Erythropoietin receptor signaling is membrane raft dependent

NARCIS (Netherlands)

K.L. McGraw (Kathy); G.M. Fuhler (Gwenny); J.O. Johnson (Joseph); J.A. Clark (Justine); G.C. Caceres (Gisela); L. Sokol (Lubomir); A.F. List (Alan)

2012-01-01

textabstractUpon erythropoietin (Epo) engagement, Epo-receptor (R) homodimerizes to activate JAK2 and Lyn, which phosphorylate STAT5. Although recent investigations have identified key negative regulators of Epo-R signaling, little is known about the role of membrane localization in controlling

Protein kinase C alpha controls erythropoietin receptor signaling.

NARCIS (Netherlands)

M.M. von Lindern (Marieke); M. Parren-Van Amelsvoort (Martine); T.B. van Dijk (Thamar); E. Deiner; B. Löwenberg (Bob); E. van den Akker (Emile); S. van Emst-de Vries (Sjenet); P.J. Willems (Patrick); H. Beug (Hartmut)

2000-01-01

textabstractProtein kinase C (PKC) is implied in the activation of multiple targets of erythropoietin (Epo) signaling, but its exact role in Epo receptor (EpoR) signal transduction and in the regulation of erythroid proliferation and differentiation remained elusive. We

Protein kinase C alpha controls erythropoietin receptor signaling

NARCIS (Netherlands)

von Lindern, M.; Parren-van Amelsvoort, M.; van Dijk, T.; Deiner, E.; van den Akker, E.; van Emst-de Vries, S.; Willems, P.; Beug, H.; Löwenberg, B.

2000-01-01

Protein kinase C (PKC) is implied in the activation of multiple targets of erythropoietin (Epo) signaling, but its exact role in Epo receptor (EpoR) signal transduction and in the regulation of erythroid proliferation and differentiation remained elusive. We analyzed the effect of PKC inhibitors

Erythropoietin Receptor in Human Tumor Cells: Expression and Aspects Regarding Functionality

NARCIS (Netherlands)

T.A. Knoch (Tobias); G. Westphal; E. Niederberger; C. Blum; Y. Wollman; W. Rebel; J. Debus; E. Friedrich

2001-01-01

textabstractRecombinant human erythropoietin (Epo)and granu l o cy t e - c o l o ny - s t i mulating factor (G-CSF) are used to stimulate hematopoiesis in patients with malignant dise a s e s . These cytokines transduce their biological signal via the Epo receptor (EpoR) and G-CSF receptor (G-CSF-R)

Erythropoietin Receptor Positive Circulating Progenitor Cells and Endothelial Progenitor Cells in Patients with Different Stages of Diabetic Retinopathy

Institute of Scientific and Technical Information of China (English)

Liu-mei Hu; Guo-xu Xu; Guo-tong XU; Wei-ye Li; Xia Lei; Bo Ma; Yu Zhang; Yan Yan; Ya-lan Wu; Ge-zhi Xu; Wen Ye; Ling Wang

2011-01-01

Objective To investigate the possible involvement of erythropoietin (EPO)/erythropoietin receptor(EPOR) system in neovascularization and vascular regeneration in diabetic retinopathy (DR).Methods EPOR positive circulating progenitor cells (CPCs: CD34+) and endothelial progenitor cells (EPCs: CD34+KDR+) were assessed by flow cytometry in type 2 diabetic patients with different stages of DR. The cohort consisted of age- and sex-matched control patients without diabetes (n=7), non-prolif-erative DR (NPDR, n=7), proliferative DR (PDR, n=8), and PDR complicated with diabetic nephropathy (PDR-DN, n=7). Results The numbers of EPOR+ CPCs and EPOR+ EPCs were reduced remarkably in NPDR compared with the control group (both P<0.01), whereas rebounded in PDR and PDR-DN groups in varying degrees. Similar changes were observed in respect of the proportion of EPOR+ CPCs in CPCs (NPDR vs.control, P< 0.01) and that of EPOR+ EPCs in EPCs (NPDR vs. control, P< 0.05). Conclusion Exogenous EPO, mediated via the EPO/EPOR system of EPCs, may alleviate the im-paired vascular regeneration in NPDR, whereas it might aggravate retinal neovascularization in PDR due to a rebound of EPOR+ EPCs associated with ischemia.

Targeting the erythropoietin receptor on glioma cells reduces tumour growth

International Nuclear Information System (INIS)

Peres, Elodie A.; Valable, Samuel; Guillamo, Jean-Sebastien; Marteau, Lena; Bernaudin, Jean-Francois; Roussel, Simon; Lechapt-Zalcman, Emmanuele; Bernaudin, Myriam; Petit, Edwige

2011-01-01

Hypoxia has been shown to be one of the major events involved in EPO expression. Accordingly, EPO might be expressed by cerebral neoplastic cells, especially in glioblastoma, known to be highly hypoxic tumours. The expression of EPOR has been described in glioma cells. However, data from the literature remain descriptive and controversial. On the basis of an endogenous source of EPO in the brain, we have focused on a potential role of EPOR in brain tumour growth. In the present study, with complementary approaches to target EPO/EPOR signalling, we demonstrate the presence of a functional EPO/EPOR system on glioma cells leading to the activation of the ERK pathway. This EPO/EPOR system is involved in glioma cell proliferation in vitro. In vivo, we show that the down-regulation of EPOR expression on glioma cells reduces tumour growth and enhances animal survival. Our results support the hypothesis that EPOR signalling in tumour cells is involved in the control of glioma growth.

In-vivo detection of the erythropoietin receptor in tumours using positron emission tomography

Energy Technology Data Exchange (ETDEWEB)

Fuge, Felix; Doleschel, Dennis; Rix, Anne; Gremse, Felix; Lederle, Wiltrud; Kiessling, Fabian [RWTH Aachen University, Department for Experimental Molecular Imaging (ExMI), Medical Faculty, Aachen (Germany); Wessner, Axel [Roche Diagnostics GmbH, R and D RPD Protein Chemistry, Penzberg (Germany); Winz, Oliver; Mottaghy, Felix [University Clinic RWTH Aachen, Clinic for Nuclear Medicine, Aachen (Germany)

2014-09-09

Recombinant human erythropoietin (rhuEpo) is used clinically to treat anaemia. However, rhuEpo-treated cancer patients show decreased survival rates and erythropoietin receptor (EpoR) expression has been found in patient tumour tissue. Thus, rhuEpo application might promote EpoR{sup +} tumour progression. We therefore developed the positron emission tomography (PET)-probe {sup 68}Ga-DOTA-rhuEpo and evaluated its performance in EpoR{sup +} A549 non-small-cell lung cancer (NSCLC) xenografts. {sup 68}Ga-DOTA-rhuEpo was generated by coupling DOTA-hydrazide to carbohydrate side-chains of rhuEpo. Biodistribution was determined in tumour-bearing mice 0.5, 3, 6, and 9 h after probe injection. Competition experiments were performed by co-injecting {sup 68}Ga-DOTA-rhuEpo and rhuEpo in five-fold excess. Probe specificity was further evaluated histologically using Epo-Cy5.5 stainings. The blood half-life of {sup 68}Ga-DOTA-rhuEpo was 2.6 h and the unbound fraction was cleared by the liver and kidney. After 6 h, the highest tumour to muscle ratio was reached. The highest {sup 68}Ga-DOTA-rhuEpo accumulation was found in liver (10.06 ± 6.26%ID/ml), followed by bone marrow (1.87 ± 0.53%ID/ml), kidney (1.58 ± 0.39 %ID/ml), and tumour (0.99 ± 0.16%ID/ml). EpoR presence in these organs was histologically confirmed. Competition experiments showed significantly (p < 0.05) lower PET-signals in tumour and bone marrow at 3 and 6 h. {sup 68}Ga-DOTA-rhuEpo shows favourable pharmacokinetic properties and detects EpoR specifically. Therefore, it might become a valuable radiotracer to monitor EpoR status in tumours and support decision-making in anaemia therapy. (orig.)

Simultaneous Expression from Both the Sense and Antisense Strand of the Erythropoietin Receptor Gene Mitigates Acute Lung Injury

Science.gov (United States)

2017-09-01

concept efficacy that increasing EpoR or RopE expression by cDNA delivery to lung cells in vitro enhances cytoprotection against hyperoxia-induced injury...oxidative damage, cell culture, rodent model, inhalation cDNA delivery, sense and antisense erythropoietin receptor transcripts 16. SECURITY...prevention of acute lung injury. 1-6 50% Subtask 1: Prepare plasmid cDNA of EpoR and RopE in nanoparticle formulation. 1 Completed 06.2017 Subtask 2

Erythropoietin and erythropoietin receptor expression in the guinea pig inner ear

DEFF Research Database (Denmark)

Cayé-Thomasen, Per; Wagner, Niels; Lidegaard Frederiksen, Birgitte

2005-01-01

, this study determines expression of EPO and EPOR in the inner ear of the guinea pig. Normal guinea pig inner ears were processed for immunohistochemistry, using poly-clonal antibodies against EPO and the EPO receptor. EPO expression was exclusively found in most, but not all spiral ganglion neurons...... expressed by several cell types within the guinea pig cochlea. We hypothesize on the existence of a local paracrine system and that EPO treatment may be feasible following inner ear damage....

Oxidative stress induces the decline of brain EPO expression in aging rats.

Science.gov (United States)

Li, Xu; Chen, Yubao; Shao, Siying; Tang, Qing; Chen, Weihai; Chen, Yi; Xu, Xiaoyu

2016-10-01

Brain Erythropoietin (EPO), an important neurotrophic factor and neuroprotective factor, was found to be associated with aging. Studies found EPO expression was significantly decreased in the hippocampus of aging rat compared with that of the youth. But mechanisms of the decline of the brain EPO during aging remain unclear. The present study utilized a d-galactose (d-gal)-induced aging model in which the inducement of aging was mainly oxidative injury, to explore underlying mechanisms for the decline of brain EPO in aging rats. d-gal-induced aging rats (2months) were simulated by subcutaneously injecting with d-gal at doses of 50mg·kg(-1), 150mg·kg(-1) and 250mg·kg(-1) daily for 8weeks while the control group received vehicle only. These groups were all compared with the aging rats (24months) which had received no other treatment. The cognitive impairment was assessed using Morris water maze (MWM) in the prepared models, and the amount of β-galactosidase, the lipid peroxidation product malondialdehyde (MDA) level and the superoxide dismutase (SOD) activity in the hippocampus was examined by assay kits. The levels of EPO, EPOR, p-JAK2 and hypoxia-inducible factor-2α (HIF-2α) in the hippocampus were detected by western blot. Additionally, the correlation coefficient between EPO/EPOR expression and MDA level was analyzed. The MWM test showed that compared to control group, the escape latency was significantly extended and the times of crossing the platform was decreased at the doses of 150mg·kg(-1) and 250mg·kg(-1) (paging rats, the expressions of EPO, EPOR, p-JAK2, and HIF-2αin the brain of d-gal-treated rats were significantly decreased (paging could result in the decline of EPO in the hippocampus and oxidative stress might be the main reason for the decline of brain EPO in aging rats, involved with the decrease of HIF-2α stability. Copyright © 2016 Elsevier Inc. All rights reserved.

Erythropoietin and its receptors in the brainstem of adults with fatal falciparum malaria

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White Nicholas J

2009-11-01

Full Text Available Abstract Background Facilitation of endogenous neuroprotective pathways, such as the erythropoietin (Epo pathway, has been proposed as adjuvant treatment strategies in cerebral malaria. Whether different endogenous protein expression levels of Epo or differences in the abundance of its receptor components could account for the extent of structural neuropathological changes or neurological complications in adults with severe malaria was investigated. Methods High sensitivity immunohistochemistry was used to assess the frequency, distribution and concordance of Epo and components of its homodimeric and heteromeric receptors, Epo receptor and CD131, within the brainstem of adults who died of severe malaria. The following relationships with Epo and its receptor components were also defined: (i sequestration and indicators of hypoxia; (ii vascular damage in the form of plasma protein leakage and haemorrhage; (iii clinical complications and neuropathological features of severe malaria disease. Brainstems of patients dying in the UK from unrelated non-infectious causes were examined for comparison. Results The incidence of endogenous Epo in parenchymal brain cells did not greatly differ between severe malaria and non-neurological UK controls at the time of death. However, EpoR and CD131 labelling of neurons was greater in severe malaria compared with non-neurological controls (P = .009. EpoR labelling of vessels was positively correlated with admission peripheral parasite count (P = .01 and cerebral sequestration (P P = .001. There were no significant correlations with indicators of vascular damage, neuronal chromatolysis, axonal swelling or vital organ failure. Conclusion Cells within the brainstem of severe malaria patients showed protein expression of Epo and its receptor components. However, the incidence of endogeneous expression did not reflect protection from vascular or neuronal injury, and/or clinical manifestations, such as coma. These

Advances in understanding the pathogenesis of primary familial and congenital polycythemia

Science.gov (United States)

Huang, Lily Jun-shen; Shen, Yu-Min; Bulut, Gamze B.

2010-01-01

Summary Primary familial and congenital polycythemia (PFCP) is an autosomal-dominant proliferative disorder characterized by erythrocytosis and hypersensitivity of erythroid progenitors to erythropoietin (Epo). Several lines of evidence suggest a causal role of truncated erythropoietin receptor (EpoR) in this disease. In this review, we discuss PFCP in the context of erythrocytosis and EpoR signaling. We focus on recent studies describing mechanisms underlying Epo-dependent EpoR down-regulation. One mechanism depends on internalization mediated through the p85 regulatory subunit of the Phosphoinositide 3-Kinase, and the other utilizes ubiquitin-based proteasomal degradation. Truncated PFCP EpoRs are not properly down-regulated upon stimulation, underscoring the importance of these mechanisms in the pathogenesis of PFCP. PMID:20096014

Erythropoietin receptor in human skeletal muscle and the effects of acute and long-term injections with recombinant human erythropoietin on the skeletal muscle

DEFF Research Database (Denmark)

Lundby, Carsten; Hellsten, Ylva; Jensen, Mie B. F.

2008-01-01

The presence and potential physiological role of the erythropoietin receptor (Epo-R) were examined in human skeletal muscle. In this study we demonstrate that Epo-R is present in the endothelium, smooth muscle cells, and in fractions of the sarcolemma of skeletal muscle fibers. To study...... the potential effects of Epo in human skeletal muscle, two separate studies were conducted: one to study the acute effects of a single Epo injection on skeletal muscle gene expression and plasma hormones and another to study the effects of long-term (14 wk) Epo treatment on skeletal muscle structure. Subjects...... was studied in subjects (n = 8) who received long-term Epo administration, and muscle biopsies were obtained before and after. Epo treatment did not alter mean fiber area (0.84 +/- 0.2 vs. 0.72 +/- 0.3 mm(2)), capillaries per fiber (4.3 +/- 0.5 vs. 4.4 +/- 1.3), or number of proliferating endothelial cells...

Identification of Cell Type-Specific Differences in Erythropoietin Receptor Signaling in Primary Erythroid and Lung Cancer Cells.

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Ruth Merkle

2016-08-01

Full Text Available Lung cancer, with its most prevalent form non-small-cell lung carcinoma (NSCLC, is one of the leading causes of cancer-related deaths worldwide, and is commonly treated with chemotherapeutic drugs such as cisplatin. Lung cancer patients frequently suffer from chemotherapy-induced anemia, which can be treated with erythropoietin (EPO. However, studies have indicated that EPO not only promotes erythropoiesis in hematopoietic cells, but may also enhance survival of NSCLC cells. Here, we verified that the NSCLC cell line H838 expresses functional erythropoietin receptors (EPOR and that treatment with EPO reduces cisplatin-induced apoptosis. To pinpoint differences in EPO-induced survival signaling in erythroid progenitor cells (CFU-E, colony forming unit-erythroid and H838 cells, we combined mathematical modeling with a method for feature selection, the L1 regularization. Utilizing an example model and simulated data, we demonstrated that this approach enables the accurate identification and quantification of cell type-specific parameters. We applied our strategy to quantitative time-resolved data of EPO-induced JAK/STAT signaling generated by quantitative immunoblotting, mass spectrometry and quantitative real-time PCR (qRT-PCR in CFU-E and H838 cells as well as H838 cells overexpressing human EPOR (H838-HA-hEPOR. The established parsimonious mathematical model was able to simultaneously describe the data sets of CFU-E, H838 and H838-HA-hEPOR cells. Seven cell type-specific parameters were identified that included for example parameters for nuclear translocation of STAT5 and target gene induction. Cell type-specific differences in target gene induction were experimentally validated by qRT-PCR experiments. The systematic identification of pathway differences and sensitivities of EPOR signaling in CFU-E and H838 cells revealed potential targets for intervention to selectively inhibit EPO-induced signaling in the tumor cells but leave the responses in

Erythropoietin promotes oligodendrogenesis and myelin repair following lysolecithin-induced injury in spinal cord slice culture

Energy Technology Data Exchange (ETDEWEB)

Cho, Yun Kyung; Kim, Gunha; Park, Serah; Sim, Ju Hee; Won, You Jin [Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736 (Korea, Republic of); Hwang, Chang Ho [Department of Physical Medicine and Rehabilitation, Ulsan University Hospital, University of Ulsan College of Medicine, 290-3 Jeonha-dong, Dong-gu, Ulsan 682-714 (Korea, Republic of); Yoo, Jong Yoon, E-mail: jyyoo@amc.seoul.kr [Department of Rehabilitation Medicine, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736 (Korea, Republic of); Hong, Hea Nam, E-mail: hnhong@amc.seoul.kr [Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736 (Korea, Republic of)

2012-01-13

Highlights: Black-Right-Pointing-Pointer Lysolecithin-induced demyelination elevated EpoR expression in OPCs. Black-Right-Pointing-Pointer In association with elevated EpoR, EPO increased OPCs proliferation. Black-Right-Pointing-Pointer EPO enhanced the oligodendrogenesis via activation of JAK2 pathway. Black-Right-Pointing-Pointer EPO promoted myelin repair following lysolecithin-induced demyelination. -- Abstract: Here, we sought to delineate the effect of EPO on the remyelination processes using an in vitro model of demyelination. We report that lysolecithin-induced demyelination elevated EPO receptor (EpoR) expression in oligodendrocyte progenitor cells (OPCs), facilitating the beneficial effect of EPO on the formation of oligodendrocytes (oligodendrogenesis). In the absence of EPO, the resultant remyelination was insufficient, possibly due to a limiting number of oligodendrocytes rather than their progenitors, which proliferate in response to lysolecithin-induced injury. By EPO treatment, lysolecithin-induced proliferation of OPCs was accelerated and the number of myelinating oligodendrocytes and myelin recovery was increased. EPO also enhanced the differentiation of neural progenitor cells expressing EpoR at high level toward the oligodendrocyte-lineage cells through activation of cyclin E and Janus kinase 2 pathways. Induction of myelin-forming oligodendrocytes by high dose of EPO implies that EPO might be the key factor influencing the final differentiation of OPCs. Taken together, our data suggest that EPO treatment could be an effective way to enhance remyelination by promoting oligodendrogenesis in association with elevated EpoR expression in spinal cord slice culture after lysolecithin-induced demyelination.

Common variants of the genes encoding erythropoietin and its receptor modulate cognitive performance in schizophrenia

DEFF Research Database (Denmark)

Kästner, Anne; Grube, Sabrina; El-Kordi, Ahmed

2012-01-01

-term memory readouts, with one particular combination of genotypes superior to all others (p 800), these associations were confirmed. A matching preclinical study with mice demonstrated cognitive processing speed and memory enhanced upon transgenic......Erythropoietin (EPO) improves cognitive performance in clinical studies and rodent experiments. We hypothesized that an intrinsic role of EPO for cognition exists, with particular relevance in situations of cognitive decline, which is reflected by associations of EPO and EPO receptor (EPOR......) genotypes with cognitive functions. To prove this hypothesis, schizophrenic patients (N > 1000) were genotyped for 5' upstream-located gene variants, EPO SNP rs1617640 (T/G) and EPORSTR(GA)(n). Associations of these variants were obtained for cognitive processing speed, fine motor skills and short...

Control of erythropoiesis by erythropoietin and stem cell factor: a novel role for Bruton's tyrosine kinase

NARCIS (Netherlands)

von Lindern, Marieke; Schmidt, Uwe; Beug, Hartmut

2004-01-01

Erythropoietin (Epo) and stem cell factor (SCF) are essential factors in the control of survival, expansion and differentiation of erythroid progenitors. Upon activation, their receptors, the EpoR and c-Kit, initiate multiple signalling pathways that control many cellular processes. To control

Epoetin Delta Reduces Oxidative Stress in Primary Human Renal Tubular Cells

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Annelies De Beuf

2010-01-01

Full Text Available Erythropoietin (EPO exerts (renal tissue protective effects. Since it is unclear whether this is a direct effect of EPO on the kidney or not, we investigated whether EPO is able to protect human renal tubular epithelial cells (hTECs from oxidative stress and if so which pathways are involved. EPO (epoetin delta could protect hTECs against oxidative stress by a dose-dependent inhibition of reactive oxygen species formation. This protective effect is possibly related to the membranous expression of the EPO receptor (EPOR since our data point to the membranous EPOR expression as a prerequisite for this protective effect. Oxidative stress reduction went along with the upregulation of renoprotective genes. Whilst three of these, heme oxygenase-1 (HO-1, aquaporin-1 (AQP-1, and B-cell CLL/lymphoma 2 (Bcl-2 have already been associated with EPO-induced renoprotection, this study for the first time suggests carboxypeptidase M (CPM, dipeptidyl peptidase IV (DPPIV, and cytoglobin (Cygb to play a role in this process.

Do All X-ray Structures of Protein-Ligand Complexes Represent Functional States? EPOR, a Case Study.

Science.gov (United States)

Corbett, Michael S P; Mark, Alan E; Poger, David

2017-02-28

Based on differences between the x-ray crystal structures of ligand-bound and unbound forms, the activation of the erythropoietin receptor (EPOR) was initially proposed to involve a cross-action scissorlike motion. However, the validity of the motions involved in the scissorlike model has been recently challenged. Here, atomistic molecular dynamics simulations are used to examine the structure of the extracellular domain of the EPOR dimer in the presence and absence of erythropoietin and a series of agonistic or antagonistic mimetic peptides free in solution. The simulations suggest that in the absence of crystal packing effects, the EPOR chains in the different dimers adopt very similar conformations with no clear distinction between the agonist and antagonist-bound complexes. This questions whether the available x-ray crystal structures of EPOR truly represent active or inactive conformations. The study demonstrates the difficulty in using such structures to infer a mechanism of action, especially in the case of membrane receptors where just part of the structure has been considered in addition to potential confounding effects that arise from the comparison of structures in a crystal as opposed to a membrane environment. The work highlights the danger of assigning functional significance to small differences between structures of proteins bound to different ligands in a crystal environment without consideration of the effects of the crystal lattice and thermal motion. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Epo Is Relevant Neither for Microvascular Formation Nor for the New Formation and Maintenance of Mice Skeletal Muscle Fibres in Both Normoxia and Hypoxia

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Luciana Hagström

2010-01-01

Full Text Available Erythropoietin (Epo and vascular growth factor (VEGF are known to be involved in the regulation of cellular activity when oxygen transport is reduced as in anaemia or hypoxic conditions. Because it has been suggested that Epo could play a role in skeletal muscle development, regeneration, and angiogenesis, we aimed to assess Epo deficiency in both normoxia and hypoxia by using an Epo-deficient transgenic mouse model (Epo-TAgh. Histoimmunology, ELISA and real time RT-PCR did not show any muscle fiber atrophy or accumulation of active HIF-1 but an improvement of microvessel network and an upregulation of VEGFR2 mRNA in Epo-deficient gastrocnemius compared with Wild-Type one. In hypoxia, both models exhibit an upregulation of VEGF120 and VEGFR2 mRNA but no accumulation of Epo protein. EpoR mRNA is not up-regulated in both Epo-deficient and hypoxic gastrocnemius. These results suggest that muscle deconditioning observed in patients suffering from renal failure is not due to Epo deficiency.

Erythropoietin: a multimodal neuroprotective agent

OpenAIRE

Byts, Nadiya; Sir?n, Anna-Leena

2009-01-01

Abstract The tissue protective functions of the hematopoietic growth factor erythropoietin (EPO) are independent of its action on erythropoiesis. EPO and its receptors (EPOR) are expressed in multiple brain cells during brain development and upregulated in the adult brain after injury. Peripherally administered EPO crosses the blood-brain barrier and activates in the brain anti-apoptotic, anti-oxidant and anti-inflammatory signaling in neurons, glial and cerebrovascular endothelial cells and ...

The Use of Soluble Transferrin Receptor in the Detection of rHuEPO abuse in Sports

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Donovan McGrowder

2010-01-01

Full Text Available Erythropoietin (EPO increases the number of circulating erythrocytes and muscle oxygenation. The recombinant forms of EPO have indiscriminately been used by athletes, mainly in endurance sports to increase their erythrocytes concentration, thus generating a better delivery of oxygen to the muscle tissue. The administration of recombinant human erythropoietin (rHuEPO except for therapeutic use was prohibited by the International Olympic Committee (IOC and its unauthorized use considered as doping. In the last few years, a number of studies using parameters indicative of accelerated erythropoiesis have investigated a number of indirect methods for the detection of rHuEPO abuse. No single indirect marker has been found that can satisfactorily demonstrated rHuEPO misuse. Soluble transferrin receptor (sTfR is a new marker of iron status and erythropoietic activity. It has been included in multivariable blood testing models for the detection of performance enhancing EPO abuse in sports. Indirect markers of altered erythropoiesis give reliable evidence of current or discontinued rHuEPO usage. This review describes the physical, biological and pharmacokinetic properties of endogenous EPO and its recombinant form. It also discusses the available strategies for the detection of rHuEPO abuse in sports, involving the use of sTfR concentration directly or in mathematical multivariate models.

A case of primary familial congenital polycythemia with a novel EPOR mutation: possible spontaneous remission/alleviation by menstrual bleeding.

Science.gov (United States)

Toriumi, Naohisa; Kaneda, Makoto; Hatakeyama, Naoki; Manabe, Hiromi; Okajima, Kazuki; Sakurai, Yukari; Yamamoto, Masayo; Sarashina, Takeo; Ikuta, Katsuya; Azuma, Hiroshi

2018-04-05

A 10-year-old girl with persistent erythrocytosis and ruddy complexion was diagnosed with primary familial congenital polycythemia (PFCP) involving a novel heterozygous mutation of c.1220C>A, p.Ser407X in exon 8 of the erythropoietin receptor gene (EPOR). This mutation causes truncation of EPOR, resulting in loss of the cytoplasmic region, which is necessary for negative regulation of erythropoietin signal transmission. Genetic analysis showed that the mutated EPOR was inherited from her mother. Her mother had polycythemia and had undergone venesection several times when she was young, but her polycythemic state appeared to have resolved. Venesection was not needed to maintain Hct levels within normal range. For the case reported here, venesection was also conducted to maintain the blood Hct level below 50%. We observed that after the patient experienced menarche, the volume and frequency of venesection needed to maintain Hct level < 50% were clearly reduced compared with those before menarche. These findings suggest that, in female patients with this type of EPOR mutation, menstruation might reduce blood volume in a manner similar to venesection. Spontaneous remission of erythrocytosis may thus occur after the start of menstrual bleeding.

Prognostic significance of erythropoietin in pancreatic adenocarcinoma.

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Thilo Welsch

Full Text Available BACKGROUND: Erythropoietin (Epo administration has been reported to have tumor-promoting effects in anemic cancer patients. We investigated the prognostic impact of endogenous Epo in patients with pancreatic ductal adenocarcinoma (PDAC. METHODOLOGY: The clinico-pathological relevance of hemoglobin (Hb, n = 150, serum Epo (sEpo, n = 87 and tissue expression of Epo/Epo receptor (EpoR, n = 104 was analyzed in patients with PDAC. Epo/EpoR expression, signaling, growth, invasion and chemoresistance were studied in Epo-exposed PDAC cell lines. RESULTS: Compared to donors, median preoperative Hb levels were reduced by 15% in both chronic pancreatitis (CP, p<0.05 and PDAC (p<0.001, reaching anemic grade in one third of patients. While inversely correlating to Hb (r = -0.46, 95% of sEPO values lay within the normal range. The individual levels of compensation were adequate in CP (observed to predicted ratio, O/P = 0.99 but not in PDAC (O/P = 0.85. Strikingly, lower sEPO values yielding inadequate Epo responses were prominent in non-metastatic M0-patients, whereas these parameters were restored in metastatic M1-group (8 vs. 13 mU/mL; O/P = 0.82 vs. 0.96; p<0.01--although Hb levels and the prevalence of anemia were comparable. Higher sEpo values (upper quartile ≥ 16 mU/ml were not significantly different in M0 (20% and M1 (30% groups, but were an independent prognostic factor for shorter survival (HR 2.20, 10 vs. 17 months, p<0.05. The pattern of Epo expression in pancreas and liver suggested ectopic release of Epo by capillaries/vasa vasorum and hepatocytes, regulated by but not emanating from tumor cells. Epo could initiate PI3K/Akt signaling via EpoR in PDAC cells but failed to alter their functions, probably due to co-expression of the soluble EpoR isoform, known to antagonize Epo. CONCLUSION/SIGNIFICANCE: Higher sEPO levels counteract anemia but worsen outcome in PDAC patients. Further trials are required to clarify how overcoming a sEPO threshold �

Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia.

Science.gov (United States)

Yang, Chunzhang; Zhuang, Zhengping; Fliedner, Stephanie M J; Shankavaram, Uma; Sun, Michael G; Bullova, Petra; Zhu, Roland; Elkahloun, Abdel G; Kourlas, Peter J; Merino, Maria; Kebebew, Electron; Pacak, Karel

2015-01-01

We have investigated genetic/pathogenetic factors associated with a new clinical entity in patients presenting with pheochromocytoma/paraganglioma (PHEO/PGL) and polycythemia. Two patients without hypoxia-inducible factor 2α (HIF2A) mutations, who presented with similar clinical manifestations, were analyzed for other gene mutations, including prolyl hydroxylase (PHD) mutations. We have found for the first time a germ-line mutation in PHD1 in one patient and a novel germ-line PHD2 mutation in a second patient. Both mutants exhibited reduced protein stability with substantial quantitative protein loss and thus compromised catalytic activities. Due to the unique association of patients' polycythemia with borderline or mildly elevated erythropoietin (EPO) levels, we also performed an in vitro sensitivity assay of erythroid progenitors to EPO and for EPO receptor (EPOR) expression. The results show inappropriate hypersensitivity of erythroid progenitors to EPO in these patients, indicating increased EPOR expression/activity. In addition, the present study indicates that HIF dysregulation due to PHD mutations plays an important role in the pathogenesis of these tumors and associated polycythemia. The PHD1 mutation appears to be a new member contributing to the genetic landscape of this novel clinical entity. Our results support the existence of a specific PHD1- and PHD2-associated PHEO/PGL-polycythemia disorder. • A novel germ-l i n e PHD1 mutation causing heochromocytoma/paraganglioma and polycythemia. • Increased EPOR activity and inappropriate hypersensitivity of erythroid progenitors to EPO.

Erythropoietin Action in Stress Response, Tissue Maintenance and Metabolism

Directory of Open Access Journals (Sweden)

Yuanyuan Zhang

2014-06-01

Full Text Available Erythropoietin (EPO regulation of red blood cell production and its induction at reduced oxygen tension provides for the important erythropoietic response to ischemic stress. The cloning and production of recombinant human EPO has led to its clinical use in patients with anemia for two and half decades and has facilitated studies of EPO action. Reports of animal and cell models of ischemic stress in vitro and injury suggest potential EPO benefit beyond red blood cell production including vascular endothelial response to increase nitric oxide production, which facilitates oxygen delivery to brain, heart and other non-hematopoietic tissues. This review discusses these and other reports of EPO action beyond red blood cell production, including EPO response affecting metabolism and obesity in animal models. Observations of EPO activity in cell and animal model systems, including mice with tissue specific deletion of EPO receptor (EpoR, suggest the potential for EPO response in metabolism and disease.

No evidence for protective erythropoietin alpha signalling in rat hepatocytes

Directory of Open Access Journals (Sweden)

Frede Stilla

2009-04-01

Full Text Available Abstract Background Recombinant human erythropoietin alpha (rHu-EPO has been reported to protect the liver of rats and mice from ischemia-reperfusion injury. However, direct protective effects of rHu-EPO on hepatocytes and the responsible signalling pathways have not yet been described. The aim of the present work was to study the protective effect of rHu-EPO on warm hypoxia-reoxygenation and cold-induced injury to hepatocytes and the rHu-EPO-dependent signalling involved. Methods Loss of viability of isolated rat hepatocytes subjected to hypoxia/reoxygenation or incubated at 4°C followed by rewarming was determined from released lactate dehydrogenase activity in the absence and presence of rHu-EPO (0.2–100 U/ml. Apoptotic nuclear morphology was assessed by fluorescence microscopy using the nuclear fluorophores H33342 and propidium iodide. Erythropoietin receptor (EPOR, EPO and Bcl-2 mRNAs were quantified by real time PCR. Activation of JAK-2, STAT-3 and STAT-5 in hepatocytes and rat livers perfused in situ was assessed by Western blotting. Results In contrast to previous in vivo studies on ischemia-reperfusion injury to the liver, rHu-EPO was without any protective effect on hypoxic injury, hypoxia-reoxygenation injury and cold-induced apoptosis to isolated cultured rat hepatocytes. EPOR mRNA was identified in these cells but specific detection of the EPO receptor protein was not possible due to the lack of antibody specificity. Both, in the cultured rat hepatocytes (10 U/ml for 15 minutes and in the rat liver perfused in situ with rHu-EPO (8.9 U/ml for 15 minutes no evidence for EPO-dependent signalling was found as indicated by missing effects of rHu-EPO on phosphorylation of JAK-2, STAT-3 and STAT-5 and on the induction of Bcl-2 mRNA. Conclusion Together, these results indicate the absence of any protective EPO signalling in rat hepatocytes. This implies that the protection provided by rHu-EPO in vivo against ischemia-reperfusion and

Thrombopoietin has a differentiative effect on late-stage human erythropoiesis.

Science.gov (United States)

Liu, W; Wang, M; Tang, D C; Ding, I; Rodgers, G P

1999-05-01

To further explore the mechanism of the effect of thrombopoietin (TPO) on erythropoiesis, we used a two-phase culture system to investigate the effect of TPO on late-stage human erythroid lineage differentiation. In serum-free suspension and semisolid cultures of human peripheral blood derived erythroid progenitors, TPO alone did not produce benzidine-positive cells. However, in serum-containing culture, TPO alone stimulated erythroid cell proliferation and differentiation, demonstrated by erythroid colony formation, production of benzidine-positive cells and haemoglobin (Hb) synthesis. Monoclonal anti-human erythropoietin antibody and anti-human erythropoietin receptor antibody completely abrogated the erythroid differentiative ability of TPO in the serum-containing systems. This implied that binding of EPO and EPO-R was essential for erythropoiesis and the resultant signal transduction may be augmented by the signals emanating from TPO-c-Mpl interaction. Experiment of withdrawal of TPO further demonstrated the involvement of TPO in late-stage erythropoiesis. RT-PCR results showed that there was EPO-R but not c-Mpl expression on developing erythroblasts induced by TPO in serum-containing system. Our results establish that TPO affects not only the proliferation of erythroid progenitors but also the differentiation of erythroid progenitors to mature erythroid cells.

Synthesis and biological evaluation of 125I-erythropoietin as a potential radiopharmaceutical agent for tumours

International Nuclear Information System (INIS)

Clemente, Goncalo dos Santos; Duarte, Vera Lucia Serra

2011-01-01

Erythropoietin (EPO) is a glycoprotein hormone responsible for regulating erythropoiesis. Expression of EPO and EPO receptors (EPOr) has recently been demonstrated in some neoplastic cell lines and tumours, suggesting a potential new target for therapy. In this work, EPO was labeled with iodine-125 using the lactoperoxidase method, known to prevent damage to protein during radioiodination, and labeling conditions were optimized. In vitro stability studies have shown that 125 I-EPO is radiochemically stable for 20 days after radiolabeling. In vitro cell binding studies have demonstrated very low binding ( 125 I-EPO. In mice with induced melanoma, only a residual fixation in the tumour was evident. Further studies are warranted on other tumoral cell lines to better understand the binding process and internalization into cells. Studies on EPO labeled with carbon-11 could be valuable, since there is a greater chance of preserving the biological activity of the protein using this method. (author)

Leukemic transformation of normal murine erythroid progenitors: v- and c-ErbB act through signaling pathways activated by the EpoR and c-Kit in stress erythropoiesis

NARCIS (Netherlands)

von Lindern, M.; Deiner, E. M.; Dolznig, H.; Parren-van Amelsvoort, M.; Hayman, M. J.; Mullner, E. W.; Beug, H.

2001-01-01

Primary erythroid progenitors can be expanded by the synergistic action of erythropoietin (Epo), stem cell factor (SCF) and glucocorticoids. While Epo is required for erythropoiesis in general, glucocorticoids and SCF mainly contribute to stress erythropoiesis in hypoxic mice. This ability of normal

Cervical spinal erythropoietin induces phrenic motor facilitation via ERK and Akt signaling

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Dale, Erica A.; Satriotomo, Irawan; Mitchell, Gordon S.

2012-01-01

Erythropoietin (EPO) is typically known for its role in erythropoiesis, but is also a potent neurotrophic/neuroprotective factor for spinal motor neurons. Another trophic factor regulated by Hypoxia-Inducible Factor-1, vascular endothelial growth factor (VEGF), signals via ERK and Akt activation to elicit long-lasting phrenic motor facilitation (pMF). Since EPO also signals via ERK and Akt activation, we tested the hypothesis that EPO elicits similar pMF. Using retrograde labeling and immunohistochemical techniques, we demonstrate in adult, male, Sprague-Dawley rats that EPO and its receptor, EPO-R, are expressed in identified phrenic motor neurons. Intrathecal EPO at C4 elicits long-lasting pMF; integrated phrenic nerve burst amplitude increased >90 min post-injection (63±12% baseline 90 min post-injection; pphrenic motor neurons; EPO also increased pAkt (1.6 fold vs controls; pphrenic motor neurons (p<0.05), indicating a complex interaction between these kinases. We conclude that EPO elicits spinal plasticity in respiratory motor control. Since EPO expression is hypoxia-sensitive, it may play a role in respiratory plasticity in conditions of prolonged or recurrent low oxygen. PMID:22539857

Stat5 signaling specifies basal versus stress erythropoietic responses through distinct binary and graded dynamic modalities.

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Ermelinda Porpiglia

2012-08-01

Full Text Available Erythropoietin (Epo-induced Stat5 phosphorylation (p-Stat5 is essential for both basal erythropoiesis and for its acceleration during hypoxic stress. A key challenge lies in understanding how Stat5 signaling elicits distinct functions during basal and stress erythropoiesis. Here we asked whether these distinct functions might be specified by the dynamic behavior of the Stat5 signal. We used flow cytometry to analyze Stat5 phosphorylation dynamics in primary erythropoietic tissue in vivo and in vitro, identifying two signaling modalities. In later (basophilic erythroblasts, Epo stimulation triggers a low intensity but decisive, binary (digital p-Stat5 signal. In early erythroblasts the binary signal is superseded by a high-intensity graded (analog p-Stat5 response. We elucidated the biological functions of binary and graded Stat5 signaling using the EpoR-HM mice, which express a "knocked-in" EpoR mutant lacking cytoplasmic phosphotyrosines. Strikingly, EpoR-HM mice are restricted to the binary signaling mode, which rescues these mice from fatal perinatal anemia by promoting binary survival decisions in erythroblasts. However, the absence of the graded p-Stat5 response in the EpoR-HM mice prevents them from accelerating red cell production in response to stress, including a failure to upregulate the transferrin receptor, which we show is a novel stress target. We found that Stat5 protein levels decline with erythroblast differentiation, governing the transition from high-intensity graded signaling in early erythroblasts to low-intensity binary signaling in later erythroblasts. Thus, using exogenous Stat5, we converted later erythroblasts into high-intensity graded signal transducers capable of eliciting a downstream stress response. Unlike the Stat5 protein, EpoR expression in erythroblasts does not limit the Stat5 signaling response, a non-Michaelian paradigm with therapeutic implications in myeloproliferative disease. Our findings show how the

Characterization of the structure of the erythropoietin receptor by ligand blotting

International Nuclear Information System (INIS)

Atkins, H.L.; Broudy, V.C.; Papayannopoulou, T.

