncol 31(31):3997-4013, 2013). Here we describe a HER2 FISH methodology to evaluate HER2 gene status in FFPE breast tumor specimens.

  19. Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5–CHRNA3–CHRNB4) interacts with maternal self-reported smoking status during pregnancy to influence birth weight

    Science.gov (United States)

    Tyrrell, Jessica; Huikari, Ville; Christie, Jennifer T.; Cavadino, Alana; Bakker, Rachel; Brion, Marie-Jo A.; Geller, Frank; Paternoster, Lavinia; Myhre, Ronny; Potter, Catherine; Johnson, Paul C.D.; Ebrahim, Shah; Feenstra, Bjarke; Hartikainen, Anna-Liisa; Hattersley, Andrew T.; Hofman, Albert; Kaakinen, Marika; Lowe, Lynn P.; Magnus, Per; McConnachie, Alex; Melbye, Mads; Ng, Jane W.Y.; Nohr, Ellen A.; Power, Chris; Ring, Susan M.; Sebert, Sylvain P.; Sengpiel, Verena; Taal, H. Rob; Watt, Graham C.M.; Sattar, Naveed; Relton, Caroline L.; Jacobsson, Bo; Frayling, Timothy M.; Sørensen, Thorkild I.A.; Murray, Jeffrey C.; Lawlor, Debbie A.; Pennell, Craig E.; Jaddoe, Vincent W.V.; Hypponen, Elina; Lowe, William L.; Jarvelin, Marjo-Riitta; Davey Smith, George; Freathy, Rachel M.

    2012-01-01

    Maternal smoking during pregnancy is associated with low birth weight. Common variation at rs1051730 is robustly associated with smoking quantity and was recently shown to influence smoking cessation during pregnancy, but its influence on birth weight is not clear. We aimed to investigate the association between this variant and birth weight of term, singleton offspring in a well-powered meta-analysis. We stratified 26 241 European origin study participants by smoking status (women who smoked during pregnancy versus women who did not smoke during pregnancy) and, in each stratum, analysed the association between maternal rs1051730 genotype and offspring birth weight. There was evidence of interaction between genotype and smoking (P = 0.007). In women who smoked during pregnancy, each additional smoking-related T-allele was associated with a 20 g [95% confidence interval (95% CI): 4–36 g] lower birth weight (P = 0.014). However, in women who did not smoke during pregnancy, the effect size estimate was 5 g per T-allele (95% CI: −4 to 14 g; P = 0.268). To conclude, smoking status during pregnancy modifies the association between maternal rs1051730 genotype and offspring birth weight. This strengthens the evidence that smoking during pregnancy is causally related to lower offspring birth weight and suggests that population interventions that effectively reduce smoking in pregnant women would result in a reduced prevalence of low birth weight. PMID:22956269

  20. ROR nuclear receptors: structures, related diseases, and drug discovery.

    Science.gov (United States)

    Zhang, Yan; Luo, Xiao-yu; Wu, Dong-hai; Xu, Yong

    2015-01-01

    Nuclear receptors (NRs) are ligand-regulated transcription factors that regulate metabolism, development and immunity. The NR superfamily is one of the major classes of drug targets for human diseases. Retinoic acid receptor-related orphan receptor (ROR) α, β and γ belong to the NR superfamily, and these receptors are still considered as 'orphan' receptors because the identification of their endogenous ligands has been controversial. Recent studies have demonstrated that these receptors are regulated by synthetic ligands, thus emerge as important drug targets for the treatment of multiple sclerosis, rheumatoid arthritis, psoriasis, etc. Studying the structural basis and ligand development of RORs will pave the way for a better understanding of the roles of these receptors in human diseases. Here, we review the structural basis, disease relevance, strategies for ligand identification, and current status of development of therapeutic ligands for RORs.

  1. Transcriptional profiling of ErbB signalling in mammary luminal epithelial cells - interplay of ErbB and IGF1 signalling through IGFBP3 regulation

    Directory of Open Access Journals (Sweden)

    Worthington Jenny

    2010-09-01

    Full Text Available Abstract Background Members of the ErbB family of growth factor receptors are intricately linked with epithelial cell biology, development and tumourigenesis; however, the mechanisms involved in their downstream signalling are poorly understood. Indeed, it is unclear how signal specificity is achieved and the relative contribution each receptor has to specific gene expression. Methods Gene expression profiling of a human mammary luminal epithelial cell model of ErbB2-overexpression was carried out using cDNA microarrays with a common RNA reference approach to examine long-term overlapping and differential responses to EGF and heregulin beta1 treatment in the context of ErbB2 overexpression. Altered gene expression was validated using quantitative real time PCR and/or immunoblotting. One gene of interest was targeted for further characterisation, where the effects of siRNA-mediated silencing on IGF1-dependent signalling and cellular phenotype were examined and compared to the effects of loss of ErbB2 expression. Results 775 genes were differentially expressed and clustered in terms of their growth factor responsiveness. As well as identifying uncharacterized genes as novel targets of ErbB2-dependent signalling, ErbB2 overexpression augmented the induction of multiple genes involved in proliferation (e.g. MYC, MAP2K1, MAP2K3, autocrine growth factor signalling (VEGF, PDGF and adhesion/cytoskeletal regulation (ZYX, THBS1, VCL, CNN3, ITGA2, ITGA3, NEDD9, TAGLN, linking them to the hyper-poliferative and altered adhesive phenotype of the ErbB2-overexpressing cells. We also report ErbB2-dependent down-regulation of multiple interferon-stimulated genes that may permit ErbB2-overexpressing cells to resist the anti-proliferative action of interferons. Finally, IGFBP3 was unique in its pattern of regulation and we further investigated a possible role for IGFBP3 down-regulation in ErbB2-dependent transformation through suppressed IGF1 signalling. We show

  2. Transcriptional profiling of ErbB signalling in mammary luminal epithelial cells - interplay of ErbB and IGF1 signalling through IGFBP3 regulation

    International Nuclear Information System (INIS)

    Worthington, Jenny; Bertani, Mariana; Chan, Hong-Lin; Gerrits, Bertran; Timms, John F

    2010-01-01

    Members of the ErbB family of growth factor receptors are intricately linked with epithelial cell biology, development and tumourigenesis; however, the mechanisms involved in their downstream signalling are poorly understood. Indeed, it is unclear how signal specificity is achieved and the relative contribution each receptor has to specific gene expression. Gene expression profiling of a human mammary luminal epithelial cell model of ErbB2-overexpression was carried out using cDNA microarrays with a common RNA reference approach to examine long-term overlapping and differential responses to EGF and heregulin beta1 treatment in the context of ErbB2 overexpression. Altered gene expression was validated using quantitative real time PCR and/or immunoblotting. One gene of interest was targeted for further characterisation, where the effects of siRNA-mediated silencing on IGF1-dependent signalling and cellular phenotype were examined and compared to the effects of loss of ErbB2 expression. 775 genes were differentially expressed and clustered in terms of their growth factor responsiveness. As well as identifying uncharacterized genes as novel targets of ErbB2-dependent signalling, ErbB2 overexpression augmented the induction of multiple genes involved in proliferation (e.g. MYC, MAP2K1, MAP2K3), autocrine growth factor signalling (VEGF, PDGF) and adhesion/cytoskeletal regulation (ZYX, THBS1, VCL, CNN3, ITGA2, ITGA3, NEDD9, TAGLN), linking them to the hyper-poliferative and altered adhesive phenotype of the ErbB2-overexpressing cells. We also report ErbB2-dependent down-regulation of multiple interferon-stimulated genes that may permit ErbB2-overexpressing cells to resist the anti-proliferative action of interferons. Finally, IGFBP3 was unique in its pattern of regulation and we further investigated a possible role for IGFBP3 down-regulation in ErbB2-dependent transformation through suppressed IGF1 signalling. We show that IGF1-dependent signalling and proliferation were

  3. Hybrid capture-based genomic profiling of circulating tumor DNA from patients with estrogen receptor-positive metastatic breast cancer.

    Science.gov (United States)

    Chung, J H; Pavlick, D; Hartmaier, R; Schrock, A B; Young, L; Forcier, B; Ye, P; Levin, M K; Goldberg, M; Burris, H; Gay, L M; Hoffman, A D; Stephens, P J; Frampton, G M; Lipson, D M; Nguyen, D M; Ganesan, S; Park, B H; Vahdat, L T; Leyland-Jones, B; Mughal, T I; Pusztai, L; O'Shaughnessy, J; Miller, V A; Ross, J S; Ali, S M

    2017-11-01

    Genomic changes that occur in breast cancer during the course of disease have been informed by sequencing of primary and metastatic tumor tissue. For patients with relapsed and metastatic disease, evolution of the breast cancer genome highlights the importance of using a recent sample for genomic profiling to guide clinical decision-making. Obtaining a metastatic tissue biopsy can be challenging, and analysis of circulating tumor DNA (ctDNA) from blood may provide a minimally invasive alternative. Hybrid capture-based genomic profiling was carried out on ctDNA from 254 female patients with estrogen receptor-positive breast cancer. Peripheral blood samples were submitted by clinicians in the course of routine clinical care between May 2016 and March 2017. Sequencing of 62 genes was carried out to a median unique coverage depth of 7503×. Genomic alterations (GAs) in ctDNA were evaluated and compared with matched tissue samples and genomic datasets of tissue from breast cancer. At least 1 GA was reported in 78% of samples. Frequently altered genes were TP53 (38%), ESR1 (31%) and PIK3CA (31%). Temporally matched ctDNA and tissue samples were available for 14 patients; 89% of mutations detected in tissue were also detected in ctDNA. Diverse ESR1 GAs including mutation, rearrangement and amplification, were observed. Multiple concurrent ESR1 GAs were observed in 40% of ESR1-altered cases, suggesting polyclonal origin; ESR1 compound mutations were also observed in two cases. ESR1-altered cases harbored co-occurring GAs in PIK3CA (35%), FGFR1 (16%), ERBB2 (8%), BRCA1/2 (5%), and AKT1 (4%). GAs relevant to relapsed/metastatic breast cancer management were identified, including diverse ESR1 GAs. Genomic profiling of ctDNA demonstrated sensitive detection of mutations found in tissue. Detection of amplifications was associated with ctDNA fraction. Genomic profiling of ctDNA may provide a complementary and possibly alternative approach to tissue-based genomic testing for

  4. Interaction of growth hormone receptor/binding protein gene disruption and caloric restriction for insulin sensitivity and attenuated aging [v2; ref status: indexed, http://f1000r.es/5a7

    Directory of Open Access Journals (Sweden)

    Oge Arum

    2015-04-01

    Full Text Available The correlation of physiological sensitivity to insulin (vis-à-vis glycemic regulation and longevity is extensively established, creating a justifiable gerontological interest on whether insulin sensitivity is causative, or even predictive, of some or all phenotypes of slowed senescence (including longevity. The growth hormone receptor/ binding protein gene-disrupted (GHR-KO mouse is the most extensively investigated insulin-sensitive, attenuated aging model. It was reported that, in a manner divergent from similar mutants, GHR-KO mice fail to respond to caloric restriction (CR by altering their insulin sensitivity. We hypothesized that maximized insulin responsiveness is what causes GHR-KO mice to exhibit a suppressed survivorship response to dietary (including caloric restriction; and attempted to refute this hypothesis by assessing the effects of CR on GHR-KO mice for varied slow-aging-associated phenotypes. In contrast to previous reports, we found GHR-KO mice on CR to be less responsive than their ad libitum (A.L. counterparts to the hypoglycemia-inducing effects of insulin. Further, CR had negligible effects on the metabolism or cognition of GHR-KO mice. Therefore, our data suggest that the effects of CR on the insulin sensitivity of GHR-KO mice do not concur with the effects of CR on the aging of GHR-KO mice.

  5. Interaction of growth hormone receptor/binding protein gene disruption and caloric restriction for insulin sensitivity and attenuated aging [v1; ref status: indexed, http://f1000r.es/4fk

    Directory of Open Access Journals (Sweden)

    Oge Arum

    2014-10-01

    Full Text Available The correlation of physiological sensitivity to insulin (vis-à-vis glycemic regulation and longevity is extensively established, creating a justifiable gerontological interest on whether insulin sensitivity is causative, or even predictive, of some or all phenotypes of slowed senescence (including longevity. The growth hormone receptor/ binding protein gene-disrupted (GHR-KO mouse is the most extensively investigated insulin-sensitive, attenuated aging model. It was reported that, in a manner divergent from similar mutants, GHR-KO mice fail to respond to caloric restriction (CR by altering their insulin sensitivity. We hypothesized that maximized insulin responsiveness is what causes GHR-KO mice to exhibit a suppressed survivorship response to dietary (including caloric restriction; and attempted to refute this hypothesis by assessing the effects of CR on GHR-KO mice for varied slow-aging-associated phenotypes. In contrast to previous reports, we found GHR-KO mice on CR to be less responsive than their ad libitum (A.L. counterparts to the hypoglycemia-inducing effects of insulin. Further, CR had negligible effects on the metabolism or cognition of GHR-KO mice. Therefore, our data suggest that the effects of CR on the insulin sensitivity of GHR-KO mice do not concur with the effects of CR on the aging of GHR-KO mice.

  6. Positive or negative allosteric modulation of metabotropic glutamate receptor 5 (mGluR5 does not alter expression of behavioral sensitization to methamphetamine [v1; ref status: indexed, http://f1000r.es/o0

    Directory of Open Access Journals (Sweden)

    Peter R Kufahl

    2013-03-01

    Full Text Available We investigated the role of metabotropic glutamate receptor type 5 (mGluR5 in methamphetamine-induced behavioral sensitization. The mGluR5 positive allosteric modulator (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl benzamide (CDPPB and negative allosteric modulator fenobam were tested in separate experiments. Sprague-Dawley rats were repeatedly injected with 1 mg/kg methamphetamine or saline, and then given a locomotor challenge test using a dose of 0.5 mg/kg methamphetamine. Prior to the challenge test session, rats were injected with CDPPB, fenobam, or a vehicle.  Doses from previous studies showed reduced drug-conditioned behavior; however in this study neither CDPPB nor fenobam pretreatment resulted in an altered expression of behavioral sensitization, indicating a lack of mGluR5 involvement in sensitized methamphetamine-induced locomotion. Additionally, the high dose (30 mg/kg of fenobam resulted in decreased methamphetamine-induced locomotion in rats regardless of drug exposure history, which suggests evidence of nonspecific behavioral inhibition.

  7. Promiscuous Seven Transmembrane Receptors Sensing L-α-amino Acids

    DEFF Research Database (Denmark)

    Smajilovic, Sanela; Wellendorph, Petrine; Bräuner-Osborne, Hans

    2014-01-01

    A number of nutrient sensing seven trans-membrane (7TM) receptors have been identified and characterized over the past few years. While the sensing mechanisms to carbohydrates and free fatty acids are well understood, the molecular basis of amino acid sensing has recently come to the limelight. T....... The present review describes the current status of promiscuous L-α-amino acid sensors, the calcium sensing receptor (CaSR), the GPRC6A receptor, the T1R1/T1R3 receptor and also their molecular pharmacology, expression pattern and physiological significance....

  8. Imaging biomarkers predict response to anti-HER2 (ErbB2) therapy in preclinical models of breast cancer.

    Science.gov (United States)

    Shah, Chirayu; Miller, Todd W; Wyatt, Shelby K; McKinley, Eliot T; Olivares, Maria Graciela; Sanchez, Violeta; Nolting, Donald D; Buck, Jason R; Zhao, Ping; Ansari, M Sib; Baldwin, Ronald M; Gore, John C; Schiff, Rachel; Arteaga, Carlos L; Manning, H Charles

    2009-07-15

    To evaluate noninvasive imaging methods as predictive biomarkers of response to trastuzumab in mouse models of HER2-overexpressing breast cancer. The correlation between tumor regression and molecular imaging of apoptosis, glucose metabolism, and cellular proliferation was evaluated longitudinally in responding and nonresponding tumor-bearing cohorts. Mammary tumors from MMTV/HER2 transgenic female mice were transplanted into syngeneic female mice. BT474 human breast carcinoma cell line xenografts were grown in athymic nude mice. Tumor cell apoptosis (NIR700-Annexin V accumulation), glucose metabolism [2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography ([18F]FDG-PET)], and proliferation [3'-[18F]fluoro-3'-deoxythymidine-PET ([18F]FLT-PET)] were evaluated throughout a biweekly trastuzumab regimen. Imaging metrics were validated by direct measurement of tumor size and immunohistochemical analysis of cleaved caspase-3, phosphorylated AKT, and Ki67. NIR700-Annexin V accumulated significantly in trastuzumab-treated MMTV/HER2 and BT474 tumors that ultimately regressed but not in nonresponding or vehicle-treated tumors. Uptake of [18F]FDG was not affected by trastuzumab treatment in MMTV/HER2 or BT474 tumors. [18F]FLT-PET imaging predicted trastuzumab response in BT474 tumors but not in MMTV/HER2 tumors, which exhibited modest uptake of [18F]FLT. Close agreement was observed between imaging metrics and immunohistochemical analysis. Molecular imaging of apoptosis accurately predicts trastuzumab-induced regression of HER2+ tumors and may warrant clinical exploration to predict early response to neoadjuvant trastuzumab. Trastuzumab does not seem to alter glucose metabolism substantially enough to afford [18F]FDG-PET significant predictive value in this setting. Although promising in one preclinical model, further studies are required to determine the overall value of [18F]FLT-PET as a biomarker of response to trastuzumab in HER2+ breast cancer.

  9. Comparative immunohistochemical expression of β-catenin, EGFR, ErbB2, and p63 in adamantinomatous and papillary craniopharyngiomas

    Directory of Open Access Journals (Sweden)

    Ghada E. Esheba

    2015-09-01

    Conclusion: Nuclear accumulation of β-catenin is a diagnostic hallmark of the ACP and is very helpful in the differential diagnosis between both ACP and PCP in the setting of small biopsies. Moreover, the restricted nuclear β-catenin accumulation in the cohesive cell clusters within the whorl-like areas supports that aberrant β-catenin expression may play a role in the morphogenesis of ACP.

