The Functional Polymorphism of Erythropoietin Gene Rs1617640 G>T Is Not Associated with Susceptibility and Clinical Outcome of Early-Stage Breast Cancer

Total Page:16

File Type:pdf, Size:1020Kb

The Functional Polymorphism of Erythropoietin Gene Rs1617640 G>T Is Not Associated with Susceptibility and Clinical Outcome of Early-Stage Breast Cancer ANTICANCER RESEARCH 32: 3473-3478 (2012) The Functional Polymorphism of Erythropoietin Gene rs1617640 G>T Is Not Associated with Susceptibility and Clinical Outcome of Early-stage Breast Cancer JOANNA SZKANDERA1,2, GUDRUN ABSENGER1,2, MICHAEL STOTZ1,2, MELANIE WEISSMUELLER1,2, THOMAS WINDER3, TANJA LANGSENLEHNER4, HELLMUT SAMONIGG1, WILFRIED RENNER2,5, WALTER SCHIPPINGER6 and ARMIN GERGER1,2 1Division of Clinical Oncology, Department of Internal Medicine, 2Research Unit Genetic Epidemiology and Pharmacogenetics, 4Department of Therapeutic Radiology and Oncology, 5Clinical Institute of Medical and Laboratory Diagnostics, Medical University of Graz, Graz, Austria; 3Department of Internal Medicine, Academic Teaching Hospital Feldkirch, Feldkirch, Austria; 6Department of Internal Medicine, Albert Schweitzer Clinic, Graz, Austria Abstract. Recent data suggest that erythropoietin (EPO) transcription factors (2). The EPO gene is activated under plays a substantial role in cancer development and clinical hypoxic conditions through binding of the HIF1α and HIF1β outcome by stimulating cell proliferation, invasion and to the promoter, respectively (3). Its main function is to angiogenesis. A functional polymorphism (rs1617640 G>T) stimulate erythropoiesis by promoting proliferation and in the promoter region of the EPO gene increases EPO differentiation, or by inhibiting apoptosis of erythroid protein expression. In the present study, we investigated the progenitors (4). Its biological effects are mediated through association of EPO rs1617640 G>T with susceptibility and the binding to the erythropoietin receptor (EPOR), which clinical outcome of early-stage breast cancer. Genomic DNA belongs to the cytokine receptor type I superfamily (1, 5). of 539 female patients with histologically confirmed early- EPO was long considered to be a specific stimulator of stage breast cancer and 804 controls was genotyped for EPO erythropoiesis, but experimental findings have shown that its rs1617640 G>T. No association was found between EPO expression is not restricted to the hematopoietic system. rs1617640 G>T and early-stage breast cancer susceptibility Differential expression of EPO has been shown in other non- and clinical outcome (hazard ratio=1.24, 95% confidence hematopoietic tissues, such as brain astrocytes, breast interval=1.82-1.90, p=0.31). In conclusion, our findings epithelial cells and human reproductive organs, suggesting a suggest a lack of influence of EPO rs1617640 G>T on early- pleiotropic mechanism of action, extending well beyond the stage breast carcinogenesis and clinical outcome. maintenance of red cell mass (6-8). Furthermore, multiple investigators have documented EPO production in various Erythropoietin (EPO) is a glycoprotein hormone mainly tumor cell lines and cancer entities, including breast cancer produced in the adult kidney and fetal liver (1). EPO gene (9-13). Major signal-transduction pathways activated by EPO expression is regulated by inhibitory [GATA binding protein involve the Janus kinase (JAK)/signal transducer and 2 (GATA2), nuclear factor kappa-light-chain-enhancer of activator of transduction (STAT) and rat sarcoma activated B cells (NF-κB)] and stimulatory [hypoxia- (RAS)/mitogen-activated protein kinase pathways, which are inducible factors (HIFs), hepatocyte nuclear factor] essential for the inhibition of apoptosis and the stimulation of cell proliferation in response to this hormone (5, 14). Moreover, it has been demonstrated that exposure of tumor cells to EPO-stimulated tyrosine phosphorylation, DNA Correspondence to: Armin Gerger, MD, Priv.