1991-01-01

Erythropoietin (Epo) regulates the growth and differentiation of erythroid cells by binding to a specific receptor. We characterized the native Epo receptor on erythroleukemia cell lines by ligand blotting. Solubilized cell membrane proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, transferred onto nitrocellulose, and probed with 125I-Epo. Specificity was demonstrated by inhibition of 125I-Epo binding by unlabeled excess Epo but not other peptide growth factors and by the cellular distribution of the Epo binding protein. A single membrane protein of 61 Kd ± 4 Kd was sufficient to bind 125I Epo in both human (OCIM2, K562) and murine (GM979, Rauscher, DA-1) cell lines. This finding is consistent with the predicted size of the Epo receptor from the murine cDNA clone. However, chemical crosslinking of 125I-Epo to its receptor has identified two Epo binding proteins of 105 Kd and 85 Kd. This difference may occur because the receptor is size fractionated before Epo binding in the ligand blot, but after Epo binding in crosslinking studies. Ligand blotting demonstrates that the native Epo receptor is composed of a single 61-Kd Epo binding protein, and suggests the presence of additional proteins of 20 to 25 Kd that associate with the receptor after Epo binding

The EPOS ICT Architecture

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Jeffery, Keith; Harrison, Matt; Bailo, Daniele

2016-04-01

The EPOS-PP Project 2010-2014 proposed an architecture and demonstrated feasibility with a prototype. Requirements based on use cases were collected and an inventory of assets (e.g. datasets, software, users, computing resources, equipment/detectors, laboratory services) (RIDE) was developed. The architecture evolved through three stages of refinement with much consultation both with the EPOS community representing EPOS users and participants in geoscience and with the overall ICT community especially those working on research such as the RDA (Research Data Alliance) community. The architecture consists of a central ICS (Integrated Core Services) consisting of a portal and catalog, the latter providing to end-users a 'map' of all EPOS resources (datasets, software, users, computing, equipment/detectors etc.). ICS is extended to ICS-d (distributed ICS) for certain services (such as visualisation software services or Cloud computing resources) and CES (Computational Earth Science) for specific simulation or analytical processing. ICS also communicates with TCS (Thematic Core Services) which represent European-wide portals to national and local assets, resources and services in the various specific domains (e.g. seismology, volcanology, geodesy) of EPOS. The EPOS-IP project 2015-2019 started October 2015. Two work-packages cover the ICT aspects; WP6 involves interaction with the TCS while WP7 concentrates on ICS including interoperation with ICS-d and CES offerings: in short the ICT architecture. Based on the experience and results of EPOS-PP the ICT team held a pre-meeting in July 2015 and set out a project plan. The first major activity involved requirements (re-)collection with use cases and also updating the inventory of assets held by the various TCS in EPOS. The RIDE database of assets is currently being converted to CERIF (Common European Research Information Format - an EU Recommendation to Member States) to provide the basis for the EPOS-IP ICS Catalog. In

Functional significance of erythropoietin in renal cell carcinoma

International Nuclear Information System (INIS)

Morais, Christudas; Johnson, David W; Vesey, David A; Gobe, Glenda C

2013-01-01

One of the molecules regulated by the transcription factor, hypoxia inducible factor (HIF), is the hypoxia-responsive hematopoietic factor, erythropoietin (EPO). This may have relevance to the development of renal cell carcinoma (RCC), where mutations of the von Hippel-Lindau (VHL) gene are major risk factors for the development of familial and sporadic RCC. VHL mutations up-regulate and stabilize HIF, which in turn activates many downstream molecules, including EPO, that are known to promote angiogenesis, drug resistance, proliferation and progression of solid tumours. HIFs typically respond to hypoxic cellular environment. While the hypoxic microenvironment plays a critical role in the development and progression of tumours in general, it is of special significance in the case of RCC because of the link between VHL, HIF and EPO. EPO and its receptor, EPOR, are expressed in many cancers, including RCC. This limits the use of recombinant human EPO (rhEPO) to treat anaemia in cancer patients, because the rhEPO may be stimulatory to the cancer. EPO may also stimulate epithelial-mesenchymal transition (EMT) in RCC, and pathological EMT has a key role in cancer progression. In this mini review, we summarize the current knowledge of the role of EPO in RCC. The available data, either for or against the use of EPO in RCC patients, are equivocal and insufficient to draw a definitive conclusion

FIN-EPOS - Finnish national initiative of the European Plate Observing System: Bringing Finnish solid Earth infrastructures into EPOS

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Vuorinen, Tommi; Korja, Annakaisa

2017-04-01

FIN-EPOS consortium is a joint community of Finnish national research institutes tasked with operating and maintaining solid-earth geophysical and geological observatories and laboratories in Finland. These national research infrastructures (NRIs) seek to join EPOS research infrastructure (EPOS RI) and further pursue Finland's participation as a founding member in EPOS ERIC (European Research Infrastructure Consortium). Current partners of FIN-EPOS are the University of Helsinki (UH), the University of and Oulu (UO), Finnish Geospatial Research Institute (FGI) of the National Land Survey (NLS), Finnish Meteorological Institute (FMI), Geological Survey of Finland (GTK), CSC - IT Center for Science and MIKES Metrology at VTT Technical Research Centre of Finland Ltd. The consortium is hosted by the Institute of Seismology, UH (ISUH). The primary purpose of the consortium is to act as a coordinating body between various NRIs and the EPOS RI. FIN-EPOS engages in planning and development of the national EPOS RI and will provide support in EPOS implementation phase (IP) for the partner NRIs. FIN-EPOS also promotes the awareness of EPOS in Finland and is open to new partner NRIs that would benefit from participating in EPOS. The consortium additionally seeks to advance solid Earth science education, technologies and innovations in Finland and is actively engaging in Nordic co-operation and collaboration of solid Earth RIs. The main short term objective of FIN-EPOS is to make Finnish geoscientific data provided by NRIs interoperable with the Thematic Core Services (TCS) in the EPOS IP. Consortium partners commit into applying and following metadata and data format standards provided by EPOS. FIN-EPOS will also provide a national Finnish language web portal where users are identified and their user rights for EPOS resources are defined.

A Novel EPO Receptor Agonist Improves Glucose Tolerance via Glucose Uptake in Skeletal Muscle in a Mouse Model of Diabetes

Directory of Open Access Journals (Sweden)

Michael S. Scully

2011-01-01

Full Text Available Patients treated with recombinant human Epo demonstrate an improvement in insulin sensitivity. We aimed to investigate whether CNTO 530, a novel Epo receptor agonist, could affect glucose tolerance and insulin sensitivity. A single administration of CNTO 530 significantly and dose-dependently reduced the area under the curve in a glucose tolerance test in diet-induced obese and diabetic mice after 14, 21, and 28 days. HOMA analysis suggested an improvement in insulin sensitivity, and this effect was confirmed by a hyperinsulinemic-euglycemic clamp. Uptake of 14C-2-deoxy-D-glucose indicated that animals dosed with CNTO 530 transported more glucose into skeletal muscle and heart relative to control animals. In conclusion, CNTO530 has a profound effect on glucose tolerance in insulin-resistant rodents likely because of improving peripheral insulin sensitivity. This effect was observed with epoetin-α and darbepoetin-α, suggesting this is a class effect, but the effect with these compounds relative to CNTO530 was decreased in duration and magnitude.

EPOS-Seismology: building the Thematic Core Service for Seismology during the EPOS Implementation Phase

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Haslinger, Florian; EPOS Seismology Consortium, the

2015-04-01

After the successful completion of the EPOS Preparatory Phase, the community of European Research Infrastructures in Seismology is now moving ahead with the build-up of the Thematic Core Service (TCS) for Seismology in EPOS, EPOS-Seismology. Seismology is a domain where European-level infrastructures have been developed since decades, often supported by large-scale EU projects. Today these infrastructures provide services to access earthquake waveforms (ORFEUS), parameters (EMSC) and hazard data and products (EFEHR). The existing organizations constitute the backbone of infrastructures that also in future will continue to manage and host the services of the TCS EPOS-Seismology. While the governance and internal structure of these organizations will remain active, and continue to provide direct interaction with the community, EPOS-Seismology will provide the integration of these within EPOS. The main challenge in the build-up of the TCS EPOS-Seismology is to improve and extend these existing services, producing a single framework which is technically, organizationally and financially integrated with the EPOS architecture, and to further engage various kinds of end users (e.g. scientists, engineers, public managers, citizen scientists). On the technical side the focus lies on four major tasks: - the construction of the next generation software architecture for the European Integrated (waveform) Data Archive EIDA, developing advanced metadata and station information services, fully integrate strong motion waveforms and derived parametric engineering-domain data, and advancing the integration of mobile (temporary) networks and OBS deployments in EIDA; - the further development and expansion of services to access seismological products of scientific interest as provided by the community by implementing a common collection and development (IT) platform, improvements in the earthquake information services e.g. by introducing more robust quality indicators and diversifying

EPOR-Based Purification and Analysis of Erythropoietin Mimetic Peptides from Human Urine by Cys-Specific Cleavage and LC/MS/MS

Science.gov (United States)

Vogel, Matthias; Thomas, Andreas; Schänzer, Wilhelm; Thevis, Mario

2015-09-01

The development of a new class of erythropoietin mimetic agents (EMA) for treating anemic conditions has been initiated with the discovery of oligopeptides capable of dimerizing the erythropoietin (EPO) receptor and thus stimulating erythropoiesis. The most promising amino acid sequences have been mounted on various different polymeric structures or carrier molecules to obtain highly active EPO-like drugs exhibiting beneficial and desirable pharmacokinetic profiles. Concomitant with creating new therapeutic options, erythropoietin mimetic peptide (EMP)-based drug candidates represent means to artificially enhance endurance performance and necessitate coverage by sports drug testing methods. Therefore, the aim of the present study was to develop a strategy for the comprehensive detection of EMPs in doping controls, which can be used complementary to existing protocols. Three model EMPs were used to provide proof-of-concept data. Following EPO receptor-facilitated purification of target analytes from human urine, the common presence of the cysteine-flanked core structure of EMPs was exploited to generate diagnostic peptides with the aid of a nonenzymatic cleavage procedure. Sensitive detection was accomplished by targeted-SIM/data-dependent MS2 analysis. Method characterization was conducted for the EMP-based drug peginesatide concerning specificity, linearity, precision, recovery, stability, ion suppression/enhancement, and limit of detection (LOD, 0.25 ng/mL). Additionally, first data for the identification of the erythropoietin mimetic peptides EMP1 and BB68 were generated, demonstrating the multi-analyte testing capability of the presented approach.

Detection of recombinant EPO in blood and urine samples with EPO WGA MAIIA, IEF and SAR-PAGE after microdose injections.

Science.gov (United States)

Dehnes, Yvette; Shalina, Alexandra; Myrvold, Linda

2013-01-01

The misuse of microdoses of performance enhancing drugs like erythropoietin (EPO) constitutes a major challenge in doping analysis. When injected intravenously, the half-life of recombinant human EPO (rhEPO) like epoetin alfa, beta, and zeta is only a few hours and hence, the window for direct detection of rhEPO in urine is small. In order to investigate the detection window for rhEPO directly in blood and urine with a combined affinity chromatography and lateral flow immunoassay (EPO WGA MAIIA), we recruited nine healthy people who each received six intravenously injected microdoses (7.5 IU/kg) of NeoRecormon (epoetin beta) over a period of three weeks. Blood and urine samples were collected in the days following the injections and analyzed with EPO WGA MAIIA as well as the current validated methods for rhEPO; isoelectric focusing (IEF) and sarcosyl polyacrylamide gel electrophoresis (SAR-PAGE). For samples collected 18 h after a microdose, the sensitivity of the EPO WGA MAIIA assay was 100% in plasma and 87.5% in urine samples at the respective 98% specificity threshold levels. In comparison, the sensitivity in plasma and urine was 75% and 100%, respectively, with IEF, and 87.5% in plasma and 100% in urine when analyzed with SAR-PAGE. We conclude that EPO WGA MAIIA is a sensitive assay for the detection of rhEPO, with the potential of being a fast, supplemental screening assay for use in doping analysis.

Recombinant human erythropoietin alpha improves the efficacy of radiotherapy of a human tumor xenograft, affecting tumor cells and microvessels

International Nuclear Information System (INIS)

Loevey, J.; Bereczky, B.; Gilly, R.; Kenessey, I.; Raso, E.; Simon, E.; Timar, J.; Dobos, J.; Vago, A.; Kasler, M.; Doeme, B.; Tovari, J.

2008-01-01

Background and purpose: tumor-induced anemia often occurs in cancer patients, and is corrected by recombinant human erythropoietins (rHuEPOs). Recent studies indicated that, besides erythroid progenitor cells, tumor and endothelial cells express erythropoietin receptor (EPOR) as well; therefore, rHuEPO may affect their functions. Here, the effect of rHuEPOα on irradiation in EPOR-positive human squamous cell carcinoma xenograft was tested. Material and methods: A431 tumor-bearing SCID mice were treated from the tumor implantation with rHuEPOα at human-equivalent dose. Xenografts were irradiated (5 Gy) on day 14, and the final tumor mass was measured on day 22. The systemic effects of rHuEPOα on the hemoglobin level, on tumor-associated blood vessels and on hypoxia-inducible factor-(HIF-)1α expression of the tumor xenografts were monitored. The proliferation, apoptosis and clonogenic capacity of A431 cancer cells treated with rHuEPOα and irradiation were also tested in vitro. Results: in vitro, rHuEPOα treatment alone did not modify the proliferation of EPOR-positive A431 tumor cells but enhanced the effect of irradiation on proliferation, apoptosis and clonogenic capacity. In vivo, rHuEPOα administration compensated the tumor-induced anemia in SCID mice and decreased tumoral HIF-1α expression but had no effect on tumor growth. At the same time rHuEPOα treatment significantly increased the efficacy of radiotherapy in vivo (tumor weight of 23.9 ± 4.7 mg and 34.9 ± 4.6 mg, respectively), mediated by increased tumoral blood vessel destruction. Conclusion: rHuEPOα treatment may modulate the efficacy of cancer radiotherapy not only by reducing systemic hypoxia and tumoral HIF-1α expression, but also by destroying tumoral vessels. (orig.)

Examination of the e{sup +} and e{sup +}e{sup -} pair emission from heavy ion collisions at the EPoS II spectrometer; Untersuchung der e{sup +}- und e{sup +}e{sup -}-Paaremission aus Schwerionenkollisionen mit dem EPoS II Spektrometer

Energy Technology Data Exchange (ETDEWEB)

Baumann, J.

1996-12-01

In the course of examination of the positron and positron-electron pair emission from heavy ion collisions at the Coulomb barrier, the research groups EPOS I and ORANGE have found a number of line structures in the measured positron energy and cumulative pair energy spectra which up to present could not be fully explained, as theoretical interpretations so far remain inconsistent in some respects. For clarification, further measurements have been made at the completely new designed EPoS II spectrometer. Reproducibility of the lines is possible at a high level of statistical significance. (orig./CB) [Deutsch] Bei Untersuchungen der Positron- und Positron- Elektron- Paaremissionaus Schwerionenkollisionen an der Coulombbarriere wurde von den Gruppen EPOS I und ORANGE eine Reihe von Linienstrukturen in den gemessenen Positronenenergie- und Paarsummenenergiespektren beobachtet, fuer die bislang keine in allen Punkten konsistente, theoretische Erklaerunggefunden werden konnte. Um ihre Ursachen zu klaeren, wurden mit dem voellig neu aufgebauten EPoS II Spektrometer weitere Messreihen durgefuehrt. Die Reproduzierbarkeit der Linien ist auf einem hohen statistischen Signifikanzniveau moeglich.

The EPOS Legal and Governance Framework : tailoring the infrastructure to fit the needs of the EPOS services

Science.gov (United States)

Kohler, Elisabeth; Pedersen, Helle; Kontkanen, Pirjo; Korja, Annakaisa; Lauterjung, Jörn; Haslinger, Florian; Sangianantoni, Agata; Bartolini, Alessandro; Consortium, Epos

2016-04-01

One of the most important issues regarding a pan-European distributed large scale research infrastructure is the setting up of its legal and governance structure as this will shape the very operation of the undertaking, i.e. the decision-making process, the allocation of tasks and resources as well as the relationship between the different bodies. Ensuring long-term operational services requires a robust, coherent and transparent legal and governance framework across all of the EPOS TCS (Thematic Core Services) and ICS (Integrated Core Services) that is well aligned to the EPOS global architecture. The chosen model for the EPOS legal entity is the ERIC (European Research Infrastructure Consortium). While the statutory seat of EPOS-ERIC will be in Rome, Italy, most of the services will be hosted in other countries. Specific agreements between EPOS-ERIC and the legal bodies hosting EPOS services will be implemented to allow proper coordination of activities. The objective is to avoid multiple agreements and, where possible, to standardize them in order to reach a harmonized situation across all services. For the governance careful attention will be paid to the decision-making process, the type of decisions and the voting rights, the definition of responsibilities, rights and duties, the reporting mechanisms, as well as other issues like who within a TCS represents the service to the 'outside' world or who advices the TCS on which subjects. Data policy is another crucial issue as EPOS aims to provide interdisciplinary services to researchers interested in geoscience, including access to data, metadata, data products, software and IT tools. EPOS also provides access to computational resources for visualization and processing. Beyond the general principles of Open Access and Open Source the following questions have to be addressed: scope and nature of data that will be accepted; intellectual property rights in data and terms under which data will be shared; openness and

Biologically active, magnICON®-expressed EPO-Fc from stably transformed Nicotiana benthamiana plants presenting tetra-antennary N-glycan structures.

Science.gov (United States)

Nagels, Bieke; Van Damme, Els J M; Callewaert, Nico; Zabeau, Lennart; Tavernier, Jan; Delanghe, Joris R; Boets, Annemie; Castilho, Alexandra; Weterings, Koen

2012-08-31

In the past two decades plants have emerged as a valuable alternative for the production of pharmaceutical proteins. Since N-glycosylation influences functionality and stability of therapeutic proteins, the plant N-glycosylation pathway should be humanized. Here, we report the transient magnICON(®) expression of the erythropoietin fusion protein (EPO-Fc) in Nicotiana benthamiana plants that produce multi-antennary N-glycans without the plant-specific β1,2-xylose and α1,3-fucose residues in a stable manner (Nagels et al., 2011). The EPO-Fc fusion protein consists of EPO with a C-terminal-linked IgG-Fc domain and is used for pulmonary delivery of recombinant EPO to patients (Bitonti et al., 2004). Plant expressed EPO-Fc was quantified using a paramagnetic-particle chemiluminescent immunoassay and shown to be active in vitro via receptor binding experiments in HEK293T cells. Mass spectrometry-based N-glycan analysis confirmed the presence of multi-antennary N-glycans on plant-expressed EPO-Fc. The described research is the next step towards the development of a production platform for pharmaceutical proteins in plants. Copyright © 2012 Elsevier B.V. All rights reserved.

The EPOS e-Infrastructure

Science.gov (United States)

Jeffery, Keith; Bailo, Daniele

2014-05-01

The European Plate Observing System (EPOS) is integrating geoscientific information concerning earth movements in Europe. We are approaching the end of the PP (Preparatory Project) phase and in October 2014 expect to continue with the full project within ESFRI (European Strategic Framework for Research Infrastructures). The key aspects of EPOS concern providing services to allow homogeneous access by end-users over heterogeneous data, software, facilities, equipment and services. The e-infrastructure of EPOS is the heart of the project since it integrates the work on organisational, legal, economic and scientific aspects. Following the creation of an inventory of relevant organisations, persons, facilities, equipment, services, datasets and software (RIDE) the scale of integration required became apparent. The EPOS e-infrastructure architecture has been developed systematically based on recorded primary (user) requirements and secondary (interoperation with other systems) requirements through Strawman, Woodman and Ironman phases with the specification - and developed confirmatory prototypes - becoming more precise and progressively moving from paper to implemented system. The EPOS architecture is based on global core services (Integrated Core Services - ICS) which access thematic nodes (domain-specific European-wide collections, called thematic Core Services - TCS), national nodes and specific institutional nodes. The key aspect is the metadata catalog. In one dimension this is described in 3 levels: (1) discovery metadata using well-known and commonly used standards such as DC (Dublin Core) to enable users (via an intelligent user interface) to search for objects within the EPOS environment relevant to their needs; (2) contextual metadata providing the context of the object described in the catalog to enable a user or the system to determine the relevance of the discovered object(s) to their requirement - the context includes projects, funding, organisations

Romanian contribution to research infrastructure database for EPOS

Science.gov (United States)

Ionescu, Constantin; Craiu, Andreea; Tataru, Dragos; Balan, Stefan; Muntean, Alexandra; Nastase, Eduard; Oaie, Gheorghe; Asimopolos, Laurentiu; Panaiotu, Cristian

2014-05-01

European Plate Observation System - EPOS is a long-term plan to facilitate integrated use of data, models and facilities from mainly distributed existing, but also new, research infrastructures for solid Earth Science. In EPOS Preparatory Phase were integrated the national Research Infrastructures at pan European level in order to create the EPOS distributed research infrastructures, structure in which, at the present time, Romania participates by means of the earth science research infrastructures of the national interest declared on the National Roadmap. The mission of EPOS is to build an efficient and comprehensive multidisciplinary research platform for solid Earth Sciences in Europe and to allow the scientific community to study the same phenomena from different points of view, in different time periods and spatial scales (laboratory and field experiments). At national scale, research and monitoring infrastructures have gathered a vast amount of geological and geophysical data, which have been used by research networks to underpin our understanding of the Earth. EPOS promotes the creation of comprehensive national and regional consortia, as well as the organization of collective actions. To serve the EPOS goals, in Romania a group of National Research Institutes, together with their infrastructures, gathered in an EPOS National Consortium, as follows: 1. National Institute for Earth Physics - Seismic, strong motion, GPS and Geomagnetic network and Experimental Laboratory; 2. National Institute of Marine Geology and Geoecology - Marine Research infrastructure and Euxinus integrated regional Black Sea observation and early-warning system; 3. Geological Institute of Romania - Surlari National Geomagnetic Observatory and National lithoteque (the latter as part of the National Museum of Geology) 4. University of Bucharest - Paleomagnetic Laboratory After national dissemination of EPOS initiative other Research Institutes and companies from the potential

Direct targets of pSTAT5 signalling in erythropoiesis.

Directory of Open Access Journals (Sweden)

Kevin R Gillinder

Full Text Available Erythropoietin (EPO acts through the dimeric erythropoietin receptor to stimulate proliferation, survival, differentiation and enucleation of erythroid progenitor cells. We undertook two complimentary approaches to find EPO-dependent pSTAT5 target genes in murine erythroid cells: RNA-seq of newly transcribed (4sU-labelled RNA, and ChIP-seq for pSTAT5 30 minutes after EPO stimulation. We found 302 pSTAT5-occupied sites: ~15% of these reside in promoters while the rest reside within intronic enhancers or intergenic regions, some >100kb from the nearest TSS. The majority of pSTAT5 peaks contain a central palindromic GAS element, TTCYXRGAA. There was significant enrichment for GATA motifs and CACCC-box motifs within the neighbourhood of pSTAT5-bound peaks, and GATA1 and/or KLF1 co-occupancy at many sites. Using 4sU-RNA-seq we determined the EPO-induced transcriptome and validated differentially expressed genes using dynamic CAGE data and qRT-PCR. We identified known direct pSTAT5 target genes such as Bcl2l1, Pim1 and Cish, and many new targets likely to be involved in driving erythroid cell differentiation including those involved in mRNA splicing (Rbm25, epigenetic regulation (Suv420h2, and EpoR turnover (Clint1/EpsinR. Some of these new EpoR-JAK2-pSTAT5 target genes could be used as biomarkers for monitoring disease activity in polycythaemia vera, and for monitoring responses to JAK inhibitors.

SIMBOL RAMA DAN EPOS RAMAYANA BAGI RAJA DAN MASYARAKAT JAWA

Directory of Open Access Journals (Sweden)

Wachid Eko Purwanto

2015-06-01

Full Text Available Epos Ramayana merupakan epos kuno yang ditulis dalam tujuh kanda terdiri atas 24.000 sloka. Di Jawa epos Ramayana pertama kali muncul secara lengkap dalam bentuk relief di Candi Lara Jonggrang yang dibangun sekitar tahun 782 hingga 872 M. Epos tua yang hidup di masyarakat Jawa ini pastilah mempunyai ajaran. Tokoh Rama sebagai tokoh utama merupakan simbol paling utama dalam epos ini. Berkait dengan simbol ajaran, tokoh Rama dalam epos Ramayana Jawa mempunyai fungsi bagi Raja Jawa dan masyarakat Jawa. Bagi raja simbol tokoh Rama memiliki tiga fungsi utama. Pertama sebagai fungsi spiritual. Kedua adalah fungsi legitimasi kekuasaan. Ketiga adalah fungsi pencitraan. Adapun bagi masyarakat Jawa, simbol tokoh Rama memiliki dua fungsi utama. Pertama adalah fungsi spiritual. Kedua adalah fungsi filosofis.

European Plate Observing System - Norway (EPOS-N): A National Consortium for the Norwegian Implementation of EPOS

Science.gov (United States)

Atakan, Kuvvet; Tellefsen, Karen

2017-04-01

The European Plate Observing System (EPOS) aims to create a pan-European infrastructure for solid Earth science to support a safe and sustainable society. The main vision of the European Plate Observing System (EPOS) is to address the three basic challenges in Earth Science: (i) unravelling the Earth's deformational processes which are part of the Earth system evolution in time, (ii) understanding geo-hazards and their implications to society, and (iii) contributing to the safe and sustainable use of geo-resources. The mission of EPOS-Norway is therefore in line with the European vision of EPOS, i.e. monitor and understand the dynamic and complex Earth system by relying on new e-science opportunities and integrating diverse and advanced Research Infrastructures for solid Earth science. The EPOS-Norway project started in January 2016 with a national consortium consisting of six institutions. These are: University of Bergen (Coordinator), NORSAR, National Mapping Authority, Geological Survey of Norway, Christian Michelsen Research and University of Oslo. EPOS-N will during the next five years focus on the implementation of three main components. These are: (i) Developing a Norwegian e-Infrastructure to integrate the Norwegian Solid Earth data from the seismological and geodetic networks, as well as the data from the geological and geophysical data repositories, (ii) Improving the monitoring capacity in the Arctic, including Northern Norway and the Arctic islands, and (iii) Establishing a national Solid Earth Science Forum providing a constant feedback mechanism for improved integration of multidisciplinary data, as well as training of young scientists for future utilization of all available solid Earth observational data through a single e-infrastructure. Currently, a list of data, data products, software and services (DDSS) is being prepared. These elements will be integrated in the EPOS-N data/web-portal, which will allow users to browse, select and download

Epo's Chronicles: A Weekly Webcomic That Teaches Space Science

Science.gov (United States)

Cominsky, Lynn R.; Prasad, K.; Simonnet, A.; John, K.; McLin, K.; Hill, L.

2009-01-01

Sonoma State University Education and Public Outreach presents Epo's Chronicles: a weekly web comic about Epo, a sentient spaceship/observatory and its humanoid companion, Alkina. Follow the adventures of Epo and Alkina as they explore the Universe and try to discover their origins. The comic employs a fictional story line incorporating both recent and classic scientific discoveries from NASA missions while educating the young and the young at heart in a creative and engaging way. Each weekly "eposode” is translated into French, Italian and Spanish, and is accompanied by supporting information including glossary entries, multi-media clips, and links to additional resources. Visit Epo's Chronicles at: http://eposchronicles.com

EPOS Data and Service Provision

Science.gov (United States)

Bailo, Daniele; Jeffery, Keith G.; Atakan, Kuvvet; Harrison, Matt

2017-04-01

EPOS is now in IP (implementation phase) after a successful PP (preparatory phase). EPOS consists of essentially two components, one ICS (Integrated Core Services) representing the integrating ICT (Information and Communication Technology) and many TCS (Thematic Core Services) representing the scientific domains. The architecture developed, demonstrated and agreed within the project during the PP is now being developed utilising co-design with the TCS teams and agile, spiral methods within the ICS team. The 'heart' of EPOS is the metadata catalog. This provides for the ICS a digital representation of the TCS assets (services, data, software, equipment, expertise…) thus facilitating access, interoperation and (re-)use. A major part of the work has been interactions with the TCS. The original intention to harvest information from the TCS required (and still requires) discussions to understand fully the TCS organisational structures linked with rights, security and privacy; their (meta)data syntax (structure) and semantics (meaning); their workflows and methods of working and the services offered. To complicate matters further the TCS are each at varying stages of development and the ICS design has to accommodate pre-existing, developing and expected future standards for metadata, data, software and processes. Through information documents, questionnaires and interviews/meetings the EPOS ICS team has collected DDSS (Data, Data Products, Software and Services) information from the TCS. The ICS team developed a simplified metadata model for presentation to the TCS and the ICS team will perform the mapping and conversion from this model to the internal detailed technical metadata model using (CERIF: a EU recommendation to Member States maintained, developed and promoted by euroCRIS www.eurocris.org ). At the time of writing the final modifications of the EPOS metadata model are being made, and the mappings to CERIF designed, prior to the main phase of (meta

EPOS data and service provision to scientists and other stakeholders

Science.gov (United States)

Cocco, Massimo; EPOS Team

2017-04-01

EPOS brings together European nations and combines solid Earth science infrastructures and their associated data and services together with the scientific expertise into one integrated delivery system for solid Earth science. By improving and facilitating the integration, access, use, and re-use of solid Earth science data, data products, services and facilities EPOS is developing a holistic, sustainable, multidisciplinary research platform to provide coordinated access to harmonized and quality controlled data from diverse Earth science disciplines, together with tools for their use in analysis and modelling. EPOS has been designed with the vision of creating a single distributed pan-European infrastructure for solid Earth science to support a safe and sustainable society. In accordance with this scientific vision, the EPOS mission is to integrate the diverse and advanced European Research Infrastructures for solid Earth relying on new e-science opportunities to monitor and unravel the dynamic and complex Earth System. EPOS is presently in its implementation phase, which consists of the EPOS IP project and the legal establishment of EPOS-ERIC. The EPOS Implementation Phase builds on the achievements of the successful EPOS Preparatory Phase project. The EPOS implementation phase will last from 2015 to 2019. The key objectives of the project are: implementing Thematic Core Services (TCS), the domain-specific service hubs for coordinating and harmonizing national resources/plans with the European dimension of EPOS; building the Integrated Core Services (ICS) to provide a novel research platform to different stakeholders; designing the access to distributed computational resources (ICS-D); ensuring sustainability and governance of TCS and EPOS-ERIC. Here we present the activities planned for the implementation phase focusing on the TCS, the ICS and on their interoperability. We will present and discuss the data and service provision focusing on the data, data

The Doppler paradigm and the APEX-EPOS-ORANGE quandary

International Nuclear Information System (INIS)

Griffin, J.J.

1995-01-01

The experimental detection of the sharp lines of the (e + e - ) Puzzle is viewed as a struggle against Doppler broadening. Gedanken experiments which are realistic in zeroth order of detail are analyzed to show that the ORANGE and EPOS/I geometries select narrower slices of a Doppler broadened line than spherically inclusive (APEX and EPOS/II -like) apparati. Roughly speaking, the latter require event-by-event Doppler reconstruction simply to regain an even footing with the former. This suggests that APEX' or EPOS/II's coincident pair distributions must be statistically superior to those of EPOS/I or ORANGE in order to support a comparable inference about sharp structure. Under such circumstances, independent alternative data is invaluable. Therefore, a corroboration of Sakai's 330.1 keV ( + or e - bombardments of U and Th targets could prove crucial

Detection of EPO gene doping in blood.

Science.gov (United States)

Neuberger, Elmo W I; Jurkiewicz, Magdalena; Moser, Dirk A; Simon, Perikles

2012-11-01

Gene doping--or the abuse of gene therapy--will continue to threaten the sports world. History has shown that progress in medical research is likely to be abused in order to enhance human performance. In this review, we critically discuss the progress and the risks associated with the field of erythropoietin (EPO) gene therapy and its applicability to EPO gene doping. We present typical vector systems that are employed in ex vivo and in vivo gene therapy trials. Due to associated risks, gene doping is not a feasible alternative to conventional EPO or blood doping at this time. Nevertheless, it is well described that about half of the elite athlete population is in principle willing to risk its health to gain a competitive advantage. This includes the use of technologies that lack safety approval. Sophisticated detection approaches are a prerequisite for prevention of unapproved and uncontrolled use of gene therapy technology. In this review, we present current detection approaches for EPO gene doping, with a focus on blood-based direct and indirect approaches. Gene doping is detectable in principle, and recent DNA-based detection strategies enable long-term detection of transgenic DNA (tDNA) following in vivo gene transfer. Copyright © 2012 John Wiley & Sons, Ltd.

Building thematic and integrated services for solid Earth sciences: the EPOS integrated approach

Science.gov (United States)

Cocco, Massimo; Consortium, Epos

2016-04-01

EPOS has been designed with the vision of creating a pan-European infrastructure for solid Earth science to support a safe and sustainable society. In accordance with this scientific vision, the EPOS mission is to integrate the diverse and advanced European Research Infrastructures for solid Earth science relying on new e-science opportunities to monitor and unravel the dynamic and complex Earth System. EPOS will enable innovative multidisciplinary research for a better understanding of the Earth's physical and chemical processes that control earthquakes, volcanic eruptions, ground instability and tsunami as well as the processes driving tectonics and Earth's surface dynamics. To accomplish its mission, EPOS is engaging different stakeholders, not limited to scientists, to allow the Earth sciences to open new horizons in our understanding of the planet. EPOS also aims at contributing to prepare society for geo-hazards and to responsibly manage the exploitation of geo-resources. Through integration of data, models and facilities, EPOS will allow the Earth science community to make a step change in developing new concepts and tools for key answers to scientific and socio-economic questions concerning geo-hazards and geo-resources as well as Earth sciences applications to the environment and human welfare. A long-term integration plan is necessary to accomplish the EPOS mission. EPOS is presently in its implementation phase further extending its pan-European dimension. The EPOS Implementation Phase builds on the achievements of the successful EPOS Preparatory Phase project and consists of two key activities: the legal establishment of the EPOS-ERIC and the EPOS IP project. The EPOS implementation phase will last from 2015 to 2019. Key objectives of the project are: implementing Thematic Core Services (TCS), the domain-specific service hubs for coordinating and harmonizing national resources/plans with the European dimension of EPOS; building the Integrated Core

The EPOS Implementation Phase: building thematic and integrated services for solid Earth sciences

Science.gov (United States)

Cocco, Massimo; Epos Consortium, the

2015-04-01

The European Plate Observing System (EPOS) has a scientific vision and approach aimed at creating a pan-European infrastructure for Earth sciences to support a safe and sustainable society. To follow this vision, the EPOS mission is integrating a suite of diverse and advanced Research Infrastructures (RIs) in Europe relying on new e-science opportunities to monitor and understand the dynamic and complex Earth system. To this goal, the EPOS Preparatory Phase has designed a long-term plan to facilitate integrated use of data and products as well as access to facilities from mainly distributed existing and new research infrastructures for solid Earth Science. EPOS will enable innovative multidisciplinary research for a better understanding of the Earth's physical processes that control earthquakes, volcanic eruptions, ground instability and tsunami as well as the processes driving tectonics and Earth surface dynamics. Through integration of data, models and facilities EPOS will allow the Earth Science community to make a step change in developing new concepts and tools for key answers to scientific and socio-economic questions concerning geo-hazards and geo-resources as well as Earth sciences applications to the environment and to human welfare. Since its conception EPOS has been built as "a single, Pan-European, sustainable and distributed infrastructure". EPOS is, indeed, the sole infrastructure for solid Earth Science in ESFRI and its pan-European dimension is demonstrated by the participation of 23 countries in its preparatory phase. EPOS is presently moving into its implementation phase further extending its pan-European dimension. The EPOS Implementation Phase project (EPOS IP) builds on the achievements of the successful EPOS preparatory phase project. The EPOS IP objectives are synergetic and coherent with the establishment of the new legal subject (the EPOS-ERIC in Italy). EPOS coordinates the existing and new solid Earth RIs within Europe and builds the

EPOS Seismology services and their users

Science.gov (United States)

Haslinger, Florian; Dupont, Aurelien; Michelini, Alberto; Rietbrock, Andreas; Sleeman, Reinoud; Wiemer, Stefan; Basili, Roberto; Bossu, Rémy; Cakti, Eser; Cotton, Fabrice; Crawford, Wayne; Crowley, Helen; Danciu, Laurentiu; Diaz, Jordi; Garth, Tom; Locati, Mario; Luzi, Lucia; Pitilakis, Kyriazis; Roumelioti, Zafeiria; Strollo, Angelo

2017-04-01

The construction of seismological community services for the European Plate Observing System Research Infrastructure (EPOS) is by now well under way. A significant number of services are already operational, largely based on those existing at established institutions or collaborations like ORFEUS, EMSC, AHEAD and EFEHR, and more are being added to be ready for internal validation by late 2017. In this presentation we focus on a number of issues related to the interaction of the community of users with the services provided by the seismological part of the EPOS research infrastructure. How users interact with a service (and how satisfied they are with this interaction) is viewed as one important component of the validation of a service within EPOS, and certainly is key to the uptake of a service and from that also it's attributed value. Within EPOS Seismology, the following aspects of user interaction have already surfaced: - user identification (and potential tracking) versus ease-of-access and openness Requesting users to identify themselves when accessing a service provides various advantages to providers and users (e.g. quantifying & qualifying the service use, customization of services and interfaces, handling access rights and quotas), but may impact the ease of access and also shy away users who don't wish to be identified for whatever reason. - service availability versus cost There is a clear and prominent connection between the availability of a service, both regarding uptime and capacity, and its operational cost (IT systems and personnel), and it is often not clear where to draw the line (and based on which considerations). In connection to that, how to best utilize third-party IT infrastructures (either commercial or public), and what the long-term cost implications of that might be, is equally open. - licensing and attribution The issue of intellectual property and associated licensing policies for data, products and services is only recently gaining

Silicon effects on formation of EPO oxide coatings on aluminum alloys

International Nuclear Information System (INIS)

Wang, L.; Nie, X.

2006-01-01

Electrolytic plasma processes (EPP) can be used for cleaning, metal-coating, carburizing, nitriding, and oxidizing. Electrolytic plasma oxidizing (EPO) is an advanced technique to deposit thick and hard ceramic coatings on a number of aluminum alloys. However, the EPO treatment on Al-Si alloys with a high Si content has rarely been reported. In this research, an investigation was conducted to clarify the effects of silicon contents on the EPO coating formation, morphology, and composition. Cast hypereutectic 390 alloys (∼ 17% Si) and hypoeutectic 319 alloys (∼ 7% Si) were chosen as substrates. The coating morphology, composition, and microstructure of the EPO coatings on those substrates were investigated using scanning electron microscopy (SEM) with energy dispersive X-ray (EDX) analysis and X-ray diffraction (XRD). A stylus roughness tester was used for surface roughness measurement. It was found that the EPO process had four stages where each stage was corresponding to various coating surface morphology, composition, and phase structures, characterised by different coating growth mechanisms

NASA Astrophysics EPO Resources For Engaging Girls in Science

Science.gov (United States)

Sharma, M.; Mendoza, D.; Smith, D.; Hasan, H.

2011-09-01

A new collaboration among the NASA Science Mission Directorate (SMD) Astrophysics EPO community is to engage girls in science who do not self-select as being interested in science, through the library setting. The collaboration seeks to (i) improve how girls view themselves as someone who knows about, uses, and sometimes contributes to science, and (ii) increase the capacity of EPO practitioners and librarians (both school and public) to engage girls in science. As part of this collaboration, we are collating the research on audience needs and best practices, and SMD EPO resources, activities and projects that focus on or can be recast toward engaging girls in science. This ASP article highlights several available resources and individual projects, such as: (i) Afterschool Universe, an out-of-school hands-on astronomy curriculum targeted at middle school students and an approved Great Science for Girls curriculum; (ii) Big Explosions and Strong Gravity, a Girl Scout patch-earning event for middle school aged girls to learn astronomy through hands-on activities and interaction with actual astronomers; and (iii) the JWST-NIRCAM Train the Trainer workshops and activities for Girl Scouts of USA leaders; etc. The NASA Astrophysics EPO community welcomes the broader EPO community to discuss with us how best to engage non-science-attentive girls in science, technology, engineering, and mathematics (STEM), and to explore further collaborations on this theme.

Sky Fest: A Model of Successful Scientist Participation in E/PO

Science.gov (United States)

Dalton, H.; Shipp, S. S.; Shaner, A. J.; LaConte, K.; Shupla, C. B.

2014-12-01

Participation in outreach events is an easy way for scientists to get involved with E/PO and reach many people with minimal time commitment. At the Lunar and Planetary Institute (LPI) in Houston, Texas, the E/PO team holds Sky Fest outreach events several times a year. These events each have a science content theme and include several activities for children and their parents, night sky viewing through telescopes, and scientist presentations. LPI scientists have the opportunity to participate in Sky Fest events either by helping lead an activity or by giving the scientist presentation (a short lecture and/or demonstration). Scientists are involved in at least one preparation meeting before the event. This allows them to ask questions, understand what activity they will be leading, and learn the key points that they should be sharing with the public, as well as techniques for effectively teaching members of the public about the event topic. During the event, each activity is run by one E/PO specialist and one scientist, enabling the scientist to learn about effective E/PO practices from the E/PO specialist and the E/PO specialist to get more science information about the event topic. E/PO specialists working together with scientists at stations provides a more complete, richer experience for event participants. Surveys of event participants have shown that interacting one-on-one with scientists is often one of their favorite parts of the events. Interviews with scientists indicated that they enjoyed Sky Fest because there was very little time involved on their parts outside of the actual event; the activities were created and/or chosen by the E/PO professionals, and setup for the events was completed before they arrived. They also enjoyed presenting their topic to people without a background in science, and who would not have otherwise sought out the information that was presented.