  10. The Role of the Rab Coupling Protein in ErbB2-Driven Mammary Tumorigenesis and Metastasis

    Science.gov (United States)

    2014-10-01

    floxed RCP funder line with FVB genetic background. During Year-1, we performed embryos implantation having floxed RCP allele within FVB female recipient...we worked with different breeding pairs of transgene bearing animal is the low efficiency to get high rate of bigenic or trigenic because of Mendelian ... genetic ratio. 8 6b. Monitor mammary gland outgrowth of RCP-MTB mice. Induction or not with doxycyclin of RCP-MTB. Mammary glands extraction, H

  11. Optimized preparation and preliminary evaluation of [64Cu]-DOTA-trastuzumab for targeting ErbB2/Neu expression

    International Nuclear Information System (INIS)

    Behrooz Alirezapour; Mohammad Javad Rasaee

    2013-01-01

    Breast cancer radioimmunoscintigraphy targeting HER2/neu expression is a growing field of work in nuclear medicine research. Trastuzumab is a monoclonal antibody that binds with high affinity to HER2/neu, which is over expressed on breast and other tumors. Developing new tracers for the detection of this cancer is of great interest. In this study, trastuzumab was successively labeled with [ 64 Cu]CuCl 2 after conjugation with DOTA-NHS-ester. The conjugate was purified by molecular filtration, the average number of DOTA conjugated per mAb was calculated and total concentration was determined by spectrophotometric method. DOTA-trastuzumab was labeled with 64 Cu produced by 68 Zn(p,αn) 64 Cu nuclear reaction (30 MeV protons at 180 μA). Radiochemical purity, integrity of protein after radiolabeling and immunoreactivity of radiolabeled mAb trastuzumab with HER2/neu antigen and SkBr3 cell line were performed by RIA. In vitro stability of radiolabeled mAb in human serum was determined by thin layer chromatography. In vitro internalization studies were performed with the SkBr3 cell line and the tissue biodistribution of the 64 Cu-DOTA-trastuzumab was evaluated in wild-type rat (90 ± 5.5 μCi, 2, 6, 12, 24 h p.i.). The radioimmunoconjugate was prepared with a radiochemical purity of higher than 96 ± 0.5 % (ITLC) and specific activity as high as 5.3 μCi/μg. The average number of chelators per antibody for the conjugate used in this study was 5.8/1. The sample was showed to have similar patterns of migration in the gel electrophoresis. The 64 Cu-DOTA-trastuzumab showed high immunoreactivity towards HER2/neu antigen and SkBr3 cell line. In vitro stability of the labeled product was found to be more than 94 % in PBS and 82 ± 0.5 % in human serum over 48 h. In vitro internalization studies of the 64 Cu-DOTA-trastuzumab showed that up to 11.5 % of the radioimmunoconjugate internalized after 10 h. The accumulation of the radiolabeled mAb in liver, skin, intestine, lung, spleen, kidney and other tissues demonstrates a similar pattern to the other radiolabeled anti-HER2 immunoconjugates. 64 Cu-DOTA-trastuzumab is a potential compound for molecular imaging of PET for diagnosis and treatment studies and follow-up of HER2 expression in oncology. (author)

  12. The Role of the Rab Coupling Protein in ErbB2-Driven Mammary Tumorigenesis and Metastasis

    Science.gov (United States)

    2015-10-01

    produced in Hybridoma facility, McGill University. Animals — An inducible RCP construct was engineered by cloning a His-RCP fragment (pcDNA3.1 cut with...SOW-Task 1.Attain ethical approval from ACURO for the use of mice (Months 2-3) Evolution. Completion: 100%. To follow the ethical approval from...ACURO guidelines our Molecular Oncology Group, currently holds an approved Animal Use Protocol # 2008-5518 with McGill University following the high

  13. PAM50 Breast Cancer Subtyping by RT-qPCR and Concordance with Standard Clinical Molecular Markers

    Directory of Open Access Journals (Sweden)

    Bastien Roy RL

    2012-10-01

    Full Text Available Abstract Background Many methodologies have been used in research to identify the “intrinsic” subtypes of breast cancer commonly known as Luminal A, Luminal B, HER2-Enriched (HER2-E and Basal-like. The PAM50 gene set is often used for gene expression-based subtyping; however, surrogate subtyping using panels of immunohistochemical (IHC markers are still widely used clinically. Discrepancies between these methods may lead to different treatment decisions. Methods We used the PAM50 RT-qPCR assay to expression profile 814 tumors from the GEICAM/9906 phase III clinical trial that enrolled women with locally advanced primary invasive breast cancer. All samples were scored at a single site by IHC for estrogen receptor (ER, progesterone receptor (PR, and Her2/neu (HER2 protein expression. Equivocal HER2 cases were confirmed by chromogenic in situ hybridization (CISH. Single gene scores by IHC/CISH were compared with RT-qPCR continuous gene expression values and “intrinsic” subtype assignment by the PAM50. High, medium, and low expression for ESR1, PGR, ERBB2, and proliferation were selected using quartile cut-points from the continuous RT-qPCR data across the PAM50 subtype assignments. Results ESR1, PGR, and ERBB2 gene expression had high agreement with established binary IHC cut-points (area under the curve (AUC ≥ 0.9. Estrogen receptor positivity by IHC was strongly associated with Luminal (A and B subtypes (92%, but only 75% of ER negative tumors were classified into the HER2-E and Basal-like subtypes. Luminal A tumors more frequently expressed PR than Luminal B (94% vs 74% and Luminal A tumors were less likely to have high proliferation (11% vs 77%. Seventy-seven percent (30/39 of ER-/HER2+ tumors by IHC were classified as the HER2-E subtype. Triple negative tumors were mainly comprised of Basal-like (57% and HER2-E (30% subtypes. Single gene scoring for ESR1, PGR, and ERBB2 was more prognostic than the corresponding IHC markers as

  14. Identifying a Mechanism for Crosstalk Between the Estrogen and Glucocorticoid Receptors | Center for Cancer Research

    Science.gov (United States)

    Estrogen has long been known to play important roles in the development and progression of breast cancer. Its receptor (ER), a member of the steroid receptor family, binds to estrogen response elements (EREs) in DNA and regulates gene transcription. More recently, another steroid receptor family member, the glucocorticoid receptor (GR), has been implicated in breast cancer progression, and ER/GR status is an important predictor of breast cancer outcome.

  15. Antitumor efficacy of IPI-504, a selective heat shock protein 90 inhibitor against human epidermal growth factor receptor 2-positive human xenograft models as a single agent and in combination with trastuzumab or lapatinib.

    Science.gov (United States)

    Leow, Ching Ching; Chesebrough, Jon; Coffman, Karen T; Fazenbaker, Christine A; Gooya, John; Weng, David; Coats, Steve; Jackson, Dowdy; Jallal, Bahija; Chang, Yong

    2009-08-01

    IPI-504 is a novel, highly soluble small-molecule inhibitor of heat shock protein 90 (Hsp90), a protein chaperone essential for regulating homeostasis of oncoproteins and cell signaling proteins. Human epidermal growth factor receptor 2 (HER2; ErbB2) oncoprotein, expressed in a subset of metastatic breast cancers, is a Hsp90 client protein. In this study, we investigated the antitumor activity and the mechanism of action of IPI-504 in HER2(+), trastuzumab-sensitive and trastuzumab-refractory cell lines in vitro and in vivo. IPI-504 exhibited potent antiproliferative activities (range of IC(50), 10-40 nmol/L) against several tumor cell lines examined, whereby mechanism of action was mediated through HER2 and Akt degradation. Both intravenous and oral administration of IPI-504 assessed in multiple schedules showed potent tumor growth inhibition in vivo with corresponding degradation of HER2. The tolerability and efficacy of IPI-504 combined with either trastuzumab or lapatinib were also investigated in HER2(+) tumor xenograft models. Combination of IPI-504 with trastuzumab significantly enhanced tumor growth delay and induced greater responses when compared with either agent alone. Although, as expected, trastuzumab alone did not exhibit any significant antitumor activity in the trastuzumab-resistant JIMT-1 model, IPI-504 administered in combination with trastuzumab yielded greater antitumor efficacy than either agent alone. Finally, combination of IPI-504 and lapatinib was well tolerated up to 50 mg/kg IPI-504 and 100 mg/kg lapatinib and resulted in significant delay in tumor growth, including partial and complete tumor responses. These lines of evidence support the development of IPI-504 in HER2-positive breast cancers as a single agent and in combination with either trastuzumab or lapatinib

  16. Anti-epidermal growth factor receptor conjugated mesoporous zinc oxide nanofibers for breast cancer diagnostics

    Science.gov (United States)

    Ali, Md. Azahar; Mondal, Kunal; Singh, Chandan; Dhar Malhotra, Bansi; Sharma, Ashutosh

    2015-04-01

    We report the fabrication of an efficient, label-free, selective and highly reproducible immunosensor with unprecedented sensitivity (femto-molar) to detect a breast cancer biomarker for early diagnostics. Mesoporous zinc oxide nanofibers (ZnOnFs) are synthesized by electrospinning technique with a fiber diameter in the range of 50-150 nm. Fragments of ZnOnFs are electrophoretically deposited on an indium tin oxide glass substrate and conjugated via covalent or electrostatic interactions with a biomarker (anti-ErbB2; epidermal growth factor receptor 2). Oxygen plasma treatment of the carbon doped ZnOnFs generates functional groups (-COOH, -OH, etc.) that are effective for the conjugation of anti-ErbB2. ZnOnFs without plasma treatment that conjugate via electrostatic interactions were also tested for comparison. Label-free detection of the breast cancer biomarker by this point-of-care device is achieved by an electrochemical impedance technique that has high sensitivity (7.76 kΩ μM-1) and can detect 1 fM (4.34 × 10-5 ng mL-1) concentration. The excellent impedimetric response of this immunosensor provides a fast detection (128 s) in a wide detection test range (1.0 fM-0.5 μM). The oxy-plasma treated ZnOnF immunoelectrode shows a higher association constant (404.8 kM-1 s-1) indicating a higher affinity towards the ErbB2 antigen compared to the untreated ZnOnF immunoelectrode (165.6 kM-1 s-1). This sensor is about an order of magnitude more sensitive than the best demonstrated in the literature based on different nanomaterials and about three orders of magnitude better than the ELISA standard for breast cancer biomarker detection. This proposed point-of-care cancer diagnostic offers several advantages, such as higher stability, rapid monitoring, simplicity, cost-effectiveness, etc., and should prove to be useful for the detection of other bio- and cancer markers.We report the fabrication of an efficient, label-free, selective and highly reproducible immunosensor

  17. Lipophorin Receptor: The Insect Lipoprotein Receptor

    Indian Academy of Sciences (India)

    IAS Admin

    physiology and develop- mental biology of silkworms, and use of silk in industrial applications. The low-density lipoprotein receptor (LDLR), one of the best characterized cell-surface receptors, mediates cholesterol ho- meostasis and other functions in mammals. The members of the LDLR superfamily are structurally related ...

  18. Lipophorin Receptor: The Insect Lipoprotein Receptor

    Indian Academy of Sciences (India)

    Permanent link: http://www.ias.ac.in/article/fulltext/reso/018/08/0748-0755. Keywords. Low-density lipoprotein receptor; lipophorin; lipophorin receptor; insects. Author Affiliations. G Ravikumar1 N B Vijayaprakash1. Seri-biotech Research Laboratory Central Silk Board Kodathi, Carmelaram Post Bangalore 560 035, India.

  19. Acetylcholine receptor antibody

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/003576.htm Acetylcholine receptor antibody To use the sharing features on this page, please enable JavaScript. Acetylcholine receptor antibody is a protein found in the blood ...

  20. Androgen receptor abnormalities

    NARCIS (Netherlands)

    A.O. Brinkmann (Albert); G.G.J.M. Kuiper (George); C. Ris-Stalpers (Carolyn); H.C.J. van Rooij (Henri); G. Romalo (G.); G. Trifiro (Gianluca); E. Mulder (Eppo); L. Pinsky (L.); H.U. Schweikert (H.); J. Trapman (Jan)

    1991-01-01

    markdownabstract__Abstract__ The human androgen receptor is a member of the superfamily of steroid hormone receptors. Proper functioning of this protein is a prerequisite for normal male sexual differentiation and development. The cloning of the human androgen receptor cDNA and the elucidation of

  1. Androgen receptor abnormalities

    NARCIS (Netherlands)

    Brinkmann, A. O.; Kuiper, G. G.; Ris-Stalpers, C.; van Rooij, H. C.; Romalo, G.; Trifiro, M.; Mulder, E.; Pinsky, L.; Schweikert, H. U.; Trapman, J.

    1991-01-01

    The human androgen receptor is a member of the superfamily of steroid hormone receptors. Proper functioning of this protein is a prerequisite for normal male sexual differentiation and development. The cloning of the human androgen receptor cDNA and the elucidation of the genomic organization of the

  2. GABA receptor imaging

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jong Doo [Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2007-04-15

    GABA is primary an inhibitory neurotransmitter that is localized in inhibitory interneurons. GABA is released from presynaptic terminals and functions by binding to GABA receptors. There are two types of GABA receptors, GABA{sub A}-receptor that allows chloride to pass through a ligand gated ion channel and GABA{sub B}-receptor that uses G-proteins for signaling. The GABA{sub A}-receptor has a GABA binding site as well as a benzodiazepine binding sites, which modulate GABA{sub A}-receptor function. Benzodiazepine GABAA receptor imaging can be accomplished by radiolabeling derivates that activates benzodiazepine binding sites. There has been much research on flumazenil (FMZ) labeled with {sup 11}C-FMZ, a benzodiazepine derivate that is a selective, reversible antagonist to GABAA receptors. Recently, {sup 18}F-fluoroflumazenil (FFMZ) has been developed to overcome {sup 11}C's short half-life. {sup 18}F-FFMZ shows high selective affinity and good pharmacodynamics, and is a promising PET agent with better central benzodiazepine receptor imaging capabilities. In an epileptic focus, because the GABA/benzodiazepine receptor amount is decreased, using '1{sup 1}C-FMZ PET instead of {sup 18}F-FDG, PET, restrict the foci better and may also help find lesions better than high resolution MR. GABA{sub A} receptors are widely distributed in the cerebral cortex, and can be used as an viable neuronal marker. Therefore it can be used as a neuronal cell viability marker in cerebral ischemia. Also, GABA-receptors decrease in areas where neuronal plasticity develops, therefore, GABA imaging can be used to evaluate plasticity. Besides these usages, GABA receptors are related with psychological diseases, especially depression and schizophrenia as well as cerebral palsy, a motor-related disorder, so further in-depth studies are needed for these areas.

  3. GABA receptor imaging

    International Nuclear Information System (INIS)

    Lee, Jong Doo

    2007-01-01

    GABA is primary an inhibitory neurotransmitter that is localized in inhibitory interneurons. GABA is released from presynaptic terminals and functions by binding to GABA receptors. There are two types of GABA receptors, GABA A -receptor that allows chloride to pass through a ligand gated ion channel and GABA B -receptor that uses G-proteins for signaling. The GABA A -receptor has a GABA binding site as well as a benzodiazepine binding sites, which modulate GABA A -receptor function. Benzodiazepine GABAA receptor imaging can be accomplished by radiolabeling derivates that activates benzodiazepine binding sites. There has been much research on flumazenil (FMZ) labeled with 11 C-FMZ, a benzodiazepine derivate that is a selective, reversible antagonist to GABAA receptors. Recently, 18 F-fluoroflumazenil (FFMZ) has been developed to overcome 11 C's short half-life. 18 F-FFMZ shows high selective affinity and good pharmacodynamics, and is a promising PET agent with better central benzodiazepine receptor imaging capabilities. In an epileptic focus, because the GABA/benzodiazepine receptor amount is decreased, using '1 1 C-FMZ PET instead of 18 F-FDG, PET, restrict the foci better and may also help find lesions better than high resolution MR. GABA A receptors are widely distributed in the cerebral cortex, and can be used as an viable neuronal marker. Therefore it can be used as a neuronal cell viability marker in cerebral ischemia. Also, GABA-receptors decrease in areas where neuronal plasticity develops, therefore, GABA imaging can be used to evaluate plasticity. Besides these usages, GABA receptors are related with psychological diseases, especially depression and schizophrenia as well as cerebral palsy, a motor-related disorder, so further in-depth studies are needed for these areas

  4. Endocannabinoids block status epilepticus in cultured hippocampal neurons

    Science.gov (United States)

    Deshpande, Laxmikant S.; Blair, Robert E.; Ziobro, Julie M.; Sombati, Sompong; Martin, Billy R.; DeLorenzo, Robert J.

    2008-01-01

    Status epilepticus is a serious neurological disorder associated with a significant morbidity and mortality. Antiepileptic drugs such as diazepam, phenobarbital and phenytoin are the mainstay of status epilepticus treatment. However, over 20% of status epilepticus cases are refractory to the initial treatment with two or more antiepileptic drugs. Endocannabinoids have been implicated as playing an important role in regulating seizure activity and seizure termination. This study evaluated the effects of the major endocannabinoids methanandamide and 2-arachidonylglycerol (2-AG) on status epilepticus in the low-Mg2+ hippocampal neuronal culture model. Status epilepticus in this model was resistant to treatment with phenobarbital and phenytoin. Methanandamide and 2-AG inhibited status epilepticus in a dose-dependent manner with an EC50 of 145±4.15 nM and 1.68±0.19 µM, respectively. In addition, the anti-status epilepticus effects of methanandamide and 2-AG were mediated by activation of the cannabinoid CB1 receptor since they were blocked by the cannabinoid CB1 receptor antagonist AM251. These results provide the first evidence that the endocannabinoids, methanandamide and 2-AG, are effective inhibitors of refractory status epilepticus in the hippocampal neuronal culture model and indicate that regulating the endocannabinoid system may provide a novel therapeutic approach for treating refractory status epilepticus. PMID:17174949

  5. Adrenergic receptors are a fallible index of adrenergic denervation hypersensitivity

    DEFF Research Database (Denmark)

    Dejgaard, Anders; Liggett, S B; Christensen, N J

    1991-01-01

    In view of evidence that neither interindividual nor induced intra-individual variations of adrenergic receptor status are related to metabolic or haemodynamic sensitivity to adrenaline in vivo, we took an alternative approach to assessment of the relevance of adrenergic receptor measurement...... densities (and binding affinities), measured with 3H-labelled yohimbine, and adrenaline-induced suppression of cyclic AMP contents did not differ among the three groups. Thus, in contrast to idiopathic autonomic failure, there is no generalized increase in adrenergic receptors in autonomic failure due...

  6. Allosteric modulation of G-protein coupled receptors

    DEFF Research Database (Denmark)

    Jensen, Anders A.; Spalding, Tracy A

    2004-01-01

    are believed to activate (agonists) or inhibit (competitive antagonists) receptor signalling by binding the receptor at the same site as the endogenous agonist, the orthosteric site. In contrast, allosteric ligands modulate receptor function by binding to different regions in the receptor, allosteric sites....... In recent years, combinatorial chemistry and high throughput screening have helped identify several allosteric GPCR modulators with novel structures, several of which already have become valuable pharmacological tools and may be candidates for clinical testing in the near future. This mini review outlines...... the current status and perspectives of allosteric modulation of GPCR function with emphasis on the pharmacology of endogenous and synthesised modulators, their receptor interactions and the therapeutic prospects of allosteric ligands compared to orthosteric ligands....