-Doz., Associate Prof., synthesis and proliferation, suggesting that EPO signaling is Research Unit: Genetic Epidemiology and Pharmacogenetics, biologically active in malignant cells (9, 10). Additionally, Division of Clinical Oncology, Department of Internal Medicine, recent data indicate that EPO is involved in angiogenesis and Medical University Graz, Auenbruggerplatz 15, 8036 Graz, Austria. Tel: +43 31638580625, Fax: +43 31638513355, e-mail: invasion of neoplastic cells and may be important in breast [email protected] tumorigenesis (12, 15, 16). Mohyeldin et al. reported an EPO-mediated invasion through the JAK/STAT pathway in Key Words: Breast cancer, germline polymorphism, erythropoietin. head and neck squamous carcinoma cells (17). Furthermore, 0250-7005/2012 $2.00+.40 3473 ANTICANCER RESEARCH 32: 3473-3478 (2012) it has been demonstrated that EPO stimulates proliferation Vienna, Austria). Polymerase chain reaction (PCR) and evaluation in renal cancer cells (18). In endometrial carcinoma, EPO of fluorescence data were carried out as described elsewhere (23). signaling was shown to contribute to tumor progression and For each sample, one negative control containing water instead of DNA was added to check for contamination. For purposes of quality increased aggressiveness, identifying increased EPO control of genotyping, a total of 10% of the analyzed samples were expression as an independent prognostic factor (19). In re-analyzed. The investigator responsible for genotyping was prostate cancer, EPO was shown to regulate an blinded to the clinical dataset. autocrine/paracrine signaling pathway that influences growth and survival of cancer cells (20). In a recent study, Acs et al. Statistics. The primary endpoint of the study was disease-free demonstrated that EPO signaling inhibits hypoxia-induced survival (DFS). DFS was calculated from the date of diagnosis of apoptosis in human breast carcinoma cells and was early-stage breast cancer to the date of the first observation of tumor recurrence. DFS was censored at the last follow-up if the patient associated with poor prognosis (21). The TT genotype of a remained tumor-free at that time. Allelic distribution of the common gene variant in EPO, rs1617640 G>T, located in the polymorphism was tested for deviation from Hardy-Weinberg promoter region, leads to increased EPO protein expression equilibrium using χ2-test. The true mode of inheritance of the through an ecotopic viral integration site 1 (EVI1)/ melatonin polymorphism tested has not been established yet and we assumed 1 (MEL1) or activator protein 1 (AP1) enhancer binding site a co-dominant, additive, dominant, or recessive genetic model was and may be associated with cancer susceptibility and clinical appropriate. The association of the polymorphism with DFS was outcome (22). In the present study, we investigated the analyzed using Kaplan Meier curves and log-rank test. In the multivariate Cox regression analysis, the model was adjusted for association of EPO rs1617640 G>T with susceptibility and menopausal status, stage, histopathological grading, receptor status, clinical outcome in patients with early-stage breast cancer. human epidermal growth factor receptor 2 (HER2)/neu status and adjuvant treatment modalities. Case-wise deletion for missing Materials and Methods genotypes was used in univariate and multivariate analyses. Genotype frequencies in patients and controls were compared using χ2 tests. All analyses were performed using the SPSS statistical Study participants. A total of 539 female patients with histologically software package (SPSS Inc., Sunnyvale, CA, USA). confirmed breast cancer without distant metastases were included in this retrospective study. All patients were included in a breast Results cancer surveillance program between 2001 and 2009 at the Division of Clinical Oncology, Department of Internal Medicine, Medical Baseline patient characteristics, tumor biological factors, University of Graz, Austria, providing follow-up care at regular treatment modalities and their association with clinical outcome intervals (3-month intervals in years 1-3, 6-month intervals in years 4-5, and 12-month intervals in years 6-10 after curative surgery). are shown in Table I. The median age at time of diagnosis was Follow-up investigations included clinical check-up, laboratory, 57 years (range 29 to 84 years). The median follow-up duration radiological (bone scan, liver scan, chest X-ray, and mammograms), was 61.1 months (range 12 to 107 months). Follow-up data was and gynecological examination. A total of 804 healthy female missing for 38 (7.1%) patients. Genotyping was successful in controls were recruited from local health screening studies, the 520 (96.5%) patients and 799 (99.4%) controls. In failed cases, Salzburger Atherosklerose Präventionsprogramm bei Personen mit genotyping was not successful due to limited quantity and/or hohem Infarkt Risiko and the Grazer Diabetes Screening Programm. quality of extracted genomic DNA. The genotyping quality Controls with previous malignant disease were excluded from the present study. Blood samples were taken from all patients and control by subsample re-analysis provided a genotype