Current status of the EPOS WG4 - GNSS and Other Geodetic Data

Science.gov (United States)

Fernandes, Rui; Bastos, Luisa; Bruyninx, Carine; D'Agostino, Nicola; Dousa, Jan; Ganas, Athanassios; Lidberg, Martin; Nocquet, Jean-Mathieu

2014-05-01

WG4 - "EPOS Geodetic Data and Other Geodetic Data" is the Working Group of the EPOS project in charge of defining and preparing the integration of the existing Pan-European Geodetic Infrastructures that will support European Geosciences, which is the ultimate goal of the EPOS project. The WG4 is formed by representatives of the participating EPOS countries (23) but it is also open to the entire geodetic community. In fact, WG4 also already includes members from countries that formally are not integrating EPOS in this first step. The geodetic component of EPOS (WG4) is dealing essentially with Research Infrastructures focused on continuous operating GNSS (cGNSS) in the current phase. The option of concentrating the efforts on the presently most generalized geodetic tool supporting research on Solid Earth was decided in order to optimize the existing resources. Nevertheless, WG4 will continue to pursue the development of tools and methodologies that permit the access of the EPOS community to other geodetic information (e.g., gravimetry). Furthermore, although the focus is on Solid Earth applications, other research and technical applications (e.g., reference frames, meteorology, space weather) can also benefit from the efforts of WG4 EPOS towards the optimization of the geodetic resources in Europe. We will present and discuss the plans for the implementation of the thematic and core services (TCS) for geodetic data within EPOS and the related business plan. We will focus on strategies towards the implementation of the best solutions that will permit to the end-users, and in particular geo-scientists, to access the geodetic data, derived solutions, and associated metadata using transparent and uniform processes. Five pillars have been defined proposed for the TCS: Dissemination, Preservation, Monitoring, and Analysis of geodetic data plus the Support and Governance Infrastructure. Current proposals and remaining open questions will be discussed.

Erythropoietin receptor is not a surrogate marker for tumor hypoxia and does not correlate with survival in head and neck squamous cell carcinomas.

NARCIS (Netherlands)

Hoogsteen, I.J.; Peeters, W.J.M.; Marres, H.A.M.; Rijken, P.F.J.W.; Hoogen, F.J.A. van den; Kogel, A.J. van der; Kaanders, J.H.A.M.

2005-01-01

BACKGROUND AND PURPOSE: To evaluate erythropoietin receptor (EPOR) expression in human head and neck squamous cell carcinomas and correlate this to the presence of tumor hypoxia and treatment outcome. PATIENTS AND METHODS: Eighty-five patients with locally advanced tumors of the head and neck were

EPOS Thematic Core Service Anthropogenic Hazards: Implementation Plan

Science.gov (United States)

Orlecka-Sikora, Beata; Lasocki, Stanislaw; Grasso, Jean Robert; Schmittbuhl, Jean; Styles, Peter; Kwiatek, Grzegorz; Sterzel, Mariusz; Garcia, Alexander

2015-04-01

EPOS Thematic Core Service ANTHROPOGENIC HAZARDS (TCS AH) aims to integrate distributed research infrastructures (RI) to facilitate and stimulate research on anthropogenic hazards (AH) especially those associated with the exploration and exploitation of geo-resources. The innovative element is the uniqueness of the integrated RI which comprises two main deliverables: (1) Exceptional datasets, called "episodes", which comprehensively describe a geophysical process; induced or triggered by human technological activity, posing hazard for populations, infrastructure and the environment, (2) Problem-oriented, bespoke services uniquely designed for the discrimination and analysis of correlations between technology, geophysical response and resulting hazard. These objectives will be achieved through the Science-Industry Synergy (SIS) built by EPOS WG10, ensuring bi-directional information exchange, including unique and previously unavailable data furnished by industrial partners. The Episodes and services to be integrated have been selected using strict criteria during the EPOS PP. The data are related to a wide spectrum of inducing technologies, with seismic/aseismic deformation and production history as a minimum data set requirement and the quality of software services is confirmed and referenced in literature. Implementation of TCS AH is planned for four years and requires five major activities: (1) Strategic Activities and Governance: will define and establish the governance structure to ensure the long-term sustainability of these research infrastructures for data provision through EPOS. (2) Coordination and Interaction with the Community: will establish robust communication channels within the whole TCS AH community while supporting global EPOS communication strategy. (3) Interoperability with EPOS Integrated Core Service (ICS) and Testing Activities: will coordinate and ensure interoperability between the RIs and the ICS. Within this modality a functional e

Tools for Scientist Engagement in E/PO: NASA SMD Community Workspace and Online Resources

Science.gov (United States)

Dalton, H.; Shipp, S. S.; Grier, J.; Gross, N. A.; Buxner, S.; Bartolone, L.; Peticolas, L. M.; Woroner, M.; Schwerin, T. G.

2014-12-01

The Science Mission Directorate (SMD) Science Education and Public Outreach (E/PO) Forums are here to help you get involved in E/PO! The Forums have been developing several online resources to support scientists who are - or who are interested in becoming - involved in E/PO. These include NASA Wavelength, EarthSpace, and the SMD E/PO online community workspace. NASA Wavelength is the one-stop shop of all peer-reviewed NASA education resources to find materials you - or your audiences - can use. Browse by audience (pre-K through 12, higher education, and informal education) or topic, or choose to search for something specific by keyword and audience. http://nasawavelength.org. EarthSpace, an online clearinghouse of Earth and space materials for use in the higher education classroom, is driven by a powerful search engine that allows you to browse the collection of resources by science topic, audience, type of material or key terms. All materials are peer-reviewed before posting, and because all submissions receive a digital object identifier (doi), submitted materials can be listed as publications. http://www.lpi.usra.edu/earthspace. The SMD E/PO online community workspace contains many resources for scientists. These include one-page guides on how to get involved, tips on how to make the most of your time spent on E/PO, and sample activities, as well as news on funding, policy, and what's happening in the E/PO community. The workspace also provides scientists and the public pathways to find opportunities for participation in E/PO, to learn about SMD E/PO projects and their impacts, to connect with SMD E/PO practitioners, and to explore resources to improve professional E/PO practice, including literature reviews, information about the Next Generation Science Standards, and best practices in evaluation and engaging diverse audiences. http://smdepo.org.

The European Plate Observing System (EPOS) Services for Solid Earth Science

Science.gov (United States)

Cocco, Massimo; Atakan, Kuvvet; Pedersen, Helle; Consortium, Epos

2016-04-01

The European Plate Observing System (EPOS) aims to create a pan-European infrastructure for solid Earth science to support a safe and sustainable society. The main vision of the European Plate Observing System (EPOS) is to address the three basic challenges in Earth Sciences: (i) unravelling the Earth's deformational processes which are part of the Earth system evolution in time, (ii) understanding the geo-hazards and their implications to society, and (iii) contributing to the safe and sustainable use of geo-resources. The mission of EPOS is to monitor and understand the dynamic and complex Earth system by relying on new e-science opportunities and integrating diverse and advanced Research Infrastructures in Europe for solid Earth Science. EPOS will enable innovative multidisciplinary research for a better understanding of the Earth's physical and chemical processes that control earthquakes, volcanic eruptions, ground instability and tsunami as well as the processes driving tectonics and Earth's surface dynamics. EPOS will improve our ability to better manage the use of the subsurface of the Earth. Through integration of data, models and facilities EPOS will allow the Earth Science community to make a step change in developing new concepts and tools for key answers to scientific and socio-economic questions concerning geo-hazards and geo-resources as well as Earth sciences applications to the environment and to human welfare. EPOS has now started its Implementation Phase (EPOS-IP). One of the main challenges during the implementation phase is the integration of multidisciplinary data into a single e-infrastructure. Multidisciplinary data are organized and governed by the Thematic Core Services (TCS) and are driven by various scientific communities encompassing a wide spectrum of Earth science disciplines. These include Data, Data-products, Services and Software (DDSS), from seismology, near fault observatories, geodetic observations, volcano observations

The Demonstrator for the European Plate Observing System (EPOS)

Science.gov (United States)

Hoffmann, T. L.; Euteneuer, F.; Ulbricht, D.; Lauterjung, J.; Bailo, D.; Jeffery, K. G.

2014-12-01

An important outcome of the 4-year Preparatory Phase of the ESFRI project European Plate Observing System (EPOS) was the development and first implementation of the EPOS Demonstrator by the project's ICT Working Group 7. The Demonstrator implements the vertical integration of the three-layer architectural scheme for EPOS, connecting the Integrated Core Services (ICS), Thematic Core Services (TCS) and the National Research Infrastructures (NRI). The demonstrator provides a single GUI with central key discovery and query functionalities, based on already existing services by the seismic, geologic and geodetic communities. More specifically the seismic services of the Demonstrator utilize webservices and APIs for data and discovery of raw seismic data (FDSN webservices by the EIDA Network), events (Geoportal by EMSC) and analytical data products (e.g., hazard maps by EFEHR via OGC WMS). For geologic services, the EPOS Demonstrator accesses OneGeology Europe which serves the community with geologic maps and point information via OGC webservices. The Demonstrator also provides access to raw geodetic data via a newly developed universal tool called GSAC. The Demonstrator itself resembles the future Integrated Core Service (ICS) and provides direct access to the end user. Its core functionality lies in a metadata catalogue, which serves as the central information hub and stores information about all RIs, related persons, projects, financial background and technical access information. The database schema of the catalogue is based on CERIF, which has been slightly adapted. Currently, the portal provides basic query functions as well as cross domain search. [www.epos.cineca.it

Setting the stage for the EPOS ERIC: Integration of the legal, governance and financial framework

Science.gov (United States)

Atakan, Kuvvet; Bazin, Pierre-Louis; Bozzoli, Sabrina; Freda, Carmela; Giardini, Domenico; Hoffmann, Thomas; Kohler, Elisabeth; Kontkanen, Pirjo; Lauterjung, Jörn; Pedersen, Helle; Saleh, Kauzar; Sangianantoni, Agata

2017-04-01

EPOS - the European Plate Observing System - is the ESFRI infrastructure serving the need of the solid Earth science community at large. The EPOS mission is to create a single sustainable, and distributed infrastructure that integrates the diverse European Research Infrastructures for solid Earth science under a common framework. Thematic Core Services (TCS) and Integrated Core Services (Central Hub, ICS-C and Distributed, ICS-D) are key elements, together with NRIs (National Research Infrastructures), in the EPOS architecture. Following the preparatory phase, EPOS has initiated formal steps to adopt an ERIC legal framework (European Research Infrastructure Consortium). The statutory seat of EPOS will be in Rome, Italy, while the ICS-C will be jointly operated by France, UK and Denmark. The TCS planned so far cover: seismology, near-fault observatories, GNSS data and products, volcano observations, satellite data, geomagnetic observations, anthropogenic hazards, geological information modelling, multiscale laboratories and geo-energy test beds for low carbon energy. In the ERIC process, EPOS and all its services must achieve sustainability from a legal, governance, financial, and technical point of view, as well as full harmonization with national infrastructure roadmaps. As EPOS is a distributed infrastructure, the TCSs have to be linked to the future EPOS ERIC from legal and governance perspectives. For this purpose the TCSs have started to organize themselves as consortia and negotiate agreements to define the roles of the different actors in the consortium as well as their commitment to contribute to the EPOS activities. The link to the EPOS ERIC shall be made by service agreements of dedicated Service Providers. A common EPOS data policy has also been developed, based on the general principles of Open Access and paying careful attention to licensing issues, quality control, and intellectual property rights, which shall apply to the data, data products

Both acute and prolonged administration of EPO reduce cerebral and systemic vascular conductance in humans

DEFF Research Database (Denmark)

Rasmussen, Peter; Kim, Yu-Sok; Krogh-Madsen, Rikke

2012-01-01

Administration of erythropoietin (EPO) has been linked to cerebrovascular events. EPO reduces vascular conductance, possibly because of the increase in hematocrit. Whether EPO in itself affects the vasculature remains unknown; here it was evaluated in healthy males by determining systemic...... and cerebrovascular variables following acute (30,000 IU/d for 3 d; n=8) and chronic (5000 IU/week for 13 wk; n=8) administration of EPO, while the responsiveness of the vasculature was challenged during cycling exercise, with and without hypoxia. Prolonged administration of EPO increased hematocrit from 42.5 ± 3...

The EPOS Vision for the Open Science Cloud

Science.gov (United States)

Jeffery, Keith; Harrison, Matt; Cocco, Massimo

2016-04-01

Cloud computing offers dynamic elastic scalability for data processing on demand. For much research activity, demand for computing is uneven over time and so CLOUD computing offers both cost-effectiveness and capacity advantages. However, as reported repeatedly by the EC Cloud Expert Group, there are barriers to the uptake of Cloud Computing: (1) security and privacy; (2) interoperability (avoidance of lock-in); (3) lack of appropriate systems development environments for application programmers to characterise their applications to allow CLOUD middleware to optimize their deployment and execution. From CERN, the Helix-Nebula group has proposed the architecture for the European Open Science Cloud. They are discussing with other e-Infrastructure groups such as EGI (GRIDs), EUDAT (data curation), AARC (network authentication and authorisation) and also with the EIROFORUM group of 'international treaty' RIs (Research Infrastructures) and the ESFRI (European Strategic Forum for Research Infrastructures) RIs including EPOS. Many of these RIs are either e-RIs (electronic-RIs) or have an e-RI interface for access and use. The EPOS architecture is centred on a portal: ICS (Integrated Core Services). The architectural design already allows for access to e-RIs (which may include any or all of data, software, users and resources such as computers or instruments). Those within any one domain (subject area) of EPOS are considered within the TCS (Thematic Core Services). Those outside, or available across multiple domains of EPOS, are ICS-d (Integrated Core Services-Distributed) since the intention is that they will be used by any or all of the TCS via the ICS. Another such service type is CES (Computational Earth Science); effectively an ICS-d specializing in high performance computation, analytics, simulation or visualization offered by a TCS for others to use. Already discussions are underway between EPOS and EGI, EUDAT, AARC and Helix-Nebula for those offerings to be

Some Empirical Notes on the Epo Epidemic in Professional Cycling

Science.gov (United States)

Lodewijkx, Hein F. M.; Brouwer, Bram

2011-01-01

The 1990-2010 period in professional cycling is labeled by some as the epo epidemic. Surprisingly, performance enhancement by epo and blood doping is not that clear-cut for endurance athletes, leading to the question whether doping indeed strongly influenced cyclists' performances from the 1990s onwards. We examined the records (1947-2008) of the…

Class I Cytokine Receptors

DEFF Research Database (Denmark)

Steinocher, Helena

, the minimal determinants for specificity between membrane spanning helices were investigated with small artificial low complexity peptides, prior found to activate the EPOR in cells. The placement of single methyl group in the so called transmembrane aptamers (traptamers) determined the stabilizing effect...... characteristics of membrane spanning helices, was designed and hGHR TMD and hEPOR TMD produced in sufficient amounts for spectroscopic investigations. The isolated hGHR TMD was revealed to associate in dimeric complexes in detergent micelles and first presumptions about the dimer interface could be made. Further...... the traptamers on the hEPOR TMD dimeric complex in detergent micelles. To gain a better understanding of hGHR regulation a point mutation in the hGHR intracellular domain (ICD), which has recently been linked to lung cancer, was characterized. The mutation was found to decrease binding of suppressor of cytokine...

The effects of erythropoietin signaling on telomerase regulation in non-erythroid malignant and non-malignant cells

International Nuclear Information System (INIS)

Uziel, Orit; Kanfer, Gil; Beery, Einat; Yelin, Dana; Shepshelovich, Daniel; Bakhanashvili, Mary; Nordenberg, Jardena; Lahav, Meir

2014-01-01

Highlights: • We assumed that some of erythropoietin adverse effects may be mediated by telomerase activity. • EPO administration increased telomerase activity, cells proliferation and migration. • The inhibition of telomerase modestly repressed the proliferative effect of erythropoietin. • Telomere shortening caused by long term inhibition of the enzyme totally abolished that effect. • This effect was mediated via the Lyn–AKT axis and not by the canonical JAK2–STAT pathway. - Abstract: Treatment with erythropoietin (EPO) in several cancers is associated with decreased survival due to cancer progression. Due to the major importance of telomerase in cancer biology we hypothesized that some of these effects may be mediated through EPO effect on telomerase. For this aim we explored the possible effects of EPO on telomerase regulation, cell migration and chemosensitivity in non-erythroid malignant and non-malignant cells. Cell proliferation, telomerase activity (TA) and cell migration increased in response to EPO. EPO had no effect on cancer cells sensitivity to cisplatinum and on the cell cycle status. The inhibition of telomerase modestly repressed the proliferative effect of EPO. Telomere shortening caused by long term inhibition of the enzyme abolished the effect of EPO, suggesting that EPO effects on cancer cells are related to telomere dynamics. TA was correlated with the levels of Epo-R. The increase in TA was mediated post-translationally through the Lyn-Src and not the canonical JAK2 pathway

The effects of erythropoietin signaling on telomerase regulation in non-erythroid malignant and non-malignant cells

Energy Technology Data Exchange (ETDEWEB)

Uziel, Orit, E-mail: Oritu@clalit.org.il [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Kanfer, Gil [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Dep. of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Beery, Einat [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Yelin, Dana; Shepshelovich, Daniel [Medicine A, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Bakhanashvili, Mary [Unit of Infectious Diseases, Sheba Medical Center, Tel-Hashomer (Israel); Nordenberg, Jardena [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Dep. of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Endocrinology Laboratory, Beilinson Medical Center, Petah-Tikva (Israel); Lahav, Meir [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Medicine A, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel)

2014-07-18

Highlights: • We assumed that some of erythropoietin adverse effects may be mediated by telomerase activity. • EPO administration increased telomerase activity, cells proliferation and migration. • The inhibition of telomerase modestly repressed the proliferative effect of erythropoietin. • Telomere shortening caused by long term inhibition of the enzyme totally abolished that effect. • This effect was mediated via the Lyn–AKT axis and not by the canonical JAK2–STAT pathway. - Abstract: Treatment with erythropoietin (EPO) in several cancers is associated with decreased survival due to cancer progression. Due to the major importance of telomerase in cancer biology we hypothesized that some of these effects may be mediated through EPO effect on telomerase. For this aim we explored the possible effects of EPO on telomerase regulation, cell migration and chemosensitivity in non-erythroid malignant and non-malignant cells. Cell proliferation, telomerase activity (TA) and cell migration increased in response to EPO. EPO had no effect on cancer cells sensitivity to cisplatinum and on the cell cycle status. The inhibition of telomerase modestly repressed the proliferative effect of EPO. Telomere shortening caused by long term inhibition of the enzyme abolished the effect of EPO, suggesting that EPO effects on cancer cells are related to telomere dynamics. TA was correlated with the levels of Epo-R. The increase in TA was mediated post-translationally through the Lyn-Src and not the canonical JAK2 pathway.

Does recombinant human Epo increase exercise capacity by means other than augmenting oxygen transport?

DEFF Research Database (Denmark)

Lundby, C; Robach, P; Boushel, R

2008-01-01

This study was performed to test the hypothesis that administration of recombinant human erythropoietin (rHuEpo) in humans increases maximal oxygen consumption by augmenting the maximal oxygen carrying capacity of blood. Systemic and leg oxygen delivery and oxygen uptake were studied during...... before rHuEpo treatment). Blood buffer capacity remained unaffected by rHuEpo treatment and hemodilution. The augmented hematocrit did not compromise peak cardiac output. In summary, in healthy humans, rHuEpo increases maximal oxygen consumption due to augmented systemic and muscular peak oxygen delivery....

The Satellite Data Thematic Core Service within the EPOS Research Infrastructure

Science.gov (United States)

Manunta, Michele; Casu, Francesco; Zinno, Ivana; De Luca, Claudio; Buonanno, Sabatino; Zeni, Giovanni; Wright, Tim; Hooper, Andy; Diament, Michel; Ostanciaux, Emilie; Mandea, Mioara; Walter, Thomas; Maccaferri, Francesco; Fernandez, Josè; Stramondo, Salvatore; Bignami, Christian; Bally, Philippe; Pinto, Salvatore; Marin, Alessandro; Cuomo, Antonio

2017-04-01

EPOS, the European Plate Observing System, is a long-term plan to facilitate the integrated use of data, data products, software and services, available from distributed Research Infrastructures (RI), for solid Earth science in Europe. Indeed, EPOS integrates a large number of existing European RIs belonging to several fields of the Earth science, from seismology to geodesy, near fault and volcanic observatories as well as anthropogenic hazards. The EPOS vision is that the integration of the existing national and trans-national research infrastructures will increase access and use of the multidisciplinary data recorded by the solid Earth monitoring networks, acquired in laboratory experiments and/or produced by computational simulations. The establishment of EPOS will foster the interoperability of products and services in the Earth science field to a worldwide community of users. Accordingly, the EPOS aim is to integrate the diverse and advanced European Research Infrastructures for solid Earth science, and build on new e-science opportunities to monitor and understand the dynamic and complex solid-Earth System. One of the EPOS Thematic Core Services (TCS), referred to as Satellite Data, aims at developing, implementing and deploying advanced satellite data products and services, mainly based on Copernicus data (namely Sentinel acquisitions), for the Earth science community. This work intends to present the technological enhancements, fostered by EPOS, to deploy effective satellite services in a harmonized and integrated way. In particular, the Satellite Data TCS will deploy five services, EPOSAR, GDM, COMET, 3D-Def and MOD, which are mainly based on the exploitation of SAR data acquired by the Sentinel-1 constellation and designed to provide information on Earth surface displacements. In particular, the planned services will provide both advanced DInSAR products (deformation maps, velocity maps, deformation time series) and value-added measurements (source model

Full-automatic measurement of the ELSA working point with 'EPOS'

International Nuclear Information System (INIS)

Goetz, T.

1990-11-01

Two years ago the Bonn Electron Stretcher Accelerator ELSA came into operation. Although the control system proved to be a valuable tool for operating the machine, there did not exist any high level application software dealing with beam diagnostics, orbit measurement and closed orbit correction. To cover these main fields of machine physics, a new program 'EPOS' was implemented on top of the existing control system. EPOS integrates data aquisition, beam diagnostics, digitial signal processing and automation of measurement and control in one interactive environment. The system is equipped with a new, easy to use programming language for machine physics and data analysis. EPOS is based on X-windows and can generate high quality diagrams and printouts for all kinds of measured or simulated data. The design and implementation of EPOS is sketched in this document. Its functionality is demonstrated by performing automatic measurements of the ELSA tune with high precision. By using a special method for error correction, the obtained precision can be increased by approximately two orders of magnitude, compared to standard Fourier analysis techniques. The resulting tune values for standard ELSA operating modes are discussed in detail. (orig.) [de

EPOS-GNSS - Improving the infrastructure for GNSS data and products in Europe

Science.gov (United States)

Fernandes, Rui; Bos, Machiel; Bruyninx, Carine; Crocker, Paul; Dousa, Jan; Socquet, Anne; Walpersdorf, Andrea; Avallone, Antonio; Ganas, Athanassios; Gunnar, Benedikt; Ionescu, Constantin; Kenyeres, Ambrus; Ozener, Haluk; Vergnolle, Mathilde; Lidberg, Martin; Liwosz, Tomek; Soehne, Wolfgang

2017-04-01

EPOS-IP WP10 - "GNSS Data & Products" is the Working Package 10 of the European Plate Observing System - Implementation Phase project in charge of implementing services for the geo-sciences community to access existing Pan-European Geodetic Infrastructures. WP10 is currently formed by representatives of participating European institutions but in the operational phase contributions will be solicited from the entire geodetic community. In fact, WP10 also includes members from other institutions/countries that formally are not participating in the EPOS-IP but will be key players in the future services to be provided by EPOS. Additionally, several partners are also key partners at EUREF, which is also actively collaborating with EPOS. The geodetic component of EPOS is dealing essentially with implementing an e-infrastructure to store and disseminate the continuous GNSS data from existing Research Infrastructures. Present efforts are on developing geodetic tools to support Solid Earth research by optimizing the existing resources. However, other research and technical applications (e.g., reference frames, meteorology, space weather) can also benefit in the future from the optimization of the geodetic resources in Europe. We present and discuss the status of the implementation of the thematic and core services (TCS) for GNSS data within EPOS and the related business plan. We explain the tools and web-services being developed towards the implementation of the best solutions that will permit to the end-users, and in particular geo-scientists, to access the geodetic data, derived solutions, and associated metadata using a transparent and standardized processes. We also detail the different DDSS (Data, Data-Products, Services, Software) that will be made available for the Operational Phase of EPOS, which will start to be tested and made available during 2017 and 2018.

Epobis is a Nonerythropoietic and Neuroprotective Agonist of the Erythropoietin Receptor with Anti-Inflammatory and Memory Enhancing Effects

Directory of Open Access Journals (Sweden)

Oksana Dmytriyeva

2016-01-01

Full Text Available The cytokine erythropoietin (EPO stimulates proliferation and differentiation of erythroid progenitor cells. Moreover, EPO has neuroprotective, anti-inflammatory, and antioxidative effects, but the use of EPO as a neuroprotective agent is hampered by its erythropoietic activity. We have recently designed the synthetic, dendrimeric peptide, Epobis, derived from the sequence of human EPO. This peptide binds the EPO receptor and promotes neuritogenesis and neuronal cell survival. Here we demonstrate that Epobis in vitro promotes neuritogenesis in primary motoneurons and has anti-inflammatory effects as demonstrated by its ability to decrease TNF release from activated AMJ2-C8 macrophages and rat primary microglia. When administered systemically Epobis is detectable in both plasma and cerebrospinal fluid, demonstrating that the peptide crosses the blood-brain barrier. Importantly, Epobis is not erythropoietic, but systemic administration of Epobis in rats delays the clinical signs of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, and the peptide has long-term, but not short-term, effects on working memory, detected as an improved social memory 3 days after administration. These data reveal Epobis to be a nonerythropoietic and neuroprotective EPO receptor agonist with anti-inflammatory and memory enhancing properties.

Studies on cationic UV curing of epoxidised palm oil (EPO) for surface coatings

International Nuclear Information System (INIS)

Mek Zah Salleh; Mohd Hilmi Mahmood; Wan Rosli Wan Daud; Kumar, R.N.

2000-01-01

Epoxidised palm oil (EPO) resin can be cured by ultraviolet (UV) radiation either by radical, cationic or hybrid system. Cationic curing system has been chosen in this study due to the fact that epoxy groups present in EPO can be utilised directly to form crosslinking. Curing was done by means of a 20 cm wide UV IST machine with the conditions of 7.5 A current and 4 m/min conveyor speed. Sulphonium and ferrocenium salts were used as cationic photoinitiator. A formulations study was performed on the selected grades of EPO with other materials. These include types and concentration of photoinitiator, monomers, concentration of EPO and post-cure. The properties of the cured film such as pendulum hardness, percentage of gel content and tensile strength were determined. It was found that triarylsulphonium hexafluorophosphate has a very low solubility in EPO. Addition of vinyl ether monomer to the formulation did not enhance pendulum hardness and gel content of the cured films. It is also found that the post cure temperature has no significant effect on the cured film

EPOS-IP WP10: services and data provision for the GNSS community

Science.gov (United States)

Fernandes, Rui

2016-04-01

The EPOS-IP WP10 - "GNSS Data & Products" is the Working Package of the EPOS-IP project in charge of implementing the necessary services in order that the geo-sciences community can access the existing Pan-European Geodetic Infrastructures. The WP10 is formed by representatives of the participating institutions (10) but it is also open to the entire geodetic community. In fact, WP10 also includes members from other institutions/countries that formally are not participating in the EPOS-IP. During the EPOS-IP project, the geodetic component of EPOS (WP10) is dealing essentially with Research Infrastructures focused on continuous operating GNSS (cGNSS). The option of concentrating the efforts on the presently most generalized geodetic tool supporting research on Solid Earth was decided in order to optimize the existing resources. Furthermore, although the focus is on Solid Earth applications, other research and technical applications (e.g., reference frames, meteorology, space weather) can also benefit from the efforts of WP10 towards the optimization of the geodetic resources in Europe. We will present and discuss the plans for the implementation of the thematic and core services (TCS) for GNSS data within EPOS and the related business plan. We will focus on strategies towards the implementation of the best solutions that will permit to the end-users, and in particular geo-scientists, to access the geodetic data, derived solutions, and associated metadata using transparent and uniform processes. The collaboration with EUREF is also an essential component of the implementation plan.

rhEPO Enhances Cellular Anti-oxidant Capacity to Protect Long-Term Cultured Aging Primary Nerve Cells.

Science.gov (United States)

Wang, Huqing; Fan, Jiaxin; Chen, Mengyi; Yao, Qingling; Gao, Zhen; Zhang, Guilian; Wu, Haiqin; Yu, Xiaorui

2017-08-01

Erythropoietin (EPO) may protect the nervous system of animals against aging damage, making it a potential anti-aging drug for the nervous system. However, experimental evidence from natural aging nerve cell models is lacking, and the efficacy of EPO and underlying mechanism of this effect warrant further study. Thus, the present study used long-term cultured primary nerve cells to successfully mimic the natural aging process of nerve cells. Starting on the 11th day of culture, cells were treated with different concentrations of recombinant human erythropoietin (rhEPO). Using double immunofluorescence labeling, we found that rhEPO significantly improved the morphology of long-term cultured primary nerve cells and increased the total number of long-term cultured primary cells. However, rhEPO did not improve the ratio of nerve cells. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to measure nerve cell activity and showed that rhEPO significantly improved the activity of long-term cultured primary nerve cells. Moreover, Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) double immunofluorescence labeling flow cytometry revealed that rhEPO reduced the apoptotic rate of long-term cultured primary nerve cells. Senescence-associated β-galactosidase (SA-β-gal) immunohistochemistry staining showed that rhEPO significantly reduced the aging rate of long-term cultured primary nerve cells. Immunochemistry revealed that rhEPO enhanced intracellular superoxide dismutase (SOD) activity and glutathione (GSH) abundance and reduced the intracellular malondialdehyde (MDA) level. In addition, this effect depended on the dose, was maximized at a dose of 100 U/ml and was more pronounced than that of vitamin E. In summary, this study finds that rhEPO protects long-term cultured primary nerve cells from aging in a dose-dependent manner. The mechanism of this effect may be associated with the enhancement of the intracellular anti

Automated Patent Searching in the EPO: From Online Searching to Document Delivery.

Science.gov (United States)

Nuyts, Annemie; Jonckheere, Charles

The European Patent Office (EPO) has recently implemented the last part of its ambitious automation project aimed at creating an automated search environment for approximately 1200 EPO patent search examiners. The examiners now have at their disposal an integrated set of tools offering a full range of functionalities from online searching, via…

Engaging Scientists in Meaningful E/PO: How the NASA SMD E/PO Community Addresses the Needs of the Higher Ed Community

Science.gov (United States)

Manning, James; Meinke, Bonnie K.; Schultz, Gregory R.; Smith, Denise A.; Lawton, Brandon L.; Gurton, Suzanne; NASA Astrophysics E/PO Community

2015-01-01

The NASA Astrophysics Science Education and Public Outreach Forum (SEPOF) coordinates the work of NASA Science Mission Directorate (SMD) Astrophysics EPO projects and their teams to bring cutting-edge discoveries of NASA missions to the introductory astronomy college classroom. The Astrophysics Forum assists scientist and educator involvement in SMD E/PO (uniquely poised to foster collaboration between scientists with content expertise and educators with pedagogy expertise) and makes SMD E/PO resources and expertise accessible to the science and education communities. We present three new opportunities for college instructors to bring the latest NASA discoveries in Astrophysics into their classrooms.To address the expressed needs of the higher education community, the Astrophysics Forum collaborated with the Astrophysics E/PO community, researchers, and Astronomy 101 instructors to place individual science discoveries and learning resources into context for higher education audiences. Among these resources are two Resource Guides on the topics of cosmology and exoplanets, each including a variety of accessible sources.The Astrophysics Forum also coordinates the development of the Astro 101 slide set series--5 to 7-slide presentations on new discoveries from NASA Astrophysics missions relevant to topics in introductory astronomy courses. These sets enable Astronomy 101 instructors to include new discoveries not yet in their textbooks into the broader context of the course: http://www.astrosociety.org/education/astronomy-resource-guides/.The Astrophysics Forum also coordinated the development of 12 monthly Universe Discovery Guides, each featuring a theme and a representative object well-placed for viewing, with an accompanying interpretive story, strategies for conveying the topics, and supporting NASA-approved education activities and background information from a spectrum of NASA missions and programs: http://nightsky.jpl.nasa.gov/news-display.cfm?News_ID=611

Characterization of a hypoxia-response element in the Epo locus of the pufferfish, Takifugu rubripes.

Science.gov (United States)

Kulkarni, Rashmi P; Tohari, Sumanty; Ho, Adrian; Brenner, Sydney; Venkatesh, Byrappa

2010-06-01

Animals respond to hypoxia by increasing synthesis of the glycoprotein hormone erythropoietin (Epo) which in turn stimulates the production of red blood cells. The gene encoding Epo has been recently cloned in teleost fishes such as the pufferfish Takifugu rubripes (fugu) and zebrafish (Danio rerio). It has been shown that the transcription levels of Epo in teleost fishes increase in response to anemia or hypoxia in a manner similar to its human ortholog. However, the cis-regulatory element(s) mediating the hypoxia response of Epo gene in fishes has not been identified. In the present study, using the human hepatoma cell line (Hep3B), we have identified and characterized a hypoxia response element (HRE) in the fugu Epo locus. The sequence of the fugu HRE (ACGTGCTG) is identical to that of the HRE in the human EPO locus. However, unlike the HRE in the mammalian Epo locus, which is located in the 3' region of the gene, the fugu HRE is located in the 5' flanking region and on the opposite strand of DNA. This HRE is conserved in other teleosts such as Tetraodon and zebrafish in a similar location. A 365-bp fragment containing the fugu HRE was able to drive GFP expression in the liver of transgenic zebrafish. However, we could not ascertain if the expression of transgene is induced by hypoxia in vivo due to the low and variable levels of GFP expression in transgenic zebrafish. Our investigations also revealed that the Epo locus has experienced extensive rearrangements during vertebrate evolution. Copyright © 2010 Elsevier B.V. All rights reserved.

Erythropoietin's Beta Common Receptor Mediates Neuroprotection in Spinal Cord Neurons.

Science.gov (United States)

Foley, Lisa S; Fullerton, David A; Mares, Joshua; Sungelo, Mitchell; Weyant, Michael J; Cleveland, Joseph C; Reece, T Brett

2017-12-01

Paraplegia from spinal cord ischemia-reperfusion (SCIR) remains an elusive and devastating complication of complex aortic operations. Erythropoietin (EPO) attenuates this injury in models of SCIR. Upregulation of the EPO beta common receptor (βcR) is associated with reduced damage in models of neural injury. The purpose of this study was to examine whether EPO-mediated neuroprotection was dependent on βcR expression. We hypothesized that spinal cord neurons subjected to oxygen-glucose deprivation would mimic SCIR injury in aortic surgery and EPO treatment attenuates this injury in a βcR-dependent fashion. Lentiviral vectors with βcR knockdown sequences were tested on neuron cell cultures. The virus with greatest βcR knockdown was selected. Spinal cord neurons from perinatal wild-type mice were harvested and cultured to maturity. They were treated with knockdown or nonsense virus and transduced cells were selected. Three groups (βcR knockdown virus, nonsense control virus, no virus control; n = 8 each) were subjected to 1 hour of oxygen-glucose deprivation. Viability was assessed. βcR expression was quantified by immunoblot. EPO preserved neuronal viability after oxygen-glucose deprivation (0.82 ± 0.04 versus 0.61 ± 0.01; p neuron preservation was similar in the nonsense virus and control mice (0.82 ± 0.04 versus 0.80 ± 0.05; p = 0.77). EPO neuron preservation was lost in βcR knockdown mice compared with nonsense control mice (0.46 ± 0.03 versus 0.80 ± 0.05; p neuronal loss after oxygen-glucose deprivation in a βcR-dependent fashion. This receptor holds immense clinical promise as a target for pharmacotherapies treating spinal cord ischemic injury. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Building Thematic and Integrated Services for European Solid Earth Sciences: the EPOS Integrated Approach

Science.gov (United States)

Harrison, M.; Cocco, M.

2017-12-01

EPOS (European Plate Observing System) has been designed with the vision of creating a pan-European infrastructure for solid Earth science to support a safe and sustainable society. In accordance with this scientific vision, the EPOS mission is to integrate the diverse and advanced European Research Infrastructures for solid Earth science relying on new e-science opportunities to monitor and unravel the dynamic and complex Earth System. EPOS will enable innovative multidisciplinary research for a better understanding of the Earth's physical and chemical processes that control earthquakes, volcanic eruptions, ground instability and tsunami as well as the processes driving tectonics and Earth's surface dynamics. To accomplish its mission, EPOS is engaging different stakeholders, to allow the Earth sciences to open new horizons in our understanding of the planet. EPOS also aims at contributing to prepare society for geo-hazards and to responsibly manage the exploitation of geo-resources. Through integration of data, models and facilities, EPOS will allow the Earth science community to make a step change in developing new concepts and tools for key answers to scientific and socio-economic questions concerning geo-hazards and geo-resources as well as Earth sciences applications to the environment and human welfare. The research infrastructures (RIs) that EPOS is coordinating include: i) distributed geophysical observing systems (seismological and geodetic networks); ii) local observatories (including geomagnetic, near-fault and volcano observatories); iii) analytical and experimental laboratories; iv) integrated satellite data and geological information services; v) new services for natural and anthropogenic hazards; vi) access to geo-energy test beds. Here we present the activities planned for the implementation phase focusing on the TCS, the ICS and on their interoperability. We will discuss the data, data-products, software and services (DDSS) presently under

Huh-7 cell line as an alternative cultural model for the production of human like erythropoietin (EPO

Directory of Open Access Journals (Sweden)

Kausar Humera

2011-11-01

Full Text Available Abstract Background and Aims Erythropoietin (EPO is a glycoprotein hormone which is required to regulate the production of red blood cells. Deficiency of EPO is known to cause anemia in chronically infected renal patients and they require regular blood transfusion. Availability of recombinant EPO has eliminated the need for blood transfusion and now it is extensively used for the treatment of anemia. Glycosylation of erythropoietin is essential for its secretion, stability, protein conformation and biological activity. However, maintenance of human like glycosylation pattern during manufacturing of EPO is a major challenge in biotechnology. Currently, Chinese hamster ovary (CHO cell line is used for the commercial production of erythropoietin but this cell line does not maintain glycosylation resembling human system. With the trend to eliminate non-human constituent from biopharmaceutical products, as a preliminary approach, we have investigated the potential of human hepatoma cell line (Huh-7 to produce recombinant EPO. Materials and methods Initially, the secretory signal and Kozak sequences was added before the EPO mature protein sequence using overlap extension PCR technique. PCR-amplified cDNA fragments of EPO was inserted into mammalian expression vector under the control of the cytomegalovirus (CMV promoter and transiently expressed in CHO and Huh-7 cell lines. After RT-PCR analysis, ELISA and Western blotting was performed to verify the immunochemical properties of secreted EPO. Results Addition of secretory signal and Kozak sequence facilitated the extra-cellular secretion and enhanced the expression of EPO protein. Significant expression (P Conclusion Huh-7 cell line has a great potential to produce glycosylated EPO, suggesting the use of this cell line to produce glycoproteins of the therapeutic importance resembling to the natural human system.

Enhancement of bioavailability by formulating rhEPO ionic complex with lysine into PEG-PLA micelle

Energy Technology Data Exchange (ETDEWEB)

Shi, Yanan; Sun, Fengying; Wang, Dan; Zhang, Renyu [Jilin University, College of Life Science (China); Dou, Changlin; Liu, Wanhui; Sun, Kaoxiang, E-mail: sunkx@ytu.edu.cn [Yantai University, School of Pharmacy (China); Li, Youxin, E-mail: liyouxin@jlu.edu.cn [Jilin University, College of Life Science (China)

2013-10-15

A composite micelle of ionic complex encapsulated into poly(ethylene glycol)-poly(d,l-lactide) (PEG-PLA) di-block copolymeric micelles was used for protein drug delivery to improve its pharmacokinetic performance. In this study, recombinant human erythropoietin (rhEPO, as a model protein) was formulated with lysine into composite micelles at a diameter of 71.5 nm with narrow polydispersity indices (PDIs < 0.3). Only a trace amount of protein was in aggregate form. The zeta potential of the spherical micelles was ranging from -0.54 to 1.39 mv, and encapsulation efficiency is high (80 %). The stability of rhEPO was improved significantly in composite micelles in vitro. Pharmacokinetic studies in rats showed significant, enhanced plasma retention of the composite micelles in comparison with native rhEPO. Areas under curve (AUCs) of the rhEPO released from the composite micelles were 4.5- and 2.3-folds higher than those of the native rhEPO and rhEPO-loaded PEG-PLA micelle, respectively. In addition, the composite micelles exhibited good biocompatibility using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay with human embryonic kidney (HEK293T) cells. All these features are preferable for utilizing the composite micelles as a novel protein delivery system.

Enhancement of bioavailability by formulating rhEPO ionic complex with lysine into PEG-PLA micelle

Science.gov (United States)

Shi, Yanan; Sun, Fengying; Wang, Dan; Zhang, Renyu; Dou, Changlin; Liu, Wanhui; Sun, Kaoxiang; Li, Youxin

2013-10-01

A composite micelle of ionic complex encapsulated into poly(ethylene glycol)-poly( d, l-lactide) (PEG-PLA) di-block copolymeric micelles was used for protein drug delivery to improve its pharmacokinetic performance. In this study, recombinant human erythropoietin (rhEPO, as a model protein) was formulated with lysine into composite micelles at a diameter of 71.5 nm with narrow polydispersity indices (PDIs protein was in aggregate form. The zeta potential of the spherical micelles was ranging from -0.54 to 1.39 mv, and encapsulation efficiency is high (80 %). The stability of rhEPO was improved significantly in composite micelles in vitro. Pharmacokinetic studies in rats showed significant, enhanced plasma retention of the composite micelles in comparison with native rhEPO. Areas under curve (AUCs) of the rhEPO released from the composite micelles were 4.5- and 2.3-folds higher than those of the native rhEPO and rhEPO-loaded PEG-PLA micelle, respectively. In addition, the composite micelles exhibited good biocompatibility using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay with human embryonic kidney (HEK293T) cells. All these features are preferable for utilizing the composite micelles as a novel protein delivery system.