  7. Dengue virus receptor

    OpenAIRE

    Hidari, Kazuya I.P.J.; Suzuki, Takashi

    2011-01-01

    Dengue virus is an arthropod-borne virus transmitted by Aedes mosquitoes. Dengue virus causes fever and hemorrhagic disorders in humans and non-human primates. Direct interaction of the virus introduced by a mosquito bite with host receptor molecule(s) is crucial for virus propagation and the pathological progression of dengue diseases. Therefore, elucidation of the molecular mechanisms underlying the interaction between dengue virus and its receptor(s) in both humans and mosquitoes is essent...

  8. Therapeutic androgen receptor ligands

    Science.gov (United States)

    Allan, George F.; Sui, Zhihua

    2003-01-01

    In the past several years, the concept of tissue-selective nuclear receptor ligands has emerged. This concept has come to fruition with estrogens, with the successful marketing of drugs such as raloxifene. The discovery of raloxifene and other selective estrogen receptor modulators (SERMs) has raised the possibility of generating selective compounds for other pathways, including androgens (that is, selective androgen receptor modulators, or SARMs). PMID:16604181

  9. Radiopharmaceuticals in China. Current status and prospects

    Energy Technology Data Exchange (ETDEWEB)

    Jia, Hong-Mei; Liu, Bo-Li [Beijing Normal Univ. (China). Key Laboratory of Radiopharmaceuticals

    2014-04-01

    The review provides an overview of the current status of radiopharmaceuticals in China for in vivo clinical use and also describes some important advances in the past three decades. Development of the diagnostic and therapeutic radiopharmaceuticals as well as basic research on radiopharmaceutical chemistry are being introduced. The radiotracers developed in China include: (1) Brain perfusion imaging agents and CNS radiotracers for β-amyloid plaques, σ{sub 1} receptors, and dopamine D{sub 2} or D{sub 4} receptors; (2) {sup 99m}Tc- and {sup 18}F-labeled myocardial perfusion imaging agents; (3) tumor imaging agents including integrin-targeting radiotracer, novel sentinel lymph node imaging agents, hypoxia imaging agents, {sup 99m}Tc-labeled glucose derivatives, σ{sub 2} receptor imaging agents, folate receptor imaging agents, and potential radiotracers for imaging of human telomerase reverse transcriptase expression; (4) Potential infection imaging agents; (5) Potential asialoglycoprotein receptor imaging agents; (6) Other imaging agents. Moreover, some prospects of research and development of radiopharmaceuticals in the near future are discussed. (orig.)

  10. Personal receptor repertoires: olfaction as a model

    Directory of Open Access Journals (Sweden)

    Olender Tsviya

    2012-08-01

    Full Text Available Abstract Background Information on nucleotide diversity along completely sequenced human genomes has increased tremendously over the last few years. This makes it possible to reassess the diversity status of distinct receptor proteins in different human individuals. To this end, we focused on the complete inventory of human olfactory receptor coding regions as a model for personal receptor repertoires. Results By performing data-mining from public and private sources we scored genetic variations in 413 intact OR loci, for which one or more individuals had an intact open reading frame. Using 1000 Genomes Project haplotypes, we identified a total of 4069 full-length polypeptide variants encoded by these OR loci, average of ~10 per locus, constituting a lower limit for the effective human OR repertoire. Each individual is found to harbor as many as 600 OR allelic variants, ~50% higher than the locus count. Because OR neuronal expression is allelically excluded, this has direct effect on smell perception diversity of the species. We further identified 244 OR segregating pseudogenes (SPGs, loci showing both intact and pseudogene forms in the population, twenty-six of which are annotatively “resurrected” from a pseudogene status in the reference genome. Using a custom SNP microarray we validated 150 SPGs in a cohort of 468 individuals, with every individual genome averaging 36 disrupted sequence variations, 15 in homozygote form. Finally, we generated a multi-source compendium of 63 OR loci harboring deletion Copy Number Variations (CNVs. Our combined data suggest that 271 of the 413 intact OR loci (66% are affected by nonfunctional SNPs/indels and/or CNVs. Conclusions These results portray a case of unusually high genetic diversity, and suggest that individual humans have a highly personalized inventory of functional olfactory receptors, a conclusion that might apply to other receptor multigene families.

  11. USCIS My Case Status

    Data.gov (United States)

    Department of Homeland Security — USCIS provide a way for the public who applied for U.S. citizenship to check the status of their application online. To view the status of a case, the application...

  12. Innovations, status, and networks

    NARCIS (Netherlands)

    P. Wang (Pengfei)

    2016-01-01

    markdownabstractTo obtain and maintain competitive advantage, firms need to implement appropriate innovation strategies (i.e. exploration or exploitation) and acquire status in external networks. In this dissertation, I investigate how innovation strategy, status, and network structure jointly

  13. AMPA receptor ligands

    DEFF Research Database (Denmark)

    Strømgaard, Kristian; Mellor, Ian

    2004-01-01

    Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player...

  14. Angiotensin type 2 receptors

    DEFF Research Database (Denmark)

    Sumners, Colin; de Kloet, Annette D; Krause, Eric G

    2015-01-01

    In most situations, the angiotensin AT2-receptor (AT2R) mediates physiological actions opposing those mediated by the AT1-receptor (AT1R), including a vasorelaxant effect. Nevertheless, experimental evidence vastly supports that systemic application of AT2R-agonists is blood pressure neutral...

  15. Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment.

    NARCIS (Netherlands)

    Kufareva, I.; Rueda, M.; Katritch, V.; Stevens, R.C.; Abagyan, R.; Vroling, B.; Sanders, M.P.A.

    2011-01-01

    The community-wide GPCR Dock assessment is conducted to evaluate the status of molecular modeling and ligand docking for human G protein-coupled receptors. The present round of the assessment was based on the recent structures of dopamine D3 and CXCR4 chemokine receptors bound to small molecule

  16. Status of GPCR Modeling and Docking as Reflected by Community-wide GPCR Dock 2010 Assessment

    NARCIS (Netherlands)

    Kufareva, I; Rueda, M; Katritch, V; Roumen, L.; de Esch, I.J.P.; Leurs, R.; de Graaf, C.; Stevens, R.C.; Abagyan, R

    2011-01-01

    The community-wide GPCR Dock assessment is conducted to evaluate the status of molecular modeling and ligand docking for human G protein-coupled receptors. The present round of the assessment was based on the recent structures of dopamine D3 and CXCR4 chemokine receptors bound to small molecule

  17. Glutamate receptor agonists

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Greenwood, Jeremy R; Bunch, Lennart

    2011-01-01

    The neurotransmitter (S)-glutamate [(S)-Glu] is responsible for most of the excitatory neurotransmission in the central nervous system. The effect of (S)-Glu is mediated by both ionotropic and metabotropic receptors. Glutamate receptor agonists are generally a-amino acids with one or more...... stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses...... mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist...

  18. P2X receptors.

    Science.gov (United States)

    North, R Alan

    2016-08-05

    Extracellular adenosine 5'-triphosphate (ATP) activates cell surface P2X and P2Y receptors. P2X receptors are membrane ion channels preferably permeable to sodium, potassium and calcium that open within milliseconds of the binding of ATP. In molecular architecture, they form a unique structural family. The receptor is a trimer, the binding of ATP between subunits causes them to flex together within the ectodomain and separate in the membrane-spanning region so as to open a central channel. P2X receptors have a widespread tissue distribution. On some smooth muscle cells, P2X receptors mediate the fast excitatory junction potential that leads to depolarization and contraction. In the central nervous system, activation of P2X receptors allows calcium to enter neurons and this can evoke slower neuromodulatory responses such as the trafficking of receptors for the neurotransmitter glutamate. In primary afferent nerves, P2X receptors are critical for the initiation of action potentials when they respond to ATP released from sensory cells such as taste buds, chemoreceptors or urothelium. In immune cells, activation of P2X receptors triggers the release of pro-inflammatory cytokines such as interleukin 1β. The development of selective blockers of different P2X receptors has led to clinical trials of their effectiveness in the management of cough, pain, inflammation and certain neurodegenerative diseases.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'. © 2016 The Author(s).

  19. Androgen Receptor Expression in Thai Breast Cancer Patients

    Directory of Open Access Journals (Sweden)

    Suthat Chottanapund

    2016-09-01

    Full Text Available The aim of this study was to investigate prevalence and related factors of androgen receptor (AR expression in Thai breast cancer patients. A descriptive study was done in 95 patients, who were admitted to Charoenkrung Pracharak Hospital, Bangkok (2011–2013. Statistical relationships were examined between AR protein expression, tumor status, and patient characteristics. Compared with those from Western countries, ethnic Thai patients were younger at age of diagnosis and had a higher proliferative index (high Ki-67 expression, which indicates unfavorable prognosis. In addition, 91% of the Thai breast tumors that were positive for any of the following receptors, estrogen receptor (ER, progesterone receptor (PR, and human epidermal growth factor receptor 2 (HER2 also expressed the AR protein, while in triple negative breast tumors only 33% were AR positive. ER and PR expression was positively related with AR expression, while AR expression was inversely correlated to Ki-67 expression. AR status was strongly correlated with ER and PR status in Thai patients. There is an inverse relationship between Ki-67 and AR, which suggests that AR may be a prognostic factor for breast cancer.

  20. Steroid hormone receptors and human breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Szamel, I.

    1985-02-01

    Steroid hormone receptor (SR) binding capacity can be measured both in the cytosol and in the nuclear fraction of the cancerous cells. Approximately 30-40% of breast cancers are hormone dependent. SR-positive tumors can be treated by endocrine therapy resulting in a favourable clinical response in 60-70% of the cases. At the National Institute of Oncology, Budapest, Hungary, estradiol (ER) and progesterone (PR) receptor assays are performed by a multipoint saturation analysis using Scatchard plot. Dextran coated charcoal technique is used for the separation of free and receptor protein-bound labelled hormones. Data obtained from 400 breast cancer patients show a correlation between the SR content of the tumor and the hormonal status of the patients. The ER binding capacity is higher after menopause compared to the premenopausal values. Specific correlation between the PR content of the tumor and the hormonal status of the patients cound not be observed. The PR binding capacity is the highest over 20 years. The highest clinical response rate, 80%, could be found in the group of patients with both ER and PR in their tumor tissues. (author).

  1. Heuristic status polling

    Science.gov (United States)

    Archer, Charles J [Rochester, MN; Blocksome, Michael A [Rochester, MN; Heidelberger, Philip [Cortlandt Manor, NY; Kumar, Sameer [White Plains, NY; Parker, Jeffrey J [Rochester, MN; Ratterman, Joseph D [Rochester, MN

    2011-06-07

    Methods, compute nodes, and computer program products are provided for heuristic status polling of a component in a computing system. Embodiments include receiving, by a polling module from a requesting application, a status request requesting status of a component; determining, by the polling module, whether an activity history for the component satisfies heuristic polling criteria; polling, by the polling module, the component for status if the activity history for the component satisfies the heuristic polling criteria; and not polling, by the polling module, the component for status if the activity history for the component does not satisfy the heuristic criteria.

  2. Muscarinic receptor oligomerization.

    Science.gov (United States)

    Marsango, Sara; Ward, Richard J; Alvarez-Curto, Elisa; Milligan, Graeme

    2017-11-14

    G protein-coupled receptors (GPCRs) have been classically described as monomeric entities that function by binding in a 1:1 stoichiometric ratio to both ligand and downstream signalling proteins. However, in recent years, a growing number of studies has supported the hypothesis that these receptors can interact to form dimers and higher order oligomers although the molecular basis for these interactions, the overall quaternary arrangements and the functional importance of GPCR oligomerization remain topics of intense speculation. Muscarinic acetylcholine receptors belong to class A of the GPCR family. Each muscarinic receptor subtype has its own particular distribution throughout the central and peripheral nervous systems. In the central nervous system, muscarinic receptors regulate several sensory, cognitive, and motor functions while, in the peripheral nervous system, they are involved in the regulation of heart rate, stimulation of glandular secretion and smooth muscle contraction. Muscarinic acetylcholine receptors have long been used as a model for the study of GPCR structure and function and to address aspects of GPCR dimerization using a broad range of approaches. In this review, the prevailing knowledge regarding the quaternary arrangement for the various muscarinic acetylcholine receptors has been summarized by discussing work ranging from initial results obtained using more traditional biochemical approaches to those generated with more modern biophysical techniques. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  3. Glutamate receptor agonists

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Greenwood, Jeremy R; Bunch, Lennart

    2011-01-01

    stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses...... mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist...

  4. P2X receptors

    OpenAIRE

    North, R. Alan

    2016-01-01

    Extracellular adenosine 5′-triphosphate (ATP) activates cell surface P2X and P2Y receptors. P2X receptors are membrane ion channels preferably permeable to sodium, potassium and calcium that open within milliseconds of the binding of ATP. In molecular architecture, they form a unique structural family. The receptor is a trimer, the binding of ATP between subunits causes them to flex together within the ectodomain and separate in the membrane-spanning region so as to open a central channel. P2...

  5. Serotonin Receptors in Hippocampus

    Science.gov (United States)

    Berumen, Laura Cristina; Rodríguez, Angelina; Miledi, Ricardo; García-Alcocer, Guadalupe

    2012-01-01

    Serotonin is an ancient molecular signal and a recognized neurotransmitter brainwide distributed with particular presence in hippocampus. Almost all serotonin receptor subtypes are expressed in hippocampus, which implicates an intricate modulating system, considering that they can be localized as autosynaptic, presynaptic, and postsynaptic receptors, even colocalized within the same cell and being target of homo- and heterodimerization. Neurons and glia, including immune cells, integrate a functional network that uses several serotonin receptors to regulate their roles in this particular part of the limbic system. PMID:22629209

  6. Pregnane X receptor and human malignancy.

    Science.gov (United States)

    Koutsounas, Ioannis; Patsouris, Efstratios; Theocharis, Stamatios

    2013-04-01

    Pregnane X Receptor (PXR) is a member of the nuclear receptor superfamily, expressed in liver, intestine and other tissues. PXR exerts transcriptional regulation by binding to its DNA response elements as an heterodimer with Retinoid X Receptor (RXR). This nuclear receptor is implicated in the homeostasis of numerous endobiotics, such as glucose, lipids, steroids and bile acids. Additionally, the activation of PXR induces expression of drug metabolizing enzymes (DMEs) and transporters, including multidrug resistance protein 1 (MDR1), leading to regulation of xenobiotic metabolism and drug-drug interactions. New roles for PXR have been established in inflammatory bowel disease, bone homeostasis, liver steatosis, antifibrogenesis and oxidative stress. PXR has, additionally, a multifactorial impact on cancer, either by directly affecting cell proliferation and apoptosis or by inducing chemotherapy resistance, in colon, breast, prostate, and endometrial cancer, and in osteosarcoma. PXR polymorphisms may also have clinical significance in certain types of cancer and their treatment. Further studies are needed in order to clarify the mechanisms involved in PXR-regulated carcinogenesis. PXR down-regulation could be considered as a novel therapeutic approach to overcome chemoresistance, while future research should be mainly focused on modulating PXR status in order to increase chemotherapy effectiveness and finally improve cancer patient prognosis.

  7. Dimers of G-Protein Coupled Receptors as Versatile Storage and Response Units

    Directory of Open Access Journals (Sweden)

    Michael S. Parker

    2014-03-01

    Full Text Available The status and use of transmembrane, extracellular and intracellular domains in oligomerization of heptahelical G-protein coupled receptors (GPCRs are reviewed and for transmembrane assemblies also supplemented by new experimental evidence. The transmembrane-linked GPCR oligomers typically have as the minimal unit an asymmetric ~180 kDa pentamer consisting of receptor homodimer or heterodimer and a G-protein αβγ subunit heterotrimer. With neuropeptide Y (NPY receptors, this assembly is converted to ~90 kDa receptor monomer-Gα complex by receptor and Gα agonists, and dimers/heteropentamers are depleted by neutralization of Gαi subunits by pertussis toxin. Employing gradient centrifugation, quantification and other characterization of GPCR dimers at the level of physically isolated and identified heteropentamers is feasible with labeled agonists that do not dissociate upon solubilization. This is demonstrated with three neuropeptide Y (NPY receptors and could apply to many receptors that use large peptidic agonists.

  8. Somatostatin receptor skintigrafi

    DEFF Research Database (Denmark)

    Rasmussen, Karin; Nielsen, Jørn Theil; Rehling, Michael

    2005-01-01

    Somatostatin receptor scintigraphy (SRS) is a very valuable imaging technique for visualisation of a diversity of neuroendocrine tumours. The sensitivity for localisation of carcinoid tumours is high, but somewhat lower for other neuroendocrine tumours. The methodology, multiple clinical aspects ...

  9. GRK2 protein-mediated transphosphorylation contributes to loss of function of μ-opioid receptors induced by neuropeptide FF (NPFF2) receptors.

    Science.gov (United States)

    Moulédous, Lionel; Froment, Carine; Dauvillier, Stéphanie; Burlet-Schiltz, Odile; Zajac, Jean-Marie; Mollereau, Catherine

    2012-04-13

    Neuropeptide FF (NPFF) interacts with specific receptors to modulate opioid functions in the central nervous system. On dissociated neurons and neuroblastoma cells (SH-SY5Y) transfected with NPFF receptors, NPFF acts as a functional antagonist of μ-opioid (MOP) receptors by attenuating the opioid-induced inhibition of calcium conductance. In the SH-SY5Y model, MOP and NPFF(2) receptors have been shown to heteromerize. To understand the molecular mechanism involved in the anti-opioid activity of NPFF, we have investigated the phosphorylation status of the MOP receptor using phospho-specific antibody and mass spectrometry. Similarly to direct opioid receptor stimulation, activation of the NPFF(2) receptor by [D-Tyr-1-(NMe)Phe-3]NPFF (1DMe), an analog of NPFF, induced the phosphorylation of Ser-377 of the human MOP receptor. This heterologous phosphorylation was unaffected by inhibition of second messenger-dependent kinases and, contrarily to homologous phosphorylation, was prevented by inactivation of G(i/o) proteins by pertussis toxin. Using siRNA knockdown we could demonstrate that 1DMe-induced Ser-377 cross-phosphorylation and MOP receptor loss of function were mediated by the G protein receptor kinase GRK2. In addition, mass spectrometric analysis revealed that the phosphorylation pattern of MOP receptors was qualitatively similar after treatment with the MOP agonist Tyr-D-Ala-Gly (NMe)-Phe-Gly-ol (DAMGO) or after treatment with the NPFF agonist 1DMe, but the level of multiple phosphorylation was more intense after DAMGO. Finally, NPFF(2) receptor activation was sufficient to recruit β-arrestin2 to the MOP receptor but not to induce its internalization. These data show that NPFF-induced heterologous desensitization of MOP receptor signaling is mediated by GRK2 and could involve transphosphorylation within the heteromeric receptor complex.