controls, and stored at −20˚C. The present study was performed concordance of >99%. The allelic frequencies for the according to the Austrian Gene Technology Act, and has been polymorphism were within the probability limits of Hardy- approved by the Institutional Reviewer Board of the Medical Weinberg equilibrium. A statistically significant correlation was University of Graz. All participants gave written informed consent found between clinical outcome and tumor size, lymph node and were Caucasian. involvement and tumor stage (Table I). There was no significant association between EPO rs1617640 G>T and Candidate polymorphisms. The following pre-defined criteria for the breast cancer susceptibility (Table II).
Recommended publications
  • Insights Into the Cellular Mechanisms of Erythropoietin-Thrombopoietin Synergy
    Papayannopoulou et al.: Epo and Tpo Synergy Experimental Hematology 24:660-669 (19961 661 @ 1996 International Society for Experimental Hematology Rapid Communication ulation with fluorescence microscopy. Purified subsets were grown in plasma clot and methylcellulose clonal cultures and in suspension cultures using the combinations of cytokines Insights into the cellular mechanisms cadaveric bone marrow cells obtained from Northwest described in the text. Single cells from the different subsets Center, Puget Sound Blood Bank (Seattle, WA), were were. also deposited (by FACS) on 96-well plates containing of erythropoietin-thrombopoietin synergy washed, and incubated overnight in IMDM with 10% medmm and cytokines. Clonal growth from single-cell wells calf serum on tissue culture plates to remove adherent were double-labeled with antiglycophorin A-PE and anti­ Thalia Papayannopoulou, Martha Brice, Denise Farrer, Kenneth Kaushansky From the nonadherent cells, CD34+ cells were isolated CD41- FITC between days 10 and 19. direct immunoadherence on anti-CD34 monoclonal anti­ University of Washington, Department of Medicine, Seattle, WA (mAb)-coated plates, as previously described [15]. Purity Immunocytochemistry Offprint requests to: Thalia Papayannopoulou, MD, DrSci, University of Washington, isolated CD34+ cells ranged from 80 to 96% by this For immunocytochemistry, either plasma clot or cytospin cell Division of Hematology, Box 357710, Seattle, WA 98195-7710 od. Peripheral blood CD34 + cells from granulocyte preparations were used. These were fixed at days 6-7 and (Received 24 January 1996; revised 14 February 1996; accepted 16 February 1996) ulating factor (G-CSF)-mobilized normal donors 12-13 with pH 6.5 Histochoice (Amresco, Solon, OH) and provided by Dr.
    [Show full text]
  • The Molecular Mechanisms That Control Thrombopoiesis
    The molecular mechanisms that control thrombopoiesis Kenneth Kaushansky J Clin Invest. 2005;115(12):3339-3347. https://doi.org/10.1172/JCI26674. Review Series Our understanding of thrombopoiesis — the formation of blood platelets — has improved greatly in the last decade, with the cloning and characterization of thrombopoietin, the primary regulator of this process. Thrombopoietin affects nearly all aspects of platelet production, from self-renewal and expansion of HSCs, through stimulation of the proliferation of megakaryocyte progenitor cells, to support of the maturation of these cells into platelet-producing cells. The molecular and cellular mechanisms through which thrombopoietin affects platelet production provide new insights into the interplay between intrinsic and extrinsic influences on hematopoiesis and highlight new opportunities to translate basic biology into clinical advances. Find the latest version: https://jci.me/26674/pdf Review series The molecular mechanisms that control thrombopoiesis Kenneth Kaushansky Department of Medicine, Division of Hematology/Oncology, University of California, San Diego, San Diego, California, USA. Our understanding of thrombopoiesis — the formation of blood platelets — has improved greatly in the last decade, with the cloning and characterization of thrombopoietin, the primary regulator of this process. Thrombopoietin affects nearly all aspects of platelet production, from self-renewal and expansion of HSCs, through stimulation of the proliferation of megakaryocyte progenitor cells, to support of the maturation of these cells into platelet-pro- ducing cells. The molecular and cellular mechanisms through which thrombopoietin affects platelet production provide new insights into the interplay between intrinsic and extrinsic influences on hematopoiesis and highlight new opportunities to translate basic biology into clinical advances.