EPOS IP - Data, Data Products, Services and Software (DDSS Master Table)

Science.gov (United States)

Michalek, Jan; Atakan, Kuvvet

2017-04-01

The "European Plate Observing System - Implementation Phase" (EPOS IP, 2014-2019) project is about building a pan-European infrastructure for accessing solid Earth science data. This ambitious plan started in 2002 already with a Conception Phase and continued by an EPOS PP (Preparatory Phase, 2010-2014) where about 20 partners joined the project. The current EPOS IP project includes 47 partners plus 6 associate partners from 25 countries from all over Europe and several international organizations (ORFEUS, EMSC, EUREF). However, the community contributing to the EPOS integration plan is larger than the official partnership of EPOS IP project, because more countries are represented by the international organizations and because within each country there are several research institutions involved. The list of Data, Data Products, Services and Software (DDSS) provided by individual institutions, consortia or organizations which will become part of the EPOS system are currently collected in document called DDSS Master Table. There are 10 work packages (WP8-WP17) creating the Thematic Core Services (TCS) always grouped by a specific topic: Seismology, Near Fault Observatories, GNSS Data and Products, Volcano Observations, Satellite Data, Geomagnetic Observations, Anthropogenic Hazards, Geological Information and Modelling, Multi-scale laboratories and Geo-Energy Test Beds for Low Carbon Energy. Each of this group declared a list of DDSS elements which are about to be implemented. Currently there are about 455 DDSS elements in the DDSS Master Table. These DDSS elements are of different maturity and about 122 are declared by TCS groups to be ready for implementation which means that the data are well described with metadata, following the standards specific for their domain and, in the best case, with some services allowing their access already. The DDSS elements differ by its complexity as well. The DDSS Master Table serves as an overview of the DDSS elements and

Validation of whole-blood transcriptome signature during microdose recombinant human erythropoietin (rHuEpo) administration.

Science.gov (United States)

Wang, Guan; Durussel, Jérôme; Shurlock, Jonathan; Mooses, Martin; Fuku, Noriyuki; Bruinvels, Georgie; Pedlar, Charles; Burden, Richard; Murray, Andrew; Yee, Brendan; Keenan, Anne; McClure, John D; Sottas, Pierre-Edouard; Pitsiladis, Yannis P

2017-11-14

Recombinant human erythropoietin (rHuEpo) can improve human performance and is therefore frequently abused by athletes. As a result, the World Anti-Doping Agency (WADA) introduced the Athlete Biological Passport (ABP) as an indirect method to detect blood doping. Despite this progress, challenges remain to detect blood manipulations such as the use of microdoses of rHuEpo. Forty-five whole-blood transcriptional markers of rHuEpo previously derived from a high-dose rHuEpo administration trial were used to assess whether microdoses of rHuEpo could be detected in 14 trained subjects and whether these markers may be confounded by exercise (n = 14 trained subjects) and altitude training (n = 21 elite runners and n = 4 elite rowers, respectively). Differential gene expression analysis was carried out following normalisation and significance declared following application of a 5% false discovery rate (FDR) and a 1.5 fold-change. Adaptive model analysis was also applied to incorporate these markers for the detection of rHuEpo. ALAS2, BCL2L1, DCAF12, EPB42, GMPR, SELENBP1, SLC4A1, TMOD1 and TRIM58 were differentially expressed during and throughout the post phase of microdose rHuEpo administration. The CD247 and TRIM58 genes were significantly up- and down-regulated, respectively, immediately following exercise when compared with the baseline both before and after rHuEpo/placebo. No significant gene expression changes were found 30 min after exercise in either rHuEpo or placebo groups. ALAS2, BCL2L1, DCAF12, SLC4A1, TMOD1 and TRIM58 tended to be significantly expressed in the elite runners ten days after arriving at altitude and one week after returning from altitude (FDR > 0.059, fold-change varying from 1.39 to 1.63). Following application of the adaptive model, 15 genes showed a high sensitivity (≥ 93%) and specificity (≥ 71%), with BCL2L1 and CSDA having the highest sensitivity (93%) and specificity (93%). Current results provide further evidence that

Lessons learned from IRIS EPO program evaluations

Science.gov (United States)

Taber, J.; Hubenthal, M.

2012-12-01

Evaluating the overall impact of EPO programs that include activities ranging from formal education through broad public outreach, is a complex issue. The impact of education activities targeted at narrowly defined audiences is generally easier to quantify than the national impact of outreach activities conducted by a relatively small program. For educational activities, our approach has been to leverage the best-practices identified through research and to continuously assess the individual elements internally with the intention of making improvements based on the data generated and the existing research. By constructing our elements on the best practices identified by the research community we feel that internal formative evaluation is a valid means to determine if an activity is effective, particularly when the results are compared to similar programs. For example, effective practices of professional development are well documented in the literature. As a result, this allows us to shape our programs and our evaluations to monitor elements that have been identified as key by the educational research community. Further, such actions allow us to avoid allocating significant resources with the intention of pinning down direct causal relationships between our programs and consumers, when similar interventions (conducted by others) have already shown such relationships. Ongoing review by an EPO advisory committee also provides regular oversight of program impact. While we find internal and external formative evaluation extremely useful in shaping the program and documenting its impact, we also recognize the value of a summative evaluation process. For example, an external summative evaluation of the IRIS EPO program was conducted in 2009, followed by an external panel review, as part of the regular review of IRIS programs. We found that the most valuable part of the external evaluation was our preparation, including clarifying the goals of each of the elements of the

Desert Research and Technology Studies (DRATS) 2010 Education and Public Outreach (EPO)

Science.gov (United States)

Paul, Heather L.

2013-10-01

The Exploration Systems Mission Directorate, Directorate Integration Office conducts analog field test activities, such as Desert Research and Technology Studies (DRATS), to validate exploration system architecture concepts and conduct technology demonstrations. Education and Public Outreach (EPO) activities have been a part of DRATS missions in the past to engage students, educators, and the general public in analog activities. However, in 2010, for the first time, EPO was elevated as a principal task for the mission and metrics were collected for all EPO activities. EPO activities were planned well in advance of the mission, with emphasis on creating a multitude of activities to attract students of all ages. Web-based and social media interaction between August 31 and September 14, 2010 resulted in 62,260 DRATS Flickr views; 10,906 views of DRATS videos on YouTube; 1,483 new DRATS Twitter followers; and a 111% increase in DRATS Facebook fan interactions. Over 7,000 outreach participants were directly involved in the DRATS 2010 analog mission via student visitations at both the integrated dry-runs prior to the field mission and during the field mission; by participating in live, interactive webcasts and virtual events; and online voting to determine a traverse site as part of the NASA initiative for Participatory Exploration (PE).

The glucocorticoid receptor cooperates with the erythropoietin receptor and c-Kit to enhance and sustain proliferation of erythroid progenitors in vitro

NARCIS (Netherlands)

von Lindern, M.; Zauner, W.; Mellitzer, G.; Steinlein, P.; Fritsch, G.; Huber, K.; Löwenberg, B.; Beug, H.

1999-01-01

Although erythropoietin (Epo) is essential for the production of mature red blood cells, the cooperation with other factors is required for a proper balance between progenitor proliferation and differentiation. In avian erythroid progenitors, steroid hormones cooperate with tyrosine kinase receptors

EUDAT and EPOS moving towards the efficient management of scientific data sets

Science.gov (United States)

Fiameni, Giuseppe; Bailo, Daniele; Cacciari, Claudio

2016-04-01

This abstract presents the collaboration between the European Collaborative Data Infrastructure (EUDAT) and the pan-European infrastructure for solid Earth science (EPOS) which draws on the management of scientific data sets through a reciprocal support agreement. EUDAT is a Consortium of European Data Centers and Scientific Communities whose focus is the development and realisation of the Collaborative Data Infrastructure (CDI), a common model for managing data spanning all European research data centres and data repositories and providing an interoperable layer of common data services. The EUDAT Service Suite is a set of a) implementations of the CDI model and b) standards, developed and offered by members of the EUDAT Consortium. These EUDAT Services include a baseline of CDI-compliant interface and API services - a "CDI Gateway" - plus a number of web-based GUIs and command-line client tools. On the other hand,the EPOS initiative aims at creating a pan-European infrastructure for the solid Earth science to support a safe and sustainable society. In accordance with this scientific vision, the mission of EPOS is to integrate the diverse and advanced European Research Infrastructures for solid Earth Science relying on new e-science opportunities to monitor and unravel the dynamic and complex Earth System. EPOS will enable innovative multidisciplinary research for a better understanding of the Earth's physical and chemical processes that control earthquakes, volcanic eruptions, ground instability and tsunami as well as the processes driving tectonics and Earth's surface dynamics. Through the integration of data, models and facilities EPOS will allow the Earth Science community to make a step change in developing new concepts and tools for key answers to scientific and socio-economic questions concerning geo-hazards and geo-resources as well as Earth sciences applications to the environment and to human welfare. To achieve this integration challenge and the

Partnerships: The Key to Sustainability and Reach for E/PO

Science.gov (United States)

Eisenhamer, Bonnie; McCallister, D.; Ryer, H.

2013-06-01

The Space Telescope Science Institute (STScI) is the home institution for the E/PO activities of the Hubble and future James Webb space telescopes. Over time, STScI’s Office of Public Outreach has established the infrastructure needed for an E/PO program that reaches various audiences at the local, regional, and national levels. Partnerships are a critical element of this infrastructure, and sustainability of our E/PO program is ensured through our ongoing partnerships with organizations and institutions with staying power and reach. We have learned from past efforts that strategic partnerships can foster innovation, support diversity initiatives, and increase impact in a cost-effective way while providing target audiences with greater access to NASA SMD science and resources. Partnerships are utilized to field-test educational products and programs, disseminate materials and initiatives, and support professional development activities. Partners are selected based upon specific criteria such as potential for reach, the percentage of underrepresented educators and students served, complementary program goals, and willingness to collect and share evaluation data and results with us. This poster will highlight examples and benefits of strategic partnerships over time.

EMSODEV and EPOS-IP: key findings for effective management of EU research infrastructure projects

Science.gov (United States)

Materia, Paola; Bozzoli, Sabrina; Beranzoli, Laura; Cocco, Massimo; Favali, Paolo; Freda, Carmela; Sangianantoni, Agata

2017-04-01

EMSO (European Multidisciplinary Seafloor and water-column Observatory, http://www.emso-eu.org) and EPOS (European Plate Observing System, https://www.epos-ip.org) are pan-European Research Infrastructures (RIs) in the ESFRI 2016 Roadmap. EMSO has recently become an ERIC (European Research Infrastructure Consortium), whilst EPOS application is in progress. Both ERICs will be hosted in Italy and the "Representing Entity" is INGV. EMSO consists of oceanic environment observation systems spanning from the Arctic through the Atlantic and Mediterranean, to the Black Sea for long-term, high-resolution, real-time monitoring of natural and man-induced processes such as hazards, climate, and marine ecosystems changes to study their evolution and interconnections. EPOS aims at creating a pan-European infrastructure for solid Earth science to support a safe and sustainable society. EPOS will enable innovative multidisciplinary research for a better understanding of Earth's physical and chemical processes controlling earthquakes, volcanic eruptions, ground instability, tsunami, and all those processes driving tectonics and Earth's surface dynamics. Following the conclusion of their Preparatory Phases the two RIs are now in their Implementation Phase still supported by the EC through the EMSODEV and EPOS-IP projects, both run by dedicated Project Management Offices at INGV with sound experience in EU projects. EMSODEV (H2020 project, 2015-2018) involves 11 partners and 9 associate partners and aims at improving the harmonization among the EMSO ERIC observation systems through the realization of EMSO Generic Instrument Modules (EGIMs), and a Data Management Platform (DMP) to implement interoperability and standardization. The DMP will provide access to data from all EMSO nodes, providing a unified, homogeneous, infrastructure-scale and user-oriented platform integrated with the increased measurement capabilities and functions provided by the EGIMs. EPOS IP (H2020 project, 2015

Worldwide nanotechnology development: a comparative study of USPTO, EPO, and JPO patents (1976-2004)

International Nuclear Information System (INIS)

Li Xin; Lin Yiling; Chen Hsinchun; Roco, Mihail C.

2007-01-01

To assess worldwide development of nanotechnology, this paper compares the numbers and contents of nanotechnology patents in the United States Patent and Trademark Office (USPTO), European Patent Office (EPO), and Japan Patent Office (JPO). It uses the patent databases as indicators of nanotechnology trends via bibliographic analysis, content map analysis, and citation network analysis on nanotechnology patents per country, institution, and technology field. The numbers of nanotechnology patents published in USPTO and EPO have continued to increase quasi-exponentially since 1980, while those published in JPO stabilized after 1993. Institutions and individuals located in the same region as a repository's patent office have a higher contribution to the nanotechnology patent publication in that repository ('home advantage' effect). The USPTO and EPO databases had similar high-productivity contributing countries and technology fields with large number of patents, but quite different high-impact countries and technology fields after the average number of received cites. Bibliographic analysis on USPTO and EPO patents shows that researchers in the United States and Japan published larger numbers of patents than other countries, and that their patents were more frequently cited by other patents. Nanotechnology patents covered physics research topics in all three repositories. In addition, USPTO showed the broadest representation in coverage in biomedical and electronics areas. The analysis of citations by technology field indicates that USPTO had a clear pattern of knowledge diffusion from highly cited fields to less cited fields, while EPO showed knowledge exchange mainly occurred among highly cited fields

E-research platform of EPOS Thematic Core Service "ANTHROPOGENIC HAZARDS"

Science.gov (United States)

Orlecka-Sikora, Beata; Lasocki, Stanisław; Grasso, Jean Robert; Schmittbuhl, Jean; Kwiatek, Grzegorz; Garcia, Alexander; Cassidy, Nigel; Sterzel, Mariusz; Szepieniec, Tomasz; Dineva, Savka; Biggare, Pascal; Saccorotti, Gilberto; Sileny, Jan; Fischer, Tomas

2016-04-01

EPOS Thematic Core Service ANTHROPOGENIC HAZARDS (TCS AH) aims to create new research opportunities in the field of anthropogenic hazards evoked by exploitation of georesources. TCS AH, based on the prototype built in the framework of the IS-EPOS project (https://tcs.ah-epos.eu/), financed from Polish structural funds (POIG.02.03.00-14-090/13-00), is being further developed within EPOS IP project (H2020-INFRADEV-1-2015-1, INFRADEV-3-2015). TCS AH is designed as a functional e-research environment to ensure a researcher the maximum possible freedom for in silico experimentation by providing a virtual laboratory in which researcher will be able to create own workspace with own processing streams. The unique integrated RI is: (i) data gathered in the so- called "episodes", comprehensively describing a geophysical process, induced or triggered by human technological activity, which under certain circumstances can become hazardous for people, infrastructure and the environment and (ii) problem-oriented, specific high-level services, with the particular attention devoted to methods analyzing correlations between technology, geophysical response and resulting hazard. Services to be implemented are grouped within six blocks: (1) Basic services for data integration and handling; (2) Services for physical models of stress/strain changes over time and space as driven by geo-resource production; (3) Services for analysing geophysical signals; (4) Services to extract the relation between technological operations and observed induced seismic/deformation; (5) Services to quantitative probabilistic assessments of anthropogenic seismic hazard - statistical properties of anthropogenic seismic series and their dependence on time-varying anthropogenesis; ground motion prediction equations; stationary and time-dependent probabilistic seismic hazard estimates, related to time-changeable technological factors inducing the seismic process; (6) Simulator for Multi

Get Involved in Education and Public Outreach! The Science Mission Directorate Science E/PO Forums Are Here to Help

Science.gov (United States)

Shipp, S. S.; Buxner, S.; Schwerin, T. G.; Hsu, B. C.; Peticolas, L. M.; Smith, D.; Meinke, B. K.

2013-12-01

NASA's Science Mission Directorate (SMD) Education and Public Outreach (E/PO) Forums help to engage, extend, support, and coordinate the efforts of the community of E/PO professionals and scientists involved in Earth and space science education activities. This work is undertaken to maximize the effectiveness and efficiency of the overall national NASA science education and outreach effort made up of individual efforts run by these education professionals. This includes facilitating scientist engagement in education and outreach. The Forums have been developing toolkits and pathways to support planetary, Earth, astrophysics, and heliophysics scientists who are - or who are interested in becoming - involved in E/PO. These tools include: 1) Pathways to learn about SMD and E/PO community announcements and opportunities, share news about E/PO programs, let the E/PO community know you are interested in becoming involved, and discover education programs needing scientist input and/or support. These pathways include weekly e-news, the SMD E/PO online community workspace, monthly community calls, conferences and meetings of opportunity. 2) Portals to help you find out what education resources already exist, obtain resources to share with students of all levels - from K-12 to graduate students, - and disseminate your materials. These include E/PO samplers and toolkits (sampling of resources selected for scientists who work with students, teachers, and the public), the one-stop shop of reviewed resources from the NASA Earth and space science education portfolio NASAWavelength.org, and the online clearinghouse of Earth and space science higher education materials EarthSpace (http://www.lpi.usra.edu/earthspace). 3) Connections to education specialists who can help you design and implement meaningful E/PO programs - small to large. Education specialists can help you understand what research says about how people learn and effective practices for achieving your goals, place your

Clinical and Pathological Significance of Autoantibodies to Erythropoietin Receptor in Type 2 Diabetic Patients With CKD

Directory of Open Access Journals (Sweden)

Akinori Hara

2018-01-01

Conclusion: Anti-EPOR antibodies might be involved in the progression of renal lesions and in the impaired erythropoiesis in type 2 diabetic patients with CKD. Furthermore, the presence of anti-EPOR antibodies may be an additional predictor for end-stage renal disease in type 2 diabetes.

Mass spectrometric analysis of EPO IEF-PAGE interfering substances in nitrile examination gloves.

Science.gov (United States)

Reichel, Christian

2012-10-01

Direct detection of doping with recombinant erythropoietins (rhEPO) is accomplished by isoelectric focusing (IEF) or sodium dodecylsulfate (SDS) polyacrylamide gel electrophoresis (PAGE). In a recent publication, Lasne et al. (Electrophoresis 2011, 32, 1444) showed that improper use of nitrile examination gloves during sample collection, sample preparation, and IEF-PAGE may lead to distorted or absent EPO IEF-profiles. In order to clarify which substances are responsible for this observation, a mass spectrometric study on water extractable compounds found in nitrile gloves was performed. Several substance classes were shown to be present, among them polyethylene glycols (PEG), anionic and nonionic surfactants, as well as alcohol ethoxylates and plasticizers. It could be demonstrated that alkylbenzenesulfonates, the main category of detectable anionic detergents, and among them sodium dodecylbenzenesulfonate (SDBS) and its homologs, are the prime reason for the interference of nitrile gloves with EPO IEF-PAGE. Copyright © 2012 John Wiley & Sons, Ltd.

Contributions of the German Research Center for Geosciences (GFZ) to the EPOS (European Plate Observing System) Implementation Phase 2015-18

Science.gov (United States)

Hoffmann, T. L.; Lauterjung, J.

2017-12-01

The European Plate Observing System project is currently approaching the end of year two of its four-year Implementation Phase 2015-18 (EPOS-IP). Under the Horizon 2020 Programme INFRADEV-3, the EPOS cyberinfrastructure is being established as an ERIC (European Research Infrastructure Consortium) and encompasses the implementation of both the EPOS Integrated Core Services (ICS) for solid Earth Science and a multitude of EPOS Thematic Core Services (TCS). During year two, a basic set of ICS and TCS services was developed and implemented, so that in October 2017 the validation phase (year 3) of EPOS is ready to be launched. Up to now, various TCS-Elements have integrated different Service Providers (SD) that are delivering Data, Data Products, Services and Software (DDSS) to their specific scientific community. As one of the 29 awardees of the EC grant, the German Research Center for Geosciences (GFZ) plays an important role in the implementation of EPOS and its Thematic and Integrated Core Services. The presented poster will give an overview of GFZ's participation in the work of nine technical EPOS Work Packages (WP7 ICS Development, WP8 Seismology, WP11 Volcano Observations, WP12 Satellite Data, WP13 Geomagnetic Observations, WP14 Anthropogenic Hazards, WP15 Geological Information and Modelling, WP16 Multi-Scale Laboratories and WP17 Geo Energy Test Beds) as well as in four administrative EPOS Work Packages (WP2 Communication, WP3 Harmonization, WP4 Legal & Governance, and WP5 Financial).

Studies on cationic UV curing of cycloaliphatic diepoxide - epoxidised palm oil (EPO) for surface coatings

International Nuclear Information System (INIS)

Mek Zah Salleh; Mohd Hilmi Mahmood; Wan Rosli Wan Daud; Kumar, R.N.

1999-01-01

In recent years, there are growing trends in using vegetables oil as raw materials in resin production. Development of new products from palm oil derivatives such as epoxidised palm oil (EPO) is of particular interest to this country. The compatibility of EPO with cycloaliphatic diepoxide allows the development of a wide range of radiation curable formulations by cationic photoinitiators. Curing was done by means of a 20 cm wide IST UV, machine with the conditions of 7.5A current and 4 m/min conveyor speed. Sulphonium and ferrocenium salts were used as the cationic photoinitiators. A study was formulated to compromise the investigation of various effects on the cured film properties. These effects include; types and concentration of photoinitiators, formulating ratios, reactive diluents, photosensitizers and postcuring conditions. The effects on the gel fraction, pendulum hardness, tensile strength and elongation at break were investigated. The results showed that 30% of EPO was the maximum value that can be used in the formulation. It was also found that triarylsulphonium hexafluorophosphate has a very low solubility in EPO

Engaging Scientists in Meaningful E/PO: How the NASA SMD E/PO Community Addresses the needs of Underrepresented Audiences through NASA Science4Girls and Their Families

Science.gov (United States)

Meinke, Bonnie K.; Smith, Denise A.; Bleacher, Lora; Hauck, Karin; Soeffing, Cassie; NASA SMD E/PO Community

2015-01-01

The NASA Astrophysics Science Education and Public Outreach Forum (SEPOF) coordinates the work of individual NASA Science Mission Directorate (SMD) Astrophysics EPO projects and their teams to bring the NASA science education resources and expertise to libraries nationwide. The Astrophysics Forum assists scientists and educators with becoming involved in SMD E/PO (which is uniquely poised to foster collaboration between scientists with content expertise and educators with pedagogy expertise) and makes SMD E/PO resources and expertise accessible to the science and education communities. The NASA Science4Girls and Their Families initiative partners NASA science education programs with public libraries to provide NASA-themed hands-on education activities for girls and their families. As such, the initiative engages girls in all four NASA science discipline areas (Astrophysics, Earth Science, Planetary Science, and Heliophysics), which enables audiences to experience the full range of NASA science topics and the different career skills each requires. The events focus on engaging this particular underserved and underrepresented audience in Science, Technology, Engineering, and Mathematics (STEM) via use of research-based best practices, collaborations with libraries, partnerships with local and national organizations, and remote engagement of audiences.

In vivo evaluation of EPO-secreting cells immobilized in different alginate-PLL microcapsules.

Science.gov (United States)

Ponce, S; Orive, G; Hernández, R M; Gascón, A R; Canals, J M; Muñoz, M T; Pedraz, J L

2006-11-01

Alginates are the most employed biomaterials for cell encapsulation due to their abundance, easy gelling properties and apparent biocompatibility. However, as natural polymers different impurities including endotoxins, proteins and polyphenols can be found in their composition. Several purification protocols as well as different batteries of assays to prove the biocompatibility of the alginates in vitro have been recently developed. However, little is known about how the use of alginates with different purity grade may affect the host immune response after their implantation in vivo. The present paper investigates the long-term functionality and biocompatibility of murine erythropoietin (EPO) secreting C2C12 cells entrapped in microcapsules elaborated with alginates with different properties (purity, composition and viscosity). Results showed that independently of the alginate type employed, the animals presented elevated hematocrit levels until day 130, remaining at values between 70-87%. However, histological analysis of the explanted devices showed higher overgrowth around non-biomedical grade alginate microcapsules which could be directly related with higher impurity content of this type of alginate. Although EPO delivery may be limited by the formation of a fibrotic layer around non-biomedical grade alginate microcapsules, the high EPO secretion of the encapsulated cells together with the pharmacodynamic behaviour and the angiogenic and immune-modulatory properties of EPO result in no direct correlation between the biocompatibility of the alginate and the therapeutic response obtained.

PI3 kinase is important for Ras, MEK and Erk activation of Epo-stimulated human erythroid progenitors

Directory of Open Access Journals (Sweden)

Schmidt Enrico K

2004-05-01

Full Text Available Abstract Background Erythropoietin is a multifunctional cytokine which regulates the number of erythrocytes circulating in mammalian blood. This is crucial in order to maintain an appropriate oxygen supply throughout the body. Stimulation of primary human erythroid progenitors (PEPs with erythropoietin (Epo leads to the activation of the mitogenic kinases (MEKs and Erks. How this is accomplished mechanistically remained unclear. Results Biochemical studies with human cord blood-derived PEPs now show that Ras and the class Ib enzyme of the phosphatidylinositol-3 kinase (PI3K family, PI3K gamma, are activated in response to minimal Epo concentrations. Surprisingly, three structurally different PI3K inhibitors block Ras, MEK and Erk activation in PEPs by Epo. Furthermore, Erk activation in PEPs is insensitive to the inhibition of Raf kinases but suppressed upon PKC inhibition. In contrast, Erk activation induced by stem cell factor, which activates c-Kit in the same cells, is sensitive to Raf inhibition and insensitive to PI3K and PKC inhibitors. Conclusions These unexpected findings contrast with previous results in human primary cells using Epo at supraphysiological concentrations and open new doors to eventually understanding how low Epo concentrations mediate the moderate proliferation of erythroid progenitors under homeostatic blood oxygen levels. They indicate that the basal activation of MEKs and Erks in PEPs by minimal concentrations of Epo does not occur through the classical cascade Shc/Grb2/Sos/Ras/Raf/MEK/Erk. Instead, MEKs and Erks are signal mediators of PI3K, probably the recently described PI3K gamma, through a Raf-independent signaling pathway which requires PKC activity. It is likely that higher concentrations of Epo that are induced by hypoxia, for example, following blood loss, lead to additional mitogenic signals which greatly accelerate erythroid progenitor proliferation.

Therapy of an incomplete spinal cord injury by intrathecal injection of EPO and subcutaneous injection of EPO, vitamin C and G-CSF.

Science.gov (United States)

Bader, Augustinus; Reinhardt, Martin; Beuthe, Achim; Röhl, Klaus; Giri, Shibashish

2017-01-01

Spinal cord injury is a rare disease with an incidence about 40 cases per million population in the USA. The most common reasons are traffic accidents, falls, violence and sports. A 53-year-old male patient presented with an incomplete tetraparesis as a result of a spinal cord injury after the accident. It was not possible to treat him with steroids because he was out of the therapeutic time period of 8 hours when he presented to the hospital. The main problem of spinal cord injuries is the secondary injury caused by inflammation and swelling of the spinal cord. To avoid this, the patient was experimentally treated with erythropoietin (EPO) intrathecal and EPO, granulocyte-colony-stimulating factor and vitamin C subcutaneous after his initial spinal cord relief surgery. These drugs might be able to relieve this secondary reaction but were never applied for this indication in human before. This study shows that it could be a promising treatment for spinal cord injuries with potential therapeutic benefits.

Working with NASA's OSS E/PO Support Network

Science.gov (United States)

Miner, E. D.; Lowes, L. L.

2001-11-01

With greater and greater emphasis on the inclusion of a public engagement component in all government-supported research funding, many members of the DPS are finding it difficult to find sufficient time and funding to develop a wide-reaching and effective E/PO program. NASA's Office of Space Science, over the last five years, has built a Support Network to assist its funded scientists to establish partnerships with local and/or national science formal or informal education organizations, who are anxious to connect with and use the expertise of space scientists. The OSS Support Network consists of four theme-based 'Forums,' including the Solar System Exploration (SSE) Forum, specifically designed for working with planetary scientists, and seven regional 'Brokers-Facilitators' who are more familiar with partnership and other potential avenues for involvement by scientists. The services provided by the Support Network are free to both the scientists and their potential partners and is not limited to NASA-funded scientists. In addition to its assistance to space scientists, the Support Network is involved in a number of other overarching efforts, including support of a Solar System Ambassador Program, a Solar System Educator Program, Space Place (web and e-mail science products for libraries and small planetariums and museums), an on-line Space Science Resource Directory, annual reports of Space Science E/PO activity, identifying and filling in 'holes' and 'over-populations' in a solar system E/PO product matrix of grade level versus product versus content, research on product effectiveness, and scientific and educational evaluation of space science products. Forum and Broker-Facilitator contact information is available at http://spacescience.nasa.gov/education/resources/ecosystem/index.htm. Handouts with additional information will be available at the meeting.

Engaging Scientists in Meaningful E/PO: How the NASA SMD E/PO Community Addresses Informal Educators' Preferences for PD and Materials

Science.gov (United States)

Bartolone, Lindsay; Nelson, Andi; Smith, Denise A.; NASA SMD Astrophysics E/PO Community

2015-01-01

The NASA Astrophysics Science Education and Public Outreach Forum (SEPOF) coordinates the work of NASA Science Mission Directorate (SMD) Astrophysics EPO projects. These teams work together to capitalize on the cutting-edge discoveries of NASA Astrophysics missions to support educators in Science, Technology, Engineering, and Math (STEM) and to enable youth to engage in doing STEM inside and outside of school. The Astrophysics Forum assists scientists and educators with becoming involved in SMD E/PO, which is uniquely poised to foster collaboration between scientists with content expertise and educators with pedagogy expertise, and makes SMD E/PO resources and expertise accessible to the science and education communities. Informal educators participated in a recent nationally-distributed survey from the NASA SMD SEPOF Informal Education Working Group. The results show the preferences of staff from museums, parks, public libraries, community/afterschool centers, and others with regard to professional development and material resources. The results of the survey will be presented during this session.In addition, we present opportunities for the astronomy community to participate in collaborations supporting the NASA SMD efforts in K-12 Formal Education, Informal Science Education, and Outreach. These efforts focus on enhancing instruction, as well as youth and public engagement, in STEM via use of research-based best practices, collaborations with libraries, partnerships with local and national organizations, and remote engagement of audiences. The Forums' efforts for the Formal, Informal Science Education and Outreach communities include a literature review, appraisal of informal educators' needs, coordination of audience-based NASA resources and opportunities, professional development, plus support with the Next Generation Science Standards. Learn how to join in our collaborative efforts to support the K-12 Formal Education community and to reach the informal

Four whole-istic aspects of schistosome granuloma biology: fractal arrangement, internal regulation, autopoietic component and closure

Directory of Open Access Journals (Sweden)

HL Lenzi

2006-10-01

Full Text Available This paper centers on some whole-istic organizational and functional aspects of hepatic Schistosoma mansoni granuloma, which is an extremely complex system. First, it structurally develops a collagenic topology, originated bidirectionally from an inward and outward assembly of growth units. Inward growth appears to be originated from myofibroblasts derived from small portal vessel around intravascular entrapped eggs, while outward growth arises from hepatic stellate cells. The auto-assembly of the growth units defines the three-dimensional scaffold of the schistosome granulomas. The granuloma surface irregularity and its border presented fractal dimension equal to 1.58. Second, it is internally regulated by intricate networks of immuneneuroendocrine stimuli orchestrated by leptin and leptin receptors, substance P and Vasoactive intestinal peptide. Third, it can reach the population of ± 40,000 cells and presents an autopoietic component evidenced by internal proliferation (Ki-67+ Cells, and by expression of c-Kit+ Cells, leptin and leptin receptor (Ob-R, granulocyte-colony stimulating factor (G-CSF-R, and erythropoietin (Epo-R receptors. Fourth, the granulomas cells are intimately connected by pan-cadherins, occludin and connexin-43, building a state of closing (granuloma closure. In conclusion, the granuloma is characterized by transitory stages in such a way that its organized structure emerges as a global property which is greater than the sum of actions of its individual cells and extracellular matrix components.

An Intranasal Formulation of Erythropoietin (Neuro-EPO) Prevents Memory Deficits and Amyloid Toxicity in the APPSwe Transgenic Mouse Model of Alzheimer's Disease.

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Rodríguez Cruz, Yamila; Strehaiano, Manon; Rodríguez Obaya, Teresita; García Rodríguez, Julío César; Maurice, Tangui

2017-01-01

Erythropoietin (EPO) is a cytokine known to have effective cytoprotective action in the brain, particularly in ischemic, traumatic, inflammatory, and neurodegenerative conditions. We previously reported the neuroprotective effect of a low sialic form of EPO, Neuro-EPO, applied intranasally in rodent models of stroke or cerebellar ataxia and in a non-transgenic mouse model of Alzheimer's disease (AD). Here we analyzed the protective effect of Neuro-EPO in APPSwe mice, a reference transgenic mouse model of AD. Mice were administered 3 times a day, 3 days in the week with Neuro-EPO (125, 250 μg/kg) intranasally, between 12 and 14 months of age. Motor responses, general activity, and memory responses were analyzed during and after treatment. The deficits in spontaneous alternation, place learning in the water-maze, and novel object recognition observed in APPSwe mice were alleviated by the low dose of Neuro-EPO. Oxidative stress, neuroinflammation, trophic factor levels, and a synaptic marker were analyzed in the hippocampus or cortex of the animals. The increases in lipid peroxidation or in GFAP and Iba-1 contents in APPSwe mice were significantly reduced after Neuro-EPO. Activation of intrinsic and extrinsic apoptotic pathways was analyzed. The increases in Bax/Bcl-2 ratio, TNFα, or Fas ligand levels observed in APPSwe mice were reduced by Neuro-EPO. Finally, immunohistochemical and ELISA analyses of Aβ1-42 levels in the APPSwe mouse cortex and hippocampus showed a marked reduction in Aβ deposits and in soluble and insoluble Aβ1-42 forms. This study therefore confirmed the neuroprotective activity of EPO, particularly for an intranasally deliverable formulation, devoid of erythropoietic side effects, in a transgenic mouse model of AD. Neuro-EPO alleviated memory alterations, oxidative stress, neuroinflammation, apoptosis induction, and amyloid load in 14-month-old APPSwe mice.

EPO for the NASA SDO Extreme Ultraviolet Variability Experiment (EVE) Learning Suite for Educators

Science.gov (United States)

Kellagher, Emily; Scherrer, D. K.

2013-07-01

EVE Education and Public Outreach (EPO) promotes an understanding of the process of science and concepts within solar science and sun-earth connections. EVE EPO also features working scientists, current research and career awareness. One of the highlights for of this years projects is the digitization of solar lessons and the collaboration with the other instrument teams to develop new resources for students and educators. Digital lesson suite: EVE EPO has taken the best solar lessons and reworked then to make then more engaging, to reflect SDO data and made them SMARTboard compatible. We are creating a website that Students and teachers can access these lesson and use them online or download them. Project team collaboration: The SDO instruments (EVE, AIA and HMI) teams have created a comic book series for upper elementary and middle school students with the SDO mascot Camilla. These comics may be printed or read on mobile devices. Many teachers are looking for resources to use with their students via the Ipad so our collaboration helps supply teachers with a great resource that teachers about solar concepts and helps dispel solar misconceptions.Abstract (2,250 Maximum Characters): EVE Education and Public Outreach (EPO) promotes an understanding of the process of science and concepts within solar science and sun-earth connections. EVE EPO also features working scientists, current research and career awareness. One of the highlights for of this years projects is the digitization of solar lessons and the collaboration with the other instrument teams to develop new resources for students and educators. Digital lesson suite: EVE EPO has taken the best solar lessons and reworked then to make then more engaging, to reflect SDO data and made them SMARTboard compatible. We are creating a website that Students and teachers can access these lesson and use them online or download them. Project team collaboration: The SDO instruments (EVE, AIA and HMI) teams have created a

Ethics issues in scientific data and service provision: evidence and challenges for the European Plate Observing System (EPOS)

Science.gov (United States)

Cocco, Massimo; Freda, Carmela; Haslinger, Florian; Consortium, Epos

2016-04-01

Addressing Ethics issues is nowadays a relevant challenge for any initiative, program or project dealing with scientific data and products provision, access to services for scientific purposes and communication with different stakeholders, including society. This is corroborated by the evidence that Ethics has very high priority in EU funded research. Indeed, all the activities carried out under Horizon 2020 must comply with ethical principles and national, Union and international legislation. This implies that "For all activities funded by the European Union, Ethics is an integral part of research from beginning to end, and ethical compliance is seen as pivotal to achieve real research excellence." Here, we present the experience of EPOS, a public pan-European research infrastructure. EPOS aims at integrating data, data products, services and software (DDSS) for solid Earth science generated and provided by monitoring networks, observing systems and facilities belonging to European countries. EPOS fosters the integrated use of multidisciplinary solid Earth data to improve the understanding of physical and chemical processes controlling earthquakes, volcanic eruptions, tsunamis as well as those driving tectonics and surface dynamics. The EPOS integration plan will make significant contributions to understanding and mitigating geo-hazards, yielding data for hazard assessment, data products for engaging different stakeholders, and services for training, education and communication to society. Numerous national research infrastructures engaged in EPOS are deployed for the monitoring of areas prone to geo-hazards and for the surveillance of the national territory including areas used for exploiting geo-resources. The EPOS community is therefore already trained to provide services to public (civil defence agencies, local and national authorities) and private (petroleum industry, mining industry, geothermal companies, aviation security) stakeholders. Our ability to

Amateur Astronomers: Secret Agents of EPO

Science.gov (United States)

Berendsen, M.; White, V.; Devore, E.; Reynolds, M.

2008-06-01

Amateur astronomers prime the public to be more interested, receptive, and excited about space science, missions, and programs. Through recent research and targeted programs, amateur astronomy outreach is being increasingly recognized by professional astronomers, educators, and other amateurs as a valued and important service. The Night Sky Network program, administered by the ASP, is the first nationwide research-based program specifically targeted to support outreach by amateur astronomers. This Network of trained and informed amateur astronomers can provide a stimulating introduction to your EPO programs as Network members share the night sky with families, students, and youth groups.

Women in EPOS: the role of women in a large pan-European Research Infrastructure for Solid Earth sciences

Science.gov (United States)

Calignano, Elisa; Freda, Carmela; Baracchi, Laura

2017-04-01

Women are outnumbered by men in geosciences senior research positions, but what is the situation if we consider large pan-European Research Infrastructures? With this contribution we want to show an analysis of the role of women in the implementation of the European Plate Observing System (EPOS): a planned research infrastructure for European Solid Earth sciences, integrating national and transnational research infrastructures to enable innovative multidisciplinary research. EPOS involves 256 national research infrastructures, 47 partners (universities and research institutes) from 25 European countries and 4 international organizations. The EPOS integrated platform demands significant coordination between diverse solid Earth disciplinary communities, national research infrastructures and the policies and initiatives they drive, geoscientists and information technologists. The EPOS architecture takes into account governance, legal, financial and technical issues and is designed so that the enterprise works as a single, but distributed, sustainable research infrastructure. A solid management structure is vital for the successful implementation and sustainability of EPOS. The internal organization relies on community-specific Working Packages (WPs), Transversal WPs in charge of the overall EPOS integration and implementation, several governing, executive and advisory bodies, a Project Management Office (PMO) and the Project Coordinator. Driven by the timely debate on gender balance and commitment of the European Commission to promote gender equality in research and innovation, we decided to conduct a mapping exercise on a project that crosses European national borders and that brings together diverse geoscience disciplines under one management structure. We present an analysis of women representation in decision-making positions in each EPOS Working Package (WP Leader, proxy, legal, financial and IT contact persons), in the Boards and Councils and in the PMO

Multi-omic profiling of EPO-producing CHO cell panel reveals metabolic adaptation to heterologous protein production

DEFF Research Database (Denmark)

Ley, Daniel; Kazemi Seresht, Ali; Engmark, Mikael

The Chinese hamster ovary (CHO) cell line is the predominant mammalian cell factory for production of therapeutic glycoproteins. In this work, we aimed to study bottlenecks in the secretory pathway associated with the production of human erythropoietin (EPO) in CHO cells. In connection to this, we...... discovered indications of metabolic adaptation of the amino acid catabolism in favor of heterologous protein production. We established a panel of stably EPO expressing CHO-K1 clones spanning a 25-fold productivity range and characterized the clones in batch and chemostat cultures. For this, we employed...... a multi-omic physiological characterization including metabolic foot printing of amino acids, metabolite fingerprinting of glycolytic intermediates, NAD(P)H-/NAD(P)+ and adenosine nucleotide phosphates. We used qPCR, qRT-PCR, western blots and Affymetrix CHO microarrays to assess EPO gene copy numbers...

The SDO Education and Outreach (E/PO) Program: Changing Perceptions One Program at a Time

Science.gov (United States)

Drobnes, E.; Littleton, A.; Pesnell, W. D.; Buhr, S.; Beck, K.; Durscher, R.; Hill, S.; McCaffrey, M.; McKenzie, D. E.; Myers, D.;

Biology of erythropoietin.