  10. Maintenance of prolactin receptors in human breast cancer

    International Nuclear Information System (INIS)

    Ben-David, M.; Dror, Y.; Biran, S.

    1981-01-01

    Breast tissue specimens of 110 women with various stages of breast cancer were tested in vitro to determine their specific binding sites for human prolactin. In contrast to the case of steroid receptors, binding sites for prolactin were found in the vast majority of breast cancer tissue. Distribution profiles giving amount of prolactin receptor and their affinity coefficients were found to be similar in the tissues of women whose ages, hormonal status, or stage of breast cancer varied. These findings show that in contrast to steroid receptors, human breast cancer tissue maintains binding sites for prolactin. The findings also indicate that there may be a higher dependency of breast cancer on prolactin than on steroids. Clinical trials must be carried out to determine the role of ''positive'' prolactin receptors in prognosis and prediction of response to future hormone therapy. (author)

  11. Muscarinic receptor oligomerization

    OpenAIRE

    Marsango, Sara; Ward, Richard J.; Alvarez-Curto, Elisa; Milligan, Graeme

    2017-01-01

    G protein-coupled receptors (GPCRs) have been classically described as monomeric entities that function by binding in a 1:1 stoichiometric ratio to both ligand and downstream signalling proteins. However, in recent years, a growing number of studies has supported the hypothesis that these receptors can interact to form dimers and higher order oligomers although the molecular basis for these interactions, the overall quaternary arrangements and the functional importance of GPCR oligomerization...

  12. Genetics of taste receptors.

    Science.gov (United States)

    Bachmanov, Alexander A; Bosak, Natalia P; Lin, Cailu; Matsumoto, Ichiro; Ohmoto, Makoto; Reed, Danielle R; Nelson, Theodore M

    2014-01-01

    Taste receptors function as one of the interfaces between internal and external milieus. Taste receptors for sweet and umami (T1R [taste receptor, type 1]), bitter (T2R [taste receptor, type 2]), and salty (ENaC [epithelial sodium channel]) have been discovered in the recent years, but transduction mechanisms of sour taste and ENaC-independent salt taste are still poorly understood. In addition to these five main taste qualities, the taste system detects such noncanonical "tastes" as water, fat, and complex carbohydrates, but their reception mechanisms require further research. Variations in taste receptor genes between and within vertebrate species contribute to individual and species differences in taste-related behaviors. These variations are shaped by evolutionary forces and reflect species adaptations to their chemical environments and feeding ecology. Principles of drug discovery can be applied to taste receptors as targets in order to develop novel taste compounds to satisfy demand in better artificial sweeteners, enhancers of sugar and sodium taste, and blockers of bitterness of food ingredients and oral medications.

  13. Service Level Status

    CERN Multimedia

    Lopienski, S

    2007-01-01

    Nowadays, IT departments provide, and people use, computing services of an increasingly heterogeneous nature. There is thus a growing need for a status display that groups these different services and reports status and availability in a uniform way. The Service Level Status (SLS) system addresses these needs by providing a web-based display that dynamically shows availability, basic information and statistics about various IT services, as well as the dependencies between them.

  14. SIS - Status Determination

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Status Determination dataset within the Species Information System (SIS) contains information related to overfishing, overfished, and approaching overfished...

  15. Expression of Eag1 K+ channel and ErbBs in human pituitary adenomas: cytoskeleton arrangement patterns in cultured cells.

    Science.gov (United States)

    del Pliego, Margarita González; Aguirre-Benítez, Elsa; Paisano-Cerón, Karina; Valdovinos-Ramírez, Irene; Rangel-Morales, Carlos; Rodríguez-Mata, Verónica; Solano-Agama, Carmen; Martín-Tapia, Dolores; de la Vega, María Teresa; Saldoval-Balanzario, Miguel; Camacho, Javier; Mendoza-Garrido, María Eugenia

    2013-01-01

    Pituitary adenomas can invade surrounded tissue, but the mechanism remains elusive. Ether à go-go-1 (Eag1) potassium channel and epidermal growth factor receptors (ErbB1 and ErbB2) have been associated to invasive phenotypes or poor prognosis in cancer patients. However, cells arrange their cytoskeleton in order to acquire a successful migration pattern. We have studied ErbBs and Eag1 expression, and cytoskeleton arrangements in 11 human pituitary adenomas. Eag1, ErbB1 and ErbB2 expression were studied by immunochemistry in tissue and cultured cells. The cytoskeleton arrangement was analyzed in cultured cells by immunofluorescence. Normal pituitary tissue showed ErbB2 expression and Eag1 only in few cells. However, Eag1 and ErbB2 were expressed in all the tumors analyzed. ErbB1 expression was observed variable and did not show specificity for a tumor characteristic. Cultured cells from micro- and macro-adenomas clinically functional organize their cytoskeleton suggesting a mesenchymal pattern, and a round leucocyte/amoeboid pattern from invasive clinically silent adenoma. Pituitary tumors over-express EGF receptors and the ErbB2 repeated expression suggests is a characteristic of adenomas. Eag 1 was express, in different extent, and could be a therapeutic target. The cytoskeleton arrangements observed suggest that pituitary tumor cells acquire different patterns: mesenchymal, and leucocyte/amoeboid, the last observed in the invasive adenomas. Amoeboid migration pattern has been associated with high invasion capacity.

  16. Status of numerical relativity

    Indian Academy of Sciences (India)

    Abstract. I describe the current status of numerical relativity from my personal point of view. Here, I focus mainly on explaining the numerical implementations necessary for simulating general relativistic phenomena such as the merger of compact binaries and stellar collapse, emphasizing the well-developed current status of ...

  17. Super Refractory Status Epilepticus

    African Journals Online (AJOL)

    user

    Background: Status Epilepticus (SE) is defined as more than five minutes of persistent seizure activity without full recovery of consciousness in between the seizures. If SE fails to respond to two antiepileptic drugs, it is called refractory status epilepticus (RSE) and if it continues or recurs 24 hours after anesthesia, it is called ...

  18. Morocco: Country Status Report.

    Science.gov (United States)

    McFerren, Margaret

    A survey of the status of language usage in Morocco begins with an overview of the distribution and usage of Arabic, the official language, the Berber dialects, and French, an unofficial second language. The continuing high status and widespread use of French despite arabization efforts is discussed. A matrix follows that rates these languages and…

  19. Status of numerical relativity

    Indian Academy of Sciences (India)

    I describe the current status of numerical relativity from my personal point of view. Here, I focus mainly on explaining the numerical implementations necessary for simulating general relativistic phenomena such as the merger of compact binaries and stellar collapse, emphasizing the well-developed current status of such ...

  20. Ionotropic crustacean olfactory receptors.

    Directory of Open Access Journals (Sweden)

    Elizabeth A Corey

    Full Text Available The nature of the olfactory receptor in crustaceans, a major group of arthropods, has remained elusive. We report that spiny lobsters, Panulirus argus, express ionotropic receptors (IRs, the insect chemosensory variants of ionotropic glutamate receptors. Unlike insects IRs, which are expressed in a specific subset of olfactory cells, two lobster IR subunits are expressed in most, if not all, lobster olfactory receptor neurons (ORNs, as confirmed by antibody labeling and in situ hybridization. Ligand-specific ORN responses visualized by calcium imaging are consistent with a restricted expression pattern found for other potential subunits, suggesting that cell-specific expression of uncommon IR subunits determines the ligand sensitivity of individual cells. IRs are the only type of olfactory receptor that we have detected in spiny lobster olfactory tissue, suggesting that they likely mediate olfactory signaling. Given long-standing evidence for G protein-mediated signaling in activation of lobster ORNs, this finding raises the interesting specter that IRs act in concert with second messenger-mediated signaling.

  1. STATUS GIZI DAN STATUS KESEHATAN SUKU BADUY

    Directory of Open Access Journals (Sweden)

    Faisal Anwar

    2012-03-01

    Full Text Available 800x600 Normal 0 false false false IN X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Calibri","sans-serif"; mso-bidi-font-family:"Times New Roman";} The objectives of the study were: (1 To analyze the socio-economic and demographic characteristics of Baduy people; (2 To analyze the health status and nutritional status of Baduy people and its influential factors. This research is an explorative and descriptive study on the socio-cultural aspects of food system. The data were collected through a direct interview and discussion with respondents as well as a direct observation at the location of respondents. A sample size of 338 households was drawn from the population. To obtain the data on the cultural aspects, history and  socio aspect of food, in-depth interviews was conducted with 19 key persons. The study was last for 12 months. In Outer Baduy, the factors significantly related to nutritional status are age, number of household size, income, nutritional knowledge, and wife’s ability to read. In Moslem Baduy, only age and income are related to the nutritional status of children. In Moslem Baduy and the Outer Baduy, the correlation between age and W/A or W/H is similar: namely, the higher the age, the lower would the Z-score for the W/A or W/H. The income is significantly correlated to the child nutritional status according to Z-score for W/A with a high correlation coefficient, that is, 0.61. This means that the higher the income, the higher would be the Z-score value for the W/A.  The distribution of adults according to BMI classification in Outer Baduy it shows that 12.7% husbands and 17.6% wives are thin (wasted, while the

  2. adrenergic receptor with preeclampsia

    African Journals Online (AJOL)

    User

    2011-05-09

    May 9, 2011 ... expenditure and lipolysis. The mechanisms underlying lipolytic resistance to catecholamines in obesity are not clear and may include desensitization of ADRB2 function. (Yamada et al., 1999). Many studies have reported on the relationship between obesity and genetic variants in β-2 adrenergic receptors ...

  3. Ginkgolides and glycine receptors

    DEFF Research Database (Denmark)

    Jaracz, Stanislav; Nakanishi, Koji; Jensen, Anders A.

    2004-01-01

    Ginkgolides from the Ginkgo biloba tree are diterpenes with a cage structure consisting of six five-membered rings and a unique tBu group. They exert a variety of biological properties. In addition to being antagonists of the platelet activating factor receptor (PAFR), it has recently been shown ...

  4. Meeting report: nuclear receptors

    DEFF Research Database (Denmark)

    Tuckermann, Jan; Bourguet, William; Mandrup, Susanne

    2010-01-01

    The biannual European Molecular Biology Organization (EMBO) conference on nuclear receptors was organized by Beatrice Desvergne and Laszlo Nagy and took place in Cavtat near Dubrovnik on the Adriatic coast of Croatia September 25-29, 2009. The meeting brought together researchers from all over...

  5. Metformin and insulin receptors

    International Nuclear Information System (INIS)

    Vigneri, R.; Gullo, D.; Pezzino, V.

    1984-01-01

    The authors evaluated the effect of metformin (N,N-dimethylbiguanide), a biguanide known to be less toxic than phenformin, on insulin binding to its receptors, both in vitro and in vivo. Specific 125 I-insulin binding to cultured IM-9 human lymphocytes and MCF-7 human breast cancer cells was determined after preincubation with metformin. Specific 125 I-insulin binding to circulating monocytes was also evaluated in six controls, eight obese subjects, and six obese type II diabetic patients before and after a short-term treatment with metformin. Plasma insulin levels and blood glucose were also measured on both occasions. Metformin significantly increased insulin binding in vitro to both IM-9 lymphocytes and MCF-7 cells; the maximum increment was 47.1% and 38.0%, respectively. Metformin treatment significantly increased insulin binding in vivo to monocytes of obese subjects and diabetic patients. Scatchard analysis indicated that the increased binding was mainly due to an increase in receptor capacity. Insulin binding to monocytes of normal controls was unchanged after metformin as were insulin levels in all groups; blood glucose was significantly reduced after metformin only in diabetic patients. These data indicate that metformin increases insulin binding to its receptors in vitro and in vivo. The effect in vivo is observed in obese subjects and in obese type II diabetic patients, paralleling the clinical effectiveness of this antidiabetic agent, and is not due to receptor regulation by circulating insulin, since no variation in insulin levels was recorded

  6. Semantic Web status model

    CSIR Research Space (South Africa)

    Gerber, AJ

    2006-06-01

    Full Text Available by researchers and practitioners, spanning a vast landscape of different fields, technologies, concepts and application areas. Furthermore, there is confusion with regards to the current status of the enabling technologies envisioned to realise the Semantic Web...

  7. NAIP Status Maps Gallery

    Data.gov (United States)

    Farm Service Agency, Department of Agriculture — NAIP Status Maps Gallery. These maps illustrate what aerial imagery collection is planned, whats been collected, when it is available and how it is available. These...

  8. Micronutrient status in phenylketonuria

    NARCIS (Netherlands)

    Robert, M.; Rocha, J. C.; van Rijn, M.; Ahring, K.; Belanger-Quintana, A.; MacDonald, A.; Dokoupil, K.; Ozel, H. Gokmen; Lammardo, A. M.; Goyens, P.; Feillet, F.

    2013-01-01

    Patients with phenylketonuria (PKU) encompass an 'at risk' group for micronutrient imbalances. Optimal nutrient status is challenging particularly when a substantial proportion of nutrient intake is from non-natural sources. In PKU patients following dietary treatment supplementation with

  9. PRESENT STATUS IN INDIA

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. PRESENT STATUS IN INDIA. FIXED LINES – 36 MILLION. MOBILE CONNECTIONS – 14 MILLION. TELEDENSITY APPROXIMATELY 5. INTERNET CONNECTIONS – 5 MILLION. INTERNET USERS NEARLY – 25 MILLION.

  10. ANAIS status report

    Energy Technology Data Exchange (ETDEWEB)

    Amare, J; Borjabad, S; Cebrian, S; Cuesta, C; Fortuno, D; Garcia, E; Gomez, H; Morales, J; Ortigoza, Y; Ortiz de Solorzano, A; Pobes, C; Puimedon, J; Rodriguez, A; Sarsa, M L; Villar, J A, E-mail: cpobes@unizar.e [University of Zaragoza. C/Pedro Cerbuna 12, 50009. Zaragoza (Spain)

    2010-01-01

    We report the status of the ANAIS (Annual modulation with NAI Scintillators) experiment focusing on the developments towards the improvement of the background level of our detectors and the reduction of the energy threshold.

  11. Safety system status monitoring

    International Nuclear Information System (INIS)

    Lewis, J.R.; Morgenstern, M.H.; Rideout, T.H.; Cowley, P.J.

    1984-03-01

    The Pacific Northwest Laboratory has studied the safety aspects of monitoring the preoperational status of safety systems in nuclear power plants. The goals of the study were to assess for the NRC the effectiveness of current monitoring systems and procedures, to develop near-term guidelines for reducing human errors associated with monitoring safety system status, and to recommend a regulatory position on this issue. A review of safety system status monitoring practices indicated that current systems and procedures do not adequately aid control room operators in monitoring safety system status. This is true even of some systems and procedures installed to meet existing regulatory guidelines (Regulatory Guide 1.47). In consequence, this report suggests acceptance criteria for meeting the functional requirements of an adequate system for monitoring safety system status. Also suggested are near-term guidelines that could reduce the likelihood of human errors in specific, high-priority status monitoring tasks. It is recommended that (1) Regulatory Guide 1.47 be revised to address these acceptance criteria, and (2) the revised Regulatory Guide 1.47 be applied to all plants, including those built since the issuance of the original Regulatory Guide

  12. Safety system status monitoring

    Energy Technology Data Exchange (ETDEWEB)

    Lewis, J.R.; Morgenstern, M.H.; Rideout, T.H.; Cowley, P.J.

    1984-03-01

    The Pacific Northwest Laboratory has studied the safety aspects of monitoring the preoperational status of safety systems in nuclear power plants. The goals of the study were to assess for the NRC the effectiveness of current monitoring systems and procedures, to develop near-term guidelines for reducing human errors associated with monitoring safety system status, and to recommend a regulatory position on this issue. A review of safety system status monitoring practices indicated that current systems and procedures do not adequately aid control room operators in monitoring safety system status. This is true even of some systems and procedures installed to meet existing regulatory guidelines (Regulatory Guide 1.47). In consequence, this report suggests acceptance criteria for meeting the functional requirements of an adequate system for monitoring safety system status. Also suggested are near-term guidelines that could reduce the likelihood of human errors in specific, high-priority status monitoring tasks. It is recommended that (1) Regulatory Guide 1.47 be revised to address these acceptance criteria, and (2) the revised Regulatory Guide 1.47 be applied to all plants, including those built since the issuance of the original Regulatory Guide.

  13. Angiotensin type 2 receptor (AT2R) and receptor Mas

    DEFF Research Database (Denmark)

    Villela, Daniel; Leonhardt, Julia; Patel, Neal

    2015-01-01

    The angiotensin type 2 receptor (AT2R) and the receptor Mas are components of the protective arms of the renin-angiotensin system (RAS), i.e. they both mediate tissue protective and regenerative actions. The spectrum of actions of these two receptors and their signalling mechanisms display striking...... the phenomenon of blockade of angiotensin-(1-7) [Ang-(1-7)] actions by AT2R antagonists and vice versa. Such mechanisms may comprise dimerization of the receptors or dimerization-independent mechanisms such as lack of specificity of the receptor ligands used in the experiments or involvement of the Ang-(1...

  14. Pan-Cancer Analyses of the Nuclear Receptor Superfamily

    Directory of Open Access Journals (Sweden)

    Mark D. Long

    2015-12-01

    Full Text Available Nuclear receptors (NR act as an integrated conduit for environmental and hormonal signals to govern genomic responses, which relate to cell fate decisions. We review how their integrated actions with each other, shared co-factors and other transcription factors are disrupted in cancer. Steroid hormone nuclear receptors are oncogenic drivers in breast and prostate cancer and blockade of signaling is a major therapeutic goal. By contrast to blockade of receptors, in other cancers enhanced receptor function is attractive, as illustrated initially with targeting of retinoic acid receptors in leukemia. In the post-genomic era large consortia, such as The Cancer Genome Atlas, have developed a remarkable volume of genomic data with which to examine multiple aspects of nuclear receptor status in a pan-cancer manner. Therefore to extend the review of NR function we have also undertaken bioinformatics analyses of NR expression in over 3000 tumors, spread across six different tumor types (bladder, breast, colon, head and neck, liver and prostate. Specifically, to ask how the NR expression was distorted (altered expression, mutation and CNV we have applied bootstrapping approaches to simulate data for comparison, and also compared these NR findings to 12 other transcription factor families. Nuclear receptors were uniquely and uniformly downregulated across all six tumor types, more than predicted by chance. These approaches also revealed that each tumor type had a specific NR expression profile but these were most similar between breast and prostate cancer. Some NRs were down-regulated in at least five tumor types (e.g., NR3C2/MR and NR5A2/LRH-1 whereas others were uniquely down-regulated in one tumor (e.g., NR1B3/RARG. The downregulation was not driven by copy number variation or mutation and epigenetic mechanisms maybe responsible for the altered nuclear receptor expression.