    [Show full text]
  • Induction of Erythropoietin Increases the Cell Proliferation Rate in a Hypoxia‑Inducible Factor‑1‑Dependent and ‑Independent Manner in Renal Cell Carcinoma Cell Lines
    ONCOLOGY LETTERS 5: 1765-1770, 2013 Induction of erythropoietin increases the cell proliferation rate in a hypoxia‑inducible factor‑1‑dependent and ‑independent manner in renal cell carcinoma cell lines YUTAKA FUJISUE1, TAKATOSHI NAKAGAWA2, KIYOSHI TAKAHARA1, TERUO INAMOTO1, SATOSHI KIYAMA1, HARUHITO AZUMA1 and MICHIO ASAHI2 Departments of 1Urology and 2Pharmacology, Faculty of Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan Received November 28, 2012; Accepted February 25, 2013 DOI: 10.3892/ol.2013.1283 Abstract. Erythropoietin (Epo) is a potent inducer of erythro- Introduction poiesis that is mainly produced in the kidney. Epo is expressed not only in the normal kidney, but also in renal cell carcinomas Erythropoietin (Epo) is a 30-kDa glycoprotein that functions (RCCs). The aim of the present study was to gain insights as an important cytokine in erythrocytes. Epo is usually into the roles of Epo and its receptor (EpoR) in RCC cells. produced by stromal cells of the adult kidney cortex or fetal The study used two RCC cell lines, Caki-1 and SKRC44, in liver and then released into the blood, with its production which Epo and EpoR are known to be highly expressed. The initially induced by hypoxia or hypotension (1-5). In the bone proliferation rate and expression level of hypoxia-inducible marrow, Epo binds to the erythropoietin receptor (EpoR) factor-1α (HIF-1α) were measured prior to and following expressed in erythroid progenitor cells or undifferentiated Epo treatment and under normoxic and hypoxic conditions. erythroblasts, which induces signal transduction mechanisms To examine whether HIF-1α or Epo were involved in cellular that protect the undifferentiated erythrocytes from apoptosis proliferation during hypoxia, these proteins were knocked and promote their proliferation and differentiation.
    [Show full text]
  • Targeted Erythropoietin Selectively Stimulates Red Blood Cell Expansion in Vivo
    Targeted erythropoietin selectively stimulates red blood cell expansion in vivo Devin R. Burrilla, Andyna Verneta, James J. Collinsa,b,c,d, Pamela A. Silvera,e,1, and Jeffrey C. Waya aWyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115; bSynthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139; cInstitute for Medical Engineering & Science, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; dBroad Institute of MIT and Harvard, Cambridge, MA 02139; and eDepartment of Systems Biology, Harvard Medical School, Boston, MA 02115 Edited by Ronald A. DePinho, University of Texas MD Anderson Cancer Center, Houston, TX, and approved March 30, 2016 (received for review December 23, 2015) The design of cell-targeted protein therapeutics can be informed peptide linker that permits simultaneous binding of both elements by natural protein–protein interactions that use cooperative phys- to the same cell surface. The targeting element anchors the mu- ical contacts to achieve cell type specificity. Here we applied this tated activity element to the desired cell surface (Fig. 1A, Middle), approach in vivo to the anemia drug erythropoietin (EPO), to direct thereby creating a high local concentration and driving receptor its activity to EPO receptors (EPO-Rs) on red blood cell (RBC) pre- binding despite the mutation (Fig. 1A, Bottom). Off-target sig- cursors and prevent interaction with EPO-Rs on nonerythroid cells, naling should be minimal (Fig. 1B) and should decrease in pro- such as platelets. Our engineered EPO molecule was mutated to portion to the mutation strength. weaken its affinity for EPO-R, but its avidity for RBC precursors Here we tested the chimeric activator strategy in vivo using was rescued via tethering to an antibody fragment that specifi- erythropoietin (EPO) as the drug to be targeted.