Science.gov (United States)

Lacombe, C; Mayeux, P

1998-08-01

Erythropoietin (Epo) controls the proliferation, differentiation and survival of the erythroid progenitors. This cytokine was cloned in 1985 and rapidly became used for treatment of anemia of renal failure, opening the way to the first clinical trials of a hematopoietic growth factor. The clonage of one chain of the Epo receptor followed in 1989, thereby opening the research on intracellular signal transduction induced by Epo. Epo is synthesized mainly by the kidney and the liver and sequences required for tissue-specific expression have been localized in the Epo gene. A 3'enhancer is responsible for hypoxia-inducible Epo gene expression. HIF-1 alpha and beta proteins bind to this enhancer. Gene regulation by hypoxia is widespread in many cells and involves numerous genes in addition to the Epo gene. The Epo receptor belongs to the cytokine receptor family and includes a p66 chain which is dimerized upon Epo activation; two accessory proteins defined by cross-linking remain to be characterized. Epo binding induces the stimulation of Jak2 tyrosine kinase. Jak2 activation leads to the tyrosine phosphorylation of several proteins including the Epo receptor itself. As a result, different intracellular pathways are activated: Ras/MAP kinase, phosphatidylinositol 3-kinase and STAT transcription factors. However, the exact mechanisms by which the proliferation and/or the differentiation of erythroid cells are regulated after Epo stimulation are not known. Furthermore, target disruption of both Epo and Epo receptor showed that Epo was not involved in the commitment of the erythroid lineage and seemed to act mainly as a survival factor.

A Planetary Geophysicist Does EPO: Lessons Learned Along the Way

Science.gov (United States)

Kiefer, W. S.

2011-12-01

My "day job" is numerical modeling of the interiors of the terrestrial planets, but I have also done EPO projects for the last 17 years while at the Lunar and Planetary Institute. These range from single, hour long talks in classrooms or astronomy clubs, to week-long summer workshops for teachers and librarians, and even semester-long programs, along with a number of curriculum development projects. EPO projects are a great way to help develop both the next generation of scientists and, more importantly, of scientifically literate citizens and taxpayers. Here are a few lessons learned along the way in the school of hard knocks. (1) An engaging delivery style is even more important in EPO presentations than it is in college lectures or conference presentations. Emphasize a few key concepts rather than numerous facts, and keep the jargon out. Good analogies can go a long way towards explaining a concept to any age group. I teach the role of size in planetary cooling by first asking students how long it takes to cook food of various sizes (a hamburger, roast beef, turkey). (2) If you will be working with a group of students for more than one class period, classroom friendly activities strengthen the learning process. Such activities do not need to be elaborate - when teaching about the Moon, I sometimes assign students to take their parents outside at night and show them how to find lava flows on the Moon. Teachers usually need to have classroom activities that are aligned to state or national teaching standards. Fortunately, many effective, standards-aligned activities already exist, so you don't need to reinvent the wheel. For a useful listing of planetary science and astronomy activities, see the LPI website www.lpi.usra.edu/education/resources/ (3) Although EPO work can be personally rewarding, it is not always well rewarded in a professional context, and it can be difficult to find the time and financial resources to sustain major projects. We sometimes use a

The use of vertical and horizontal surface displacements at EPOS GNSS stations in Greenland to study ice sheet mass balance

DEFF Research Database (Denmark)

Khan, Shfaqat Abbas

2014-01-01

The European Plate Observing System (EPOS) includes e.g. seismic and geodetic permanent national monitoring networks on a European scale. The main purpose is to create data platforms for monitoring and study geophysics processes like earthquakes, volcanoes, surface dynamics and tectonics. Here we...... present data from arctic GNSS stations included in the EPOS network. The arctic EPOS GNSS network consists of 16 continuous GPS stations spread across Greenland. This network is able to map the velocity fields associated with, plate motion, postglacial rebound and improve our understanding of tectonic...

The role of renal function loss on circadian misalignment of cytokines EPO, IGF-1, IL-6 and TNF-alfa in chronic renal disease.

Science.gov (United States)

van der Putten, Karien; Koch, Birgit; van Someren, Eus; Wielders, Jos; Ter Wee, Piet; Nagtegaal, Elsbeth; Gaillard, Carlo

2011-01-01

Chronic inflammation plays a pivotal role in the development of renal disease. Circadian sleep-wake rhythm is disturbed in renal disease. Awareness of other disturbed rhythms, such as inflammation processes, can affect the treatment of patients with renal disease. Knowledge of possibly related circadian misalignment of the cytokines erythropoietin (EPO), Insulin Growth Factor-1 (IGF-1) and interleukins (IL) however is limited. We therefore performed an observational study. The objective of this study was to characterize levels of EPO, IGF-1 and inflammation markers IL-6 and TNF-α, related to renal function. The study population consisted of patients with various degrees of renal function, admitted to our hospital. During 24 hours, blood of 28 subjects with various degrees of renal function was collected every 2 hours. The patients were stable, not acutely ill and they were waiting for a procedure, such as elective surgery. Circadian parameters of EPO, IGF-1, IL-6 and TNF-α were measured in serum and were correlated with glomerular filtration rate (GFR) and Hb, using Pearson correlations. Although diurnal variations in EPO level were found in 15 out of 28 patients, the curves did not show a consistent phase. The presence of an EPO rhythm was not related to GFR. No diurnal rhythm could be detected for IGF-1, IL-6 and TNF-α. Mean levels of IGF-1 were correlated inversely to mean levels of EPO (p=0.03). When divided based on GFR and Hb subjects with GFR 10-30 ml/min and lower Hb had the highest IGF-1 levels (p=0.02). A relationship between Il-6, TNF-α and EPO or GFR was not found. The existence of a circadian (mis)alignment of EPO, IGF-1, IL-6 and TNF-α was not found. The association between high IGF-1 and low Hb suggests that EPO and IGF-1 have an alternating role, dependent on GFR, in stimulating erythropoiesis. These results could have consequences for the treatment of anemia.

Multiscale Laboratory Infrastructure and Services to users: Plans within EPOS

Science.gov (United States)

Spiers, Chris; Willingshofer, Ernst; Drury, Martyn; Funiciello, Francesca; Rosenau, Matthias; Scarlato, Piergiorgio; Sagnotti, Leonardo; EPOS WG6, Corrado Cimarelli

2015-04-01

The participant countries in EPOS embody a wide range of world-class laboratory infrastructures ranging from high temperature and pressure experimental facilities, to electron microscopy, micro-beam analysis, analogue modeling and paleomagnetic laboratories. Most data produced by the various laboratory centres and networks are presently available only in limited "final form" in publications. Many data remain inaccessible and/or poorly preserved. However, the data produced at the participating laboratories are crucial to serving society's need for geo-resources exploration and for protection against geo-hazards. Indeed, to model resource formation and system behaviour during exploitation, we need an understanding from the molecular to the continental scale, based on experimental data. This contribution will describe the plans that the laboratories community in Europe is making, in the context of EPOS. The main objectives are: • To collect and harmonize available and emerging laboratory data on the properties and processes controlling rock system behaviour at multiple scales, in order to generate products accessible and interoperable through services for supporting research activities. • To co-ordinate the development, integration and trans-national usage of the major solid Earth Science laboratory centres and specialist networks. The length scales encompassed by the infrastructures included range from the nano- and micrometer levels (electron microscopy and micro-beam analysis) to the scale of experiments on centimetre sized samples, and to analogue model experiments simulating the reservoir scale, the basin scale and the plate scale. • To provide products and services supporting research into Geo-resources and Geo-storage, Geo-hazards and Earth System Evolution. If the EPOS Implementation Phase proposal presently under construction is successful, then a range of services and transnational activities will be put in place to realize these objectives.

Applying e-procurement system in the healthcare: the EPOS paradigm

Science.gov (United States)

Ketikidis, Panayiotis H.; Kontogeorgis, Apostolos; Stalidis, George; Kaggelides, Kostis

2010-03-01

One of the goals of procurement is to establish a competitive price, while e-procurement utilises electronic commerce to identify potential sources of supply, to purchase goods and services, to exchange contractual information and to interact with suppliers. Extensive academic work has been extensively devoted to e-procurement in diverse industries. However, applying e-procurement in the healthcare sector remains unexplored. It lacks an efficient e-procurement mechanism that will enable hospitals and healthcare suppliers to electronically exchange contractual information, aided by the technologies of optimisation and business rules. The development and deployment of e-procurement requires a major effort in the coordination of complex interorganisational business process. This article presents an e-procurement optimised system (EPOS) for the healthcare marketplace, a complete methodological approach for deploying and operating such system, as piloted in public and private hospitals in three European countries (Greece, Spain and Belgium) and suppliers of healthcare items in the fourth country (Italy). The efficient e-procurement mechanism that EPOS suggests enables hospitals and pharmaceutical and medical equipment suppliers to electronically exchange contractual information.

A Conjugated Aptamer-Gold Nanoparticle Fluorescent Probe for Highly Sensitive Detection of rHuEPO-α

Directory of Open Access Journals (Sweden)

Zhaoyang Zhang

2011-11-01

Full Text Available We present here a novel conjugated aptamer-gold nanoparticle (Apt-AuNPs fluorescent probe and its application for specific detection of recombinant human erythropoietin-α (rHuEPO-α. In this nanobiosensor, 12 nm AuNPs function as both a nano-scaffold and a nano-quencher (fluorescent energy acceptor, on the surface of which the complementary sequences are linked (as cODN-AuNPs and pre-hybridized with carboxymethylfluorescein (FAM-labeled anti-rHuEPO-α aptamers. Upon target protein binding, the aptamers can be released from the AuNP surface and the fluorescence signal is restored. Key variables such as the length of linker, the hybridization site and length have been designed and optimized. Full performance evaluation including sensitivity, linear range and interference substances are also described. This nanobiosensor provides a promising approach for a simple and direct quantification of rHuEPO-α concentrations as low as 0.92 nM within a few hours.

Clinical significance of measurement of plasma relevant cytokines (GM-CSF, IL-2, TPO, EPO) levels in patients with aplastic anemia

International Nuclear Information System (INIS)

Yu Tintin

2006-01-01

Objective: To investigate the role of relevant cytokines in the development and pathogenesis of aplastic anemia. Methods: Plasma GM-CSF, IL-2, TPO (with RIA) and EPO (with CLIA) contents were measured in 100 patients (acute 43, chronic 57) with aplastic anemia and 50 controls. Complete blood count was also performed in all these subjects. Results: The peripheral RBC, WBC, platelet counts and GM-CSF contents were significantly lower in the patients with aplastic anemia than those in the controls (P<0.05), while the IL-2, EPO and TPO contents were significantly higher in the patients (P<0.05). GM-CSF contents were positively correlated with the WBC numbers. EPO contents were negatively correlated with the RBC counts and TPO contents were correlated (negatively) with the platelet counts. Conclusion: There was correlationship between each blood elements (WBC, RBC, platelet) and its corresponding cytokine (GS-CSF, EPO, TPO respectively). IL-2 contents were not correlated with WBC counts. (authors)

Chronic preclinical safety evaluation of EPO-018B, a pegylated peptidic erythropoiesis-stimulating agent in monkeys and rats

International Nuclear Information System (INIS)

Gong, Xue-Lian; Gu, Xiao-Lei; Chen, Yong-Chun; Zhu, Hai; Xia, Zhen-Na; Li, Jian-Zhong; Lu, Guo-Cai

2016-01-01

EPO-018B, a synthetic peptide-based erythropoiesis stimulating agent (ESA), is mainly designed for treatment of anemia caused by chronic renal failure and chemotherapy against cancer. It overcomes the deficiencies of currently approved ESA, including the frequent administration of temperature-sensitive recombinant protein and anti-EPO antibody-mediated pure red cell aplasia (PRCA). This study was designed to evaluate the potential chronic toxicity of EPO-018B. Subcutaneous administration doses were designed as 0, 0.2, 1 and 10 mg/kg for six months for 160 rats (20/gender/group) and 0, 0.3, 3 and 20 mg/kg for nine months for 32 monkeys (4/gender/group) once every three weeks. The vehicles received the same volume of physiological saline injection. All animals survived to the scheduled necropsies after six weeks (for rats) and fourteen weeks (for monkeys) recovery period, except for the two high-dose female rats and two high-dose male monkeys, which were considered related to the increased RBCs, chronic blood hyperviscosity and chronic cardiac injury. EPO-018B is supposed to be subcutaneously injected once every month and the intended human therapeutic dose is 0.025 mg/kg. The study findings at 0.2 mg/kg for rats and 0.3 mg/kg for monkeys were considered to be the study NOAEL (the no observed adverse effect level), which were more than ten times the intended human therapeutic dose. Higher doses caused adverse effects related to the liver toxicity, cardiotoxicity, appearance of neutralizing antibodies of EPO-018B and the decrease of serum glucose and cholesterol. Most treatment-induced effects were reversible or revealed ongoing recovery upon the discontinuation of treatment. The sequelae occurred in rats and monkeys were considered secondary to exaggerated pharmacology and would less likely occur in the intended patient population. As to the differences between human beings and animals, the safety of EPO-018B need to be further confirmed in the future clinical

Chronic preclinical safety evaluation of EPO-018B, a pegylated peptidic erythropoiesis-stimulating agent in monkeys and rats

Energy Technology Data Exchange (ETDEWEB)

Gong, Xue-Lian; Gu, Xiao-Lei [Department of Hygiene and Toxicology, Second Military Medical University, Shanghai 200433 (China); Chen, Yong-Chun [Department of Hygiene and Toxicology, Second Military Medical University, Shanghai 200433 (China); Department of Pharmacy, No.422 Hospital, Zhanjiang 524005 (China); Zhu, Hai; Xia, Zhen-Na [Department of Hygiene and Toxicology, Second Military Medical University, Shanghai 200433 (China); Li, Jian-Zhong, E-mail: lijianzhong1234@hotmail.com [Department of Biochemical Pharmacy, Second Military Medical University, Shanghai 200433 (China); Lu, Guo-Cai, E-mail: newdrug@smmu.edu.cn [Department of Hygiene and Toxicology, Second Military Medical University, Shanghai 200433 (China)

2016-09-15

EPO-018B, a synthetic peptide-based erythropoiesis stimulating agent (ESA), is mainly designed for treatment of anemia caused by chronic renal failure and chemotherapy against cancer. It overcomes the deficiencies of currently approved ESA, including the frequent administration of temperature-sensitive recombinant protein and anti-EPO antibody-mediated pure red cell aplasia (PRCA). This study was designed to evaluate the potential chronic toxicity of EPO-018B. Subcutaneous administration doses were designed as 0, 0.2, 1 and 10 mg/kg for six months for 160 rats (20/gender/group) and 0, 0.3, 3 and 20 mg/kg for nine months for 32 monkeys (4/gender/group) once every three weeks. The vehicles received the same volume of physiological saline injection. All animals survived to the scheduled necropsies after six weeks (for rats) and fourteen weeks (for monkeys) recovery period, except for the two high-dose female rats and two high-dose male monkeys, which were considered related to the increased RBCs, chronic blood hyperviscosity and chronic cardiac injury. EPO-018B is supposed to be subcutaneously injected once every month and the intended human therapeutic dose is 0.025 mg/kg. The study findings at 0.2 mg/kg for rats and 0.3 mg/kg for monkeys were considered to be the study NOAEL (the no observed adverse effect level), which were more than ten times the intended human therapeutic dose. Higher doses caused adverse effects related to the liver toxicity, cardiotoxicity, appearance of neutralizing antibodies of EPO-018B and the decrease of serum glucose and cholesterol. Most treatment-induced effects were reversible or revealed ongoing recovery upon the discontinuation of treatment. The sequelae occurred in rats and monkeys were considered secondary to exaggerated pharmacology and would less likely occur in the intended patient population. As to the differences between human beings and animals, the safety of EPO-018B need to be further confirmed in the future clinical

Integrating Near Fault Observatories (NFO) for EPOS Implementation Phase

Science.gov (United States)

Chiaraluce, Lauro

2015-04-01

Following the European Plate Observing System (EPOS) project vision aimed at creating a pan-European infrastructure for Earth sciences to support science for a more sustainable society, we are working on the integration of Near-Fault Observatories (NFOs). NFOs are state of the art research infrastructures consisting of advanced networks of multi-parametric sensors continuously monitoring the chemical and physical processes related to the common underlying earth instabilities governing active faults evolution and the genesis of earthquakes. Such a methodological approach, currently applicable only at the local scale (areas of tens to few hundreds of kilometres), is based on extremely dense networks and less common instruments deserving an extraordinary work on data quality control and multi-parameter data description. These networks in fact usually complement regional seismic and geodetic networks (typically with station spacing of 50-100km) with high-density distributions of seismic, geodetic, geochemical and geophysical sensors located typically within 10-20 km of active faults where large earthquakes are expected in the future. In the initial phase of EPOS-IP, seven NFO nodes will be linked: the Alto Tiberina and Irpinia Observatories in Italy, the Corinth Observatory in Greece, the South-Iceland Seismic Zone, the Valais Observatory in Switzerland, Marmara Sea GEO Supersite in Turkey (EU MARSite) and the Vrancea Observatory in Romania. Our work is aimed at establishing standards and integration within this first core group of NFOs while other NFOs are expected to be installed in the next years adopting the standards established and developed within the EPOS Thematic Core Services (TCS). The goal of our group is to build upon the initial development supported by these few key national observatories coordinated under previous EU projects (NERA and REAKT), inclusive and harmonised TCS supporting the installation over the next decade of tens of near

Ethical implication of providing scientific data and services to diverse stakeholders: the case of the EPOS research infrastructure

Science.gov (United States)

Freda, Carmela; Atakan, Kuvvet; Cocco, Massimo

2017-04-01

EPOS, the European Plate Observing System, is an ESFRI infrastructure serving the needs of the solid Earth science community as a whole. EPOS promotes the use of multidisciplinary solid Earth data to improve the understanding of physical and chemical processes controlling earthquakes, volcanic eruptions, tsunamis as well as those driving tectonics and surface dynamics. The EPOS mission is to create a single, sustainable, and distributed infrastructure that integrates the diverse European research infrastructures for solid Earth science under a common framework with the final goal of delivering a suite of domain-specific and multidisciplinary data, products, and services in one single and integrated platform. Addressing ethics issues is a relevant challenge for any initiative, program or project dealing with scientific data and products provision, access to services for scientific purposes and communication with different stakeholders, including industry and society at large. In examining the role of EPOS on openly and freely delivering scientific data and products to diverse stakeholders including but not limited to scientists, we are looking at ethical issues associated with the use and re-use of these data and products possibly leading to a malevolent use and/or misuse of the data with implications on, for example, national security, environmental protection and risk communication. Moreover, EPOS is aware that the research promoted by the use of data delivered through its platform can have a profound influence on the environment, human health and wellbeing, economic development, and other facets of societies. We know there is nothing intrinsically bad about openly and freely delivering scientific data, as it serves as a tool for leveraging researches leading to solutions for a responsible management of Earth's resources and mitigation of natural hazards. However, we must evaluate the effects of such a data provision and feel the obligation to adopt a responsible

Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen-glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures

DEFF Research Database (Denmark)

Montero, Maria; Rom Poulsen, Frantz; Noraberg, Jens

2007-01-01

of hematopoietic bioactivity, is the chemically modified, EPO-derivative carbamylerythropoietin (CEPO). For comparison of the neuroprotective effects of CEPO and EPO, we subjected organotypic hippocampal slice cultures to oxygen-glucose deprivation (OGD) or N-methyl-d-aspartate (NMDA) excitotoxicity. Hippocampal...... slice cultures were pretreated for 24 h with 100 IU/ml EPO (=26 nM) or 26 nM CEPO before OGD or NMDA lesioning. Exposure to EPO and CEPO continued during OGD and for the next 24 h until histology, as well as during the 24 h exposure to NMDA. Neuronal cell death was quantified by cellular uptake...... of propidium iodide (PI), recorded before the start of OGD and NMDA exposure and 24 h after. In cultures exposed to OGD or NMDA, CEPO reduced PI uptake by 49+/-3 or 35+/-8%, respectively, compared to lesion-only controls. EPO reduced PI uptake by 33+/-5 and 15+/-8%, respectively, in the OGD and NMDA exposed...

Training Young Astronomers in EPO: An Update on the AAS Astronomy Ambassadors Program

Science.gov (United States)

Fraknoi, A.; Fienberg, R. T.; Gurton, S.; Schmitt, A. H.; Schatz, D.; Prather, E. E.

2014-07-01

The American Astronomical Society, with organizations active in EPO, has launched professional-development workshops and a community of practice to help improve early-career astronomers' ability to communicate effectively. Called “Astronomy Ambassadors,” the program provides mentoring and training for participants, from advanced undergraduates to beginning faculty. By learning to implement effective EPO strategies, Ambassadors become better teachers, meeting presenters, and representatives of our science to the public and government. Because young astronomers are a more diverse group than those who now do most outreach, they help the astronomy community present a more multicultural and gender-balanced face to the public, enabling underserved groups to see themselves as scientists. Ambassadors are given a library of outreach activities and materials, including many developed by cooperating organizations such as the ASP, plus some that have been created by Andrew Fraknoi specifically for this program.

Nurturing The STEM Pipeline: Graduate Student Leadership In NIRCam's Ongoing E/PO Mission For JWST

Science.gov (United States)

Schlingman, Wayne M.; Stock, N.; Teske, J.; Tyler, K.; Biller, B.; Donley, J.; Hedden, A.; Knierman, K.; Young, P.

2011-01-01

The Astronomy Camp for Girl Scout Leaders is an education and public outreach (E/PO) program offered by the science team of the Near-InfraRed Camera (NIRCam) for NASA's 6.5-meter James Webb Space Telescope (JWST). Since 2003, astronomy graduate students have helped design and lead biannual "Train the Trainer” workshops for adults from the Girl Scouts of the USA (GSUSA), engaging these trainers in the process of scientific inquiry and equipping them to host astronomy-related activities at the troop level. These workshops have helped revise the national GSUSA badge curriculum and directly benefitted thousands of young girls of all ages, not only in general science and math education but also in specific astronomical and technological concepts relating to JWST. To date, nine graduate students have become members of NIRCam's E/PO team. They have developed curriculum and activities used to teach concepts in stellar nucleosynthesis, lookback time, galaxy classification, etc. They have also contributed to the overall strategic approach and helped lead more general activities in basic astronomy (night sky, phases of the Moon, the scale of the Solar System and beyond, stars, galaxies, telescopes, etc.) as well as JWST-specific research areas in extrasolar planetary systems and cosmology, to pave the way for girls and women to understand the first images from JWST. The resulting experience has empowered these students to propose and to develop their own E/PO programs after graduation as postdocs and young faculty. They also continue as part of NIRCam's growing worldwide network of 160 trainers teaching young women essential STEM-related concepts using astronomy, the night sky environment, applied math, engineering, and critical thinking. NIRCam and its E/PO program are funded by NASA under contract NAS5-02105.

2017 Solar Eclipse in Hopkinsville, KY: E/PO Feedback from Two Venues

Science.gov (United States)

Dowling, Timothy E.; Consolmagno, Guy

2017-10-01

Hopkinsville, Kentucky was the largest town in the region of maximum totality for the 21 August 2017 Solar Eclipse, and transformed itself into “Eclipseville” with extensive media attention. Here we give 2 on-the-ground reports on education and public outreach (E/PO) activities from Hopkinsville. One of us (TD) partnered with the Kentucky Division of Emergency Management (KYEM) and was in the Hopkinsville VIP area, and the other (GC) led a series of E/PO events at the Hopkinsville Church of Ss. Peter & Paul, which were nationally advertised in diocesan newspapers. In addition, both of us were interviewed extensively by local and national media before the event. Pre-event planning by KYEM extended for over a year, and culminated in a 6-hour, 12 July 2017 Tabletop Exercise (TTX) run by FEMA. This face-to-face workshop drew over 250 participants, including Kentucky’s Lt. Governor, health and public safety officials at the state-level and from the 21 Kentucky counties in the path of totality, mayors and convention-bureau officials from the affected KY towns, the KY National Guard, the U.S. Depts. of Health and Human Services, Homeland Security, and Transportation, the National Weather Service, the U.S. Coast Guard for riverboat traffic, the U.S. Forest Service, the American Red Cross, representatives from ATT, Verizon and Sprint, and representatives from local universities—it was the largest TTX in Kentucky’s history. Here, we report on E/PO feedback we assembled from the VIP and parochial sites, including the most frequently asked questions, which types of answers seemed to be most effective, and how actual events compared with the large-crowd preparations and planning.

[Overview of erythropoietin].

Science.gov (United States)

Lacombe, C; Mayeux, P; Casadevall, N

1991-01-01

Erythropoietin (Epo) is a glycoprotein that promotes the proliferation and differentiation of erythrocyte precursors. The major site of Epo production is the kidney and the liver is the main extra renal site of Epo production. Epo producing cells were identified by in situ hybridization, in the kidney, they are peritubular cells, most likely endothelial cells of the cortex and outer medulla; in the liver, they are mainly hepatocytes. The Epo secretion is stimulated by hypoxia, which is detected by an oxygen sensor. The Epo receptor is a multimeric protein, one chain which binds Epo has been cloned. However the structure of the Epo receptor is still puzzling, and one or more accessory chains remain to be identified. Since the clonage of the Epo gene, recombinant Epo has been available and allowed the treatment of patients with renal diseases with a constant efficacy.

A Database of EPO-Patenting Firms in Denmark

DEFF Research Database (Denmark)

Nielsen, Anders Østergaard

1998-01-01

The first section gives a brief introduction of the basic stages to be observed by the patent applicant from idea to the patent is granted. Section two presents three examples of how patents are registered in the online patent database INPADOC. Section three accounts for the initial analysis...... of the existing patent stock issued to firms with domicile in Denmark. Sections four and five report the basic characteristics of the EPO-patent sample and the procedures for linking the patent statistics to accounting data at the firm level, and finally they present the basic properties of the resulting database...

Therapeutic levels of erythropoietin (EPO) achieved after gene electrotransfer to skin in mice

DEFF Research Database (Denmark)

Gothelf, A; Hojman, P; Gehl, Julie

2010-01-01

Gene electrotransfer refers to gene transfection by electroporation and is an effective non-viral method for delivering naked DNA into cells and tissues. This study presents data from gene electrotransfer with erythropoietin (EPO) to mouse skin. Nine-week-old female NMRI mice received one, two...

The Solar Dynamics Observatory (SDO) Education and Outreach (E/PO) Program: Changing Perceptions One Program at a Time

Science.gov (United States)

Drobnes, Emilie; Littleton, A.; Pesnell, William D.; Beck, K.; Buhr, S.; Durscher, R.; Hill, S.; McCaffrey, M.; McKenzie, D. E.; Myers, D.;

Observation on the changes of serum erythropoietin (EPO) and ferritin (SF) levels after preserved red cells (PRC) transfusion in patients with iron deficiency anemia (IDA)

International Nuclear Information System (INIS)

Li Keqin; Lv Haijun; Li Xinghua

2008-01-01

Objective: To study the changes of serum EPO and SF levels after preserved red cells transfusion in patients with IDA. Methods: Serum EPO and SF levels were detected with RIA both before and after transfusing preserved red cells in 35 patients with IDA as well as in 30 controls. Results: Before transfusion serum EPO levels in the patients were significantly higher than those in the controls (P 0.05). Conclusion: Transfusing preserved red cells is an effective treatment and has important role in clinical application. (authors)

Engaging Scientists in Meaningful E/PO: NASA Science4Girls and Their Families

Science.gov (United States)

Meinke, B. K.; Smith, D. A.; Bleacher, L.; Hauck, K.; Soeffing, C.

2014-12-01

The NASA Science Mission Directorate (SMD) Science Education and Public Outreach Forums coordinate the participation of SMD education and public outreach (EPO) programs in Women's History Month through the NASA Science4Girls and Their Families initiative. The initiative partners NASA science education programs with public libraries to provide NASA-themed hands-on education activities for girls and their families. These NASA science education programs are mission- and grant-based E/PO programs are uniquely poised to foster collaboration between scientists with content expertise and educators with pedagogy expertise. As such, the initiative engages girls in all four NASA science discipline areas (Astrophysics, Earth Science, Planetary Science, and Heliophysics), which enables audiences to experience the full range of NASA science topics and the different career skills each requires. The events focus on engaging underserved and underrepresented audiences in Science, Technology, Engineering, and Mathematics (STEM) via use of research-based best practices, collaborations with libraries, partnerships with local and national organizations, and remote engagement of audiences.

The European Plate Observing System (EPOS): Integrating Thematic Services for Solid Earth Science

Science.gov (United States)

Atakan, Kuvvet; Bailo, Daniele; Consortium, Epos

2016-04-01

The mission of EPOS is to monitor and understand the dynamic and complex Earth system by relying on new e-science opportunities and integrating diverse and advanced Research Infrastructures in Europe for solid Earth Science. EPOS will enable innovative multidisciplinary research for a better understanding of the Earth's physical and chemical processes that control earthquakes, volcanic eruptions, ground instability and tsunami as well as the processes driving tectonics and Earth's surface dynamics. Through integration of data, models and facilities EPOS will allow the Earth Science community to make a step change in developing new concepts and tools for key answers to scientific and socio-economic questions concerning geo-hazards and geo-resources as well as Earth sciences applications to the environment and to human welfare. EPOS, during its Implementation Phase (EPOS-IP), will integrate multidisciplinary data into a single e-infrastructure. Multidisciplinary data are organized and governed by the Thematic Core Services (TCS) and are driven by various scientific communities encompassing a wide spectrum of Earth science disciplines. These include Data, Data-products, Services and Software (DDSS), from seismology, near fault observatories, geodetic observations, volcano observations, satellite observations, geomagnetic observations, as well as data from various anthropogenic hazard episodes, geological information and modelling. In addition, transnational access to multi-scale laboratories and geo-energy test-beds for low-carbon energy will be provided. TCS DDSS will be integrated into Integrated Core Services (ICS), a platform that will ensure their interoperability and access to these services by the scientific community as well as other users within the society. This requires dedicated tasks for interactions with the various TCS-WPs, as well as the various distributed ICS (ICS-Ds), such as High Performance Computing (HPC) facilities, large scale data storage

Comparison between two treatment protocols with recombinant Human Erythropoietin (rHuEpo in the treatment of late anemia in neonates with Rh-Isoimmunization

Directory of Open Access Journals (Sweden)

A.A. Zuppa

2012-08-01

Full Text Available Objectve. The Rh-hemolytic disease can lead to a late anemia by hemolytic and hyporigenerative mechanism. We compared the effectiveness of rHuEPO in two care protocols that differ for doses of rHuEPO administrated and for timing of administration. Methods. A cohort of 14 neonates was investigated. The neonates were treated with two different protocols. Protocol A: a dose of 200 U/kg/day of rHuEpo administered subcutaneously starting from the end of the second week of life; Protocol B: a dose of 400 U/kg/day of rHuEpo administered subcutaneously starting from the end of the first week of life. Results. The hematocrit values in the protocol A group decreased during treatment (32,5% vs 25,2%, whereas the hematocrit value in protocol B group remained almost stable (38,7% vs 42,8%. The mean numbers of platelets remained stable in both groups while neutrophils increased in protocol A group and decreased in protocol B (p<0,05. Reticulocyte count increased during treatment in both groups, although only in protocol B group it was statistically significative (p<0,05. Conclusions. Our results suggest a similar efficacy between the two treatment protocols. Increasing doses of rHuEPO do not seem enhancing their effectiveness and the incidence of side effects.

[The effect of hypoxia preconditioning no binding activity of HIF-1 on the HRE with EPO in the hippocampus of mice].

Science.gov (United States)

Shao, Guo; Zhou, Wei-Hua; Gao, Cui-Ying; Zhang, Ran; Lu, Guo-Wei

2007-02-01

To observe change of binding activity of HIF-1 with erythropoietin (EPO) hypoxia response element (HRE) in the hippocampus of mice preconditioned to hypoxia and explore relationship between the changes and the preconditioning. The hippocampus was removed from mice exposed to hypoxia for 0 run (control group), 1 run (H1 group) and 4 runs(H4 group). Electrophoretic mobility shift assays (EMSA), chromatin immunoprecipitation (ChIP)and real time PCR were used to detect the change of activity of HIF-1 on HRE of EPO. Both in vitro and in vivo binding tests showed that the HIF-1 DNA-binding activities were increased in group H1 and markedly increased in group H4. The increase of HIF-1 and HRE of EPO binding activities is thought be involved in hypoxic preconditioning.

Correlation of EPO resistance with oxidative stress response and inflammatory response in patients with maintenance hemodialysis

Directory of Open Access Journals (Sweden)

Xiao-Hui Yan

2017-08-01

Full Text Available Objective: To study the correlation of erythropoietin (EPO resistance with oxidative stress response and inflammatory response in patients with maintenance hemodialysis. Methods: A total of 184 patients with end-stage renal disease who received maintenance hemodialysis in Shaanxi Provincial People’s Hospital between March 2015 and October 2016 were selected as dialysis group, 102 volunteers who received physical examination in Shaanxi Provincial People’s Hospital during the same period were selected as control group, the EPO resistance index was assessed, the median was calculated, and serum oxidative stress and inflammatory response indexes were detected. Results: Serum T-AOC, SOD and CAT levels in dialysis group were significantly lower than those in control group while MDA, AOPP, IFN-γ, HMGB-1, ICAM-1, IL-4 and IL-10 levels were significantly higher than those in control group; serum T-AOC, SOD and CAT levels in patients with high ERI were significantly lower than those in patients with low ERI while MDA, AOPP, IFN-γ, HMGB-1, ICAM-1, IL-4 and IL-10 levels were significantly higher than those in patients with low ERI. Conclusion: The degree of EPO resistance in patients with maintenance hemodialysis is closely related to the activation of oxidative stress response and inflammatory response.

Circulation of progenitor cells after intensive chemotherapy followed by combination G-CSF and EPO in breast carcinoma

International Nuclear Information System (INIS)

Filip, S.; Vanasek, J.; Blaha, M.; Vavrova, J.

1997-01-01

Hematologic effects of granulocyte colony-stimulating factor (G-CSF) and erythropoietic (EPO) combination after priming intensive chemotherapy in the treatment of female breast carcinoma are presented. In a previous group treated with G-CSF alone, 36% of patients became anemic and to be transfused for correction of their anemia. To the present study consecutive patients with different stages of breast carcinoma were admitted. All were given priming intensive chemotherapy (epirubicin 150 m/m 2 and cyclophosphamide 1300 mg/m 2 ) followed by subcutaneous application of G-CSF at a dose of 5 μg/kg/day and EPO 250 IU/kg/day. In cases where leucocyte counts dropped below 1 x 10 9 /dm 3 and hemoglobin level fell to 85 g/dm 3 administration of growth factors was started. The therapy was stopped when normal leukocyte count reached 4 x 10 9 /dm 3 for G-CSF and hemoglobin level rose to 115 g/dm 3 for EPO. Our results show significant difference between MNC/Tl (min.), CD34 + cells/μl (min.), CFU-GM/ml (min.), BFU-E/ml (min) and MNC/μl (max.), CD34 + cells/μl (max.), CFU-GM/ml (max.), BFU-E/ml (ml) p + cells/μl, 23.4-fold for CFU-GM/ml and 28.7-fold increase for BFU-E/ml. Side effects were minimal, no infectious complications occurred, body temperature did not rise over 3 grad C and no corrections of anemia were needed. It is concluded that the administration of G-CSF plus EPO combination following intensive chemotherapy reduces hematologic toxicity and induces large amount of hemopoietic progenitors suitable for autologous transplantation in women with breast carcinoma. (author)

EPOS Thematic Core Service ANTHROPOGENIC HAZARDS (TCS AH) - development of e-research platform

Science.gov (United States)

Orlecka-Sikora, Beata

2017-04-01

TCS AH is based on IS-EPOS Platform. The Platform facilitates research on anthropogenic hazards and is available online, free of charge https://tcs.ah-epos.eu/. The Platform is a final product of the IS-EPOS project, founded by the national programme - POIG - which was implemented in 2013-2015 (POIG.02.03.00-14-090/13-00). The platform is a result of a joint work of scientific community and industrial partners. Currently, the development of TCS AH is carried under EPOS IP project (H2020-INFRADEV-1-2015-1, INFRADEV-3-2015). Platform is an open virtual access point for researchers and Ph. D. students interested in anthropogenic seismicity and related hazards. This environment is designed to ensure a researcher the maximum possible liberty for experimentation by providing a virtual laboratory, in which the researcher can design own processing streams and process the data integrated on the platform. TCS AH integrates: data and specific high-level services. Data gathered in the so-called "episodes", comprehensively describing a geophysical process, induced or triggered by human technological activity, which, under certain circumstances can become hazardous for people, infrastructure and the environment. 7 sets of seismic, geological and technological data were made available on the Platform. The data come from Poland, Germany, UK and Vietnam, and refer to underground mining, reservoir impoundment, shale gas exploitation and geothermal energy production. The next at least 19 new episodes related to conventional hydrocarbon extraction, reservoir treatment, underground mining and geothermal energy production are being integrated within the framework of EPOS IP project. The heterogeneous multi-disciplinary data (seismic, displacement, geomechanical data, production data etc.) are transformed to unified structures to form integrated and validated datasets. To deal with this various data the problem-oriented services were designed and implemented. The particular attention

Development and evaluation of gastroretentive raft forming systems incorporating curcumin-Eudragit® EPO solid dispersions for gastric ulcer treatment.

Science.gov (United States)

Kerdsakundee, Nattha; Mahattanadul, Sirima; Wiwattanapatapee, Ruedeekorn

2015-08-01

Novel raft forming systems incorporating curcumin-Eudragit® EPO solid dispersions were developed to prolong the gastric residence time and provide for a controlled release therapy of curcumin to treat gastric ulcers. The solid dispersions of curcumin with Eudragit® EPO were prepared by the solvent evaporation method at various ratios to improve the solubility and the dissolution of curcumin. The optimum weight ratio of 1:5 for curcumin to Eudragit® EPO was used to incorporate into the raft forming systems. The raft forming formulations were composed of curcumin-Eudragit® EPO solid dispersions, sodium alginate as a gelling polymer and calcium carbonate for generating divalent Ca(2+) ions and carbon dioxide to form a floating raft. All formulations formed a gelled raft in 1min and sustained buoyancy on the 0.1N hydrochloric acid (pH 1.2) surface with a 60-85% release of curcumin within 8h. The curative effect on the acetic acid-induced chronic gastric ulcer in rats was determined. The curcumin raft forming formulations at 40mg/kg once daily showed a superior curative effect on the gastric ulcer in terms of the ulcer index and healing index than the standard antisecretory agent: lansoprazole (1mg/kg, twice daily) and a curcumin suspension (40mg/kg, twice daily). These studies demonstrated that the new raft forming systems containing curcumin solid dispersions are promising carriers for a stomach-specific delivery of poorly soluble lipophilic compounds. Copyright © 2015 Elsevier B.V. All rights reserved.

Increasing the use of evaluation data collection in an EPO program

Science.gov (United States)

Taber, J. J.; Bohon, W.; Bravo, T. K.; Dordevic, M.; Dorr, P. M.; Hubenthal, M.; Johnson, J. A.; Sumy, D.; Welti, R.; Davis, H. B.

2017-12-01

Over the past two years, the Incorporated Research Institutions for Seismology Education and Public Outreach (EPO) program has sought to increase the evaluation rigor of its programs and products. Specifically we sought to make evaluation an integral part of our work; enabling staff to demonstrate why we do the activities we do, enhancing the impact or our products/programs, and empowering staff to make evidence-based claims. The Collaborative Impact Analysis Method (Davis and Scalice, 2015) was selected as it allowed us to combine staff's knowledge of programs, audiences and content with the expertise of an outside evaluation expert, through consultations and a qualitative rubric assessing the initial state of each product/program's evaluation. Staff then developed action plans to make improvements to the programs over time. A key part of the initial action plans has been the collection and analysis of new evaluation data. The most frequently used tools were surveys as they were relatively straightforward to implement and analyze, and could be adapted for different situations. Examples include: brand awareness, value of booth interactions, assessing community interest in a data app, and user surveys of social media and specific web pages. Other evaluation activities included beta testing of new software, and interviews with students and faculty involved in summer field experiences. The surveys have allowed us to document increased impact in some areas, to improve the usability of products and activities, and to provide baseline impact data. The direct involvement of staff in the process has helped staff appreciate the value of evaluation, but there are also challenges to this approach. Since many of the surveys are developed and conducted by EPO staff, rather than being primarily handled by the evaluator, the process takes considerably more staff time to implement. We are still determining how to best manage and present the data and analysis; our current approach

The EPOS-CC Score: An Integration of Independent, Tumor- and Patient-Associated Risk Factors to Predict 5-years Overall Survival Following Colorectal Cancer Surgery.