  15. Immunohistochemical detection of estrogen receptors in canine mammary tumors

    OpenAIRE

    Elena Atanaskova Petrov; Ivica Gjurovski; Trpe Ristoski; Goran Nikolovski; Pandorce Trenkoska; Plamen Trojacanec; Ksenija Ilievska; Toni Dovenski; Gordana Petrushevska

    2016-01-01

    Mammary tumors are among the most common neoplasms in intact female dogs.They have a complex morphology, usually affecting middle age and older bitches. Almost 50% of the mammary tumors in dogs are malignant neoplasms. Prognosis is based on several factors: stage, age, tumor size, metastasis, histopathology, ovariectomy status and hormone-receptor activity. Immunohistochemical (IHC) measurement has become increasingly an important diagnostic and prognostic parameter, with the development of m...

  16. Prostaglandin Receptor Signaling in Disease

    Directory of Open Access Journals (Sweden)

    Toshiyuki Matsuoka

    2007-01-01

    Full Text Available Prostanoids, consisting of the prostaglandins (PGs and the thromboxanes (TXs, are a group of lipid mediators formed in response to various stimuli. They include PGD2, PGE2, PGF2α, PGI2, and TXA2. They are released outside of the cells immediately after synthesis, and exert their actions by binding to a G-protein coupled rhodopsin-type receptor on the surface of target cells. There are eight types of the prostanoid receptors conserved in mammals from mouse to human. They are the PGD receptor (DP, four subtypes of the PGE receptor (EP1, EP2, EP3, and EP4, the PGF receptor (FP, PGI receptor (IP, and TXA receptor (TP. Recently, mice deficient in each of these prostanoid receptors were generated and subjected to various experimental models of disease. These studies have revealed the roles of PG receptor signaling in various pathological conditions, and suggest that selective manipulation of the prostanoid receptors may be beneficial in treatment of the pathological conditions. Here we review these recent findings of roles of prostanoid receptor signaling and their therapeutic implications.

  17. Refractory status epilepticus

    Directory of Open Access Journals (Sweden)

    Sanjay P Singh

    2014-01-01

    Full Text Available Refractory status epilepticus is a potentially life-threatening medical emergency. It requires early diagnosis and treatment. There is a lack of consensus upon its semantic definition of whether it is status epilepticus that continues despite treatment with benzodiazepine and one antiepileptic medication (AED, i.e., Lorazepam + phenytoin. Others regard refractory status epilepticus as failure of benzodiazepine and 2 antiepileptic medications, i.e., Lorazepam + phenytoin + phenobarb. Up to 30% patients in SE fail to respond to two antiepileptic drugs (AEDs and 15% continue to have seizure activity despite use of three drugs. Mechanisms that have made the treatment even more challenging are GABA-R that is internalized during status epilepticus and upregulation of multidrug transporter proteins. All patients of refractory status epilepticus require continuous EEG monitoring. There are three main agents used in the treatment of RSE. These include pentobarbital or thiopental, midazolam and propofol. RSE was shown to result in mortality in 35% cases, 39.13% of patients were left with severe neurological deficits, while another 13% had mild neurological deficits.

  18. Receptors for enterovirus 71.

    Science.gov (United States)

    Yamayoshi, Seiya; Fujii, Ken; Koike, Satoshi

    2014-07-01

    Enterovirus 71 (EV71) is one of the major causative agents of hand, foot and mouth disease (HFMD). Occasionally, EV71 infection is associated with severe neurological diseases, such as acute encephalitis, acute flaccid paralysis and cardiopulmonary failure. Several molecules act as cell surface receptors that stimulate EV71 infection, including scavenger receptor B2 (SCARB2), P-selectin glycoprotein ligand-1 (PSGL-1), sialylated glycan, heparan sulfate and annexin II (Anx2). SCARB2 plays critical roles in attachment, viral entry and uncoating, and it can facilitate efficient EV71 infection. The three-dimensional structures of the mature EV71 virion, procapsid and empty capsid, as well as the exofacial domain of SCARB2, have been elucidated. This structural information has greatly increased our understanding of the early steps of EV71 infection. Furthermore, SCARB2 plays essential roles in the development of EV71 neurological disease in vivo. Adult mice are not susceptible to infection by EV71, but transgenic mice that express human SCARB2 become susceptible to EV71 infection and develop similar neurological diseases to those found in humans. This mouse model facilitates the in vivo investigation of many issues related to EV71. PSGL-1, sialylated glycan, heparan sulfate and Anx2 are attachment receptors, which enhance viral infection by retaining the virus on the cell surface. These molecules also contribute to viral infection in vitro either by interacting with SCARB2 or independently of SCARB2. However, the cooperative effects of these receptors, and their contribution to EV71 pathogenicity in vivo, remain to be elucidated.

  19. The interleukin-4 receptor: signal transduction by a hematopoietin receptor.

    Science.gov (United States)

    Keegan, A D; Pierce, J H

    1994-02-01

    Over the last several years, the receptors for numerous cytokines have been molecularly characterized. Analysis of their amino acid sequences shows that some of these receptors bear certain motifs in their extracellular domains that define a family of receptors called the Hematopoietin receptor superfamily. Significant advances in characterizing the structure, function, and mechanisms of signal transduction have been made for several members of this family. The purpose of this review is to discuss the recent advances made for one of the family members, the interleukin (IL) 4 receptor. Other receptor systems have recently been reviewed elsewhere. The IL-4 receptor consists of, at the minimum, the cloned 140 kDa IL-4-binding chain with the potential for associating with other chains. The IL-4 receptor transduces its signal by activating a tyrosine kinase that phosphorylates cellular substrates, including the receptor itself, and the 170 kDa substrate called 4PS. Phosphorylated 4PS interacts with the SH2 domain of the enzyme PI-3'-kinase and increases its enzymatic activity. These early events in the IL-4 receptor initiated signaling pathway may trigger a series of signals that will ultimately lead to an IL-4 specific biologic outcome.

  20. Fukushima Daiichi Status Report

    International Nuclear Information System (INIS)

    2012-01-01

    The IAEA issues regular status reports to the public on the current status of the Fukushima Daiichi Nuclear Power Plant, including information on environmental radiation monitoring, the status of workers, and current conditions on-site at the plant. The information cited in this report is compiled from official Japanese sources, including the Ministry of Economy, Trade and Industry (METI), the Nuclear and Industrial Safety Agency (NISA), the Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Ministry of Land, Infrastructure, Transport and Tourism (MLIT), the Ministry of Health, Labour and Welfare (MHLW) and the Ministry of Foreign Affairs (MOFA) through the Japanese Permanent Mission in Vienna and the Cabinet's Office of the Prime Minister. Information is also provided by the Tokyo Electric Power Company (TEPCO), the operator of the Fukushima Daiichi Nuclear Power Plant.

  1. Alterations in three biomarkers (estrogen receptor, progesterone receptor and human epidermal growth factor 2) and the Ki67 index between primary and metastatic breast cancer lesions.

    Science.gov (United States)

    Fujii, Kimihito; Watanabe, Rie; Ando, Takahito; Kousaka, Junko; Mouri, Yukako; Yoshida, Miwa; Imai, Tsuneo; Nakano, Shogo; Fukutomi, Takashi

    2017-12-01

    In recurrent breast cancer, the tumor phenotype, as assessed by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) status, occasionally changes. This change, in addition to the Ki67 index were evaluated at sites of recurrence and the correlation between changes in tumor phenotype and survival were assessed in breast cancer patients. Comparisons in pathological parameters between primary and metastatic lesions were drawn between ER, PR, HER2, and the Ki67 index in 70 patients with recurrent breast cancer. The association between changes in tumor phenotype and patient survival was assessed. The hormone receptor status changed from positive, in the primary lesions, to negative, in the metastatic lesions in 19.8% (ER) and 39.5% (PR) of patients, respectively. Conversion from negative to positive status was confirmed in 27.2% (ER) and 31.2% (PR) of patients, respectively. A change in HER2 status from negative (primary lesion) to positive (metastatic lesion) occurred in seven patients (10%). The mean Ki67 index of primary lesions with positive hormone receptor status was significantly lower than at sites of recurrence with any hormone receptor status, from 10.9±9.8 standard deviation (SD) to 22.9±18.6 (P=0.031) and 12.2±10.5 SD to 27.4±20.9 (P=0.023), for ER and PR, respectively. The mean overall survival of patients with ER status conversion from positive to negative was 7.4±1.2 standard error (SE) years, and 14.8±1.4 SE years for patients who retained positive ER status (P=0.005, log-rank), with a hazard ratio of 3.44 (95% confidence interval, 1.36-8.33). This difference in survival based upon change in ER status was similarly observed in patients with PR status conversion in the same direction. Thus, ER and PR status conversion at the time of recurrence strongly impact survival, particularly if the change is from positive (primary lesion) to negative (metastatic lesion). Monitoring the biological behavior of breast

  2. New Service Status Board

    CERN Multimedia

    2013-01-01

    On Monday 14 October, the Service Status Board for GS and IT will change. The new Status Board will be integrated with the CERN Service Portal and with the CERN Service Catalogue.   As of today, the SSB will display “Service Incidents”, “Planned Interventions” and “Service Changes”. References valid from 14 October: CERN SSB at https://cern.ch/ssb Computing SSB (previously IT SSB) at https://cern.ch/itssb   Nicole Cremel, IT and GS Service Management Support

  3. FRIB Cryogenic Plant Status

    Energy Technology Data Exchange (ETDEWEB)

    Dixon, Kelly D. [Thomas Jefferson National Accelerator Facility (TJNAF), Newport News, VA (United States); Ganni, Venkatarao [Thomas Jefferson National Accelerator Facility (TJNAF), Newport News, VA (United States); Knudsen, Peter N. [Thomas Jefferson National Accelerator Facility (TJNAF), Newport News, VA (United States); Casagranda, Fabio [Michigan State Univ., East Lansing, MI (United States)

    2015-12-01

    After practical changes were approved to the initial conceptual design of the cryogenic system for MSU FRIB and an agreement was made with JLab in 2012 to lead the design effort of the cryogenic plant, many activities are in place leading toward a cool-down of the linacs prior to 2018. This is mostly due to using similar equipment used at CHLII for the 12 GeV upgrade at JLab and an aggressive schedule maintained by the MSU Conventional Facilities department. Reported here is an updated status of the cryogenic plant, including the equipment procurement status, plant layout, facility equipment and project schedule.

  4. Ketogenic diet treatment for pediatric super-refractory status epilepticus.

    Science.gov (United States)

    Appavu, Brian; Vanatta, Lisa; Condie, John; Kerrigan, John F; Jarrar, Randa

    2016-10-01

    We aimed to study whether ketogenic diet (KD) therapy leads to resolution of super-refractory status epilepticus in pediatric patients without significant harm. A retrospective review was performed at Phoenix Children's Hospital on patients with super-refractory status epilepticus undergoing ketogenic diet therapy from 2011 to 2015. Ten children with super-refractory status epilepticus, ages 2-16 years, were identified. 4/10 patients had immune mediated encephalitis, including Rasmussen encephalitis, anti-N-methyl-d-aspartate receptor encephalitis, and post-infectious mycoplasma encephalitis. Other etiologies included Lennox Gastaut Syndrome, non-ketotic hyperglycinemia, PCDH19 and GABRG2 genetic epilepsy, New Onset Refractory Status Epilepticus, and Febrile Infection-Related Epilepsy Syndrome. 4/10 patients' EEG features suggested focal with status epilepticus, and 6/10 suggested generalized with status epilepticus. Median hospital length was 61days and median ICU length was 27days. The median number of antiepileptic medications prior to diet initiation was 3.0 drugs, and the median after ketogenic diet treatment was 3.5 drugs. Median duration of status epilepticus prior to KD was 18days. 9/10 patients had resolution of super-refractory status epilepticus in a median of 7days after diet initiation. 8/9 patients were weaned off anesthesia within 15days of diet initiation, and within 1day of achieving ketonuria. 1/10 patients experienced side effects on the diet requiring supplementation. Most patients achieved resolution of status epilepticus on KD therapy, suggesting it could be an effective therapy that can be utilized early in the treatment of children with super refractory status epilepticus. Copyright © 2016. Published by Elsevier Ltd.

  5. Molecular and biochemical analyses of platelet-derived growth factor receptor (PDGFR) B, PDGFRA, and KIT receptors in chordomas.

    Science.gov (United States)

    Tamborini, Elena; Miselli, Francesca; Negri, Tiziana; Lagonigro, M Stefania; Staurengo, Samantha; Dagrada, Gian Paolo; Stacchiotti, Silvia; Pastore, Elisa; Gronchi, Alessandro; Perrone, Federica; Carbone, Antonino; Pierotti, Marco A; Casali, Paolo G; Pilotti, Silvana

    2006-12-01

    We have previously shown the presence of an activated platelet-derived growth factor (PDGF) receptor (PDGFR) B and its ligand PDGFB in a limited number of patients with clinical and radiological responses to imatinib mesylate treatment. This article describes the results of comprehensive molecular/biochemical analyses of the three receptors targeted by the drug (PDGFRB, PDGFRA, and KIT) in a series of 31 chordoma patients. The presence and activation status of PDGFRB, PDGFRA, and KIT receptors were investigated by means of immunoprecipitation and Western blot analyses complemented by immunohistochemistry, their expression level was analyzed by means of real-time PCR, and the occurrence of activating point mutations was investigated by means of cDNA sequencing. The PDGFB, PDGFA, and stem cell factor cognate ligands were investigated by reverse transcription-PCR, and gene status was assessed by fluorescence in situ hybridization. The results show that PDGFRB was highly expressed and phosphorylated, whereas PDGFRA and KIT were less expressed but phosphorylated and thus activated. These findings, together with the absence of gain-of-function mutations and the presence of the cognate ligands, strongly support the hypothesis that the activation mechanism is the autocrine/paracrine loop. No role seems to be played by gene amplification. In the light of our findings, the clinical benefit observed in chordoma patients treated with imatinib seems to be attributable to the switching off of all three receptors.

  6. Evolutionary analysis of functional divergence among chemokine receptors, decoy receptors and viral receptors

    Directory of Open Access Journals (Sweden)

    Hiromi eDaiyasu

    2012-07-01

    Full Text Available Chemokine receptors (CKRs function in the inflammatory response and in vertebrate homeostasis. Decoy and viral receptors are two types of CKR homologues with modified functions from those of the typical CKRs. The decoy receptors are able to bind ligands without signaling. On the other hand, the viral receptors show constitutive signaling without ligands. We examined the sites related to the functional difference. At first, the decoy and viral receptors were each classified into five groups, based on the molecular phylogenetic analysis. A multiple amino acid sequence alignment between each group and the CKRs was then constructed. The difference in the amino acid composition between the group and the CKRs was evaluated as the Kullback-Leibler (KL information value at each alignment site. The KL information value is considered to reflect the difference in the functional constraints at the site. The sites with the top 5% of KL information values were selected and mapped on the structure of a CKR. The comparisons with decoy receptor groups revealed that the detected sites were biased on the intracellular side. In contrast, the sites detected from the comparisons with viral receptor groups were found on both the extracellular and intracellular sides. More sites were found in the ligand-binding pocket in the analyses of the viral receptor groups, as compared to the decoy receptor groups. Some of the detected sites were located in the GPCR motifs. For example, the DRY motif of the decoy receptors was often degraded, although the motif of the viral receptors was basically conserved. The observations for the viral receptor groups suggested that the constraints in the pocket region are loose and that the sites on the intracellular side are different from those for the decoy receptors, which may be related to the constitutive signaling activity of the viral receptors.

  7. Melatonin Receptor Genes in Vertebrates

    Directory of Open Access Journals (Sweden)

    Hua Dong Yin

    2013-05-01

    Full Text Available Melatonin receptors are members of the G protein-coupled receptor (GPCR family. Three genes for melatonin receptors have been cloned. The MT1 (or Mel1a or MTNR1A and MT2 (or Mel1b or MTNR1B receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype, Mel1c (or MTNR1C, has been identified in fish, amphibians and birds. Another melatonin related orphan receptor, GPR50, which does not bind melatonin, is found exclusively in mammals. The hormone melatonin is secreted primarily by the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone acts systemically in numerous organs. In the brain, it is involved in the regulation of various neural and endocrine processes, and it readjusts the circadian pacemaker, the suprachiasmatic nucleus. This article reviews recent studies of gene organization, expression, evolution and mutations of melatonin receptor genes of vertebrates. Gene polymorphisms reveal that numerous mutations are associated with diseases and disorders. The phylogenetic analysis of receptor genes indicates that GPR50 is an outgroup to all other melatonin receptor sequences. GPR50 may have separated from a melatonin receptor ancestor before the split between MTNR1C and the MTNR1A/B ancestor.

  8. Worldwide vitamin D status

    NARCIS (Netherlands)

    van Schoor, N.M.; Lips, P.T.A.M.

    2011-01-01

    The aim of the present study is to summarize existing literature on vitamin D levels in adults in different continents and different countries woldwide. The best determinant of vitamin D status is the serum concentration of 25-hydroxyvitamin D (25(OH)D). Most investigators agree that serum 25(OH)D

  9. Status, Numbers and Influence

    Science.gov (United States)

    Melamed, David; Savage, Scott V.

    2013-01-01

    We develop a theoretical model of social influence in n-person groups. We argue that disagreement between group members introduces uncertainty into the social situation, and this uncertainty motivates people to use status characteristics to evaluate the merits of a particular opinion. Our model takes the numerical distribution of opinions and the…

  10. Assessing intravascular fluid status

    African Journals Online (AJOL)

    perfusion such as urine output. or titration of fluid therapy with the goal of optimising haemodynamic status. Most practitioners agree that an underlying theme is ... their work is the understanding that at steady state venous return and cardiac output are equal, and that factors increasing venous return would enable a greater.