    [Show full text]
  • And Insulin-Like Growth Factor-I (IGF-I) in Regulating Human Erythropoiesis
    Leukemia (1998) 12, 371–381 1998 Stockton Press All rights reserved 0887-6924/98 $12.00 The role of insulin (INS) and insulin-like growth factor-I (IGF-I) in regulating human erythropoiesis. Studies in vitro under serum-free conditions – comparison to other cytokines and growth factors J Ratajczak, Q Zhang, E Pertusini, BS Wojczyk, MA Wasik and MZ Ratajczak Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA The role of insulin (INS), and insulin-like growth factor-I (IGF- has been difficult to assess. The fact that EpO alone fails to I) in the regulation of human erythropoiesis is not completely stimulate BFU-E in serum-free conditions, but does do in understood. To address this issue we employed several comp- lementary strategies including: serum free cloning of CD34؉ serum containing cultures indicates that serum contains some cells, RT-PCR, FACS analysis, and mRNA perturbation with oli- crucial growth factors necessary for the BFU-E development. godeoxynucleotides (ODN). In a serum-free culture model, both In previous studies from our laboratory, we examined the ؉ INS and IGF-I enhanced survival of CD34 cells, but neither of role of IGF-I12 and KL9,11,13 in the regulation of early human these growth factors stimulated their proliferation. The influ- erythropoiesis. Both of these growth factors are considered to ence of INS and IGF-I on erythroid colony development was be crucial for the BFU-E growth.3,6,8,14 Unexpectedly, that dependent on a combination of growth factors used for stimul- + ating BFU-E growth.
    [Show full text]
  • Immunohistochemical Expression of Erythropoietin in Invasive Breast Carcinoma with Metastasis to Lymph Nodes
    Review and Research on Cancer Treatment Volume 4, Issue 1 (2018) ISSN 2544-2147 Immunohistochemical expression of erythropoietin in invasive breast carcinoma with metastasis to lymph nodes Maksimiuk M.* Students' Scientific Organization at the Medical University of Warsaw, Oczki 1a, 02-007 Warsaw Sobiborowicz A. Students' Scientific Organization at the Medical University of Warsaw, Oczki 1a, 02-007 Warsaw Sobieraj M. Students' Scientific Organization at the Medical University of Warsaw, Oczki 1a, 02-007 Warsaw Liszcz A. Students' Scientific Organization at the Medical University of Warsaw, Oczki 1a, 02-007 Warsaw Sobol M. Department of Biophysics and Human Physiology, Medical University of Warsaw, Chałubińskiego 5, 02-004 Warsaw Patera J. Department of Pathomorphology, Military Institute of Health Services, Warsaw, Poland Badowska-Kozakiewicz A.M. Department of Biophysics and Human Physiology, Medical University of Warsaw, Chałubińskiego 5, 02-004 Warsaw *corresponding author: Marta Maksimiuk, Department of Biophysics and Human Physiology, Medical University of Warsaw, Chałubińskiego 5, 02-004 Warsaw, [email protected], tel: 691 – 230 – 268 Abstract: Introduction: Tumor characteristics, such as size, lymph node status, histological type of the neoplasm and its grade, are well known prognostic factors in breast cancer. The ongoing search for new prognostic factors include Bcl2, Bax, Cox-2 or HIF1- alpha, which plays a key role in phenomenon of tumor hypoxia and might induce transcription of the EPO gene. Erythropoietin may influence lymph node metastasis or stimulate tumor progression, thus it seemed interesting to determine its expression in invasive breast cancers with lymph node metastases presenting different basic immunohistochemical profiles (ER, PR, HER2). Aim: To evaluate the relationship between histological grade, tumor size, lymph node status, expression of ER, PR, HER2 and immunohistochemical expression of erythropoietin in invasive breast cancer with metastasis to lymph nodes.