Science.gov (United States)

Haga, Yoshio; Ikejiri, Koji; Wada, Yasuo; Ikenaga, Masakazu; Koike, Shoichiro; Nakamura, Seiji; Koseki, Masato

2015-06-01

Surgical audit is an essential task for the estimation of postoperative outcome and comparison of quality of care. Previous studies on surgical audits focused on short-term outcomes, such as postoperative mortality. We propose a surgical audit evaluating long-term outcome following colorectal cancer surgery. The predictive model for this audit is designated as 'Estimation of Postoperative Overall Survival for Colorectal Cancer (EPOS-CC)'. Thirty-one tumor-related and physiological variables were prospectively collected in 889 patients undergoing elective resection for colorectal cancer between April 2005 and April 2007 in 16 Japanese hospitals. Postoperative overall survival was assessed over a 5-years period. The EPOS-CC score was established by selecting significant variables in a uni- and multivariate analysis and allocating a risk-adjusted multiplication factor to each variable using Cox regression analysis. For validation, the EPOS-CC score was compared to the predictive power of UICC stage. Inter-hospital variability of the observed-to-estimated 5-years survival was assessed to estimate quality of care. Among the 889 patients, 804 (90%) completed the 5-years follow-up. Univariate analysis displayed a significant correlation with 5-years survival for 14 physiological and nine tumor-related variables (p model for the prediction of survival. Risk-adjusted multiplication factors between 1.5 (distant metastasis) and 0.16 (serum sodium level) were accorded to the different variables. The predictive power of EPOS-CC was superior to the one of UICC stage; area under the curve 0.87, 95% CI 0.85-0.90 for EPOS-CC, and 0.80, 0.76-0.83 for UICC stage, p < 0.001. Quality of care did not differ between hospitals. The EPOS-CC score including the independent variables age, performance status, serum sodium level, TNM stage, and lymphatic invasion is superior to the UICC stage in the prediction of 5-years overall survival. This higher accuracy might be explained by the

Effect of mild hypothermia combined with VitC and EPO therapy on target organ damage in children with neonatal asphyxia

Directory of Open Access Journals (Sweden)

Shu-Yun Wang

2017-10-01

Full Text Available Objective: To study the effect of mild hypothermia combined with vitamin C (VitC and erythropoietin (EPO therapy on target organ damage in children with neonatal asphyxia. Methods: Children with neonatal asphyxia who were treated in Taihe County People’s Hospital between April 2014 and February 2017 were selected and randomly divided into two groups, mild hypothermia group received mild hypothermia combined VitC and EPO therapy, and control group received VitC and EPO therapy. Serum levels of of target organ damage markers, oxidative stress indexes and apoptosis indexes were measured before treatment as well as 3 d and 7 d after treatment. Results: 3 d and 7 d after treatment, serum NSE, H-FABP, cTnI, CysC, MDA, Caspase-3, PDCD5, sFas and sFasL levels of both groups of children were significantly lower than those before treatment while TAS, SOD, GSH and Bcl-2 levels were significantly higher than those before treatment, and serum NSE, H-FABP, cTnI, CysC, MDA, Caspase-3, PDCD5, sFas and sFasL levels of mild hypothermia group were significantly lower than those of control group while TAS, SOD, GSH and Bcl-2 levels were significantly higher than those of control group. Conclusion: Mild hypothermia combined with VitC and EPO therapy can reduce the target organ damage of children with neonatal asphyxia by inhibiting oxidative stress and apoptosis.

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...

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......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...

Progress of the intense positron beam project EPOS

International Nuclear Information System (INIS)

Krause-Rehberg, R.; Brauer, G.; Jungmann, M.; Krille, A.; Rogov, A.; Noack, K.

2008-01-01

EPOS (the ELBE POsitron Source) is a running project to build an intense, bunched positron beam for materials research. It makes use of the bunched electron beam of the ELBE radiation source (Electron Linac with high Brilliance and low Emittance) at the Research Centre Dresden-Rossendorf (40 MeV, 1 mA). ELBE has unique timing properties, the bunch length is <5 ps and the repetition time is 77 ns. In contrast to other Linacs made for Free Electron Lasers (e.g., TTF at DESY, Hamburg), ELBE can be operated in full cw-mode, i.e., with an uninterrupted sequence of bunches. The article continues an earlier publication. It concentrates on details of the timing system and describes issues of radiation protection

The extrahepatic role of TFR2 in iron homeostasis

Directory of Open Access Journals (Sweden)

Laura eSilvestri

2014-05-01

Full Text Available Transferrin receptor 2 (TFR2, a protein homologous to the cell iron importer transferrin receptor 1 (TFR1, is expressed in the liver and erythroid cells and is reported to bind diferric transferrin, although at lower affinity than TFR1. TFR2 gene is mutated in type 3 hemochromatosis, a disorder characterized by iron overload and inability to upregulate hepcidin in response to iron. Liver TFR2 is considered a sensor of diferric transferrin, possibly in a complex with HFE. In erythroid cells TFR2 is a partner of erythropoietin receptor (EPOR and stabilizes the receptor on the cell surface. However, Tfr2 null mice as well as TFR2 hemochromatosis patients do not show defective erythropoiesis and tolerate repeated phlebotomy. The iron deficient Tfr2-Tmprss6 double knock out mice have higher red cells count and more severe microcytosis than the liver specific Tfr2 and Tmprss6 double knock out mice. TFR2 in the bone marrow might be a sensor of iron deficiency that protects against excessive microcytosis in a way that involves EPOR, although the mechanisms remain to be worked out.

Practicing IEF-PAGE of EPO: the impact of detergents and sample application methods on analytical performance in doping control.

Science.gov (United States)

Reichel, Christian

2010-01-01

Electrophoretic techniques, namely isoelectric focusing polyacrylamide gel electrophoresis (IEF-PAGE) and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) are key techniques used for confirming the doping-related abuse of recombinant erythropoietins and analogs. IEF-PAGE is performed on horizontal slab-gels with samples applied to the surface of the gel. Different sample application techniques can be employed, but application pieces and applicator strips are most frequently used. However, defective application pieces cause lane streaking during IEF of erythropoietin (EPO), which is especially pronounced in the acidic region of the gel. The effect is due to an incompatibility of the substance used for enhancing the wettability of the cellulose-based commercial product and is batch-dependent. A detailed mass spectrometric study was performed, which revealed that defective sample application pieces (bought between 2007 and 2010) contained a complex mixture of alcohol ethoxylates, alcohol ethoxysulfates, and alkyl sulfates (e.g. SDS). Anionic detergents, like the sulfates contained in these application pieces, are in general incompatible with IEF. Alternative application techniques proved partly useful. While homemade pieces made of blotting paper are a good alternative, the usage of applicator strips or shims is hampered by the risk of leaking wells, which lead to laterally diffused samples. Casting IEF-gels with wells appears to be the best solution, since sustained release of retained proteins from the application pieces can be avoided. Edge effects do not occur if wells are correctly filled with the samples. The evaluation of EPO-profiles with defects is prohibited by the technical document on EPO-analytics (TD2009EPO) of the World Anti-Doping Agency (WADA). Copyright © 2010 John Wiley & Sons, Ltd.

EPOS-WP16: A Platform for European Multi-scale Laboratories

Science.gov (United States)

Spiers, Chris; Drury, Martyn; Kan-Parker, Mirjam; Lange, Otto; Willingshofer, Ernst; Funiciello, Francesca; Rosenau, Matthias; Scarlato, Piergiorgio; Sagnotti, Leonardo; W16 Participants

2016-04-01

The participant countries in EPOS embody a wide range of world-class laboratory infrastructures ranging from high temperature and pressure experimental facilities, to electron microscopy, micro-beam analysis, analogue modeling and paleomagnetic laboratories. Most data produced by the various laboratory centres and networks are presently available only in limited "final form" in publications. As such many data remain inaccessible and/or poorly preserved. However, the data produced at the participating laboratories are crucial to serving society's need for geo-resources exploration and for protection against geo-hazards. Indeed, to model resource formation and system behaviour during exploitation, we need an understanding from the molecular to the continental scale, based on experimental data. This contribution will describe the work plans that the laboratories community in Europe is making, in the context of EPOS. The main objectives are: - To collect and harmonize available and emerging laboratory data on the properties and processes controlling rock system behaviour at multiple scales, in order to generate products accessible and interoperable through services for supporting research activities. - To co-ordinate the development, integration and trans-national usage of the major solid Earth Science laboratory centres and specialist networks. The length scales encompassed by the infrastructures included range from the nano- and micrometer levels (electron microscopy and micro-beam analysis) to the scale of experiments on centimetre sized samples, and to analogue model experiments simulating the reservoir scale, the basin scale and the plate scale. - To provide products and services supporting research into Geo-resources and Geo-storage, Geo-hazards and Earth System Evolution.

Soluble transferrin receptor as a marker of erythropoiesis in patients undergoing high-flux hemodialysis

Directory of Open Access Journals (Sweden)

Pei Yin

2017-11-01

Full Text Available Anemia is a common complication in chronic kidney disease (CKD patients receiving hemodialysis. The effect of high-flux dialysis (HFD on anemia remains unclear. This prospective study aimed to evaluate the effect of HFD on anemia, and the potential of soluble transferrin receptor (sTfR as a marker of iron status and erythropoiesis in CKD patients on hemodialysis. Forty patients, who switched from conventional low-flux dialysis to HFD for 12 months, were enrolled in this study. The levels of sTfR, hemoglobin (Hb, iron, and nutritional markers, as well as the dose of recombinant human erythropoietin (rhEPO and use of chalybeate were determined at 0, 2, 6, and 12 months after starting HFD. HFD significantly increased the hemoglobin level and reduced sTfR level in CKD patients (p < 0.05. In addition, significant decreasing linear trends were observed for rhEPO dosage and chalybeate use (p < 0.05. The level of sTfR was positively correlated with the percentage of reticulocytes (RET%, rhEPO dose, and chalybeate use, while it was negatively correlated with Hb levels and total iron-binding capacity results (all p < 0.05. A univariate generalized estimating equation (GEE model showed that the Hb level, RET%, rhEPO dose, and chalybeate use were the variables associated with sTfR levels. A multivariate GEE model showed that the time points when hemodialysis was performed were the variables associated significantly with sTfR levels. Overall, our findings suggest that HFD can effectively improve renal anemia in hemodialysis patients, and sTfR could be used as a marker of erythropoiesis in HFD patients.

Engaging Scientists in Meaningful E/PO: The Universe Discovery Guides

Science.gov (United States)

Meinke, B. K.; Lawton, B.; Gurton, S.; Smith, D. A.; Manning, J. G.

2014-12-01

For the 2009 International Year of Astronomy, the then-existing NASA Origins Forum collaborated with the Astronomical Society of the Pacific (ASP) to create a series of monthly "Discovery Guides" for informal educator and amateur astronomer use in educating the public about featured sky objects and associated NASA science themes. Today's NASA Astrophysics Science Education and Public Outreach Forum (SEPOF), one of a new generation of forums coordinating the work of NASA Science Mission Directorate (SMD) EPO efforts—in collaboration with the ASP and NASA SMD missions and programs--has adapted the Discovery Guides into "evergreen" educational resources suitable for a variety of audiences. The Guides focus on "deep sky" objects and astrophysics themes (stars and stellar evolution, galaxies and the universe, and exoplanets), showcasing EPO resources from more than 30 NASA astrophysics missions and programs in a coordinated and cohesive "big picture" approach across the electromagnetic spectrum, grounded in best practices to best serve the needs of the target audiences. Each monthly guide features a theme and a representative object well-placed for viewing, with an accompanying interpretive story, finding charts, strategies for conveying the topics, and complementary supporting NASA-approved education activities and background information from a spectrum of NASA missions and programs. The Universe Discovery Guides are downloadable from the NASA Night Sky Network web site at nightsky.jpl.nasa.gov. We will share the Forum-led Collaborative's experience in developing the guides, how they place individual science discoveries and learning resources into context for audiences, and how the Guides can be readily used in scientist public outreach efforts, in college and university introductory astronomy classes, and in other engagements between scientists, students and the public.

EPOS1 - a multiparameter measuring system to earthquake prediction research

Energy Technology Data Exchange (ETDEWEB)

Streil, T.; Oeser, V. [SARAD GmbH, Dresden (Germany); Heinicke, J.; Koch, U.; Wiegand, J.

1998-12-31

The approach to earthquake prediction by geophysical, geochemical and hydrological measurements is a long and winding road. Nevertheless, the results show a progress in that field (e.g. Kobe). This progress is also a result of a new generation of measuring equipment. SARAD has developed a versatile measuring system (EPOS1) based on experiences and recent results from different research groups. It is able to record selected parameters suitable to earthquake prediction research. A micro-computer system handles data exchange, data management and control. It is connected to a modular sensor system. Sensor modules can be selected according to the actual needs at the measuring site. (author)

Epobis is a Nonerythropoietic and Neuroprotective Agonist of the Erythropoietin Receptor with Anti-Inflammatory and Memory Enhancing Effects

DEFF Research Database (Denmark)

Dmytriyeva, Oksana; Pankratova, Stanislava; Korshunova, Irina

2016-01-01

, but systemic administration of Epobis in rats delays the clinical signs of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, and the peptide has long-term, but not short-term, effects on working memory, detected as an improved social memory 3 days after administration....... These data reveal Epobis to be a nonerythropoietic and neuroprotective EPO receptor agonist with anti-inflammatory and memory enhancing properties....

Recombinant erythropoietin and analogues: a challenge for doping control.

Science.gov (United States)

Pascual, J A; Belalcazar, V; de Bolos, C; Gutiérrez, R; Llop, E; Segura, J

2004-04-01

Erythropoietin (EPO) increases the number of circulating erythrocytes and thus muscle oxygenation. The availability of the recombinant protein (rEPO) has increased the risk of its illegal use in sports, its detection being a difficult challenge. Five different hematopoietic parameters were initially chosen as indirect markers of rEPO abuse: concentration of serum EPO, concentration of serum-soluble transferrin receptors (sTFr), hematocrit, percentage of reticulocytes, and percentage of macrocytes. New models considering only hemoglobin, serum EPO concentration, and percentage of reticulocytes are simpler and seem to be more sensitive when low doses of rEPO are used. A more direct method of urine analysis (isoelectrofocusing, double blotting, and chemiluminescent detection) based on the charge differences between rEPO and endogenous EPO, related to their carbohydrate composition, provides proof of rEPO use. Furthermore, this approach permits the detection of darbepoetin, a direct analogue of EPO also known as NESP ("new erythropoiesis stimulating protein"). Recently a protein conjugate, "synthetic erythropoiesis protein" (SEP), containing precision-length, monodisperse, negatively charged polymers instead of oligosaccharides has been synthesized. Finally, EPO-mimetics are molecules capable of acting as EPO in dimerizing the EPO receptor. Two kinds of EPO-mimetics have been described: peptides and nonpeptides. The enhancement of oxygen availability to muscles by rEPO, analogues, and mimetics constitutes one of the main challenges to doping control. Major steps have already been developed for detection ofrEPO and some analogues. In the near future, the transfection to an athlete's body of genes that code for erythropoietin might be an emerging doping issue, and sports authorities have incorporated "gene doping" among the prohibited practices.

Designing, Supporting, and Sustaining an Online Community of Practice: NASA EPO Workspace as an Ongoing Exploration of the Value of Community

Science.gov (United States)

Davey, B.; Davis, H. B.

2015-12-01

Increasingly, geographically diverse organizations, like NASA's Science Mission Directorate Education and Public Outreach personnel (SMD EPO), are looking for ways to facilitate group interactions in meaningful ways while limiting costs. Towards this end, of particular interest, and showing great potential are communities of practice. Communities of practice represent relationships in real-time between and among people sharing a common practice. They facilitate the sharing of information, building collective knowledge, and growing of the principles of practice. In 2010-11, SMD EPO established a website to support EPO professionals, facilitate headquarters reporting, and foster a community of practice. The purpose of this evaluation is to examine the design and use of the workspace and the value created for both individual community members and SMD EPO, the sponsoring organization. The online workspace was launched in 2010-11 for the members of NASA's SMDEPO community. The online workspace was designed to help facilitate the efficient sharing of information, be a central repository for resources, help facilitate and support knowledge creation, and ultimately lead to the development of an online community of practice. This study examines the role of the online workspace component of a community in the work of a community of practice. Much has been studied revealing the importance of communities of practice to organizations, project success, and knowledge management and some of these same successes hold true for virtual communities of practice. Additionally, we look at the outcomes of housting the online community for these past years in respect to knowledge building and personal and organizational value, the affects on professional dvelopment opportunities, how community members have benefited, and how the workspace has evolved to better serve the community.

EPOS Multi-Scale Laboratory platform: a long-term reference tool for experimental Earth Sciences

Science.gov (United States)

Trippanera, Daniele; Tesei, Telemaco; Funiciello, Francesca; Sagnotti, Leonardo; Scarlato, Piergiorgio; Rosenau, Matthias; Elger, Kirsten; Ulbricht, Damian; Lange, Otto; Calignano, Elisa; Spiers, Chris; Drury, Martin; Willingshofer, Ernst; Winkler, Aldo

2017-04-01

With continuous progress on scientific research, a large amount of datasets has been and will be produced. The data access and sharing along with their storage and homogenization within a unique and coherent framework is a new challenge for the whole scientific community. This is particularly emphasized for geo-scientific laboratories, encompassing the most diverse Earth Science disciplines and typology of data. To this aim the "Multiscale Laboratories" Work Package (WP16), operating in the framework of the European Plate Observing System (EPOS), is developing a virtual platform of geo-scientific data and services for the worldwide community of laboratories. This long-term project aims at merging the top class multidisciplinary laboratories in Geoscience into a coherent and collaborative network, facilitating the standardization of virtual access to data, data products and software. This will help our community to evolve beyond the stage in which most of data produced by the different laboratories are available only within the related scholarly publications (often as print-version only) or they remain unpublished and inaccessible on local devices. The EPOS multi-scale laboratory platform will provide the possibility to easily share and discover data by means of open access, DOI-referenced, online data publication including long-term storage, managing and curation services and to set up a cohesive community of laboratories. The WP16 is starting with three pilot cases laboratories: (1) rock physics, (2) palaeomagnetic, and (3) analogue modelling. As a proof of concept, first analogue modelling datasets have been published via GFZ Data Services (http://doidb.wdc-terra.org/search/public/ui?&sort=updated+desc&q=epos). The datasets include rock analogue material properties (e.g. friction data, rheology data, SEM imagery), as well as supplementary figures, images and movies from experiments on tectonic processes. A metadata catalogue tailored to the specific communities

Brain mitochondrial function in a murine model of cerebral malaria and the therapeutic effects of rhEPO

DEFF Research Database (Denmark)

Karlsson, Michael; Hempel, Casper; Sjövall, Fredrik

2013-01-01

and no connection between disease severity and mitochondrial respiratory function. Treatment with rhEPO similarly had no effect on respiratory function. Thus cerebral metabolic dysfunction in CM does not seem to be directly linked to altered mitochondrial respiratory capacity as analyzed in brain homogenates ex...

THE EFFECTS OF IL-1 AND IL-4 ON THE EPO-INDEPENDENT ERYTHROID PROGENITOR IN POLYCYTHEMIA-VERA

NARCIS (Netherlands)

DEWOLF, JTM; HENDRIKS, DW; ESSELINK, MT; HALIE, MR; VELLENGA, E

1994-01-01

Human recombinant interleukin-1 (IL-1) was studied for its effects on the erythroid progenitors from normal subjects and from patients with polycythaemia vera (PV). No supportive effect of IL-1 was noticed on the normal, erythropoietin (Epo) dependent, erythroid burst-forming unit (BFU-E) using

A propos de la formule homérique « enenipen epos t’ephat’ ek t’onomazen »

Directory of Open Access Journals (Sweden)

Rossella Saetta-Cottone

2006-05-01

Full Text Available Cet article propose une analyse des huit occurrences de la formule homérique epos t’ephat’ ek t’onomazen qui sont précédées, dans le premier hémistiche de l’hexamètre, par le verbe enenipein, dans le but de mettre en lumière la signification particulière qu’y recouvre le verbe onomazein  « apostropher par des mots injurieux ».This article aims to analyze the eight cases of the homeric formula epos t’ephat’ ek t’onomazen they are preceeded, within the first hemistich of the hexametre, by the verb enenipein, so as to clarify the particular meaning that recovers here the verb onomazein « to shout at with injurious words ».

Satellite cell response to erythropoietin treatment and endurance training in healthy young men

DEFF Research Database (Denmark)

Hoedt, Andrea; Christensen, Britt; Nellemann, Birgitte

2016-01-01

KEY POINT: Erythropoietin (Epo) treatment may induce myogenic differentiation factor (MyoD) expression and prevent apoptosis in satellite cells (SCs) in murine and in vitro models. Endurance training stimulates SC proliferation in vivo in murine and human skeletal muscle. In the present study, we......-receptor interaction. Moreover, endurance training, but not Epo treatment, increases the SC content in type II myofibres, as well as the content of MyoD(+) SCs. Collectively, our results suggest that Epo treatment can regulate human SCs in vivo, supported by Epo receptor mRNA expression in human SCs. In effect, long......-term Epo treatment during disease conditions involving anaemia may impact SCs and warrants further investigation. Satellite cell (SC) proliferation is observed following erythropoitin treatment in vitro in murine myoblasts and endurance training in vivo in human skeletal muscle. The present study aimed...

Erythropoietin and radiotherapy; Erythropoietine et radiotherapie

Energy Technology Data Exchange (ETDEWEB)

Le Fur, E.; Albarghach, M.N.; Pradier, O. [CHU de Morvan, Dept. de radiotherapie, 29 - Brest (France)

2010-01-15

Erythropoietin (E.P.O.) is a glycoprotein hormone. This hormone is a growth factor for red blood cells precursors in the bone marrow. The decrease of oxygen partial pressure, a reduced number of erythrocytes caused by bleeding or excessive destruction, or increased tissues oxygen requirements lead to increased secretion of E.P.O.. Its action takes place on bone marrow erythroblastic cells through specific receptors. E.P.O. stimulates the proliferation of red cell precursors stem cells in the bone marrow, thus increasing their production in one to two weeks. The effectiveness of E.P.O. at increasing haemoglobin and improving patients quality of life has been demonstrated by several studies. However, its use in radiotherapy remains controversial. While tumour hypoxia caused by anaemia is a factor of radio resistance and thus a source of local failure, tumour expression of E.P.O. receptors presents a significant risk for tumour progression and neo-angiogenesis, which would be increased during the administration of E.P.O.. The purpose of this article is to answer the question: is there a place for E.P.O. in combination with radiotherapy in the management of cancer?

Erythropoietin and radiotherapy

International Nuclear Information System (INIS)

Le Fur, E.; Albarghach, M.N.; Pradier, O.

2010-01-01

Erythropoietin (E.P.O.) is a glycoprotein hormone. This hormone is a growth factor for red blood cells precursors in the bone marrow. The decrease of oxygen partial pressure, a reduced number of erythrocytes caused by bleeding or excessive destruction, or increased tissues oxygen requirements lead to increased secretion of E.P.O.. Its action takes place on bone marrow erythroblastic cells through specific receptors. E.P.O. stimulates the proliferation of red cell precursors stem cells in the bone marrow, thus increasing their production in one to two weeks. The effectiveness of E.P.O. at increasing haemoglobin and improving patients quality of life has been demonstrated by several studies. However, its use in radiotherapy remains controversial. While tumour hypoxia caused by anaemia is a factor of radio resistance and thus a source of local failure, tumour expression of E.P.O. receptors presents a significant risk for tumour progression and neo-angiogenesis, which would be increased during the administration of E.P.O.. The purpose of this article is to answer the question: is there a place for E.P.O. in combination with radiotherapy in the management of cancer?

Enduring Power of Attorney (EPoA – comparison between Austrian and German Law

Directory of Open Access Journals (Sweden)

Michael Ganner

2015-04-01

Full Text Available ENGLISH: With the establishment of the United Nations Convention on the Rights of Persons with Disabilities (CRPD the treatment of people with disabilities is changing from a protective perspective to a rights - based approach. The Enduring Power of Attorney (EPoA is an important instrument, which helps with the implementation of the CRPD into national law. As an instrument of self - determined substituted decision - making it is recognised as the best practice model to safeguard the autonomy of people suffering the deprivations of age and other disabilities. This article touches briefly on general supported and substituted decision - making instruments and then goes on to examine the differences and similarities, advantages and disadvantages b e- tween Austrian and German laws concerning EPoAs. DEUTSCH: Mit der Umsetzung der UN-Behindertenrechtskonvention findet ein Paradigmenwechsel und Umdenken im Umgang mit Personen mit Behinderungen statt. Der Primat der Fürsorge weicht einem liberalen, auf Menschenrechten basierenden Ansatz. In diesem Kontext ist die Vorsorgevollmacht ein effektives Mittel, das die Implementation der UN-Behindertenrechtskonvention in nationales Recht vorantreibt und die Selbstbestimmung und Eigenständigkeit altersbedingt eingeschränkter Menschen und von Menschen mit Behinderungen gewährleistet. Dieser Artikel beschäftigt sich einleitend mit allgemeinen Rechtsinstrumenten der (unterstützten Entscheidungsfindung bei nicht selbst entscheidungsfähigen Personen und analysiert in weiterer Folge Gemeinsamkeiten und Unterschiede sowie Vor- und Nachteile der Vorsorgevollmacht nach österreichischem und deutschem Recht.

EPOS-An intense positron beam project at the ELBE radiation source in Rossendorf

International Nuclear Information System (INIS)

Krause-Rehberg, R.; Sachert, S.; Brauer, G.; Rogov, A.; Noack, K.

2006-01-01

EPOS, the acronym of ELBE Positron Source, describes a running project to build an intense pulsed beam of mono-energetic positrons (0.2-40 keV) for materials research. Positrons will be created via pair production at a tungsten target using the pulsed 40 MeV electron beam of the superconducting linac electron linac with high brilliance and low emittance (ELBE) at Forschungszentrum Rossendorf (near Dresden, Germany). The chosen design of the system under construction is described and results of calculations simulating the interaction of the electron beam with the target are presented, and positron beam formation and transportation is also discussed

The Invisible Universe Online for Teachers - A SOFIA and SIRTF EPO Project

Science.gov (United States)

Gauthier, A.; Bennett, M.; Buxner, S.; Devore, E.; Keller, J.; Slater, T.; Thaller, M.; Conceptual Astronomy; Physics Education Research CAPER Team

2003-12-01

The SOFIA and SIRTF EPO Programs have partnered with the Conceptual Astronomy and Physics Education Research (CAPER) Team in designing, evaluating, and facilitating an online program for K-12 teachers to experience multiwavelength astronomy. An aggressive approach to online course design and delivery has resulted in a highly successful learning experience for teacher-participants. Important aspects of the Invisible Universe Online will eventually be used as a part of SOFIA's Airborne Ambassadors Program for pre-flight training of educators. The Invisible Universe Online is delivered via WebCT through the Montana State University National Teacher Enhancement Network (http://btc.montana.edu/). Currently in its fourth semester, the course has served 115 K-12 teachers. This distance learning online class presents our search for astronomical origins and provides an enhanced understanding of how astronomers use all energies of light to unfold the secrets of the universe. We cover the long chain of events from the birth of the universe through the formation of galaxies, stars, and planets by focusing on the scientific questions, technological challenges, and space missions pursuing this search for origins. Through textbook and internet readings, inquiry exploration with interactive java applets, and asynchronous discussions, we help our students achieve the following course goals: develop scientific background knowledge of astronomical objects and phenomena at multiple wavelengths; understand contemporary scientific research questions related to how galaxies formed in the early universe and how stars and planetary systems form and evolve; describe strategies and technologies for using non-visible wavelengths of EM radiation to study various phenomena; and integrate related issues of astronomical science and technology into K-12 classrooms. This course is being developed, evaluated, and offered through the support of SOFIA and SIRTF EPO Programs, two NASA infrared missions

Our Place in Space: Exploring the Earth-Moon System and Beyond with NASA's CINDI E/PO Program

Science.gov (United States)

Urquhart, M. L.; Hairston, M. R.

2010-12-01

Where does space begin? How far is the Moon? How far is Mars? How does our dynamic star, the Sun, affect its family of planets? All of these questions relate to exploration of our Solar System, and are also part of the Education/Public Outreach (E/PO) Program for NASA’s CINDI project, a space weather mission of opportunity. The Coupled Ion Neutral Dynamics Investigation has been flying aboard the US Air Force Communication/Navigation Outage Forecast System (C/NOFS) satellite in the upper atmosphere of the Earth since April 2008. The Earth’s ionosphere, the part of the atmosphere CINDI studies, is also in space. The CINDI E/PO program uses this fact in lessons designed to help students in middle schools and introductory astronomy classes develop a sense of their place in space. In the activity "How High is Space?" students’ start by building an 8-page scale model of the Earth’s atmosphere with 100 km/page. The peak of Mount Everest, commercial airplanes, and the tops of thunderheads all appear at the bottom of the first page of the model, with astronaut altitude -where space begins- at the top of the same sheet of paper. In "Where Would CINDI Be?" the idea of scale is further developed by modeling the Earth-Moon system to scale first in size, then in distance, using half of standard containers of play dough. With a lowest altitude of about 400 km, similar to that of the International Space Station and orbiting Space Shuttle, CINDI is close to the Earth when compared with the nearly thousand times greater distance to the Moon. Comparing and combining the atmosphere and Earth-Moon system models help reinforce ideas of scale and build student understanding of how far away the Moon actually is. These scale models have also been adapted for use in Family Science Nights, and to include the planet Mars. In this presentation, we will show how we use CINDI’s scale modeling activities and others from our broader space sciences E/PO program in formal and informal

Characterization of Odorant Receptors from a Non-ditrysian Moth, Eriocrania semipurpurella Sheds Light on the Origin of Sex Pheromone Receptors in Lepidoptera.

Science.gov (United States)

Yuvaraj, Jothi Kumar; Corcoran, Jacob A; Andersson, Martin N; Newcomb, Richard D; Anderbrant, Olle; Löfstedt, Christer

2017-11-01

Pheromone receptors (PRs) are essential in moths to detect sex pheromones for mate finding. However, it remains unknown from which ancestral proteins these specialized receptors arose. The oldest lineages of moths, so-called non-ditrysian moths, use short-chain pheromone components, secondary alcohols, or ketones, so called Type 0 pheromones that are similar to many common plant volatiles. It is, therefore, possible that receptors for these ancestral pheromones evolved from receptors detecting plant volatiles. Hence, we identified the odorant receptors (ORs) from a non-ditrysian moth, Eriocrania semipurpurella (Eriocraniidae, Lepidoptera), and performed functional characterization of ORs using HEK293 cells. We report the first receptors that respond to Type 0 pheromone compounds; EsemOR3 displayed highest sensitivity toward (2S, 6Z)-6-nonen-2-ol, whereas EsemOR5 was most sensitive to the behavioral antagonist (Z)-6-nonen-2-one. These receptors also respond to plant volatiles of similar chemical structures, but with lower sensitivity. Phylogenetically, EsemOR3 and EsemOR5 group with a plant volatile-responding receptor from the tortricid moth Epiphyas postvittana (EposOR3), which together reside outside the previously defined lepidopteran PR clade that contains the PRs from more derived lepidopteran families. In addition, one receptor (EsemOR1) that falls at the base of the lepidopteran PR clade, responded specifically to β-caryophyllene and not to any other additional plant or pheromone compounds. Our results suggest that PRs for Type 0 pheromones have evolved from ORs that detect structurally-related plant volatiles. They are unrelated to PRs detecting pheromones in more derived Lepidoptera, which, in turn, also independently may have evolved a novel function from ORs detecting plant volatiles. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Recommendations for the clinical practice: Standards, options and recommendations 2003 for the use of recombinant erythropoietin (alpha and beta epoetine, alpha darbepoetine, EPO) in the taking charge of anemia in oncology for the patients treated by radiotherapy, update

International Nuclear Information System (INIS)

Marchal, Ch.; Spaeth, C.; Casadevall, N.; Daouphars, M.; Marec-Berard, P.; Fabre, N.; Haugh, M.

2004-01-01

Standards, Options and Recommendations for the use of recombinant erythropoietin (epoietin alpha and beta darbepoietin alpha, EPO) in the management of anaemia in oncology for patient undergoing radiotherapy - UPDATE 2003. Context. - 'The Standards, Options and Recommendations' (SOR) project, started in 1993, is a collaboration between the Federation of French Cancer Centres (FNCLCC), the twenty French cancer centres, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. Objectives. - To update the Standards, Options and Recommendations clinical practice guidelines for the use of recombinant erythropoietin (epoietin alpha and beta darbepoietin-alpha, EPO) in the management of anaemia in oncology for patient undergoing radiotherapy. Methods. - The working group identified the questions requiring up-dating from the previous guideline. Medline and Embase were searched using specific search strategies from January 1999 to October 2002. Literature monitoring was performed to identify randomized clinical trials published between October 2002 to November 2003. In addition several Internet sites were searched in October 2002. Results. - There is no standard attitude for use of rHuEPO in patients undergoing radiotherapy. There is no evidence to support use of rHuEPO in patients with ENT cancer receiving radiotherapy alone. In patients undergoing curative radiotherapy, it is recommended to correct anaemia under 10 g/dL using transfusion rather than rHuEPO. When the haemoglobin concentration is between 12 g/dL and 14 g/dL initial use of rHuEPO can be an option under certain conditions for radio-chemotherapy if the risk of anaemia is

Minimal doses of a sequence-optimized transgene mediate high-level and long-term EPO expression in vivo: challenging CpG-free gene design.

Science.gov (United States)

Kosovac, D; Wild, J; Ludwig, C; Meissner, S; Bauer, A P; Wagner, R

2011-02-01

Advanced gene delivery techniques can be combined with rational gene design to further improve the efficiency of plasmid DNA (pDNA)-mediated transgene expression in vivo. Herein, we analyzed the influence of intragenic sequence modifications on transgene expression in vitro and in vivo using murine erythropoietin (mEPO) as a transgene model. A single electro-gene transfer of an RNA- and codon-optimized mEPOopt gene into skeletal muscle resulted in a 3- to 4-fold increase of mEPO production sustained for >1 year and triggered a significant increase in hematocrit and hemoglobin without causing adverse effects. mEPO expression and hematologic levels were significantly lower when using comparable amounts of the wild type (mEPOwt) gene and only marginal effects were induced by mEPOΔCpG lacking intragenic CpG dinucleotides, even at high pDNA amounts. Corresponding with these observations, in vitro analysis of transfected cells revealed a 2- to 3-fold increased (mEPOopt) and 50% decreased (mEPOΔCpG) erythropoietin expression compared with mEPOwt, respectively. RNA analyses demonstrated that the specific design of the transgene sequence influenced expression levels by modulating transcriptional activity and nuclear plus cytoplasmic RNA amounts rather than translation. In sum, whereas CpG depletion negatively interferes with efficient expression in postmitotic tissues, mEPOopt doses <0.5 μg were sufficient to trigger optimal long-term hematologic effects encouraging the use of sequence-optimized transgenes to further reduce effective pDNA amounts.

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

Activation of the EPOR-β common receptor complex by cibinetide ameliorates impaired wound healing in mice with genetic diabetes.

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Bitto, Alessandra; Irrera, Natasha; Pizzino, Gabriele; Pallio, Giovanni; Mannino, Federica; Vaccaro, Mario; Arcoraci, Vincenzo; Aliquò, Federica; Minutoli, Letteria; Colonna, Michele R; Galeano, Maria Rosaria; Brines, Michael; De Ponte, Chiara; Collino, Massimo; Squadrito, Francesco; Altavilla, Domenica

2018-02-01

Diabetes is characterized by poor wound healing which currently lacks an efficacious treatment. The innate repair receptor (IRR) is a master regulator of tissue protection and repair which is expressed as a response injury or metabolic stress, including in diabetes. Activation of the IRR might provide benefit for diabetic wound healing. A specific IRR agonist cibinetide was administered in an incisional wound healing model performed mice with genetic diabetes (db + /db + ) and compared to the normal wild-type. Animals were treated daily with cibinetide (30μg/kg/s.c.) or vehicle and euthanized 3, 7, and 14days after the injury to quantitate vascular endothelial growth factor (VEGF), malondialdehyde (MAL), phospho-Akt (pAkt), phospho e-NOS (p-eNOS), and nitrite/nitrate content within the wound. Additional evaluations included quantification of skin histological change, angiogenesis, scar strength, and time to complete wound closure. Throughout the wound healing process diabetic animals treated with vehicle exhibited increased wound MAL with reduced VEGF, pAkt, peNOS and nitrite/nitrate, all associated with poor re-epitheliziation, angiogenesis, and wound breaking strength. Cibenitide administration significantly improved these abnormalities. The results suggest that cibinetide-mediated IRR activation may represent an interesting strategy to treat diabetes-associated wound healing. Copyright © 2017 Elsevier B.V. All rights reserved.

Erythropoietin--en ny terapi ved cerebral iskaemi?

DEFF Research Database (Denmark)

Kalialis, Louise Vennegaard; Olsen, Niels Vidiendal

2003-01-01

as an anti-inflammatory and neuroprotective drug. EPO and its receptor are expressed in neurons, glial cells and brain capillary endothelial cells, and the system is upregulated in conditions of cerebral ischaemia and hypoxia. Animal studies have now established that intracerebroventricular administration...... of recombinant EPO exerts neuroprotection in models of stroke. The mechanisms appear to involve an upregulation of specific anti-apoptotic and anti-inflammatory pathways. In addition, neurotrophic and angiogenetic effects of EPO may contribute in a long latency protection. Interestingly, also systemic...... administration of recombinant EPO ameliorates neuronal damage after brain ischaemia, and prevents the loss of autoregulation of cerebral blood flow following experimental subarachnoid haemorrhage. Recombinant human EPO is a safe and non-toxic drug, and clinical studies are currently investigating...