  11. Fusion safety status report

    International Nuclear Information System (INIS)

    1986-10-01

    This report includes information on a) tritium handling and safety; b) activation product generation and release; c) lithium safety; d) superconducting magnet safety; e) operational safety and shielding; f) environmental impact; g) recycling, decommissioning and waste management; and h) accident analysis. Recommendations for high priority research and development are presented, as well as the current status in each area

  12. Status and the brain.

    Directory of Open Access Journals (Sweden)

    Amanda V Utevsky

    2014-09-01

    Full Text Available Social hierarchy is a fact of life for many animals. Navigating social hierarchy requires understanding one's own status relative to others and behaving accordingly, while achieving higher status may call upon cunning and strategic thinking. The neural mechanisms mediating social status have become increasingly well understood in invertebrates and model organisms like fish and mice but until recently have remained more opaque in humans and other primates. In a new study in this issue, Noonan and colleagues explore the neural correlates of social rank in macaques. Using both structural and functional brain imaging, they found neural changes associated with individual monkeys' social status, including alterations in the amygdala, hypothalamus, and brainstem--areas previously implicated in dominance-related behavior in other vertebrates. A separate but related network in the temporal and prefrontal cortex appears to mediate more cognitive aspects of strategic social behavior. These findings begin to delineate the neural circuits that enable us to navigate our own social worlds. A major remaining challenge is identifying how these networks contribute functionally to our social lives, which may open new avenues for developing innovative treatments for social disorders.

  13. Super Refractory Status Epilepticus

    African Journals Online (AJOL)

    user

    Mayer st et al did retrospective cohort study from 1 January st. 1994 to 31 March 1998 at Presbyterian Medical. Centre in Columbia, to determine the frequency, risk factors and impact on the outcome of RSE. They found out that 69% of seizures recurred after. Key Words: Super refractory status epilepticus, Zambia. Medical ...

  14. Experimental status of physics

    Indian Academy of Sciences (India)

    In a short period of time, we will have a large amount of results from -factories including ones on CP violation. In this talk, we briefly review the current experimental status of -physics. After a quick description of -facilities, we divide this vast field into two categories: (1) weak interaction and QCD, (2) unitarity triangle and ...

  15. Health status ofhostel dwellers

    African Journals Online (AJOL)

    1991-06-15

    Jun 15, 1991 ... Cape Town tuberculosis notification rates for the hostel dwellers of Langa and Guguletu emphasise the ... Department of Social Anthropology, University of Cape. Town. M. A. RAMPHELE, M.B. CH.B., D.C.H. ... health status of hostel dwellers in Langa, Nyanga and Guguletu. Health data were collected from ...

  16. Status of TRISTAN operation

    International Nuclear Information System (INIS)

    Satoh, Kotaro

    1990-01-01

    The present status of the TRISTAN operation is summarized mainly after the installation of superconducting cavities in the 1988 summer shutdown. The paper describes the initial experience of the superconducting cavity operation, the colliding operation at 30.4 GeV and the beam injection. Future improvement is also reported. (author)

  17. COMPASS Status Report 2010

    CERN Document Server

    COMPASS Collaboration

    2010-01-01

    This report gives an overview of the setup and the performance of the COMPASS experiment during the 2009 hadron beam run and describes the preparation and startup of the 2010 muon beam run with the polarised target. The status of analysis is presented both for the hadron and muon data with emphasis on the 2008/2009 hadron data.

  18. HIV status and tuberculosis

    African Journals Online (AJOL)

    User

    This hospital based study was done to estimate the magnitude of pulmonary and extra-pulmonary tuberculosis and to determine predictors of tuberculosis ..... Patient`s risk factors associated with increased risk of tuberculosis includes chronic cough, wasting, advanced age, HIV status, Diabetes Mellitus, Malnutrition etc ...

  19. Status of numerical relativity

    Indian Academy of Sciences (India)

    Keywords. Numerical relativity; gravitational waves; black hole; neutron star. Abstract. I describe the current status of numerical relativity from my personal point of view. Here, I focus mainly on explaining the numerical implementations necessary for simulating general relativistic phenomena such as the merger of compact ...

  20. NASA Armstrong Status

    Science.gov (United States)

    Jacobson, Steven R.

    2014-01-01

    Armstrong (formerly Dryden) Flight Research Center continues it's legacy of exciting work in the area of dynamics and control of advanced vehicle concepts. This status presentation highlights the research and technology development that Armstrong's Control and Dynamics branch is performing in the areas of Control of Flexible Structures and Automated Cooperative Trajectories.

  1. Angola: Country Status Report.

    Science.gov (United States)

    Bruhn, Thea C.

    A survey of the status of language usage in Angola begins with an overview of the usage and distribution of Portuguese as the official language, and the four most significant native languages and dialects spoken there: Umbundu, Kimbundu, Kikongo, and Lunda-Chokwe. The introduction of Spanish through Cuban trainers, teachers, and military advisors…

  2. HESYRL control system status

    International Nuclear Information System (INIS)

    Yao Chihyuan

    1992-01-01

    HESYRL synchrotron radiation storage ring was completed in 1989 and has been in commissioning since then. Now it has met its design specification and is ready for synchrotron light experiments. Control system of the project was completed in 1989 and some modifications were made during commissioning. This paper describes its present configuration, status and upgrading plan. (author)

  3. Intact coupling of M1 receptors and preserved M2 and M4 receptors in the cortex in progressive supranuclear palsy: contrast with other dementias.

    Science.gov (United States)

    Warren, Naomi M; Piggott, Margaret A; Lees, Andrew J; Perry, Elaine K; Burn, David J

    2008-05-01

    Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterised clinically by motor and cognitive symptoms. Cholinergic dysfunction is thought to be responsible for much of the cognitive symptomatology. To date, however, cholinergic replacement therapies have been ineffective. We used receptor specific radioligand autoradiography to measure M1, M2, and M4 receptor density, and the functional status of the principal cortical subtype, M1, in the frontal cortex in post-mortem brain tissue of PSP patients (n=14). Results were compared to normal controls (n=17) and patients with dementia with Lewy bodies (DLB, n=12) and Alzheimer's disease (AD, n=15). In PSP there were no changes in M1, M2, or M4 muscarinic receptor densities or M1 coupling. DLB cases showed a non-significant increase in M1 receptors. In AD there was a reduction in M1 receptors and coupling in most frontal cortical areas which reached significance, compared to DLB, for M1 receptors in the cingulate (p<0.05). We conclude from this first systematic study of cortical muscarinic receptors in PSP that functioning cortical muscarinic receptors are preserved. A further, larger trial of cholinergic therapy, such as an M1 agonist, may be warranted.

  4. Cocaine potentiates multiple 5-HT2A receptor signaling pathways and is associated with decreased phosphorylation of 5-HT2A receptors in vivo.

    Science.gov (United States)

    Franklin, Jade M; Carrasco, Gonzalo A

    2015-03-01

    Cocaine addiction is a chronic relapsing disorder in which the underlying mechanisms are not well understood. Here, we used Sprague-Dawley rats injected with either saline (1 ml/kg) or cocaine (15 mg/kg) for 7 days (b.i.d, i.p) to study the effect of cocaine on several components of 5-HT2A receptor signaling in prefrontal cortex (PFCx). We detected enhanced activation of 5-HT2A receptor-mediated phospholipase C beta (PLCβ) and extracellular regulated kinase 1/2 activity in PFCx of cocaine-treated rats. Although we were unable to detect changes in the protein levels of several proteins associated with 5-HT2A receptor signaling such as caveolin-1, postsynaptic density protein 95, β-arrestin 2, etc., we found a significant reduction in the phosphorylation status of cortical 5-HT2A receptors. This phenomenon was associated with reduced levels of G-protein receptor kinase 5 (GRK5), but not GRK2 or RSK2, proteins. Our results suggest that decreased phosphorylation of 5-HT2A receptors could mediate, at least in part, the cocaine-induced potentiation of multiple 5-HT2A receptor signaling pathways in rat PFCx. As discussed in this manuscript, we hypothesize that preventing these neuroadaptations in 5-HT2A receptor signaling may alleviate some of the aversive withdrawal-associated symptoms that contribute to relapse to cocaine abuse.

  5. Rac1 contributes to trastuzumab resistance of breast cancer cells: Rac1 as a potential therapeutic target for the treatment of trastuzumab-resistant breast cancer.

    Science.gov (United States)

    Dokmanovic, Milos; Hirsch, Dianne S; Shen, Yi; Wu, Wen Jin

    2009-06-01

    Although treatment with trastuzumab improves outcomes for women with ErbB2-positive breast cancer, many patients who achieve an initial response to trastuzumab subsequently acquire resistance within 1 year. Rac1, a Ras-like small GTPase, has been implicated in the control of cell growth and morphology and is believed to be associated with breast cancer progression and metastasis. Here, we show that when parental SKBR3 cells become resistant to trastuzumab, Rac1 activity is increased, leading to altered cell morphology, which is accompanied by significant cytoskeleton disorganization. Furthermore, both trastuzumab-mediated down-regulation of ErbB2 and epidermal growth factor-induced down-regulation of epidermal growth factor receptor are impaired in the trastuzumab-resistant SKBR3 cells, indicating that the endocytic down-regulation of ErbB receptors is compromised in the resistant cells. This results in an aberrant accumulation of ErbB2 on the cell surface and enhanced ErbB2 and extracellular signal-regulated kinase activity in trastuzumab-resistant SKBR3 cells. Additionally, overexpression of constitutively active Rac1G12V in parental SKBR3 cells reduces sensitivity to trastuzumab. After reduction of Rac1 activity by NSC23766, a specific Rac1 inhibitor, trastuzumab-resistant SKBR3 cells display a cellular morphology similar to parental SKBR3 cells. Moreover, we show that NSC23766 restores trastuzumab-mediated endocytic down-regulation of ErbB2 and reduces extracellular signal-regulated kinase activity in resistant SKBR3 cells. Our findings highlight an important role for Rac1 in trastuzumab resistance of human breast cancer cells and identify the impaired trastuzumab-mediated endocytic down-regulation of ErbB2 as a novel mechanism of trastuzumab resistance. The significant effects of NSC23766 on trastuzumab-resistant SKBR3 cells warrant further study of NSC23766 as a potential treatment of trastuzumab-resistant breast cancers.

  6. Molecular characterization of apocrine salivary duct carcinoma.

    Science.gov (United States)

    Chiosea, Simion I; Williams, Lindsay; Griffith, Christopher C; Thompson, Lester D R; Weinreb, Ilan; Bauman, Julie E; Luvison, Alyssa; Roy, Somak; Seethala, Raja R; Nikiforova, Marina N

    2015-06-01

    Contemporary classification and treatment of salivary duct carcinoma (SDC) require its thorough molecular characterization. Thirty apocrine SDCs were analyzed by the Ion Ampliseq Cancer HotSpot panel v2 for mutations in 50 cancer-related genes. Mutational findings were corroborated by immunohistochemistry (eg, TP53, BRAF, β-catenin, estrogen, and androgen receptors) or Sanger sequencing/SNaPshot polymerase chain reaction. ERBB2 (HER2), PTEN, FGFR1, CDKN2A/P16, CMET, EGFR, MDM2, and PIK3CA copy number changes were studied by fluorescence in situ hybridization. TP53 mutations (15/27, 56%), PTEN loss (11/29, 38%, including 2 cases with PTEN mutation), PIK3CA hotspot mutations (10/30, 33%), HRAS hotspot mutations (10/29; 34%), and ERBB2 amplification (9/29, 31%, including 1 case with mutation) represented the 5 most common abnormalities. There was no correlation between genetic changes and clinicopathologic parameters. There was substantial overlap between genetic changes: 8 of 9 cases with ERBB2 amplification also harbored a PIK3CA, HRAS, and TP53 mutation and/or PTEN loss. Six of 10 cases with PIK3CA mutation also had an HRAS mutation. These findings provide a molecular rationale for dual targeting of mitogen-activated protein kinase and phosphoinositide 3-kinase pathways in SDC. FGFR1 amplification (3/29, 10%) represents a new potential target. On the basis of studies of breast carcinomas, the efficacy of anti-ERBB2 therapy will likely be decreased in SDC with ERBB2 amplification co-occurring with PIK3CA mutation or PTEN loss. Therefore, isolated ERBB2 testing is insufficient for theranostic stratification of apocrine SDC. On the basis of the prevalence and type of genetic changes, apocrine SDC appears to resemble one subtype of breast carcinoma-"luminal androgen receptor positive/molecular apocrine."

  7. ErbB4 Overexpression as an Antagonist of ErbB2/HER2/Neu Induced Human Breast Cancer Cell Proliferation

    Science.gov (United States)

    2006-08-01

    Sophia Y. Tsai , Ming -Jer Tsai , and Bert W. O’Malley. MEKK1 increases SRC-3 protein stability by targeting Ub- dependent 26s proteasome pathway. Jun...cancers. Oncogene 1998;17:919–24. 24. Sattler M, Liang H, Nettesheim D, et al. Structure of Bcl-xL-Bak peptide complex: recognition between reg- ulators

  8. [Targeted tumor suppression by a secreted fusion protein consisting of anti- erbB2 antibody and reversed caspase-3 to SKBr3 cells].

    Science.gov (United States)

    Zhang, Li-hong; Jia, Lin-tao; Yu, Cui-juan; Qu, Ping; Dong, Hai-long; Zhao, Jing; Xu, Yan-ming; Wang, Cheng-Ji; Yang, An-gang

    2003-04-10

    To investigate the targeted killing effect to SKBr3 cells due to the expression of a secreted fusion protein consisting of anti-erbB2 antibody and reversed caspase-3. A recombinant plasmid pCMV-e23scFv-PEII-revcasp 3 was constructed by subcloning reversed caspase-3 gene to the downstream of anti-erbB2 antibody and transfected into Jurkat cells. The cell lines which secreted expressing fusion protein stably were selected. The fusion protein in media was detected by ELISA and the media was used to culture human breast cancer SKBr3 cells. The recombinant plasmids with liposomes was administrated to BALB/C nude mouses bearing SKBr3 tumor by intramuscular injection. The targetting effect of the recombinant fusion protein caspase-3 was detected by indirect immunofluorescence staining. Fusion protein can be expressed and secreted by Jurkat cells stably and kill SKBr3 cells. Significant prolonged survival time (prolonged by 72%) and inhibition of tumor growth in vivo (within inhibition ratio of 77%) were seen in the group administered with recombinant plasmids. Indirect immunofluorescence staining showed that the recombinant fusion protein caspase-3 has targetting effect. Secreted expression of the fusion protein consisting of anti-erbB2 antibody and reversed caspase-3 can targetedly induce SKBr3 cells to death.

  9. Fatty acid synthase inhibition by amentoflavone suppresses HER2/neu (erbB2) oncogene in SKBR3 human breast cancer cells.

    Science.gov (United States)

    Lee, Jin Sun; Sul, Ji Young; Park, Jun Beom; Lee, Myung Sun; Cha, Eun Young; Song, In Sang; Kim, Je Ryong; Chang, Eil Sung

    2013-05-01

    Fatty acid synthase (FASN) is a potential therapeutic target for treatment of cancer and obesity, and is highly elevated in 30% of HER2-overexpressing breast cancers. Considerable interest has developed in searching for novel FASN inhibitors as therapeutic agents in treatment of HER2-overexpressing breast cancers. Amentoflavone was found to be effective in suppressing FASN expression in HER2-positive SKBR3 cells. Pharmacological inhibition of FASN by amentoflavone specifically down-regulated HER2 protein and mRNA, and caused an up-regulation of PEA3, a transcriptional repressor of HER2. In addition, pharmacological blockade of FASN by amentoflavone preferentially decreased cell viability and induced cell death in SKBR3 cells. Palmitate reduced the cytotoxic effect of amentoflavone, as the percentage of viable cells was increased after the addition of exogenous palmitate. Amentoflavone-induced FASN inhibition inhibited the translocation of SREBP-1 in SKBR3 cells. Amentoflavone inhibited phosphorylation of AKT, mTOR, and JNK. The use of pharmacological inhibitors revealed that the modulation of AKT, mTOR, and JNK phosphorylation required synergistic amentoflavone-induced FASN inhibition and HER2 activation in SKBR3 cells. These results suggest that amentoflavone modulated FASN expression by regulation of HER2-pathways, and induced cell death to enhance chemopreventive or chemotherapeutic activity in HER2-positive breast cancers. Copyright © 2012 John Wiley & Sons, Ltd.

  10. VALUE OF P-GLYCOPROTEIN, GLUTATHIONE-S-TRANSFERASE-PI, C-ERBB-2, AND P53 AS PROGNOSTIC FACTORS IN OVARIAN CARCINOMAS

    NARCIS (Netherlands)

    VANDERZEE, AGJ; HOLLEMA, H; SUURMEIJER, AJH; KRANS, M; SLUITER, WJ; WILLEMSE, PHB; AALDERS, JG; DEVRIES, EGE

    Purpose: To determine the prognostic value of immunostaining of P-glycoprotein (P-gp), glutathione S-transferase (GST) pi, c-erbB-2, and p53 in patients with advanced-stage ovarian carcinoma. Patients and Methods: Immunostaining of P-gp, GST pi, c-erbB-2, and p53 was performed on 89 primary tumors

  11. The Role of Novel Substituted Diindolyl Methane Analogues in the Treatment of Triple-Negative and ErbB2-Positive Breast Cancer

    Science.gov (United States)

    2016-05-01

    DIM-10 liposomes: We have developed a CREKA (A tumor endothelial cell targeted peptide, cysteine– arginine – glutamic acid– lysine –alanine) coated...report (2014-2015) we have studied the novel mechanism of DIM analogs (DIM-C-pPhCO2Me and DIM-C-pPhCN) in the treatment of TNBC by antagonizing an

  12. Investigating the Role of Fatty Acid Metabolism and DecR1 Expression ErbB2-Driven Mammary Tumorigenesis and Metastasis Using a Transgenic Mouse Model Approach

    Science.gov (United States)

    2011-07-01

    pregnancy /lactation and involution. Lactation is a process that relies heavily on fatty acid synthesis, so induction of DecR1 expression could have a...generating data will be slightly appended . 14    References:   1.  Dang, C.V. and G.L. Semenza, Oncogenic alterations of metabolism. Trends Biochem

  13. Assessment of Mental Status.

    Science.gov (United States)

    Finney, Glen R; Minagar, Alireza; Heilman, Kenneth M

    2016-02-01

    Assessing the mental status of patients with a neurobehavioral disorder is a critical element in the diagnosis and treatment of these patients. This assessment should always be performed after the patient's history it taken and a general physical as well as a neurologic examination is completed. The mental status examination commences with observing the patient's appearance and level of consciousness. The examiner should also pay attention to patient's social behavior, emotional state and mood. There are 3 major means of assessing a patient's mental status. One type attempts to determine if the patient is demented and the severity of the dementia as it pertains to their ability to perform activities of daily living as well as instrumental activities. A second type of assessment utilizes what may be termed as "screening tests" or "omnibus tests". These brief tests are performed independent of the patient's history and examination. The two most frequently used screening tests are the Mini-Mental Status Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). The third means of assessing a patient's mental status is by using specific neuropsychological tests that focus on specific domains of cognition, such as frontal executive functions, attention, episodic verbal and visuospatial memory, declarative knowledge such as language (speech, reading and writing) and arithmetical, as well as visuospatial and perceptual abilities. These neurobehavioral, neuropsychiatric and neuropsychological assessments of patients with a cognitive decline and behavioral abnormalities should often be accompanied by laboratory tests, and neuroimaging that can help determine the underlying pathologic process so that effective therapeutic and management approaches can be provided. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Differences of IL-1β Receptors Expression by Immunocompetent Cells Subsets in Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Alina A. Alshevskaya

    2015-01-01

    Full Text Available IL-1β is involved in the induction and maintenance of chronic inflammation in rheumatoid arthritis (RA. Its activity is regulated and induced by soluble and membrane-bound receptors, respectively. The effectiveness of the cytokine depends not only on the percentage of receptor-positive cells in an immunocompetent subset but also on the density of receptor expression. The objective of this study was to investigate the expression of IL-1β membrane-bound receptors (IL-1R1 and IL-1R2 in terms of the percentage of receptor-positive cells and the number of receptors per cell in different subsets of immune cells in RA patients before and after a course of basic (excluding anticytokine therapy and in healthy individuals. The resulting data indicate differences in the expression of IL-1β receptors among T cells, B cells, and monocytes in healthy volunteers and in rheumatoid arthritis patients. The importance of determining both the relative percentage of cells expressing receptors to immunomodulatory cytokines and the number of membrane-bound receptors per cell is highlighted by evidence of unidirectional or multidirectional changing of these parameters according to cell subset and health status.