    [Show full text]
  • The Thrombopoietin Receptor : Revisiting the Master Regulator of Platelet Production
    This is a repository copy of The thrombopoietin receptor : revisiting the master regulator of platelet production. White Rose Research Online URL for this paper: https://eprints.whiterose.ac.uk/175234/ Version: Published Version Article: Hitchcock, Ian S orcid.org/0000-0001-7170-6703, Hafer, Maximillian, Sangkhae, Veena et al. (1 more author) (2021) The thrombopoietin receptor : revisiting the master regulator of platelet production. Platelets. pp. 1-9. ISSN 0953-7104 https://doi.org/10.1080/09537104.2021.1925102 Reuse This article is distributed under the terms of the Creative Commons Attribution (CC BY) licence. This licence allows you to distribute, remix, tweak, and build upon the work, even commercially, as long as you credit the authors for the original work. More information and the full terms of the licence here: https://creativecommons.org/licenses/ Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Platelets ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iplt20 The thrombopoietin receptor: revisiting the master regulator of platelet production Ian S. Hitchcock, Maximillian Hafer, Veena Sangkhae & Julie A. Tucker To cite this article: Ian S. Hitchcock, Maximillian Hafer, Veena Sangkhae & Julie A. Tucker (2021): The thrombopoietin receptor: revisiting the master regulator of platelet production, Platelets, DOI: 10.1080/09537104.2021.1925102 To link to this article: https://doi.org/10.1080/09537104.2021.1925102 © 2021 The Author(s).
    [Show full text]
  • As a Key Regulator of Erythropoiesis, Bone Remodeling and Endothelial
    cells Review Erythropoietin (EPO) as a Key Regulator of Erythropoiesis, Bone Remodeling and Endothelial Transdifferentiation of Multipotent Mesenchymal Stem Cells (MSCs): Implications in Regenerative Medicine Asterios S. Tsiftsoglou Laboratory of Pharmacology, Department of Pharmaceutical Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; [email protected] Abstract: Human erythropoietin (EPO) is an N-linked glycoprotein consisting of 166 aa that is pro- duced in the kidney during the adult life and acts both as a peptide hormone and hematopoietic growth factor (HGF), stimulating bone marrow erythropoiesis. EPO production is activated by hypoxia and is regulated via an oxygen-sensitive feedback loop. EPO acts via its homodimeric erythropoietin receptor (EPO-R) that increases cell survival and drives the terminal erythroid mat- uration of progenitors BFU-Es and CFU-Es to billions of mature RBCs. This pathway involves the activation of multiple erythroid transcription factors, such as GATA1, FOG1, TAL-1, EKLF and BCL11A, and leads to the overexpression of genes encoding enzymes involved in heme biosynthesis Citation: Tsiftsoglou, A.S. and the production of hemoglobin. The detection of a heterodimeric complex of EPO-R (consist- Erythropoietin (EPO) as a Key ing of one EPO-R chain and the CSF2RB β-chain, CD131) in several tissues (brain, heart, skeletal Regulator of Erythropoiesis, Bone muscle) explains the EPO pleotropic action as a protection factor for several cells, including the Remodeling and Endothelial multipotent MSCs as well as cells modulating the innate and adaptive immunity arms. EPO induces Transdifferentiation of Multipotent the osteogenic and endothelial transdifferentiation of the multipotent MSCs via the activation of Mesenchymal Stem Cells (MSCs): EPO-R signaling pathways, leading to bone remodeling, induction of angiogenesis and secretion Implications in Regenerative of a large number of trophic factors (secretome).