The role of tumor suppressor p15Ink4b in the regulation of hematopoietic progenitor cell fate

International Nuclear Information System (INIS)

Humeniuk, R; Rosu-Myles, M; Fares, J; Koller, R; Bies, J; Wolff, L

2013-01-01

Epigenetic silencing of the tumor suppressor gene p15Ink4b (CDKN2B) is a frequent event in blood disorders like acute myeloid leukemia and myelodysplastic syndromes. The molecular function of p15Ink4b in hematopoietic differentiation still remains to be elucidated. Our previous study demonstrated that loss of p15Ink4b in mice results in skewing of the differentiation pattern of the common myeloid progenitor towards the myeloid lineage. Here, we investigated a function of p15Ink4b tumor suppressor gene in driving erythroid lineage commitment in hematopoietic progenitors. It was found that p15Ink4b is expressed more highly in committed megakaryocyte–erythroid progenitors than granulocyte–macrophage progenitors. More importantly, mice lacking p15Ink4b have lower numbers of primitive red cell progenitors and a severely impaired response to 5-fluorouracil- and phenylhydrazine-induced hematopoietic stress. Introduction of p15Ink4b into multipotential progenitors produced changes at the molecular level, including activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) signaling, increase GATA-1, erythropoietin receptor (EpoR) and decrease Pu1, GATA-2 expression. These changes rendered cells more permissive to erythroid commitment and less permissive to myeloid commitment, as demonstrated by an increase in early burst-forming unit-erythroid formation with concomitant decrease in myeloid colonies. Our results indicate that p15Ink4b functions in hematopoiesis, by maintaining proper lineage commitment of progenitors and assisting in rapid red blood cells replenishment following stress

EPOS-WP16: A coherent and collaborative network of Solid Earth Multi-scale laboratories

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Calignano, Elisa; Rosenau, Matthias; Lange, Otto; Spiers, Chris; Willingshofer, Ernst; Drury, Martyn; van Kan-Parker, Mirjam; Elger, Kirsten; Ulbricht, Damian; Funiciello, Francesca; Trippanera, Daniele; Sagnotti, Leonardo; Scarlato, Piergiorgio; Tesei, Telemaco; Winkler, Aldo

2017-04-01

Laboratory facilities are an integral part of Earth Science research. The diversity of methods employed in such infrastructures reflects the multi-scale nature of the Earth system and is essential for the understanding of its evolution, for the assessment of geo-hazards and for the sustainable exploitation of geo-resources. In the frame of EPOS (European Plate Observing System), the Working Package 16 represents a developing community of European Geoscience Multi-scale laboratories. The participant and collaborating institutions (Utrecht University, GFZ, RomaTre University, INGV, NERC, CSIC-ICTJA, CNRS, LMU, C4G-UBI, ETH, CNR*) embody several types of laboratory infrastructures, engaged in different fields of interest of Earth Science: from high temperature and pressure experimental facilities, to electron microscopy, micro-beam analysis, analogue tectonic and geodynamic modelling and paleomagnetic laboratories. The length scales encompassed by these infrastructures range from the nano- and micrometre levels (electron microscopy and micro-beam analysis) to the scale of experiments on centimetres-sized samples, and to analogue model experiments simulating the reservoir scale, the basin scale and the plate scale. The aim of WP16 is to provide two services by the year 2019: first, providing virtual access to data from laboratories (data service) and, second, providing physical access to laboratories (transnational access, TNA). Regarding the development of a data service, the current status is such that most data produced by the various laboratory centres and networks are available only in limited "final form" in publications, many data remain inaccessible and/or poorly preserved. Within EPOS the TCS Multi-scale laboratories is collecting and harmonizing available and emerging laboratory data on the properties and process controlling rock system behaviour at all relevant scales, in order to generate products accessible and interoperable through services for supporting

TNF-alpha-induced apoptosis is prevented by erythropoietin treatment on SH-SY5Y cells

International Nuclear Information System (INIS)

Pregi, Nicolas; Wenker, Shirley; Vittori, Daniela; Leiros, Claudia Perez; Nesse, Alcira

2009-01-01

The growth factor erythropoietin (Epo) has shown neuronal protective action in addition to its well known proerythroid activity. Furthermore, Epo has dealt with cellular inflammation by inhibiting the expression of several proinflammatory cytokines, such as IL-1 and TNF-α. The action of TNF can have both apoptotic and antiapoptotic consequences due to altered balance between different cell signalling pathways. This work has focused on the apoptotic effects of this cytokine and the potential protective action of Epo. The model we used was neuroblastoma SH-SY5Y cells cultured in the presence of 25 ng/ml TNF-α or pretreated with 25 U/ml Epo for 12 h before the addition of TNF-α. Apoptosis was evaluated by differential cell count after Hoechst staining, analysis of DNA ladder pattern, and measurement of caspase activity. Despite its ability to induce NF-κB nuclear translocation, TNF-α induced cell death, which was found to be associated to upregulation of TNF Receptor 1 expression. On the other hand, cells activated by Epo became resistant to cell death. Prevention of death receptor upregulation and caspase activation may explain this antiapoptotic effect of Epo, which may be also favoured by the induction of a higher expression of protective factors, such as Bcl-2 and NF-κB, through mechanisms involving Jak/STAT and PI3K signalling pathways

Sustainable access to data, products, services and software from the European seismological Research Infrastructures: the EPOS TCS Seismology

Science.gov (United States)

Haslinger, Florian; Dupont, Aurelien; Michelini, Alberto; Rietbrock, Andreas; Sleeman, Reinoud; Wiemer, Stefan; Basili, Roberto; Bossu, Rémy; Cakti, Eser; Cotton, Fabrice; Crawford, Wayne; Diaz, Jordi; Garth, Tom; Locati, Mario; Luzi, Lucia; Pinho, Rui; Pitilakis, Kyriazis; Strollo, Angelo

2016-04-01

Easy, efficient and comprehensive access to data, data products, scientific services and scientific software is a key ingredient in enabling research at the frontiers of science. Organizing this access across the European Research Infrastructures in the field of seismology, so that it best serves user needs, takes advantage of state-of-the-art ICT solutions, provides cross-domain interoperability, and is organizationally and financially sustainable in the long term, is the core challenge of the implementation phase of the Thematic Core Service (TCS) Seismology within the EPOS-IP project. Building upon the existing European-level infrastructures ORFEUS for seismological waveforms, EMSC for seismological products, and EFEHR for seismological hazard and risk information, and implementing a pilot Computational Earth Science service starting from the results of the VERCE project, the work within the EPOS-IP project focuses on improving and extending the existing services, aligning them with global developments, to at the end produce a well coordinated framework that is technically, organizationally, and financially integrated with the EPOS architecture. This framework needs to respect the roles and responsibilities of the underlying national research infrastructures that are the data owners and main providers of data and products, and allow for active input and feedback from the (scientific) user community. At the same time, it needs to remain flexible enough to cope with unavoidable challenges in the availability of resources and dynamics of contributors. The technical work during the next years is organized in four areas: - constructing the next generation software architecture for the European Integrated (waveform) Data Archive EIDA, developing advanced metadata and station information services, fully integrate strong motion waveforms and derived parametric engineering-domain data, and advancing the integration of mobile (temporary) networks and OBS deployments in

Near Fault Observatories (NFO) services and integration plan for European Plate Observing System (EPOS) Implementation Phase

Science.gov (United States)

Chiaraluce, Lauro

2016-04-01

Coherently with the EPOS vision aimed at creating a pan-European infrastructure for Earth Sciences supporting research for a more sustainable society, we are working on the integration of NFOs and services implementation facilitating their data and products discovery and usage. NFOs are National Research Infrastructures (NRI) consisting of advanced networks of multi-parametric sensors continuously monitoring the chemical and physical processes related to the common underlying Earth instabilities governing active faults evolution and the genesis of earthquakes. These infrastructures will enable advancements in understanding of earthquakes generation processes and associated ground shaking due to their high-quality near-source multidisciplinary data. In EPOS-IP seven NFOs are going to be linked: 1) the Altotiberina and 2) Irpinia Observatories in Italy, 3) Corinth in Greece, 4) South-Iceland Seismic Zone, 5) Valais in Switzerland, 6) Marmara Sea (GEO Supersite) in Turkey and 7) Vrancea in Romania. EPOS-IP aims to implement integrated services from a technical, legal, governance and financial point of view. Accordingly, our first effort within this first core group of NFOs will be establishing legal governance for such a young community to ensure a long-term sustainability of the envisaged services including the full adoption of the EPOS data policy. The establishment of a Board including representatives of each NFO formally appointed by the Institutions supporting the NRI is a basic requirement to provide and validate a stable governance mechanism supporting the initiatives finalised to the services provision. Extremely dense networks and less common instruments deserve an extraordinary work on data quality control and description. We will work on linking all the NFOs in a single distributed network of observatories with instrumental and monitoring standards based on common protocols for observation, analysis, and data access and distributed channels. We will rely on

Central nervous system frontiers for the use of erythropoietin

DEFF Research Database (Denmark)

Olsen, Niels Vidiendal

2003-01-01

Recombinant human erythropoietin (r-HuEPO; epoetin alfa) is well established as safe and effective for the treatment of anemia. In addition to the erythropoietic effects of endogenous erythropoietin (EPO), recent evidence suggests that it may elicit a neuroprotective effect in the central nervous...... system (CNS). Preclinical studies have demonstrated the presence of EPO receptors in the brain that are up-regulated under hypoxic or ischemic conditions. Intracerebral and systemic administration of epoetin alfa have been demonstrated to elicit marked neuroprotective effects in multiple preclinical...

Specific binding of 125I-rErythropoietin to Friend polycythemia virus-transformed erythroleukemia cells purified by centrifugal elutriation

International Nuclear Information System (INIS)

Correa, P.N.; Bard, V.; Axelrad, A.A.

1990-01-01

We have used countercurrent centrifugal elutriation (CCE) to determine the distribution of cells with respect to cell volume and buoyant density for an erythroleukemia cell line (JG6) transformed by the polycythemia strain of Friend virus (FV-P), and to determine the effect of inducing the cells to differentiate with dimethylsulfoxide (DMSO) on this distribution. CCE made it possible to obtain suspensions of modal JG6 populations virtually free of dead cells and uniform with respect to volume and buoyant density. These modal populations were assayed for specific binding of erythropoietin (Epo). Between 500 and 550 Epo receptors per cell were detected. These belonged to a single class having a dissociation constant of 0.36 nM. DMSO induction of differentiation of the JG6 cells had no effect on the number of Epo receptors expressed

A role for heme oxygenase-1 in the antioxidant and antiapoptotic effects of erythropoietin: the start of a good news/bad news story?

Science.gov (United States)

Calò, Lorenzo A; Davis, Paul A; Piccoli, Antonio; Pessina, Achille C

2006-01-01

Erythropoietin (EPO) is the major regulator of erythropoiesis. EPO's actions have been shown to be antiapoptotic and dependent on JAK2 signaling and Akt phosphorylation. These effects serve as link between EPO and heme oxygenase-1 (HO-1). HO-1 is an inducible enzyme with potent antioxidant and antiapoptotic activities which are regulated by Akt signaling. EPO's ability to alter cellular systems that involve apoptosis and oxidants suggests that EPO treatments are likely to have multiple and different effects which may start a good news/bad news story. Recombinant human EPO is the recognized treatment of choice to address anemia and to stimulate erythropoiesis in chronic renal failure patients, through its antiapoptotic action which likely involves HO-1. On the other hand, EPO treatment to address anemia in cancer patients, while providing significant improvements in cancer patients' quality of life, its effects on survival are equivocal, likely due to its linkage with HO-1. Two clinical trials of EPO in patients with solid tumors have, in fact, shown specific negative effects on survival. However, EPO's effect on tumor growth and survival is not uniformily pro growth and pro survival, as EPO may act synergistically with chemotherapy to induce apoptosis. Finally, compounds have been synthesized that do not trigger EPO receptor and thus may allow experimental distinction and, therefore, at least potentially affect at the clinical level the tissue-protective effects of EPO (e.g., antiapoptosis) without provoking its other potentially detrimental effects. Copyright 2006 S. Karger AG, Basel

EPOS Thematic Core Service Anthropogenic Hazards for SHEER project: maintain, process and manage your project research data

Science.gov (United States)

Orlecka-Sikora, Beata; Lasocki, Stanislaw; Staszek, Monika; Olszewska, Dorota; Urban, Pawel; Jaroslawski, Janusz; Cielesta, Szymon; Mirek, Janusz; Wiszniowski, Jan; Picozzi, Matteo; Solaro, Giuseppe; Pringle, Jamie; Toon, Sam; Cesca, Simone; Kuehn, Daniela; Ruigrok, Elmer; Gunning, Andrew; Isherwood, Catherine

2017-04-01

The main objective of the "Shale gas exploration and exploitation induced risks - SHEER" project (Horizon 2020, call LCE 16-2014) is to develop a probabilistic methodology to assess and mitigate the short- and the long-term environmental risks associated with the exploration and exploitation of shale gas. To this end, the SHEER project makes use of a large amount of heterogeneous data of various types. This data, from different disciplines of science e.g. geophysical, geochemical, geological, technological, etc., must be homogenized, harmonized and made accessible exclusively for all project participants. This requires to develop an over-arching structure for high-level multidisciplinary data integration. The bespoke solution is provided by Thematic Core Service Anthropogenic Hazards (TCS AH) developed in the framework of European Plate Observing System Program (https://tcs.ah-epos.eu/, infrastructural projects IS-EPOS, POIG.02.03.00-14-090/13-00 and EPOS IP, H2020-INFRADEV-1-2015-1). TCS AH provides virtual access to a comprehensive, wide-scale and high quality research infrastructure in the field of induced seismicity and other anthropogenic hazards evoked by exploration and exploitation of geo-resources. TCS AH is designed as a functional e-research environment to ensure a researcher the maximum possible freedom for experimentation by providing a virtual laboratory flexible to create own workspace for processing streams. A data-management process promotes the use of research infrastructure in novel ways providing an access to (i) data gathered in the so-called "episodes", comprehensively describing a geophysical process, induced or triggered by human technological activity, which under certain circumstances can become hazardous for people, infrastructure and the environment, (ii) problem-oriented, specific services, with the particular attention devoted to methods analyzing correlations between technology, geophysical response and resulting hazards, (iii) the

Cytoprotective effect of recombinant human erythropoietin produced in transgenic tobacco plants.

Directory of Open Access Journals (Sweden)

Farooqahmed S Kittur

Full Text Available Asialo-erythropoietin, a desialylated form of human erythropoietin (EPO lacking hematopoietic activity, is receiving increased attention because of its broader protective effects in preclinical models of tissue injury. However, attempts to translate its protective effects into clinical practice is hampered by unavailability of suitable expression system and its costly and limit production from expensive mammalian cell-made EPO (rhuEPO(M by enzymatic desialylation. In the current study, we took advantage of a plant-based expression system lacking sialylating capacity but possessing an ability to synthesize complex N-glycans to produce cytoprotective recombinant human asialo-rhuEPO. Transgenic tobacco plants expressing asialo-rhuEPO were generated by stably co-expressing human EPO and β1,4-galactosyltransferase (GalT genes under the control of double CaMV 35S and glyceraldehyde-3-phosphate gene (GapC promoters, respectively. Plant-produced asialo-rhuEPO (asialo-rhuEPO(P was purified by immunoaffinity chromatography. Detailed N-glycan analysis using NSI-FTMS and MS/MS revealed that asialo-rhuEPO(P bears paucimannosidic, high mannose-type and complex N-glycans. In vitro cytoprotection assays showed that the asialo-rhuEPO(P (20 U/ml provides 2-fold better cytoprotection (44% to neuronal-like mouse neuroblastoma cells from staurosporine-induced cell death than rhuEPO(M (21%. The cytoprotective effect of the asialo-rhuEPO(P was found to be mediated by receptor-initiated phosphorylation of Janus kinase 2 (JAK2 and suppression of caspase 3 activation. Altogether, these findings demonstrate that plants are a suitable host for producing cytoprotective rhuEPO derivative. In addition, the general advantages of plant-based expression system can be exploited to address the cost and scalability issues related to its production.

Skeletal muscle alterations and exercise performance decrease in erythropoietin-deficient mice: a comparative study

Directory of Open Access Journals (Sweden)

Mille-Hamard Laurence

2012-06-01

Full Text Available Abstract Background Erythropoietin (EPO is known to improve exercise performance by increasing oxygen blood transport and thus inducing a higher maximum oxygen uptake (VO2max. Furthermore, treatment with (or overexpression of EPO induces protective effects in several tissues, including the myocardium. However, it is not known whether EPO exerts this protective effect when present at physiological levels. Given that EPO receptors have been identified in skeletal muscle, we hypothesized that EPO may have a direct, protective effect on this tissue. Thus, the objectives of the present study were to confirm a decrease in exercise performance and highlight muscle transcriptome alterations in a murine EPO functional knock-out model (the EPO-d mouse. Methods We determined VO2max peak velocity and critical speed in exhaustive runs in 17 mice (9 EPO-d animals and 8 inbred controls, using treadmill enclosed in a metabolic chamber. Mice were sacrificed 24h after a last exhaustive treadmill exercise at critical speed. The tibialis anterior and soleus muscles were removed and total RNA was extracted for microarray gene expression analysis. Results The EPO-d mice’s hematocrit was about 50% lower than that of controls (p  1.4 and 115 were strongly down-regulated (normalized ratio  Conclusions Our results showed that the lack of functional EPO induced a decrease in the aerobic exercise capacity. This decrease was correlated with the hematocrit and reflecting poor oxygen supply to the muscles. The observed alterations in the muscle transcriptome suggest that physiological concentrations of EPO exert both direct and indirect muscle-protecting effects during exercise. However, the signaling pathway involved in these protective effects remains to be described in detail.

What We Need: The 2012 NASA EPO Forum Survey on Two-Year College STEM Teaching

Science.gov (United States)

Low, R.; CoBabe-Ammann, E.; Schultz, G.

2014-07-01

A survey of community college STEM faculty, administered by the NASA SMD Higher Education Working Group (HEWG), was administered in fall 2012 in an effort to document the demographic make-up and views of community college faculty who teach NASA science-related STEM courses in astronomy, physics, Earth science, and engineering. Nearly half of respondents reported that less than 10% of students in their classroom are “STEMward bound” and indicated the need for STEM resources that can relate science course content and be relevant to the daily life of their students. A number of respondents also noted a new or renewed emphasis on outreach activities within the community served by their institution as part of their job description. The survey suggests specific directions and ways that the NASA SMD EPO forum can support two-year college stakeholders.

Purinergic P2Y12 Receptor Activation in Eosinophils and the Schistosomal Host Response.

Science.gov (United States)

Muniz, Valdirene S; Baptista-Dos-Reis, Renata; Benjamim, Claudia F; Mata-Santos, Hilton A; Pyrrho, Alexandre S; Strauch, Marcelo A; Melo, Paulo A; Vicentino, Amanda R R; Silva-Paiva, Juliana; Bandeira-Melo, Christianne; Weller, Peter F; Figueiredo, Rodrigo T; Neves, Josiane S

2015-01-01

Identifying new target molecules through which eosinophils secrete their stored proteins may reveal new therapeutic approaches for the control of eosinophilic disorders such as host immune responses to parasites. We have recently reported the expression of the purinergic P2Y12 receptor (P2Y12R) in human eosinophils; however, its functional role in this cell type and its involvement in eosinophilic inflammation remain unknown. Here, we investigated functional roles of P2Y12R in isolated human eosinophils and in a murine model of eosinophilic inflammation induced by Schistosoma mansoni (S. mansoni) infection. We found that adenosine 5'-diphosphate (ADP) induced human eosinophils to secrete eosinophil peroxidase (EPO) in a P2Y12R dependent manner. However, ADP did not interfere with human eosinophil apoptosis or chemotaxis in vitro. In vivo, C57Bl/6 mice were infected with cercariae of the Belo Horizonte strain of S. mansoni. Analyses performed 55 days post infection revealed that P2Y12R blockade reduced the granulomatous hepatic area and the eosinophilic infiltrate, collagen deposition and IL-13/IL-4 production in the liver without affecting the parasite oviposition. As found for humans, murine eosinophils also express the P2Y12R. P2Y12R inhibition increased blood eosinophilia, whereas it decreased the bone marrow eosinophil count. Our results suggest that P2Y12R has an important role in eosinophil EPO secretion and in establishing the inflammatory response in the course of a S. mansoni infection.

Polycythemia and high levels of erythropoietin in blood and brain blunt the hypercapnic ventilatory response in adult mice.

Science.gov (United States)

Menuet, Clément; Khemiri, Hanan; de la Poëze d'Harambure, Théodora; Gestreau, Christian

2016-05-15

Changes in arterial Po2, Pco2, and pH are the strongest stimuli sensed by peripheral and central chemoreceptors to adjust ventilation to the metabolic demand. Erythropoietin (Epo), the main regulator of red blood cell production, increases the hypoxic ventilatory response, an effect attributed to the presence of Epo receptors in both carotid bodies and key brainstem structures involved in integration of peripheral inputs and control of breathing. However, it is not known whether Epo also has an effect on the hypercapnic chemoreflex. In a first attempt to answer this question, we tested the hypothesis that Epo alters the ventilatory response to increased CO2 levels. Basal ventilation and hypercapnic ventilatory response (HCVR) were recorded from control mice and from two transgenic mouse lines constitutively expressing high levels of human Epo in brain only (Tg21) or in brain and plasma (Tg6), the latter leading to polycythemia. To tease apart the potential effects of polycythemia and levels of plasma Epo in the HCVR, control animals were injected with an Epo analog (Aranesp), and Tg6 mice were treated with the hemolytic agent phenylhydrazine after splenectomy. Ventilatory parameters measured by plethysmography in conscious mice were consistent with data from electrophysiological recordings in anesthetized animals and revealed a blunted HCVR in Tg6 mice. Polycythemia alone and increased levels of plasma Epo blunt the HCVR. In addition, Tg21 mice with an augmented level of cerebral Epo also had a decreased HCVR. We discuss the potential implications of these findings in several physiopathological conditions. Copyright © 2016 the American Physiological Society.

Concentrations of serum soluble transferring receptors in anemic children suffering from chronic renal failure

International Nuclear Information System (INIS)

Nassar, E.M.; Mostafa, A. M E.; Abdel-Latif, A. E.; El-Nashar, N.A.

2004-01-01

Inappropriate erythropoietin production is the main reason responsiblefor anemia in chronic renal failure children. Iron deficiency is the commonest cause of erythropoietin resistance in dialyzed children treated w ith recombinant human erythropoietin (r-HuEPO). Early detection of iron deficiency is vital to optimize management of chronic anemia associated with renal failure that is being treated with r-HuEPO but bclinical or functional iron deficiency is difficult to be diagnosed in these patients by the commonly used tests. This study was conducted in order to evaluate the role of serum soluble transferrin receptor (sTfR) in identifying iron deficiency among uremic children. Twenty-five patients with end stage renal failure were studied. They were classified into two groups; group I included 15 patients under conservative treatment and their ages ranged between 2-1] years with a mean value of 9.3 ± 3.79. Group II included 10 patients under regular hemodialysis treatment. This group was evaluated before receiving treatment (group IIa) and after treatment of anemia by r-HuEPO and intravenous iron for 8 weeks (group IIb). Their ages ranged between 4-10 years with a mean value of 8.1 ± 1.79 years. Ten healthy subjects, matched in age and sex, were served as controls (group III). All subjects were evaluated regarding renal function test, hematopoietic indices am ferrokinetic parameters including hypochromic cell percentage, serum iron, serum ferritin, total iron binding capacity (TIBC), sTfR and sTfR/log ferritu index. The study showed that the hypochromic cell percentage was significantly increased in both groups I and Ila when compared to controls (P < 0.0001). Also, a highly significant increase was detected in group Ila when compared with group I (P < 0.0001). Serum iron values showed reduction in both studied groups, which were not statistically significant. Serum ferritin showed high significant elevation in all the studied groups as compared to controls

Does Erythropoietin Regulate TRPC Channels in Red Blood Cells?

Directory of Open Access Journals (Sweden)

Jens Danielczok

2017-03-01

Full Text Available Background: Cation channels play an essential role in red blood cells (RBCs ion homeostasis. One set of ion channels are the transient receptor potential channels of canonical type (TRPC channels. The abundance of these channels in primary erythroblasts, erythroid cell lines and RBCs was associated with an increase in intracellular Ca2+ upon stimulation with Erythropoietin (Epo. In contrast two independent studies on Epo-treated patients revealed diminished basal Ca2+ concentration or reduced phosphatidylserine exposure to the outer membrane leaflet. Methods: To resolve the seemingly conflicting reports we challenged mature human and mouse RBCs of several genotypes with Epo and Prostaglandin E2 (PGE2 and recorded the intracellular Ca2+ content. Next Generation Sequencing was utilised to approach a molecular analysis of reticulocytes. Results/Conclusions: Our results allow concluding that Epo and PGE2 regulation of the Ca2+ homeostasis is distinctly different between murine and human RBCs and that changes in intracellular Ca2+ upon Epo treatment is a primary rather than a compensatory effect. In human RBCs, Epo itself has no effect on Ca2+ fluxes but inhibits the PGE2-induced Ca2+ entry. In murine mature RBCs functional evidence indicates TRPC4/C5 mediated Ca2+ entry activated by Epo whereas PGE2 leads to a TRPC independent Ca2+ entry.

Therapy-resistant anaemia in congenital nephrotic syndrome of the Finnish type--implication of EPO, transferrin and transcobalamin losses.

Science.gov (United States)

Toubiana, Julie; Schlageter, Marie-Hélène; Aoun, Bilal; Dunand, Olivier; Vitkevic, Renata; Bensman, Albert; Ulinski, Tim

2009-04-01

Congenital nephrotic syndrome of the Finnish type (CNF) is due to NPHS1 mutation and is responsible for a variety of urinary protein losses. We report the case of a 4-month-old girl with a particularly severe form (proteinuria approximately 150 g/l) of CNF. She developed severe non-regenerative anaemia requiring bi-monthly blood transfusions despite daily EPO (600 UI/kg) and iron supplementation. Epoetin pharmacokinetics revealed a urinary loss of 27% of the given dose within the first 24 h after IV injection. However, plasma levels remained increased after 24 h (228 UI/l). Plasma transferrin and transcobalamin levels were undetectable. Atransferrinaemia and atranscobalaminaemia seem to be responsible for disturbed erythropoiesis.

Leishmania donovani infection induces anemia in hamsters by differentially altering erythropoiesis in bone marrow and spleen.

Directory of Open Access Journals (Sweden)

William P Lafuse

Full Text Available Leishmania donovani is a parasite that causes visceral leishmaniasis by infecting and replicating in macrophages of the bone marrow, spleen, and liver. Severe anemia and leucopenia is associated with the disease. Although immune defense mechanisms against the parasite have been studied, we have a limited understanding of how L. donovani alters hematopoiesis. In this study, we used Syrian golden hamsters to investigate effects of L. donovani infection on erythropoiesis. Infection resulted in severe anemia and leucopenia by 8 weeks post-infection. Anemia was associated with increased levels of serum erythropoietin, which indicates the hamsters respond to the anemia by producing erythropoietin. We found that infection also increased numbers of BFU-E and CFU-E progenitor populations in the spleen and bone marrow and differentially altered erythroid gene expression in these organs. In the bone marrow, the mRNA expression of erythroid differentiation genes (α-globin, β-globin, ALAS2 were inhibited by 50%, but mRNA levels of erythroid receptor (c-kit, EpoR and transcription factors (GATA1, GATA2, FOG1 were not affected by the infection. This suggests that infection has a negative effect on differentiation of erythroblasts. In the spleen, erythroid gene expression was enhanced by infection, indicating that the anemia activates a stress erythropoiesis response in the spleen. Analysis of cytokine mRNA levels in spleen and bone marrow found that IFN-γ mRNA is highly increased by L. donovani infection. Expression of the IFN-γ inducible cytokine, TNF-related apoptosis-inducing ligand (TRAIL, was also up-regulated. Since TRAIL induces erythroblasts apoptosis, apoptosis of bone marrow erythroblasts from infected hamsters was examined by flow cytometry. Percentage of erythroblasts that were apoptotic was significantly increased by L. donovani infection. Together, our results suggest that L. donovani infection inhibits erythropoiesis in the bone marrow by

Applications and biomonitoring issues of recombinant erythropoietins for doping control.

Science.gov (United States)

Tsitsimpikou, Christina; Kouretas, Demetrios; Tsarouhas, Konstantinos; Fitch, Kenneth; Spandidos, Demetrios A; Tsatsakis, Aristides

2011-02-01

The biochemical actions and side effects of recombinant erythropoietins (rhEPOs), their analogs and mimetics, their misuse as doping agents, and the principal analytical strategies developed to identify them in athletes' biologic fluids are reviewed. Patients who experience a range of pathologies have benefited from the administration of rhEPOs to correct severe anemia. Currently, monitoring the biologic effect of rhEPO in patients under treatment is by measuring the hemoglobin concentration. However, it may be valuable to directly monitor the actual levels of the administered drug and determine a dose-dependent correlation with any clinical adverse effect observed. This may permit the adoption of a patient-specific administration regime. Currently, the method of detecting EPO approved for doping control is an isoelectric-focusing, double-blotting, chemiluminescence assay based on charge differences between isoforms of rhEPOs and endogenous EPO in urine. The advantages and limitations of this method are presented. A new approach using sodium dodecyl sulfate-polyacrylamide gel electrophoresis as a complementary tool to the established method is discussed. The application of matrix-assisted laser desorption/ionization mass spectrometry and liquid chromatography combined with tandem mass spectrometry for the direct detection of the rhEPO molecules may prove to be promising. Indirect evidence of rhEPO abuse by athletes is based on the analysis of blood parameters (hemoglobin hematocrit, reticulocytes, macrocytes, etc) and serum markers (concentration of EPO and serum transferrin receptors, etc). Enrichment of the screened parameters with gene or biochemical markers revealing altered erythropoiesis and adoption of longitudinal monitoring of athletes' hematologic and biochemical parameters could also be a complementary approach in the fight against doping.

The "Volcano Observations" Thematic Core Service of the European Plate Observing System (EPOS): status of the implementation.

Science.gov (United States)

Puglisi, Giuseppe

2017-04-01

The European volcanological community contributes to implementation of European Plate Observing System (EPOS) by making operational an integrated platform to guarantee a seamless access to the data provided by the European Solid Earth communities. To achieve this objective, the Volcano Observations Work Package (WP11) will implement a Thematic Core Services (TCS) which is planned to give access to the data and services provided by the European Volcano Observatories (VO) and some Volcanological Research Institutions (VRI; as university departments, laboratories, etc.); both types are considered as national research infrastructures (RI) over which to build the TCS. Currently, the networks on European volcanoes consist of thousands of stations or sites where volcanological parameters are continuously or periodically measured. These sites are equipped with instruments for geophysical (seismic, geodetic, gravimetric, electromagnetic), geochemical (volcanic plumes, fumaroles, groundwater, rivers, soils), environmental observations (e.g. meteorological and air quality parameters), as well as various prototypal monitoring systems (e.g. Doppler radars, ground based SAR). In Europe also operate laboratories for sample analysis (rocks, gases, isotopes, etc.), and almost continuous analysis of space-borne data (SAR, thermal imagery, SO2 and ash), as well as high-performance computing centres. All these RIs provide high-quality information (observations) on the current status of European volcanoes and the geodynamic background of the surrounding areas. The implementation of the Volcano Observations TCS is addressing technical and management issues, both considering the current heterogeneous state of the art of the volcanological research infrastructures in Europe. Indeed, the frame of the VO and VRI is now too fragmented to be considered as a unique distributed infrastructure, thus the main effort planned in the frame of the EPOS-IP is focused to create services aimed at

Methoxy polyethylene glycol-epoetin beta for the treatment of anemia associated with chronic renal failure.

Science.gov (United States)

Schmid, Holger

2016-01-01

Since more than two decades erythropoiesis-stimulating agents are the main pillar for treatment of anemia associated with chronic kidney disease. Methoxy polyethylene glycol-epoetin beta (MPG-EPO), also called continuous erythropoietin receptor activator, is the longest acting erythropoiesis-stimulating agent currently available. MPG-EPO is characterized by an elimination half-life of approximately 137 h and offers extended dosing intervals up to 4 weeks. Numerous phase I/II studies and a comprehensive clinical phase III program demonstrated the feasibility of MPG-EPO therapy for anemia correction and maintenance of stable hemoglobin levels in adult chronic kidney disease patients. Due to patent disputes MPG-EPO was only available outside the US market so far. In view of a prevailing US market introduction, this review focuses on efficacy and safety data from pivotal trials, summarizes recent clinical research and finally tries to substantiate potential benefits associated with the use of this anti-anemic drug.

The AIA Solar Learning Center: Taking Inquiry-based EPO Online

Science.gov (United States)

Wills-Davey, Meredith; Attrill, G. D. R.; Engell, A.

2009-05-01

The observations of the Atmospheric Imaging Assembly aboard the Solar Dynamics Observatory (SDO-AIA) are expected to be groundbreaking within the field of heliophysics. To properly promote and explain the data produced by AIA, it is important that an innovative EPO effort be put forth. This has led to the development of "The AIA Solar Learning Center” (SLC), an inquiry-based educational website geared towards teaching about AIA and the Sun in general. The goal of the SLC is to provide K-12 students, teachers, parents, and homeschoolers with information and education about the Sun, primarily through hands-on activity modules that explain different aspects of our nearest star and the methods of observing it. While each module ultimately aims to impart information about the Sun or some related physical process, the activities also range across a host of different disciplines, including geology, chemistry, history, music, and art. In order to make the content applicable and accessible, activities are tailored to multiple difficulty levels, catering to different age groups. There is also a strong push towards facilitating teachers; activities are designed to fulfill specific teaching standards, and a host of additional teaching material is provided, including lesson plans and powerpoint presentations. Ultimately, the SLC aims to make science and the Sun inviting and accessible. The "Meet the Scientists” page will provide pictures and personal bios of participating scientists. Students will have the opportunity to interactively ask solar-related questions. There is even a host of lighter fare, such as a solar music playlist and links to relevant Facebook pages.

Systemic administration of erythropoietin inhibits retinopathy in RCS rats.

Directory of Open Access Journals (Sweden)

Weiyong Shen

Full Text Available OBJECTIVE: Royal College of Surgeons (RCS rats develop vasculopathy as photoreceptors degenerate. The aim of this study was to examine the effect of erythropoietin (EPO on retinopathy in RCS rats. METHODS: Fluorescein angiography was used to monitor retinal vascular changes over time. Changes in retinal glia and vasculature were studied by immunostaining. To study the effects of EPO on retinal pathology, EPO (5000 IU/kg was injected intraperitoneally in 14 week old normal and RCS rats twice a week for 4 weeks. Changes in the retinal vasculature, glia and microglia, photoreceptor apoptosis, differential expression of p75 neurotrophin receptor (p75NTR, pro-neurotrophin 3 (pro-NT3, tumour necrosis factor-α (TNFα, pigment epithelium derived factor (PEDF and vascular endothelial growth factor-A (VEGF-A, the production of CD34(+ cells and mobilization of CD34(+/VEGF-R2(+ cells as well as recruitment of CD34(+ cells into the retina were examined after EPO treatment. RESULTS: RCS rats developed progressive capillary dropout and subretinal neovascularization which were accompanied by retinal gliosis. Systemic administration of EPO stabilized the retinal vasculature and inhibited the development of focal vascular lesions. Further studies showed that EPO modulated retinal gliosis, attenuated photoreceptor apoptosis and p75NTR and pro-NT3 upregulation, promoted the infiltration of ramified microglia and stimulated VEGF-A expression but had little effect on TNFα and PEDF expression. EPO stimulated the production of red and white blood cells and CD34(+ cells along with effective mobilization of CD34(+/VEGF-R2(+ cells. Immunofluorescence study demonstrated that EPO enhanced the recruitment of CD34+ cells into the retina. CONCLUSIONS: Our results suggest that EPO has therapeutic potentials in treatment of neuronal and vascular pathology in retinal disease. The protective effects of EPO on photoreceptors and the retinal vasculature may involve multiple

Erythropoietin in radiotherapy

International Nuclear Information System (INIS)

Guttenburger, R.

2003-01-01

A high blood hemoglobin level is an independent factor for good prognosis as demonstrated in retrospective and prospective studies in a number of cancer sites. However, there is still debate on how hemoglobin affects outcome after radiotherapy. The issues are: 1. How about the predictive power and the magnitude of effect in various tumor entities? 2. Are all potential mechanisms for the hemoglobin effect considered? 3. Do EPO receptors found on tumor and normal cells outside the bone marrow play a role? Experimental and clinical data on anemia and its treatment have been extensively discussed. So far, the means to manipulate the hemoglobin level, their indication and administration are to be clarified. The issues are: 1. Why does transfusion not improve prognosis? 2. What have we learned from trials using EPO to stimulate endogenous Hb production? 3. What are the potential pitfalls of correcting anemia with EPO? 4. What is the optimal design of EPO-RT trials? Although there are still more questions than answers, the therapeutic potential of erythropoietin is of considerable interest to radiation oncologists. This report gives a summary reviewing the topic and ends on a note of caution: Mild anemia in cancer patients is no indication to use EPO outside clinical trials

Erythropoietin and a nonerythropoietic peptide analog promote aortic endothelial cell repair under hypoxic conditions: role of nitric oxide

Directory of Open Access Journals (Sweden)

Heikal L

2016-08-01

Full Text Available Lamia Heikal,1 Pietro Ghezzi,1 Manuela Mengozzi,1 Blanka Stelmaszczuk,2 Martin Feelisch,2 Gordon AA Ferns1 1Brighton and Sussex Medical School, Falmer, Brighton, 2Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital and Institute for Life Sciences, Southampton, UK Abstract: The cytoprotective effects of erythropoietin (EPO and an EPO-related nonerythropoietic analog, pyroglutamate helix B surface peptide (pHBSP, were investigated in an in vitro model of bovine aortic endothelial cell injury under normoxic (21% O2 and hypoxic (1% O2 conditions. The potential molecular mechanisms of these effects were also explored. Using a model of endothelial injury (the scratch assay, we found that, under hypoxic conditions, EPO and pHBSP enhanced scratch closure by promoting cell migration and proliferation, but did not show any effect under normoxic conditions. Furthermore, EPO protected bovine aortic endothelial cells from staurosporine-induced apoptosis under hypoxic conditions. The priming effect of hypoxia was associated with stabilization of hypoxia inducible factor-1α, EPO receptor upregulation, and decreased Ser-1177 phosphorylation of endothelial nitric oxide synthase (NOS; the effect of hypoxia on the latter was rescued by EPO. Hypoxia was associated with a reduction in nitric oxide (NO production as assessed by its oxidation products, nitrite and nitrate, consistent with the oxygen requirement for endogenous production of NO by endothelial NOS. However, while EPO did not affect NO formation in normoxia, it markedly increased NO production, in a manner sensitive to NOS inhibition, under hypoxic conditions. These data are consistent with the notion that the tissue-protective actions of EPO-related cytokines in pathophysiological settings associated with poor oxygenation are mediated by NO. These findings may be particularly relevant to atherogenesis and postangioplasty restenosis. Keywords

Climate Discovery: Integrating Research With Exhibit, Public Tours, K-12, and Web-based EPO Resources

Science.gov (United States)

Foster, S. Q.; Carbone, L.; Gardiner, L.; Johnson, R.; Russell, R.; Advisory Committee, S.; Ammann, C.; Lu, G.; Richmond, A.; Maute, A.; Haller, D.; Conery, C.; Bintner, G.

2005-12-01

The Climate Discovery Exhibit at the National Center for Atmospheric Research (NCAR) Mesa Lab provides an exciting conceptual outline for the integration of several EPO activities with other well-established NCAR educational resources and programs. The exhibit is organized into four topic areas intended to build understanding among NCAR's 80,000 annual visitors, including 10,000 school children, about Earth system processes and scientific methods contributing to a growing body of knowledge about climate and global change. These topics include: 'Sun-Earth Connections,' 'Climate Now,' 'Climate Past,' and 'Climate Future.' Exhibit text, graphics, film and electronic media, and interactives are developed and updated through collaborations between NCAR's climate research scientists and staff in the Office of Education and Outreach (EO) at the University Corporation for Atmospheric Research (UCAR). With funding from NCAR, paleoclimatologists have contributed data and ideas for a new exhibit Teachers' Guide unit about 'Climate Past.' This collection of middle-school level, standards-aligned lessons are intended to help students gain understanding about how scientists use proxy data and direct observations to describe past climates. Two NASA EPO's have funded the development of 'Sun-Earth Connection' lessons, visual media, and tips for scientists and teachers. Integrated with related content and activities from the NASA-funded Windows to the Universe web site, these products have been adapted to form a second unit in the Climate Discovery Teachers' Guide about the Sun's influence on Earth's climate. Other lesson plans, previously developed by on-going efforts of EO staff and NSF's previously-funded Project Learn program are providing content for a third Teachers' Guide unit on 'Climate Now' - the dynamic atmospheric and geological processes that regulate Earth's climate. EO has plans to collaborate with NCAR climatologists and computer modelers in the next year to develop

MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.

Directory of Open Access Journals (Sweden)

Yana Pikman

2006-07-01

Full Text Available The JAK2V617F allele has recently been identified in patients with polycythemia vera (PV, essential thrombocytosis (ET, and myelofibrosis with myeloid metaplasia (MF. Subsequent analysis has shown that constitutive activation of the JAK-STAT signal transduction pathway is an important pathogenetic event in these patients, and that enzymatic inhibition of JAK2V617F may be of therapeutic benefit in this context. However, a significant proportion of patients with ET or MF are JAK2V617F-negative. We hypothesized that activation of the JAK-STAT pathway might also occur as a consequence of activating mutations in certain hematopoietic-specific cytokine receptors, including the erythropoietin receptor (EPOR, the thrombopoietin receptor (MPL, or the granulocyte-colony stimulating factor receptor (GCSFR.DNA sequence analysis of the exons encoding the transmembrane and juxtamembrane domains of EPOR, MPL, and GCSFR, and comparison with germline DNA derived from buccal swabs, identified a somatic activating mutation in the transmembrane domain of MPL (W515L in 9% (4/45 of JAKV617F-negative MF. Expression of MPLW515L in 32D, UT7, or Ba/F3 cells conferred cytokine-independent growth and thrombopoietin hypersensitivity, and resulted in constitutive phosphorylation of JAK2, STAT3, STAT5, AKT, and ERK. Furthermore, a small molecule JAK kinase inhibitor inhibited MPLW515L-mediated proliferation and JAK-STAT signaling in vitro. In a murine bone marrow transplant assay, expression of MPLW515L, but not wild-type MPL, resulted in a fully penetrant myeloproliferative disorder characterized by marked thrombocytosis (Plt count 1.9-4.0 x 10(12/L, marked splenomegaly due to extramedullary hematopoiesis, and increased reticulin fibrosis.Activation of JAK-STAT signaling via MPLW515L is an important pathogenetic event in patients with JAK2V617F-negative MF. The bone marrow transplant model of MPLW515L-mediated myeloproliferative disorders (MPD exhibits certain features of

MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.

Science.gov (United States)

Pikman, Yana; Lee, Benjamin H; Mercher, Thomas; McDowell, Elizabeth; Ebert, Benjamin L; Gozo, Maricel; Cuker, Adam; Wernig, Gerlinde; Moore, Sandra; Galinsky, Ilene; DeAngelo, Daniel J; Clark, Jennifer J; Lee, Stephanie J; Golub, Todd R; Wadleigh, Martha; Gilliland, D Gary; Levine, Ross L

2006-07-01

The JAK2V617F allele has recently been identified in patients with polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis with myeloid metaplasia (MF). Subsequent analysis has shown that constitutive activation of the JAK-STAT signal transduction pathway is an important pathogenetic event in these patients, and that enzymatic inhibition of JAK2V617F may be of therapeutic benefit in this context. However, a significant proportion of patients with ET or MF are JAK2V617F-negative. We hypothesized that activation of the JAK-STAT pathway might also occur as a consequence of activating mutations in certain hematopoietic-specific cytokine receptors, including the erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte-colony stimulating factor receptor (GCSFR). DNA sequence analysis of the exons encoding the transmembrane and juxtamembrane domains of EPOR, MPL, and GCSFR, and comparison with germline DNA derived from buccal swabs, identified a somatic activating mutation in the transmembrane domain of MPL (W515L) in 9% (4/45) of JAKV617F-negative MF. Expression of MPLW515L in 32D, UT7, or Ba/F3 cells conferred cytokine-independent growth and thrombopoietin hypersensitivity, and resulted in constitutive phosphorylation of JAK2, STAT3, STAT5, AKT, and ERK. Furthermore, a small molecule JAK kinase inhibitor inhibited MPLW515L-mediated proliferation and JAK-STAT signaling in vitro. In a murine bone marrow transplant assay, expression of MPLW515L, but not wild-type MPL, resulted in a fully penetrant myeloproliferative disorder characterized by marked thrombocytosis (Plt count 1.9-4.0 x 10(12)/L), marked splenomegaly due to extramedullary hematopoiesis, and increased reticulin fibrosis. Activation of JAK-STAT signaling via MPLW515L is an important pathogenetic event in patients with JAK2V617F-negative MF. The bone marrow transplant model of MPLW515L-mediated myeloproliferative disorders (MPD) exhibits certain features of human MF

Comparison of cell-based and non-cell-based assay platforms for the detection of clinically relevant anti-drug neutralizing antibodies for immunogenicity assessment of therapeutic proteins.