  15. Neuroprotection by NMDA receptor antagonists in a variety of neuropathologies.

    Science.gov (United States)

    Palmer, G C

    2001-09-01

    Because of adverse reactions, early efforts to introduce high affinity competitive or use-dependent NMDA receptor antagonists into patients suffering from stroke, head trauma or epilepsy met with failure. Later it was discovered that both low affinity use-dependent NMDA receptor antagonists and compounds with selective affinity for the NR2B receptor subunit met the criteria for safe administration into patients. Furthermore, these low affinity antagonists exhibit significant mechanistic differences from their higher affinity counterparts. Success of the latter is attested to the ability of the following low affinity compounds to be marketed: 1) Cough suppressant-dextromethorphan (available for decades); 2) Parkinson's disease--amantadine, memantine and budipine; 3) Dementia--memantine; and 4) Epilepsy--felbamate. Moreover, Phase III clinical trials are ongoing with remacemide for epilepsy and Huntington's disease and head trauma for HU-211. A host of compounds are or were under evaluation for the possible treatment of stroke, head trauma, hyperalgesia and various neurodegenerative disorders. Despite the fact that other drugs with associated NMDA receptor mechanisms have reached clinical status, this review focuses only on those competitive and use-dependent NMDA receptor antagonists that reached clinical trails. The ensuing discussions link the in vivo pharmacological investigations that led to the success/mistakes/ failures for eventual testing of promising compounds in the clinic.

  16. Flavivirus Entry Receptors: An Update

    Directory of Open Access Journals (Sweden)

    Manuel Perera-Lecoin

    2013-12-01

    Full Text Available Flaviviruses enter host cells by endocytosis initiated when the virus particles interact with cell surface receptors. The current model suggests that flaviviruses use at least two different sets of molecules for infectious entry: attachment factors that concentrate and/or recruit viruses on the cell surface and primary receptor(s that bind to virions and direct them to the endocytic pathway. Here, we present the currently available knowledge regarding the flavivirus receptors described so far with specific attention to C-type lectin receptors and the phosphatidylserine receptors, T-cell immunoglobulin and mucin domain (TIM and TYRO3, AXL and MER (TAM. Their role in flavivirus attachment and entry as well as their implication in the virus biology will be discussed in depth.

  17. Clustering nuclear receptors in liver regeneration identifies candidate modulators of hepatocyte proliferation and hepatocarcinoma.

    Directory of Open Access Journals (Sweden)

    Michele Vacca

    Full Text Available Liver regeneration (LR is a valuable model for studying mechanisms modulating hepatocyte proliferation. Nuclear receptors (NRs are key players in the control of cellular functions, being ideal modulators of hepatic proliferation and carcinogenesis.We used a previously validated RT-qPCR platform to profile modifications in the expression of all 49 members of the NR superfamily in mouse liver during LR. Twenty-nine NR transcripts were significantly modified in their expression during LR, including fatty acid (peroxisome proliferator-activated receptors, PPARs and oxysterol (liver X receptors, Lxrs sensors, circadian masters RevErbα and RevErbβ, glucocorticoid receptor (Gr and constitutive androxane receptor (Car. In order to detect the NRs that better characterize proliferative status vs. proliferating liver, we used the novel Random Forest (RF analysis to selected a trio of down-regulated NRs (thyroid receptor alpha, Trα; farsenoid X receptor beta, Fxrβ; Pparδ as best discriminators of the proliferating status. To validate our approach, we further studied PPARδ role in modulating hepatic proliferation. We first confirmed the suppression of PPARδ both in LR and human hepatocellular carcinoma at protein level, and then demonstrated that PPARδ agonist GW501516 reduces the proliferative potential of hepatoma cells.Our data suggest that NR transcriptome is modulated in proliferating liver and is a source of biomarkers and bona fide pharmacological targets for the management of liver disease affecting hepatocyte proliferation.

  18. Olfactory Plasticity: Variation in the Expression of Chemosensory Receptors in Bactrocera dorsalis in Different Physiological States

    Directory of Open Access Journals (Sweden)

    Sha Jin

    2017-09-01

    Full Text Available Changes in physiological conditions could influence the perception of external odors, which is important for the reproduction and survival of insect. With the alteration of physiological conditions, such as, age, feeding state, circadian rhythm, and mating status, insect can modulate their olfactory systems accordingly. Ionotropic, gustatory, and odorant receptors (IR, GR, and ORs are important elements of the insect chemosensory system, which enable insects to detect various external stimuli. In this study, we investigated the changes in these receptors at the mRNA level in Bactrocera dorsalis in different physiological states. We performed transcriptome analysis to identify chemosensory receptors: 21 IRs, 12 GRs, and 43 ORs were identified from B. dorsalis antennae, including almost all previously known chemoreceptors in B. dorsalis and a few more. Quantitative real-time polymerase chain reaction analysis revealed the effects of feeding state, mating status and time of day on the expression of IR, GR, and OR genes. The results showed that expression of chemosensory receptors changed in response to different physiological states, and these changes were completely different for different types of receptors and between male and female flies. Our study suggests that the expressions of chemosensory receptors change to adapt to different physiological states, which may indicate the significant role of these receptors in such physiological processes.

  19. Stable isotope labeling by amino acids in cell culture (SILAC) and quantitative comparison of the membrane proteomes of self-renewing and differentiating human embryonic stem cells

    DEFF Research Database (Denmark)

    Prokhorova, Tatyana A; Rigbolt, Kristoffer T G; Johansen, Pia T

    2009-01-01

    : Glypican-4, Neuroligin-4, ErbB2, receptor-type tyrosine-protein phosphatase zeta (PTPRZ), and Glycoprotein M6B. Our study also revealed 17 potential markers of hESC differentiation as their corresponding protein expression levels displayed a dramatic increase in differentiated embryonic stem cell...

  20. TRASTUZUMAB EMTANSINE Tumor-Activated Prodrug (TAP) Immunoconjugate Oncolytic

    DEFF Research Database (Denmark)

    Kümler, Iben; Nielsen, Dorte Lisbet; Mortensen, C Ehlers

    2011-01-01

    Trastuzumub emtansine (T-DM1) is a novel antibody-drug conjugate. The conjugate is comprised of the antibody trastuzurnab, which is directed against the receptor tyrosine-protein kinase erbB-2 (HERZ), a derivative of the cytostatic agent maytansinoid DM1(mertansine), and a linker that covalently ...

  1. Antibody Probes to Estrogen Receptor-Alpha Transcript-Specific Upstream Peptides: Alternate ER-Alpha Promoter Use and Breast Cancer Etiology/Outcome

    National Research Council Canada - National Science Library

    Pentecost, Brian

    2002-01-01

    Positive Estrogen Receptor alpha (ER) status correlates with a reduced incidence of breast cancer recurrence in the first years after resection of tumors, and predicts a favorable response to adjuvant anti-estrogens...

  2. Laboratory assessment of iron status in pregnancy.

    LENUS (Irish Health Repository)

    Walsh, Thomas

    2012-02-01

    BACKGROUND: Efforts to improve maternal nutrition during pregnancy prompted an observational study of the occurrence of maternal iron deficiency and its laboratory diagnosis in almost 500 pregnancies. METHODS: In this longitudinal study, the biochemical and haematological iron indices of women (n=492) attending a prenatal clinic in a Dublin maternity hospital were assessed at first booking (mean 15.9 weeks), and after 24 weeks, and 36 weeks of gestation. Full blood counts were measured. Serum ferritin (SF), zinc protoporphyrin (ZPP), and transferrin receptor (sTfR) concentrations were assayed and transferrin receptor index (sTfR-Index) was calculated. The occurrence of low values and their diagnostic values were considered. RESULTS: A high occurrence iron deficiency (ID) at first booking (SF<12 mug\\/L) had increased over six-fold by 24 weeks, and all biochemical iron indices reflected progressive iron depletion right up to term. The WHO recommended anaemia "cut-off" (Hb<110 g\\/L) was insensitive to biochemical iron deficiency at booking, missing over 90% of the low SF values (SF<12 mug\\/L) which were mostly associated with much higher Hb levels. CONCLUSIONS: This study stresses the importance of including a biochemical index of iron status in prenatal screening and supports SF as the best indicator of biochemical ID overall. sTfR was insensitive to iron deficiency in early pregnancy, whereas the sTfR-Index, as a ratio, has the potential to distinguish between ID and physiological anaemia, and may offer stability in the assessment of iron stores from early pregnancy to full term. A policy of early screening of both Hb and SF concentrations is recommended as the minimum requirement for surveillance of maternal iron status in pregnancy.

  3. Dimerization of nuclear receptors.

    Science.gov (United States)

    Germain, Pierre; Bourguet, William

    2013-01-01

    Multicellular organisms require specific intercellular communication to properly organize the complex body plan during embryogenesis and maintain its properties and functions during the entire life. While growth factors, neurotransmitters, and peptide hormones bind to membrane receptors, thereby inducing the activity of intracellular kinase cascades or the JAK-STAT signaling pathways, other small signaling compounds such as steroid hormones, certain vitamins, and metabolic intermediates enter, or are generated, within the target cells and bind to members of a large family of nuclear receptors (NRs). NRs are ligand-inducible transcription factors that control a plethora of biological phenomena, thus orchestrating complex events like development, organ homeostasis, immune function, and reproduction. NR-NR interactions are of major importance in these regulatory processes, as NRs regulate their target genes by binding to cognate DNA response elements essentially as homo- or heterodimers. A number of structural and functional studies have provided significant insights as to how combinatorial NRs rely on protein-protein contacts that discriminate geometric features of their DNA response elements, thereby allowing both binding site diversity and physiological specificity. Here, we will review our current understanding of NR-NR interactions and provide protocols for a number of experimental approaches that are useful for their study. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Status of memory loss.

    LENUS (Irish Health Repository)

    Iyer, Parameswaran Mahadeva

    2012-01-01

    A 72-year-old woman presented with first onset of seizure with no prior history of cognitive dysfunction. EEG revealed focal non-convulsive status epilepticus. MRI brain showed a left temporal non-enhancing lesion. Temporal pole biopsy showed acute neuronal necrosis and astrocyte hyperplasia together with extensive amyloid plaques and neurofibrillary tangles. Perivascular oligodendroglial hyperplasia was present. Postmortem examination revealed extensive plaque and tangle disease. Perivascular oligodendroglial hyperplasia was limited to the left temporal area. The presence of focal perivascular oligodendroglial hyperplasia in the left temporal cortex, combined with extensive plaque and tangle disease may have contributed to the focal status epilepticus in this patient. Although the presence of focal perivascular oligodendroglial hyperplasia has been reported in cases of temporal lobe epilepsy, it has not been reported as a cause of seizure in patients with Alzheimer\\'s disease previously. Further studies for clinical-pathologic correlation would be required to confirm this hypothesis.

  5. Status of MARS Code

    Energy Technology Data Exchange (ETDEWEB)

    N.V. Mokhov

    2003-04-09

    Status and recent developments of the MARS 14 Monte Carlo code system for simulation of hadronic and electromagnetic cascades in shielding, accelerator and detector components in the energy range from a fraction of an electronvolt up to 100 TeV are described. these include physics models both in strong and electromagnetic interaction sectors, variance reduction techniques, residual dose, geometry, tracking, histograming. MAD-MARS Beam Line Build and Graphical-User Interface.

  6. Status of fusion maintenance

    International Nuclear Information System (INIS)

    Fuller, G.M.

    1984-01-01

    Effective maintenance will be an essential ingredient in determining fusion system productivity. This level of productivity will result only after close attention is paid to the entire system as an entity and appropriate integration of the elements is made. The status of fusion maintenance is reviewed in the context of the entire system. While there are many challenging developmental tasks ahead in fusion maintenance, the required technologies are available in several high-technology industries, including nuclear fission

  7. Tritium monitoring : present status

    International Nuclear Information System (INIS)

    Rathnakaran, M.; Singh, A.N.

    1993-01-01

    The report summarizes the present status of techniques employed for the monitoring of tritium in water, air and other samples. A brief mention of the work done by numerous workers in the field, critical comments about the work and a fairly exhaustive list of references about the work done during the last 4 decades has been presented. On-line monitoring on real time basis in nuclear reactors is also discussed. (author). 83 refs., 10 refs., 2 tabs

  8. Status of gluonium searches

    International Nuclear Information System (INIS)

    Heusch, C.A.; California Univ., Santa Cruz, CA

    1991-01-01

    Quantum chromodynamics predicts the existence of quarkless mesons. The search for these hadrons has been ingenious and persevering. A review is presented of the current status of research that considers all model-dependent theoretical prejudice when searching for specific states. Early hints for candidate states have been investigated in the light of recent data, mostly from the Mark III Collaboration, in radiative charmonium decay. No 'smoking-gun' candidate stands out. (R.P.) 25 refs., 20 figs., 2 tabs

  9. Receptor studies in biological psychiatry

    International Nuclear Information System (INIS)

    Fujiwara, Yutaka

    1992-01-01

    Recent advances in the pharmacological treatment of endogenous psychosis have led to the development of biological studies in psychiatry. Studies on neurotransmitter receptors were reviewed in order to apply positron-emission tomograph (PET) for biological psychiatry. The dopamine (DA) hypothesis for schizophrenia was advanced on the basis of the observed effects of neuroleptics and methamphetamine, and DA(D 2 ) receptor supersensitivity measured by PET and receptor binding in the schizophrenic brain. The clinical potencies of neuroleptics for schizophrenia were correlated with their abilities to inhibit the D 2 receptor, and not other receptors. The σ receptor was expected to be a site of antipsychotic action. However, the potency of drugs action on it was not correlated with clinical efficacy. Haloperidol binds with high affinity to the σ receptor, which may mediate acute dystonia, an extrapyramidal side effect of neuroleptics. Behavioral and neurochemical changes induced by methamphetamine treatment were studied as an animal model of schizophrenia, and both a decrease of D 2 receptor density and an increase of DA release were detected. The monoamine hypothesis for manic-depressive psychosis was advanced on the basis of the effect of reserpine, monoamine oxidase inhibitor and antidepressants. 3 H-clonidine binding sites were increased in platelet membranes of depressive patients, 3 H-imipramine binding sites were decreased. The GABA A receptor is the target site for the action of anxiolytics and antiepileptics such as benzodiazepines and barbiturates. Recent developments in molecular biology techniques have revealed the structure of receptor proteins, which are classified into two receptor families, the G-protein coupled type (D 2 ) and the ion-channel type (GABA A ). (J.P.N.)

  10. Possible Relevance of Receptor-Receptor Interactions between Viral- and Host-Coded Receptors for Viral-Induced Disease

    Directory of Open Access Journals (Sweden)

    Luigi F. Agnati

    2007-01-01

    Full Text Available It has been demonstrated that some viruses, such as the cytomegalovirus, code for G-protein coupled receptors not only to elude the immune system, but also to redirect cellular signaling in the receptor networks of the host cells. In view of the existence of receptor-receptor interactions, the hypothesis is introduced that these viral-coded receptors not only operate as constitutively active monomers, but also can affect other receptor function by interacting with receptors of the host cell. Furthermore, it is suggested that viruses could also insert not single receptors (monomers, but clusters of receptors (receptor mosaics, altering the cell metabolism in a profound way. The prevention of viral receptor-induced changes in host receptor networks may give rise to novel antiviral drugs that counteract viral-induced disease.

  11. Activation of overexpressed receptors for insulin and epidermal growth factor interferes in mitogenic signaling without affecting the activation of p21ras

    NARCIS (Netherlands)

    Osterop, A.P.R.M.; Medema, R.H.; Ouwens, D.M.; Zon, G.C.M. van der; Möller, W.; Maassen, J.A.

    1994-01-01

    Activated receptors with a tyrosine kinase activity induce a variety of responses like changes in the differentiation and mitogenic status of cells. These responses are mediated in part by p21ras. Some of these activated receptors induce in certain cell types a pronounced, but transient, increase in

  12. Peptide Receptor Radionuclide Therapy & Oncology

    NARCIS (Netherlands)

    H. Bergsma (Hendrik)

    2017-01-01

    markdownabstractNeuroendocrine tumors (NETs) are rare neoplasms with differences in clinical presentation, course and prognosis. Most of the NETs express the somatostatine receptor, which can be utilized for imaging and therapy. Radiolabeled somatostatin analogs can be used for peptide receptor

  13. Hydrocarbon Receptor Pathway in Dogs

    NARCIS (Netherlands)

    Steenbeek, F.G. van; Spee, B.; Penning, L.C.; Kummeling, A.; Gils, I.H.M.; Grinwis, G.C.M.; Leenen, D. van; Holstege, F.C.P.; Vos-Loohuis, M.; Rothuizen, J.; Leegwater, P.A.J.

    The aryl hydrocarbon receptor (AHR) mediates biological responses to toxic chemicals. An unexpected role for AHR in vascularization was suggested when mice lacking AHR displayed impaired closure of the ductus venosus after birth, as did knockout mice for aryl hydrocarbon receptor interacting

  14. Coronavirus spike-receptor interactions

    NARCIS (Netherlands)

    Mou, H.