    [Show full text]
  • Correlation with Vasculogenic Mimicry and Poor Prognosis
    Int J Clin Exp Pathol 2015;8(4):4033-4043 www.ijcep.com /ISSN:1936-2625/IJCEP0006586 Original Article Erythropoietin and erythropoietin receptor in hepatocellular carcinoma: correlation with vasculogenic mimicry and poor prognosis Zhihong Yang1,2*, Baocun Sun1,2,3*, Xiulan Zhao1,2*, Bing Shao1, Jindan An1, Qiang Gu1,2, Yong Wang1, Xueyi Dong1, Yanhui Zhang1,3, Zhiqiang Qiu1,3 1Department of Pathology, Tianjin Medical University, Tianjin 300070, China; 2Department of Pathology, General Hospital of Tianjin Medical University, Tianjin 300052, China; 3Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin 300060, China. *Equal contributors. Received February 1, 2015; Accepted March 30, 2015; Epub April 1, 2015; Published April 15, 2015 Abstract: To evaluate erythropoietin (Epo) and erythropoietin receptor (EpoR) expression, its relationship with vas- culogenic mimicry (VM) and its prognostic value in human hepatocellular carcinoma (HCC), we examined Epo/EpoR expression and VM formation using immunohistochemistry and CD31/PAS (periodic acid-Schiff) double staining on 92 HCC specimens. The correlation between Epo/EpoR expression and VM formation was analyzed using two-tailed Chi-square test and Spearman correlation analysis. Survival curves were generated using Kaplan-Meier method. Multivariate analysis was performed using Cox regression model to assess the prognostic values. Results showed positive correlation between Epo/EpoR expression and VM formation (P < 0.05). Patients with Epo or EpoR expres- sion exhibited poorer overall survival (OS) than Epo-negative or EpoR-negative patients (P < 0.05). Epo-positive/VM- positive and EpoR-positive/VM-positive patients had the worst OS (P < 0.05). In multivariate survival analysis, age, Epo and EpoR were independent prognostic factors related to OS.
    [Show full text]
  • Erythropoietin Prevents Haloperidol Treatment-Induced Neuronal Apoptosis Through Regulation of BDNF
    Neuropsychopharmacology (2008) 33, 1942–1951 & 2008 Nature Publishing Group All rights reserved 0893-133X/08 $30.00 www.neuropsychopharmacology.org Erythropoietin Prevents Haloperidol Treatment-Induced Neuronal Apoptosis through Regulation of BDNF ,1,2 3 1,2 4 Anilkumar Pillai* , Krishnan M Dhandapani , Bindu A Pillai , Alvin V Terry Jr and 1,2 Sahebarao P Mahadik 1 2 Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta, GA, USA; Medical Research Service Line, Veterans Affairs 3 4 Medical Center, Augusta, GA, USA; Department of Neurosurgery, Medical College of Georgia, Augusta, GA, USA; Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA, USA Functional alterations in the neurotrophin, brain-derived neurotrophic factor (BDNF) have recently been implicated in the pathophysiology of schizophrenia. Furthermore, animal studies have indicated that several antipsychotic drugs have time-dependent (and differential) effects on BDNF levels in the brain. For example, our previous studies in rats indicated that chronic treatment with the conventional antipsychotic, haloperidol, was associated with decreases in BDNF (and other neurotrophins) in the brain as well as deficits in cognitive function (an especially important consideration for the therapeutics of schizophrenia). Additional studies indicate that haloperidol has other deleterious effects on the brain (eg increased apoptosis). Despite such limitations, haloperidol remains one of the more commonly prescribed antipsychotic agents worldwide due to its efficacy for the positive symptoms of schizophrenia and its low cost. Interestingly, the hematopoietic hormone, erythropoietin, in its recombinant human form rhEPO has been reported to increase the expression of BDNF in neuronal tissues and to have neuroprotective effects.