    2015-01-01

    Coronaviruses cause important diseases in humans and animals. Coronavirus infection starts with the virus binding with its spike proteins to molecules present on the surface of host cells that act as receptors. This spike-receptor interaction is highly specific and determines the virus’ cell, tissue

  15. Treatment of status migrainosus by general anesthesia: a case report.

    Science.gov (United States)

    Udelsmann, Artur; Saccomani, Priscila; Dreyer, Elisabeth; da Costa, Alberto Luiz Cunha

    2015-01-01

    The status migrainosus is a complication of migraine characterized by severe headache for more than 72h that did not respond to treatment, with risk of stroke and suicide. Researches on treatment are directed to drugs that stimulate GABA receptors; propofol and isoflurane act on sub-GABAa receptors and theoretically could be interesting. The first has been the subject of research in severe migraine. Opioids are employed in pain, and its use in chronic headache is debatable, but these agents are employed in acute cases. The goal is to present a case of refractory status migrainosus in that we decided to break the pain cycle by general anesthesia. Female patient, aged 50 years, with status migrainosus, in the last five days with visits to the emergency department, medicated parenterally with various agents without result. Without comorbidities, dehydrated, described her pain as "well over 10" in Visual Numeric Scale (VNS). After consulting the literature, and given the apparent severity of the condition, we opted for a general anesthesia: induction with fentanyl, propofol, and vecuronium and maintenance with isoflurane and propofol for two hours. Following the treatment, in the postanesthetic recuperation (PAR), the patient related her pain as VNS 3, and was released after five hours with VNS 2. Subsequently, her preventive treatment was resumed. Status migrainosus is a rare disabling complication and anesthetics have been the subject of research in its treatment; the option for general anesthesia with agents that stimulate GABA receptors, propofol and isoflurane, in association with fentanyl, proved effective and should encourage new research. Copyright © 2013 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.

  16. [Treatment of status migrainosus by general anesthesia: a case report].

    Science.gov (United States)

    Udelsmann, Artur; Saccomani, Priscila; Dreyer, Elisabeth; Costa, Alberto Luiz Cunha da

    2015-01-01

    The status migrainosus is a complication of migraine characterizedby severe headache for more than 72 h that did not respond to treatment, with risk of strokeand suicide. Researches on treatment are directed to drugs that stimulate GABA receptors; propofol and isoflurane act on sub-GABAa receptors and theoretically could be interesting. The first has been the subject of research in severe migraine. Opioids are employed in pain, and its use in chronic headache is debatable, but these agents are employed in acute cases. The goalis to present a case of refractory status migrainosus in that we decided to break the pain cycle by general anesthesia. Female patient, aged 50 years, with status migrainosus, in the last five days withvisits to the emergency department, medicated parenterally with various agents without result. Without comorbidities, dehydrated, described her pain as "well over 10" in Visual NumericScale (VNS). After consulting the literature, and given the apparent severity of the condition, we opted for a general anesthesia: induction with fentanyl, propofol, and vecuroniumand maintenance with isoflurane and propofol for two hours. Following the treatment, in the postanesthetic recuperation (PAR), the patient related her pain as VNS 3, and was released after five hours with VNS 2. Subsequently, her preventive treatment was resumed. Status migrainosus is a rare disabling complication and anesthetics have been the subject of research in its treatment; the option for general anesthesia with agents that stimulate GABA receptors, propofol and isoflurane, in association with fentanyl, proved effective and should encourage new research. Copyright © 2013 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

  17. Neurobeachin regulates neurotransmitter receptor trafficking to synapses

    NARCIS (Netherlands)

    Nair, R.; Lauks, J.; Jung, S; Cooke, N.E.; de Wit, H.; Brose, N.; Kilimann, M.W.; Verhage, M.; Rhee, J.

    2013-01-01

    The surface density of neurotransmitter receptors at synapses is a key determinant of synaptic efficacy. Synaptic receptor accumulation is regulated by the transport, postsynaptic anchoring, and turnover of receptors, involving multiple trafficking, sorting, motor, and scaffold proteins. We found

  18. Probing Biased Signaling in Chemokine Receptors

    DEFF Research Database (Denmark)

    Amarandi, Roxana Maria; Hjortø, Gertrud Malene; Rosenkilde, Mette Marie

    2016-01-01

    The chemokine system mediates leukocyte migration during homeostatic and inflammatory processes. Traditionally, it is described as redundant and promiscuous, with a single chemokine ligand binding to different receptors and a single receptor having several ligands. Signaling of chemokine receptor...

  19. Dopamine Receptors and Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Shin Hisahara

    2011-01-01

    Full Text Available Parkinson's disease (PD is a progressive extrapyramidal motor disorder. Pathologically, this disease is characterized by the selective dopaminergic (DAergic neuronal degeneration in the substantia nigra. Correcting the DA deficiency in PD with levodopa (L-dopa significantly attenuates the motor symptoms; however, its effectiveness often declines, and L-dopa-related adverse effects emerge after long-term treatment. Nowadays, DA receptor agonists are useful medication even regarded as first choice to delay the starting of L-dopa therapy. In advanced stage of PD, they are also used as adjunct therapy together with L-dopa. DA receptor agonists act by stimulation of presynaptic and postsynaptic DA receptors. Despite the usefulness, they could be causative drugs for valvulopathy and nonmotor complication such as DA dysregulation syndrome (DDS. In this paper, physiological characteristics of DA receptor familyare discussed. We also discuss the validity, benefits, and specific adverse effects of pharmaceutical DA receptor agonist.

  20. Mental Representations of Social Status

    Science.gov (United States)

    Chiao, Joan Y.; Bordeaux, Andrew R.; Ambady, Nalni

    2004-01-01

    How do people think about social status? We investigated the nature of social status and number representations using a semantic distance latency test. In Study 1, 21 college students compared words connoting different social status as well as numbers, which served as a control task. Participants were faster at comparing occupations and numbers…

  1. Health status of hostel dwellers

    African Journals Online (AJOL)

    Assessment of nutritional status provides an inexpensive, quick and objective measure of the health status of children.I The nutritional status of children (0 - 5 years) in the Zones, an urban migrant hostel complex in Langa outside Cape Town,. Department of Social Anthropology, University of Cape. Town. M. A. RAMPHELE ...

  2. Ryanodine receptor channelopathies

    Science.gov (United States)

    Betzenhauser, Matthew J.

    2010-01-01

    Ryanodine receptors (RyR) are intracellular Ca2+-permeable channels that provide the sarcoplasmic reticulum Ca2+ release required for skeletal and cardiac muscle contractions. RyR1 underlies skeletal muscle contraction, and RyR2 fulfills this role in cardiac muscle. Over the past 20 years, numerous mutations in both RyR isoforms have been identified and linked to skeletal and cardiac diseases. Malignant hyperthermia, central core disease, and catecholaminergic polymorphic ventricular tachycardia have been genetically linked to mutations in either RyR1 or RyR2. Thus, RyR channelopathies are both of interest because they cause significant human diseases and provide model systems that can be studied to elucidate important structure–function relationships of these ion channels. PMID:20179962

  3. Molecular characterization of opioid receptors

    Energy Technology Data Exchange (ETDEWEB)

    Howard, A.D.

    1986-01-01

    The aim of this research was to purify and characterize active opioid receptors and elucidate molecular aspects of opioid receptor heterogeneity. Purification to apparent homogeneity of an opioid binding protein from bovine caudate was achieved by solubilization in the non-ionic detergent, digitonin, followed by sequential chromatography on the opiate affinity matrix, ..beta..-naltrexylethylenediamine-CH-Sepharose 4B, and on the lectine affinity matrix, wheat germ agglutinin-agarose. Polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate (SDS-PAGE) followed by autoradiography revealed that radioiodinated purified receptor gave a single band. Purified receptor preparations showed a specific activity of 12,000-15,000 fmol of opiate bound per mg of protein. Radioiodinated human beta-endorphin (/sup 125/I-beta-end/sub H/) was used as a probe to investigate the ligand binding subunits of mu and delta opioid receptors. /sup 125/I-beta-end/sub H/ was shown to bind to a variety of opioid receptor-containing tissues with high affinity and specificity with preference for mu and delta sites, and with little, if any, binding to kappa sites. Affinity crosslinking techniques were employed to covalently link /sup 125/I-beta-end/sub H/ to opioid receptors, utilizing derivatives of bis-succinimidyl esters that are bifunctional crosslinkers with specificities for amino and sulfhydryl groups. This, and competition experiments with high type-selective ligands, permitted the assignment of two labeled peptides to their receptor types, namely a peptide of M/sub r/ = 65,000 for mu receptors and one of M/sub r/ = 53,000 for delta receptors.

  4. Hormonally up-regulated neu-associated kinase: A novel target for breast cancer progression.

    Science.gov (United States)

    Zambrano, Joelle N; Neely, Benjamin A; Yeh, Elizabeth S

    2017-05-01

    Hormonally up-regulated neu-associated Kinase (Hunk) is a protein kinase that was originally identified in the murine mammary gland and has been shown to be highly expressed in Human Epidermal Growth Factor Receptor 2 positive (HER2 + /ErbB2 + ) breast cancer cell lines as well as MMTV-neu derived mammary tumor cell lines. However, the physiological role of Hunk has been largely elusive since its identification. Though Hunk is predicted to be a Serine/Threonine (Ser/Thr) protein kinase with homology to the SNF1/AMPK family of protein kinases, there are no known Hunk substrates that have been identified to date. Recent work demonstrates a role for Hunk in HER2 + /ErbB2 + breast cancer progression, including drug resistance to HER2/ErbB2 inhibitors, with Hunk potentially acting downstream of HER2/ErbB2 and the PI3K/Akt pathway. These studies have collectively shown that Hunk plays a vital role in promoting mammary tumorigenesis, as Hunk knockdown via shRNA in xenograft tumor models or crossing MMTV-neu or Pten-deficient genetically engineered mouse models into a Hunk knockout (Hunk-/-) background impairs mammary tumor growth in vivo. Because the majority of HER2 + /ErbB2 + breast cancer patients acquire drug resistance to HER2/ErbB2 inhibitors, the characterization of novel drug targets like Hunk that have the potential to simultaneously suppress tumorigenesis and potentially enhance efficacy of current therapeutics is an important facet of drug development. Therefore, work aimed at uncovering specific regulatory functions for Hunk that could contribute to this protein kinase's role in both tumorigenesis and drug resistance will be informative. This review focuses on what is currently known about this under-studied protein kinase, and how targeting Hunk may prove to be a potential therapeutic target for the treatment of breast cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Toll-like receptors 4 and 9 expression in systemic lupus ...

    African Journals Online (AJOL)

    Toll-like receptors 4 and 9 expression in systemic lupus erythematosus and dermatomyositis: Relation to clinical status and disease activity. ... Systemic Lupus Erythematosus (SLE) is an autoimmune disorder affecting almost all organs and tissues. Dermatomyositis (DM) is a chronic muscle disorder that leads to muscle ...

  6. Neuroendocrine-immune interaction: regulation of inflammation via G-protein coupled receptors

    NARCIS (Netherlands)

    Verburg-van Kemenade, B.M.L.; Aa, van der L.M.; Chadzinska, M.K.

    2013-01-01

    Neuroendocrine- and immune systems interact in a bi-directional fashion to communicate the status of pathogen recognition to the brain and the immune response is influenced by physiological changes. The network of ligands and their receptors involved includes cytokines and chemokines,

  7. Status of APE projects

    CERN Document Server

    Alfieri, R; Onofri, E; Bartoloni, A; Battista, C; Cabibbo, Nicola; Cosimi, M; Lonardo, A; Michelotti, A; Proietti, B; Rapuano, F; Rossetti, D; Sacco, G; Tassa, S; Torelli, M; Vicini, P; Pène, O; Errico, W; Magazzù, G; Sartori, L; Schiiano, F; Tripiccione, R; De Riso, P; Petronzio, Roberto; Destri, C; Frezzotti, R; Marchesini, G; Gensch, Ulrich; Jansen, K; Kretzschmann, A; Leich, H; Paschedag, N; Pleiter, D; Schwendicke, U; Simma, H; Sommer, Rainer; Sulanke, K; Wegner, P; Fucci, A; Martin, B; Pech, J; Panizzi, E; Petricola, A

    2001-01-01

    This talk is divided in two parts. In the first part, we will summarize the status of the APEmille project that will be completed by the end of the year. We will then devote the rest of the talk to the description of a new project for a multi-TeraFlop machine, ape NEXT. The interested reader will find a much more detailed discussion of all the items touched upon here in the full proposal of the project that will shortly appear on hep-lat. (9 refs).

  8. Model Validation Status Review

    International Nuclear Information System (INIS)

    E.L. Hardin

    2001-01-01

    The primary objective for the Model Validation Status Review was to perform a one-time evaluation of model validation associated with the analysis/model reports (AMRs) containing model input to total-system performance assessment (TSPA) for the Yucca Mountain site recommendation (SR). This review was performed in response to Corrective Action Request BSC-01-C-01 (Clark 2001, Krisha 2001) pursuant to Quality Assurance review findings of an adverse trend in model validation deficiency. The review findings in this report provide the following information which defines the extent of model validation deficiency and the corrective action needed: (1) AMRs that contain or support models are identified, and conversely, for each model the supporting documentation is identified. (2) The use for each model is determined based on whether the output is used directly for TSPA-SR, or for screening (exclusion) of features, events, and processes (FEPs), and the nature of the model output. (3) Two approaches are used to evaluate the extent to which the validation for each model is compliant with AP-3.10Q (Analyses and Models). The approaches differ in regard to whether model validation is achieved within individual AMRs as originally intended, or whether model validation could be readily achieved by incorporating information from other sources. (4) Recommendations are presented for changes to the AMRs, and additional model development activities or data collection, that will remedy model validation review findings, in support of licensing activities. The Model Validation Status Review emphasized those AMRs that support TSPA-SR (CRWMS M and O 2000bl and 2000bm). A series of workshops and teleconferences was held to discuss and integrate the review findings. The review encompassed 125 AMRs (Table 1) plus certain other supporting documents and data needed to assess model validity. The AMRs were grouped in 21 model areas representing the modeling of processes affecting the natural and

  9. Model Validation Status Review

    Energy Technology Data Exchange (ETDEWEB)

    E.L. Hardin

    2001-11-28

    The primary objective for the Model Validation Status Review was to perform a one-time evaluation of model validation associated with the analysis/model reports (AMRs) containing model input to total-system performance assessment (TSPA) for the Yucca Mountain site recommendation (SR). This review was performed in response to Corrective Action Request BSC-01-C-01 (Clark 2001, Krisha 2001) pursuant to Quality Assurance review findings of an adverse trend in model validation deficiency. The review findings in this report provide the following information which defines the extent of model validation deficiency and the corrective action needed: (1) AMRs that contain or support models are identified, and conversely, for each model the supporting documentation is identified. (2) The use for each model is determined based on whether the output is used directly for TSPA-SR, or for screening (exclusion) of features, events, and processes (FEPs), and the nature of the model output. (3) Two approaches are used to evaluate the extent to which the validation for each model is compliant with AP-3.10Q (Analyses and Models). The approaches differ in regard to whether model validation is achieved within individual AMRs as originally intended, or whether model validation could be readily achieved by incorporating information from other sources. (4) Recommendations are presented for changes to the AMRs, and additional model development activities or data collection, that will remedy model validation review findings, in support of licensing activities. The Model Validation Status Review emphasized those AMRs that support TSPA-SR (CRWMS M&O 2000bl and 2000bm). A series of workshops and teleconferences was held to discuss and integrate the review findings. The review encompassed 125 AMRs (Table 1) plus certain other supporting documents and data needed to assess model validity. The AMRs were grouped in 21 model areas representing the modeling of processes affecting the natural and

  10. Status of Wheeler Reservoir

    Energy Technology Data Exchange (ETDEWEB)

    1990-09-01

    This is one in a series of status reports prepared by the Tennessee Valley Authority (TVA) for those interested in the conditions of TVA reservoirs. This overview of Wheeler Reservoir summarizes reservoir purposes and operation, reservoir and watershed characteristics, reservoir uses and use impairments, and water quality and aquatic biological conditions. The information presented here is from the most recent reports, publications, and original data available. If no recent data were available, historical data were summarized. If data were completely lacking, environmental professionals with special knowledge of the resource were interviewed. 12 refs., 2 figs.

  11. NESTOR: A status report

    CERN Document Server

    Anassontzis, E G; Barone, M; Foudas, C; Grammatikakis, G; Katsanevas, S; Kourkoumelis, C; Manousakis-Katsikakis, A; Resvanis, L K; Siotis, I; Sotiriou, S A; Voulgaris, G; Minkowski, P; Grieder, P K F; Ball, A E; Bottai, S; Cartacci, A M; Monteleoni, B; Naumov, Vadim A; Trasatti, L; Fahrun, E; Keusen, U; Koske, P; Rathlev, J; Schmidt, N P; Voight, G; Bezrukov, Leonid B; Butkevich, A V; Dedenko, L G; Karaevsky, S K; Mironovich, A A; Zakharov, L M; Zheleznykh, I M; Zhukov, V A; Demidova, T A; Deineko, A O; Eremeev, A P; Paka, V T; Permyakov, A A; Platonov, M N; Rukol, V Kh; Sheremet, N A; Surin, N M; Albul, V I; Ledenev, V V

    2000-01-01

    NESTOR is an underwater neutrino astrophysics laboratory to be located in the international waters of the southwest of Greece. The first phase of this experiment is the construction and deployment of one hexagonal tower consisting of 168 optical modules, with effective are of 20000m2 for E ⩾ TeV neutrinos. Over the past few years detailed studies of the site have been carried out while many tests have been performed. The current status of the preparation of the experiment and the future plans will be presented.

  12. The status of molecules

    International Nuclear Information System (INIS)

    Barnes, T.

    1994-01-01

    The experimental and theoretical status of hadronic molecules, which are weakly-bound states of two or more hadrons are summarized. A brief history of the subject is given, and a few good candidates are discussed. Some signatures for molecules which may be of interest in the classification of possible molecule states are studied. It is shown that a more general understanding of 2 → 2 hadron-hadron scattering amplitudes will be crucial for molecule searches. A few more recent molecule candidates which are not well established as molecules but satisfy some of the expected signatures are also discussed. (author). 50 refs

  13. Teleradiology - current status

    International Nuclear Information System (INIS)

    Baltadjiev, D.; Charakchiev

    2000-01-01

    Tele-radiology is a term becoming increasingly popular in the medical literature. Nevertheless, terminological definitions in this particular field are still rather vague. The scope of applications extend from simple image presenting via analogue telephone lines to transmission of 3-D medical images through a satellite. It is a matter of standards highly differing in terms of data transmission rates, safety, technical demands on the systems and the like. In this article new information technologies, technical aspects, as well as some major applications of tele-radiology are discussed. The current status of tele-medicine/tele-radiology in this country is likewise briefly outlined

  14. 1998 status report

    International Nuclear