    [Show full text]
  • Phase II Study of Sorafenib Plus 5-Azacitidine for the Initial Therapy of Patients with Acute Myeloid Leukemia and High Risk
    2014-0076 March 9, 2015 Page 1 Protocol Page Phase II Study of Sorafenib Plus 5-Azacitidine for the Initial Therapy of Patients with Acute Myeloid Leukemia and High Risk Myelodysplastic Syndrome with FLT3-ITD Mutation 2014-0076 Core Protocol Information Short Title Sorafenib Plus 5-Azacitidine initial therapy of patients with AML and high risk MS with FLT3-ITD Mutation Study Chair: Farhad Ravandi-Kashani Additional Contact: Andrea L. Booker Mary Ann Richie Leukemia Protocol Review Group Department: Leukemia Phone: 713-792-7305 Unit: 428 Full Title: Phase II Study of Sorafenib Plus 5-Azacitidine for the Initial Therapy of Patients with Acute Myeloid Leukemia and High Risk Myelodysplastic Syndrome with FLT3-ITD Mutation Protocol Type: Standard Protocol Protocol Phase: Phase II Version Status: Terminated 11/27/2018 Version: 12 Submitted by: Andrea L. Booker--2/23/2017 1:07:00 PM OPR Action: Accepted by: Julie Arevalo -- 3/3/2017 2:39:37 PM Which Committee will review this protocol? The Clinical Research Committee - (CRC) 2014-0076 March 9, 2015 Page 2 Protocol Body Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 March 05, 2015 1 Phase II Study Of Sorafenib Plus 5-Azacitidine For The Initial Therapy Of Patients With Acute Myeloid Leukemia And High Risk Myelodysplastic Syndrome With FLT3-ITD Mutation Short Title: Sorafenib Plus 5-Azacitidine initial therapy of patients with AML and high risk MS with FLT3-ITD mutation PI: Farhad Ravandi, MD Professor of Medicine, Department of Leukemia University of Texas – MD Anderson Cancer Center 1 Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 March 05, 2015 2 Contents 1.0 Objectives ........................................................................................................................................
    [Show full text]
  • Lab Dept: Hematology Test Name: ERYTHROPOIETIN
    Lab Dept: Hematology Test Name: ERYTHROPOIETIN General Information Lab Order Codes: EPOS Synonyms: Erythropoietin (EPO), Serum CPT Codes: 82668 - Erythropoietin Test Includes: Erythropoietin level reported in mIU/mL. Logistics Test Indications: This test is mainly used for the differential diagnosis of primary and secondary polycythemia and to determine the cause of anemia. In the diagnosis of primary polycythemia (polycythemia rubra vera) due to an uncontrolled increase in the number of erythrocytes carrying high concentrations of oxygen, the EPO level is suppressed. The test is also useful for diagnosis of appropriate secondary polycythemia caused by high-altitude living, pulmonary disease, and tobacco use, which increase EPO levels. In patients with inappropriate secondary polycythemia caused by renal tumors and extrarenal tumors, the EPO level is also increased. Patients with anemia of bone marrow failure, iron deficiency, or thalassemia also have increased EPO levels Lab Testing Sections: Hematology - Sendouts Referred to: Mayo Medical Laboratories (MML Test: EPO) Phone Numbers: MIN Lab: 612-813-6280 STP Lab: 651-220-6550 Test Availability: Daily, 24 hours Turnaround Time: 2 - 4 days, test set up Monday - Saturday Special Instructions: N/A Specimen Specimen Type: Blood Container: SST (Gold, marble or red) tube Draw Volume: 1.8 mL (Minumum: 1.5 mL) blood Processed Volume: 0.6 mL (Minimum: 0.5 mL) serum Collection: Routine blood collection Special Processing: Lab Staff: Centrifuge specimen, aliquot into a screw-capped plastic vial. Store and ship at refrigerated temperatures. Forward promptly. Patient Preparation: None Sample Rejection: Mislabeled or unlabeled specimen; gross hemolysis Interpretive Reference Range: 2.6 – 18.5 mIU/mL Interpretation: In the appropriate clinical setting (eg, confirmed elevation of hemoglobin >18.5 gm/dL, persistent leukocytosis, persistent thrombocystosis, unusual thrombosis, splenomegaly, and erythromegaly), polycythemia vera is unlikely when EPO levels are elevated and polycythemia vera is likely when EPO levels are suppressed.
    [Show full text]