Science.gov (United States)

Hu, Jenny; Wala, Iwona; Han, Hong; Nagatani, Janice; Barger, Troy; Civoli, Francesca; Kaliyaperumal, Arunan; Zhuang, Yao; Gupta, Shalini

2015-04-01

Anti-drug neutralizing antibodies (NAbs) formed due to unwanted immunogenicity of a therapeutic protein point towards a mature immune response. NAb detection is important in interpreting the therapeutic's efficacy and safety in vivo. In vitro cell-based NAb assays provide a physiological system for NAb detection, however are complex assays. Non-cell-based competitive ligand binding (CLB) approaches are also employed for NAb detection. Instead of cells, CLB assays use soluble receptor and conjugated reagents and are easier to perform, however have reduced physiological relevance. The aim of this study was to compare the performance of CLB assays to established cell-based assays to determine the former's ability to detect clinically relevant NAbs towards therapeutics that (i) acted as an agonist or (ii) acted as antagonists by binding to a target receptor. We performed a head-to-head comparison of the performance of cell-based and CLB NAb assays for erythropoietin (EPO) and two anti-receptor monoclonal antibodies (AMG-X and AMG 317). Clinically relevant NAb-positive samples identified previously by a cell-based assay were assessed in the corresponding CLB format(s). A panel of 12 engineered fully human anti-EPO monoclonal antibodies (MAbs) was tested in both EPO NAb assay formats. Our results showed that the CLB format was (i) capable of detecting human anti-EPO MAbs of differing neutralizing capabilities and affinities and (ii) provided similar results as the cell-based assay for detecting NAbs in patient samples. The cell-based and CLB assays also behaved comparably in detecting NAbs in clinical samples for AMG-X. In the case of anti-AMG 317 NAbs, the CLB format failed to detect NAbs in more than 50% of the tested samples. We conclude that assay sensitivity, drug tolerance and the selected assay matrix played an important role in the inability of AMG 317 CLB assays to detect clinically relevant NAbs. Copyright © 2015 Elsevier B.V. All rights reserved.

Two large preoperative doses of erythropoietin do not reduce the systemic inflammatory response to cardiac surgery

DEFF Research Database (Denmark)

Poulsen, Troels Dirch; Andersen, Lars Willy; Steinbrüchel, Daniel

2008-01-01

concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, IL-1beta receptor antagonist, IL-6, IL-10, and N-terminal probrain natriuretic peptide (NT-proBNP). Compared with placebo, EPO at day 3 after CPB augmented the TNF-alpha response (p

Federal STEM Policy and Politics and Their Impact on Astronomy EPO: Reflections and Provocations

Science.gov (United States)

Schultz, G.; Storksdieck, M.; Canright, S.

2015-11-01

The federal government invests more than $3 billion each year across its various units in supporting STEM education and outreach. Efforts in recent years to understand and better coordinate these investments have resulted in considerable pushback, particularly those efforts that aimed at consolidation and elimination of programs deemed ineffective or duplicative. While initial plans to streamline federal STEM education were defeated, many agencies nonetheless saw cuts and elimination, and a high-level effort to coordinate STEM education at the cross-agency level is now gaining steam (CoSTEM: Committee on Science, Technology, Engineering, and Mathematics Education). What do all of these developments mean for education and public outreach in astronomy and related fields? How should this community operate within the opportunities and threats that CoSTEM might pose? Former director of the National Academy of Science's Board on Science Education, and now director of the Center for Research on Lifelong STEM Learning, Martin Storksdieck, reflected on past and recent developments from the perspective of a close observer, and from the perspective of someone who has been involved in astronomy education research and evaluation for nearly 20 years. Shelley Canright, Senior Advisor for Education Integration at the NASA Office of Education, shared her insights and perspectives with respect to CoSTEM and EPO, in particular from co-chairing the Federal Coordination in Science, Technology, Engineering, and Mathematics Education (FC-STEM) group.

Overview of the Education and Public Outreach (EPO) program of the Caltech Tectonics Observatory

Science.gov (United States)

Kovalenko, L.; Jain, K.; Maloney, J.

2009-12-01

The Caltech Tectonics Observatory (TO) is an interdisciplinary center, focused on geological processes occurring at the boundaries of Earth's tectonic plates (http://www.tectonics.caltech.edu). Over the past year, the TO has made a major effort to develop an Education and Public Outreach (EPO) program. Our goals are to (1) stimulate the interest of students and the general public in Earth Sciences, particularly in the study of tectonic processes, (2) inform and educate the general public about science in the context of TO discoveries and advancements, and (3) provide opportunities for graduate students, postdocs, and faculty to do outreach in the local K-12 schools. We have hosted local high school students and teachers to provide them with research experience (as part of Caltech’s “Summer Research Connection”); participated in teacher training workshops (organized by the local school district); hosted tours for local elementary school students; and brought hands-on activities into local elementary and middle school classrooms, science clubs, and science nights. We have also led local school students and teachers on geology field trips through nearby parks. In addition, we have developed education modules for undergraduate classes (as part of MARGINS program), and have written educational web articles on TO research (http://www.tectonics.caltech.edu/outreach). The presentation will give an overview of these activities and their impact on our educational program.

The utility of immature reticulocyte fraction as an indicator of erythropoietic response to altitude training in elite cyclists.

Science.gov (United States)

Nadarajan, V S; Ooi, C H; Sthaneshwar, P; Thompson, M W

2010-02-01

Altitude training is sometimes employed by elite endurance athletes to improve their sea level performance. This improvement results from the increased red cell mass consequent upon the boost in erythropoietin (EPO) level that occurs as a response to the relatively hypoxic environment at high altitudes. We measured serum EPO levels together with various red cell and reticulocyte parameters including immature reticulocyte fraction (IRF) in eight national track-endurance cyclists, resident at sea-level, prior to and upon return from an altitude of approximately 1905 m. Reticulocytes and soluble transferrin receptor (sTfR) were significantly increased with reduction in ferritin levels immediately on return from high altitude indicating increased erythropoietic activity. IRF in particular showed a significant peak immediately on return but decline to sub-baseline levels by day 9, and recovery to baseline by day 16. Our results indicate that IRF is a sensitive marker of erythropoietic status in athletes undergoing altitude training and subsequent loss of EPO stimuli on return to sea level.

Shift working in the Chilean Andes (> 3,600 m) and its influence on erythropoietin and the low-pressure system.

Science.gov (United States)

Gunga, H C; Röcker, L; Behn, C; Hildebrandt, W; Koralewski, E; Rich, I; Schobersberger, W; Kirsch, K

1996-08-01

It was hypothesized that, in shift workers with a history of intermittent hypoxic stress (working 10 days at > 3,600 m, then resting for 4 days at sea level) for > 5 yr, the initial erythropoietin (EPO) response and the changes in central venous pressure (CVP) are different from those in Caucasian lowlanders. We studied the kitchen personnel (n = 11) of a mine (3,600 m) and a group of Caucasian lowlanders (n = 5). Blood samples were taken, and CVP was determined several times before, during, and after a typical shift. At baseline data collection (BDC) before transition, the shift workers had EPO concentrations of 5.2 +/- 2.4 mU/ml, which increased at altitude (P < 0.01) and returned to BDC values on the recovery (day 16). The Caucasians showed the same time course. Serum transferrin receptor concentrations did not change in either group. CVP values were generally higher in the shift workers than in the Caucasians. In conclusion, the hypothesis that the initial EPO response to a hypoxic stimulus is altered in these shift workers has to be refuted. Higher hemoglobin concentrations and/or CVP values in shift workers might be responsible for the rather low EPO concentrations in shift workers at BDC.

Characterization of pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia with kinase fusions in Japan

International Nuclear Information System (INIS)

Imamura, T; Kiyokawa, N; Kato, M; Imai, C; Okamoto, Y

2016-01-01

Recent studies revealed that a substantial proportion of patients with high-risk B-cell precursor acute lymphoblastic leukemia (BCP-ALL) harbor fusions involving tyrosine kinase and cytokine receptors, such as ABL1, PDGFRB, JAK2 and CRLF2, which are targeted by tyrosine kinase inhibitors (TKIs). In the present study, transcriptome analysis or multiplex reverse transcriptase–PCR analysis of 373 BCP-ALL patients without recurrent genetic abnormalities identified 29 patients with kinase fusions. Clinically, male predominance (male/female: 22/7), older age at onset (mean age at onset: 8.8 years) and a high white blood cell count at diagnosis (mean: 94 200/μl) reflected the predominance of National Cancer Institute high-risk (NCI-HR) patients (NCI-standard risk/HR: 8/21). Genetic analysis identified three patients with ABL1 rearrangements, eight with PDGFRB rearrangements, two with JAK2 rearrangements, three with IgH-EPOR and one with NCOR1-LYN. Of the 14 patients with CRLF2 rearrangements, two harbored IgH-EPOR and PDGFRB rearrangements. IKZF1 deletion was present in 16 of the 22 patients. The 5-year event-free and overall survival rates were 48.6±9.7% and 73.5±8.6%, respectively. The outcome was not satisfactory without sophisticated minimal residual disease-based stratification. Furthermore, the efficacy of TKIs combined with conventional chemotherapy without allogeneic hematopoietic stem cell transplantation in this cohort should be determined

Developing an Education and Public Outreach (EPO) program for Caltech's Tectonics Observatory

Science.gov (United States)

Kovalenko, L.; Jain, K.; Maloney, J.

2012-12-01

The Caltech Tectonics Observatory (TO) is an interdisciplinary center, focused on geological processes occurring at the boundaries of Earth's tectonic plates (http://www.tectonics.caltech.edu). Over the past four years, the TO has made a major effort to develop an Education and Public Outreach (EPO) program. Our goals are to (1) inspire students to learn Earth Sciences, particularly tectonic processes, (2) inform and educate the general public about science in the context of TO discoveries, and (3) provide opportunities for graduate students, postdocs, and faculty to do outreach in the local K-12 schools and community colleges. Our work toward these goals includes hosting local high school teachers and students each summer for six weeks of research experience (as part of Caltech's "Summer Research Connection"); organizing and hosting an NAGT conference aimed at Geoscience teachers at community colleges; participating in teacher training workshops (organized by the local school district); hosting tours for K-12 students from local schools as well as from China; and bringing hands-on activities into local elementary, middle, and high school classrooms. We also lead local school students and teachers on geology field trips through nearby canyons; develop education modules for undergraduate classes (as part of MARGINS program); write educational web articles on TO research (http://www.tectonics.caltech.edu/outreach/highlights/), and regularly give presentations to the general public. This year, we started providing content expertise for the development of video games to teach Earth Science, being created by GameDesk Institute. And we have just formed a scientist/educator partnership with a 6th grade teacher, to help in the school district's pilot program to incorporate new national science standards (NSTA's Next Generation Science Standards, current draft), as well as use Project-Based Learning. This presentation gives an overview of these activities.

Impact of the erythropoietin-derived peptide mimetic Epotris on the histopathological consequences of status epilepticus

DEFF Research Database (Denmark)

Zellinger, Christina; Seeger, Natalie; Hadamitzky, Martin

2011-01-01

the microglial response caused by prolonged seizure activity in the thalamus but not in other brain regions. The study renders support that the Epotris' sequences from binding site 2 in helix C of Epo play a role in receptor interaction and cytokine function. In addition, the data demonstrate that Epotris can...

The Receptor-Binding Domain in the VP1u Region of Parvovirus B19.

Science.gov (United States)

Leisi, Remo; Di Tommaso, Chiarina; Kempf, Christoph; Ros, Carlos

2016-02-24

Parvovirus B19 (B19V) is known as the human pathogen causing the mild childhood disease erythema infectiosum. B19V shows an extraordinary narrow tissue tropism for erythroid progenitor cells in the bone marrow, which is determined by a highly restricted uptake. We have previously shown that the specific internalization is mediated by the interaction of the viral protein 1 unique region (VP1u) with a yet unknown cellular receptor. To locate the receptor-binding domain (RBD) within the VP1u, we analyzed the effect of truncations and mutations on the internalization capacity of the recombinant protein into UT7/Epo cells. Here we report that the N-terminal amino acids 5-80 of the VP1u are necessary and sufficient for cellular binding and internalization; thus, this N-terminal region represents the RBD required for B19V uptake. Using site-directed mutagenesis, we further identified a cluster of important amino acids playing a critical role in VP1u internalization. In silico predictions and experimental results suggest that the RBD is structured as a rigid fold of three α-helices. Finally, we found that dimerization of the VP1u leads to a considerably enhanced cellular binding and internalization. Taken together, we identified the RBD that mediates B19V uptake and mapped functional and structural motifs within this sequence. The findings reveal insights into the uptake process of B19V, which contribute to understand the pathogenesis of the infection and the neutralization of the virus by the immune system.

A novel biological function of soluble biglycan: Induction of erythropoietin production and polycythemia.

Science.gov (United States)

Frey, Helena; Moreth, Kristin; Hsieh, Louise Tzung-Harn; Zeng-Brouwers, Jinyang; Rathkolb, Birgit; Fuchs, Helmut; Gailus-Durner, Valérie; Iozzo, Renato V; de Angelis, Martin Hrabě; Schaefer, Liliana

2017-06-01

Secondary polycythemia, a disease characterized by a selective increase in circulating mature erythrocytes, is caused by enhanced erythropoietin (Epo) concentrations triggered by hypoxia-inducible factor-2α (HIF-2α). While mechanisms of hypoxia-dependent stabilization of HIF-2α protein are well established, data regarding oxygen-independent regulation of HIF-2α are sparse. In this study, we generated a novel transgenic mouse model, in which biglycan was constitutively overexpressed and secreted by hepatocytes (BGN Tg ), thereby providing a constant source of biglycan released into the blood stream. We discovered that although the mice were apparently normal, they harbored an increase in mature circulating erythrocytes. In addition to erythrocytosis, the BGN Tg mice showed elevated hemoglobin concentrations, hematocrit values and enhanced total iron binding capacity, revealing a clinical picture of polycythemia. In BGN Tg mice markedly enhanced Epo mRNA expression was observed in the liver and kidney, while elevated Epo protein levels were found in liver, kidney and blood. Mechanistically, we showed that the transgenic animals had an abundance of HIF-2α protein in the liver and kidney. Finally, by transiently overexpressing circulating biglycan in mice deficient in various Toll-like receptors (TLRs), we determined that this novel function of biglycan to promote Epo synthesis was specifically mediated by a selective interaction with TLR2. Thus, we discovered a novel biological pathway of soluble biglycan inducing HIF-2α protein stabilization and Epo production presumably in an oxygen-independent manner, ultimately giving rise to secondary polycythemia.

Aspectos de especificação e implementação da camada de apresentação do padrão map utilizando o ambiente epos

OpenAIRE

Paulo Cesar Minoru Inazumi

1990-01-01

Resumo: Este trabalho apresenta a implementacão do prolocolo de apresentacão do modelo OSI/ISO para o projelo SISDI-MAP (Sislema Didático MAP). Utilizou-se o ambiente EPOS ("Engineering Project Oriented System") como suporte de desenvolvimento principalmente para a especificação formal da implementação e geração automática de código. Apresentam-se os conceitos referentes à camada de apresentação, o modelo de implementação, alguns aspectos da implementação e da geração automática de código e, ...

Tools You Can Use! E/PO Resources for Scientists and Faculty to Use and Contribute To: EarthSpace and the NASA SMD Scientist Speaker’s Bureau

Science.gov (United States)

Buxner, Sanlyn; Shupla, C.; CoBabe-Ammann, E.; Dalton, H.; Shipp, S.

2013-10-01

The Planetary Science Education and Public Outreach (E/PO) Forum has helped to create two tools that are designed to help scientists and higher-education science faculty make stronger connections with their audiences: EarthSpace, an education clearinghouse for the undergraduate classroom; and NASA SMD Scientist Speaker’s Bureau, an online portal to help bring science - and scientists - to the public. Are you looking for Earth and space science higher education resources and materials? Come explore EarthSpace, a searchable database of undergraduate classroom materials for faculty teaching Earth and space sciences at both the introductory and upper division levels! In addition to classroom materials, EarthSpace provides news and information about educational research, best practices, and funding opportunities. All materials submitted to EarthSpace are peer reviewed, ensuring that the quality of the EarthSpace materials is high and also providing important feedback to authors. Your submission is a reviewed publication! Learn more, search for resources, join the listserv, sign up to review materials, and submit your own at http://www.lpi.usra.edu/earthspace. Join the new NASA SMD Scientist Speaker’s Bureau, an online portal to connect scientists interested in getting involved in E/PO projects (e.g., giving public talks, classroom visits, and virtual connections) with audiences! The Scientist Speaker’s Bureau helps educators and institutions connect with NASA scientists who are interested in giving presentations, based upon the topic, logistics, and audience. The information input into the database will be used to help match scientists (you!) with the requests being placed by educators. All Earth and space scientists funded by NASA - and/or engaged in active research using NASA’s science - are invited to become part of the Scientist Speaker’s Bureau. Submit your information into the short form at http://www.lpi.usra.edu/education/speaker.

Erythropoietin and carbamylated erythropoietin promote histone deacetylase 5 phosphorylation and nuclear export in rat hippocampal neurons

International Nuclear Information System (INIS)

Jo, Hye-Ryeong; Kim, Yong-Seok; Son, Hyeon

2016-01-01

Erythropoietin (EPO) produces neurotrophic effects in animal model of neurodegeneration. However, clinical use of EPO is limited due to thrombotic risk. Carbamylated EPO (cEPO), devoid of thrombotic risk, has been proposed as a novel neuroprotective and neurotrophic agent although the molecular mechanisms of cEPO remain incomplete. Here, we show a previously unidentified role of histone deacetylase 5 (HDAC5) in the actions of EPO and cEPO. EPO and cEPO regulate the HDAC5 phosphorylation at two critical sites, Ser259 and Ser498 through a protein kinase D (PKD) dependent pathway. In addition, EPO and cEPO rapidly stimulates nuclear export of HDAC5 in rat hippocampal neurons which expressing HDAC5-GFP. Consequently, EPO and cEPO enhanced the myocyte enhancer factor-2 (MEF2) target gene expression. Taken together, our results reveal that EPO and cEPO mediate MEF2 target gene expression via the regulation of HDAC5 phosphorylation at Ser259/498, and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of EPO and cEPO.

Erythropoietin and carbamylated erythropoietin promote histone deacetylase 5 phosphorylation and nuclear export in rat hippocampal neurons

Energy Technology Data Exchange (ETDEWEB)

Jo, Hye-Ryeong [Department of Biomedical Sciences, Graduate School of Biomedical Science and Engineering (Korea, Republic of); Kim, Yong-Seok [Department of Biomedical Sciences, Graduate School of Biomedical Science and Engineering (Korea, Republic of); Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791 (Korea, Republic of); Son, Hyeon, E-mail: hyeonson@hanyang.ac.kr [Department of Biomedical Sciences, Graduate School of Biomedical Science and Engineering (Korea, Republic of); Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791 (Korea, Republic of)

2016-01-29

Erythropoietin (EPO) produces neurotrophic effects in animal model of neurodegeneration. However, clinical use of EPO is limited due to thrombotic risk. Carbamylated EPO (cEPO), devoid of thrombotic risk, has been proposed as a novel neuroprotective and neurotrophic agent although the molecular mechanisms of cEPO remain incomplete. Here, we show a previously unidentified role of histone deacetylase 5 (HDAC5) in the actions of EPO and cEPO. EPO and cEPO regulate the HDAC5 phosphorylation at two critical sites, Ser259 and Ser498 through a protein kinase D (PKD) dependent pathway. In addition, EPO and cEPO rapidly stimulates nuclear export of HDAC5 in rat hippocampal neurons which expressing HDAC5-GFP. Consequently, EPO and cEPO enhanced the myocyte enhancer factor-2 (MEF2) target gene expression. Taken together, our results reveal that EPO and cEPO mediate MEF2 target gene expression via the regulation of HDAC5 phosphorylation at Ser259/498, and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of EPO and cEPO.

Student artistry sparks eclipse excitement on Maui: NSO/DKIST EPO for the 2016 Partial Solar Eclipse

Science.gov (United States)

Schad, Thomas A.; Penn, Matthew J.; Armstrong, James

2016-05-01

Local creativity and artistry is a powerful resource that enhances education programs and helps us generate excitement for science within our communities. In celebration of the 2016 Solar Eclipse, the National Solar Observatory (NSO) and its Daniel K Inouye Solar Telescope (DKIST) project were pleased to engage with students across Maui County, Hawai`i, via the 2016 Maui Eclipse Art Contest. With the help of the Maui Economic Development Board and the University of Hawai'is Institute for Astronomy, we solicited art entries from all K-12 schools in Maui County approximately 6 months prior to the eclipse. Along with divisional prizes, a grand prize was selected by a panel of local judges, which was subsequently printed on 25,000 solar eclipse viewing glasses and distributed to all Maui students. We found that the impact of a locally-sourced glasses design cannot be understated. Overall, the success of this program relied upon reaching out to individual teachers, supplying educational flyers to all schools, and visiting classrooms. On the day of the eclipse, all of the art entries were prominently displayed during a community eclipse viewing event at Kalama Beach Park in Kihei, HI, that was co-hosted by NSO and the Maui Science Center. This eclipse art contest was integral to making local connections to help promote science education on Maui, and we suggest that it could be adapted to the solar community's EPO activities for the upcoming 2017 Great American Solar Eclipse.

Biosimilar versus patented erythropoietins: learning from 5 years of European and Japanese experience.

Science.gov (United States)

Bocquet, François; Paubel, Pascal; Fusier, Isabelle; Cordonnier, Anne-Laure; Sinègre, Martine; Le Pen, Claude

2015-02-01

Patent expiries on leading biologics are creating new momentum in the market for biosimilars (copies of off-patent biologics), paving the way for their development. However, little is known about the factors influencing the competition between biosimilars and their reference products (REF). The aim of this study was to analyse key global erythropoietin (EPO) markets and factors affecting biosimilar EPO (BIOSIM-EPO) uptakes, and to identify countries where BIOSIM-EPOs have gained significant market shares. Inclusion criteria for countries in the study were a biosimilar regulatory framework similar to the EU framework, and biological market value higher than US$2.5 billion. Factors evaluated included EPO market size, EPO retail/hospital distribution mix, national incentives to use biosimilars and BIOSIM-EPO/REF price differences. IMS Health provided EPO consumption in volumes, values, and EPO ex-manufacturer prices from 2007 to 2012. Japan: large-sized market, mixed retail/hospital distribution, no incentives, low BIOSIM-EPO uptake (6.8 % in 2012). France: large-sized market, dominant retail distribution, no incentives, low BIOSIM-EPO uptake (5.8 %). Spain and Italy: medium-sized market, dominant hospital distribution, no incentives, moderate BIOSIM-EPO uptakes (11.5 and 8.6 %). Germany: small-sized market, dominant retail distribution, presence of incentives, high BIOSIM-EPO uptake (30.4 %). UK: small-sized market, mixed retail/hospital distribution, no incentives, low BIOSIM-EPO uptake (2.0 %). BIOSIM-EPO/REF price differences play no role at a global level (-10.8 % in Germany and -26.9 % in Japan). EPO markets have proven to be highly country-specific. EPO market sizes, EPO retail/hospital distribution mixes and BIOSIM-EPO/REF price differences may not be determining factors of BIOSIM-EPO uptakes. Prescription and substitution incentives to use BIOSIM-EPO appear to be determining factors in Germany. The heterogeneity of national EPO markets makes it

Effect of occasional epoetin use in combination with a stable darbepoetin dosage on anemia management in hemodialysis patients

Directory of Open Access Journals (Sweden)

Shimamatsu K

2014-12-01

Full Text Available Kazumasa Shimamatsu Shimamatsu Naika Iin (Clinic, Shiseikai Medical Corporation, Chikushino City, Japan Aim: Taking advantage of the characteristics of both darbepoetin (DA and epoetin (EPO might be a reasonable option for stabilizing hemoglobin (Hb control in hemodialysis (HD patients. The effect of DA assisted by EPO (DA/EPO on Hb control was evaluated retrospectively in comparison with that of EPO monotherapy. Methods: Twenty-six HD patients whose annual mean Hb values were available for both an EPO monotherapy period and a DA/EPO period were selected for analysis. During the DA/EPO period, DA was given on the second HD day of a week, and EPO was given if needed on the first and third HD days. Under stable DA dosage, when Hb rose >12 g/dL, EPO was eliminated. When Hb decreased <10 g/dL, EPO was added again. The variability of annual mean Hb values from the 26 HD patients during the DA/EPO period was compared with that during the EPO period. Additionally, the distance in Hb (d-Hb; absolute value of difference between the annual mean Hb values and the target Hb (11 g/dL during the DA/EPO period was compared with that during the EPO period. Results: The variability of annual mean Hb values during the DA/EPO period was significantly smaller than that during the EPO period (11.2±0.25 g/dL versus [vs] 11.0±0.50 g/dL; the F-test for equality of variance, P<0.001. Additionally, the d-Hb during the DA/EPO period was significantly smaller than that during the EPO period (0.22±0.21 g/dL vs 0.38±0.31 g/dL, P<0.03. The total doses (as EPO equivalents of DA with EPO were reduced to 82.2% of the baseline EPO dose during the EPO monotherapy period. The expenditure for the DA/EPO period was significantly reduced to 80.9% of that for the EPO monotherapy. Also, the annual total amount of intravenous iron supplementation during the DA/EPO period was significantly reduced compared with that during the EPO period (546±304 mg/year vs 684±314 mg/year, P<0

Receptor-receptor interactions within receptor mosaics. Impact on neuropsychopharmacology.

Science.gov (United States)

Fuxe, K; Marcellino, D; Rivera, A; Diaz-Cabiale, Z; Filip, M; Gago, B; Roberts, D C S; Langel, U; Genedani, S; Ferraro, L; de la Calle, A; Narvaez, J; Tanganelli, S; Woods, A; Agnati, L F

2008-08-01

Future therapies for diseases associated with altered dopaminergic signaling, including Parkinson's disease, schizophrenia and drug addiction or drug dependence may substantially build on the existence of intramembrane receptor-receptor interactions within dopamine receptor containing receptor mosaics (RM; dimeric or high-order receptor oligomers) where it is believed that the dopamine D(2) receptor may operate as the 'hub receptor' within these complexes. The constitutive adenosine A(2A)/dopamine D(2) RM, located in the dorsal striato-pallidal GABA neurons, are of particular interest in view of the demonstrated antagonistic A(2A)/D(2) interaction within these heteromers; an interaction that led to the suggestion and later demonstration that A(2A) antagonists could be used as novel anti-Parkinsonian drugs. Based on the likely existence of A(2A)/D(2)/mGluR5 RM located both extrasynaptically on striato-pallidal GABA neurons and on cortico-striatal glutamate terminals, multiple receptor-receptor interactions within this RM involving synergism between A(2A)/mGluR5 to counteract D(2) signaling, has led to the proposal of using combined mGluR5 and A(2A) antagonists as a future anti-Parkinsonian treatment. Based on the same RM in the ventral striato-pallidal GABA pathways, novel strategies for the treatment of schizophrenia, building on the idea that A(2A) agonists and/or mGluR5 agonists will help reduce the increased dopaminergic signaling associated with this disease, have been suggested. Such treatment may ensure the proper glutamatergic drive from the mediodorsal thalamic nucleus to the prefrontal cortex, one which is believed to be reduced in schizophrenia due to a dominance of D(2)-like signaling in the ventral striatum. Recently, A(2A) receptors also have been shown to counteract the locomotor and sensitizing actions of cocaine and increases in A(2A) receptors have also been observed in the nucleus accumbens after extended cocaine self-administration, probably

Epoetin Alpha and Epoetin Zeta: A Comparative Study on Stimulation of Angiogenesis and Wound Repair in an Experimental Model of Burn Injury.

Science.gov (United States)

Irrera, Natasha; Bitto, Alessandra; Pizzino, Gabriele; Vaccaro, Mario; Squadrito, Francesco; Galeano, Mariarosaria; Stagno d'Alcontres, Francesco; Stagno d'Alcontres, Ferdinando; Buemi, Michele; Minutoli, Letteria; Colonna, Michele Rosario; Altavilla, Domenica

2015-01-01

Deep second-degree burns are characterized by delayed formation of granulation tissue and impaired angiogenesis. Erythropoietin (EPO) is able to stimulate angiogenesis and mitosis, activating vascularization and cell cycle. The aim of our study was to investigate whether two biosimilar recombinant human erythropoietins, EPO-α and EPO-Z, may promote these processes in an experimental model of burn injury. A total of 84 mice were used and a scald burn was produced on the back after shaving, in 80°C water for 10 seconds. Mice were then randomized to receive EPO-α (400 units/kg/day/sc) or EPO-Z (400 units/kg/day/sc) or their vehicle (100 μL/day/sc 0.9% NaCl solution). After 12 days, both EPO-α and EPO-Z increased VEGF protein expression. EPO-α caused an increased cyclin D1/CDK6 and cyclin E/CDK2 expression compared with vehicle and EPO-Z (p<0.001). Our study showed that EPO-α and EPO-Z accelerated wound closure and angiogenesis; however EPO-α resulted more effectively in achieving complete skin regeneration. Our data suggest that EPO-α and EPO-Z are not biosimilars for the wound healing effects. The higher efficacy of EPO-α might be likely due to its different conformational structure leading to a more efficient cell proliferation and skin remodelling.

Stability of erythropoietin repackaging in polypropylene syringes for clinical use

Directory of Open Access Journals (Sweden)

Angela Marsili

2017-02-01

Full Text Available Introduction: Epoetin alfa (Eprex® is a subcutaneous, injectable formulation of short half-life recombinant human erythropoietin (rHuEPO. To current knowledge there are no published studies regarding the stability of rHuEPO once repackaging occurs (r-EPO for clinical trial purposes. Materials and methods: We assessed EPO concentration in Eprex® and r-EPO syringes at 0, 60, 90, and 120 days after repackaging in polypropylene syringes. R-EPO was administered to 56 patients taking part in a clinical trial in Friedreich Ataxia. Serum EPO levels were measured at baseline and 48 h after r-EPO administration. Results: No differences were found between r-EPO and Eprex® syringes, but both globally decreased in total EPO content during storage at 4 °C. Patients receiving r-EPO had similar levels in EPO content as expected from previous trials in Friedreich Ataxia and from pharmacokinetics studies in healthy volunteers. Discussion: We demonstrate that repackaging of EPO does not alter its concentration if compared to the original product (Eprex®. This is true both for repackaging procedures and for the stability in polypropylene tubes. The expiration date of r-EPO can be extended from 1 to 4 months after repackaging, in accordance with pharmacopeia rules.

Designing a Long Acting Erythropoietin by Fusing Three Carboxyl-Terminal Peptides of Human Chorionic Gonadotropin β Subunit to the N-Terminal and C-Terminal Coding Sequence

Directory of Open Access Journals (Sweden)

Fuad Fares

2011-01-01

Full Text Available A new analog of EPO was designed by fusing one and two CTPs to the N-terminal and C-terminal ends of EPO (EPO-(CTP3, respectively. This analog was expressed and secreted efficiently in CHO cells. The in vitro test shows that the activity of EPO-(CTP3 in TFI-1 cell proliferation assay is similar to that of EPO-WT and commercial rHEPO. However, in vivo studies indicated that treatment once a week with EPO-(CTP3 (15 μg/kg dramatically increased (~8 folds haematocrit as it was compared to rHuEPO. Moreover, it was found that EPO-(CTP3 is more effective than rHuEPO and Aranesp in increasing reticulocyte number in mice blood. The detected circulatory half-lives of rHuEPO, Aranesp, and EPO-(CTP3 following IV injection of 20 IU were 4.4, 10.8, and 13.1 h, respectively. These data established the rational for using this chimera as a long-acting EPO analog in clinics. The therapeutic efficacy of EPO-CTP analog needs to be established in higher animals and in human clinical trials.

Time course of the hemoglobin mass response to natural altitude training in elite endurance cyclists.

Science.gov (United States)

Garvican, L; Martin, D; Quod, M; Stephens, B; Sassi, A; Gore, C

2012-02-01

To determine the time course of hemoglobin mass (Hb(mass)) to natural altitude training, Hb(mass), erythropoietin [EPO], reticulocytes, ferritin and soluble transferrin receptor (sTfR) were measured in 13 elite cyclists during, and 10 days after, 3 weeks of sea level (n=5) or altitude (n=8, 2760 m) training. Mean Hb(mass), with a typical error of ∼2%, increased during the first 11 days at altitude (mean ± standard deviation 2.9 ± 2.0%) and was 3.5 ± 2.5% higher than baseline after 19 days. [EPO] increased 64.2 ± 18.8% after 2 nights at altitude but was not different from baseline after 12 nights. Hb(mass) and [EPO] did not increase in sea level. Reticulocytes (%) were slightly elevated in altitude at Days 5 and 12 (18.9 ± 17.7% and 20.4 ± 25.3%), sTfR was elevated at Day 12 (18.9 ± 15.0%), but both returned to baseline by Day 20. Hb(mass) and [EPO] decreased on descent to sea level while ferritin increased. The mean increase in Hb(mass) observed after 11 days (∼300 h) of altitude training was beyond the measurement error and consitent with the mean increase after 300 h of simulated live high:train low altitude. Our results suggest that in elite cyclists, Hb(mass) increases progressively with 3 weeks of natural altitude exposure, with greater increases expected as exposure persists. © 2010 John Wiley & Sons A/S.

Profile of peginesatide and its potential for the treatment of anemia in adults with chronic kidney disease who are on dialysis.

Science.gov (United States)

Mikhail, Ashraf

2012-01-01

Peginesatide is a synthetic, dimeric peptide that is covalently linked to polyethylene glycol (PEG). The amino acid sequence of peginesatide is unrelated to that of erythropoietin (EPO) and is not immunologically cross-reactive with EPO. Peginesatide binds to and activates the human EPO receptor, stimulating the proliferation and differentiation of human red cell precursors in vitro in a manner similar to other EPO-stimulating agents (ESAs). In Phase II and III studies in dialysis and predialysis patients, peginesatide administered once monthly was as effective as epoetin alfa given thrice weekly (dialysis patients) or darbepoetin given once weekly (nondialysis patients), in correcting anemia of chronic kidney disease as well as maintaining hemoglobin within the desired target range. In the dialysis population, the reported side-effect profile of peginesatide was comparable to that known with other marketed ESAs. In the nondialysis studies, compared with those treated with darbepoetin, patients treated with peginesatide experienced a higher adverse-effect profile. Peginesatide is likely to be licensed for treatment of renal anemia in dialysis patients and not in nondialysis patients. Despite this limitation, peginesatide is likely to prove valuable in treating dialysis patients because of its infrequent mode of administration, thereby allowing for a reduced number of injections, with associated better compliance, reduced cold storage requirement, and improved stock accountability. PEGylated therapeutic proteins can elicit immunological response to the PEG moiety of the therapeutic complex. Only long-term experience and post-marketing surveillance will address whether this immunological response will have any impact on the clinical efficacy or safety of peginesatide in clinical practice.

Lack of acute cardioprotective effect from preischaemic erythropoietin administration in a porcine coronary occlusion model

DEFF Research Database (Denmark)

Kristensen, Jens; Mæng, Michael; Rehling, Michael

2005-01-01

preconditioning may be involved. Before clinical testing such possible cardioprotective effects needs assessment in an experimental large animal model with closer similarity to human ischaemic pathophysiology. METHODS: A control group and two rhEPO groups were studied. EPO1 pigs were given EPO corresponding...... by myocardial perfusion imaging (MPI) and postmortem by a histochemical procedure (at 150 min of reperfusion). RESULTS: IS/AAR did not differ significantly between control (C), EPO1 and EPO2 groups, neither measured by MPI (mean+/-SD for C: 0.87+/-0.13; EPO1: 0.92+/-0.08; EPO2: 0.87+/-0.11), nor histochemically...... (mean+/-SD for C: 0.64+/-0.20; EPO1: 0.75+/-0.17; EPO2: 0.80+/-0.07). In the EPO2 group mean arterial pulmonary pressure and dP/dtmax were increased compared with control group. CONCLUSION: Despite promising results from studies in rodents, rhEPO did not reduce infarct size measured after 2.5 h...

Vitamin K3-2,3-epoxide induction of apoptosis with activation of ROS-dependent ERK and JNK protein phosphorylation in human glioma cells.

Science.gov (United States)

Wu, Jender; Chien, Chih-Chiang; Yang, Liang-Yo; Huang, Guan-Cheng; Cheng, Min-Chi; Lin, Che-Tong; Shen, Shing-Chuan; Chen, Yen-Chou

2011-08-15

2-Methyl-1,4-naphthoquinone (menadione or vitamin K3; EPO) and K3-2,3-epoxide (EPO1), but not vitamin K3-3-OH (EPO2), exhibited cytotoxicity that caused DNA fragmentation and chromatin condensation in U87 and C6 cells. EPO1 showed more-potent cytotoxicity than EPO, and the IC(50) values of EPO and EPO1 in U87 cells were 37.5 and 15.7μM, respectively. Activation of caspase 3 enzyme activity with cleavage of caspase 3 protein was detected in EPO1-treated U87 and C6 cells, and the addition of the caspase 3 peptidyl inhibitor, DEVD-FMK, reduced the cytotoxic effect of EPO1. An increase in the intracellular ROS level by EPO1 was observed in the DCHF-DA analysis, and EPO1-induced apoptosis and caspase 3 protein cleavage were prevented by adding the antioxidant, N-acetyl-cysteine (NAC), with decreased ROS production elicited by EPO1. Activation of ERK and JNK, but not p38, via phosphorylation induction was identified in EPO1- but not EPO- or EPO2-treated U87 and C6 cells, and this was blocked by adding NAC. However, the ERK inhibitor, PD98059, and the JNK inhibitor, SP600125, showed no effect on EPO1-induced cytotoxicity in either cell type. Our findings demonstrate that 2,3-epoxide substitution significantly potentiates the apoptotic effect of vitamin K3 via stimulating ROS production, which may be useful in the chemotherapy of glioblastoma cells. Copyright © 2011. Published by Elsevier Ireland Ltd.

Communities of Practice Transition Online - Lessons learned from NASA's EPO Online Workspace

Science.gov (United States)

Davey, B.

2012-12-01

The Earth Forum Education and Public Outreach (EP/O) community has long interacted to better their practice as a community as well as individually. Working together to share knowledge and grow, they function as a community of practice. In 2009, NASA designed and implemented an online workspace in hopes of promoting the communities continued interactions. This study examines the role of an online workspace component of a community in the work of a community of practice. Much has been studied revealing the importance of communities of practice to organizations, project success, and knowledge management and some of these same successes hold true for virtual communities of practice. Study participants were 75 Education and Public Outreach community members of NASA's Science Mission Directorate Earth Forum. In this mixed methods study, online workspace metrics were used to track participation and a survey completed by 21 members was used to quantify participation. For a more detailed analysis, 15 community members (five highly active users, five average users, and five infrequent users) selected based on survey responses, were interviewed. Finally, survey data was gathered from seven online facilitators to understand their role in the community. Data collected from these 21 community members and five facilitating members suggest that highly active users (logging into the workspace daily), were more likely to have transformative experiences, co-create knowledge, feel ownership of community knowledge, have extended opportunities for community exchange, and find new forms of evaluation. Average users shared some similar characteristics with both the highly active members and infrequent users, representing a group in transition as they become more engaged and active in the online workspace. Inactive users viewed the workspace as having little value, being difficult to navigate, being mainly for gaining basic information about events and community news, and as another demand

Adoption of the B2SAFE EUDAT replication service by the EPOS community

Science.gov (United States)

Cacciari, Claudio; Fares, Massimo; Fiameni, Giuseppe; Michelini, Alberto; Danecek, Peter; Wittenburg, Peter

2014-05-01

B2SAFE is the EUDAT service for moving and replicating data between sites and storage systems for different purposes. The goal of B2SAFE is to keep the data from a repository safe by replicating it across different geographical and administrative zones according to a set of well-defined policies. It is also a way to store large volumes of data permanently at those sites which are providing powerful on-demand data analysis facilities. In particular, B2SAFE operates on the domain of registered data where data objects are referable via persistent identifiers (PIDs). B2SAFE is more than just copying data because the PIDs must be carefully managed when data objects are moved or replicated. The EUDAT B2SAFE Service offers functionality to replicate datasets across different data centres in a safe and efficient way while maintaining all information required to easily find and query information about the replica locations. The information about the replica locations and other important information is stored in PID records, each managed in separate administrative domains. The B2SAFE Service is implemented as an iRODS module providing a set of iRODS rules or policies to interface with the EPIC handle API and uses the iRODS middleware to replicate datasets from a source data (or community) centre to a destination data centre. The definition of the dataset(s) to replicate is flexible and up to the communities using the B2SAFE service. While the B2SAFE is internally using the EPIC handle API, communities have the choice to use any PID system they prefer to assign PIDs to their digital objects. A reference to one or more EUDAT B2SAFE PIDs is returned by the B2SAFE service when a dataset is replicated. The presentation will introduce the problem space of B2SAFE, presents the achievements that have been made during the last year for enabling communities to make use of the B2SAFE service, demonstrates a EPOS use cases, outlines the commonalities and differences between the policies

Aberrant expression of erythropoietin in uterine leiomyoma: implications in tumor growth.

Science.gov (United States)

Asano, Ryoko; Asai-Sato, Mikiko; Miyagi, Yohei; Mizushima, Taichi; Koyama-Sato, Makiko; Nagashima, Yoji; Taguri, Masataka; Sakakibara, Hideya; Hirahara, Fumiki; Miyagi, Etsuko

2015-08-01

Myomatous erythrocytosis syndrome is a rare complication of uterine leiomyoma caused by erythropoietin (EPO) that is produced by tumor cells. We assessed the EPO expression in leiomyomas and investigated the effects of EPO on the tumor growth. Tissue samples were collected from 114 patients with uterine leiomyomas who underwent myomectomy or hysterectomy in Yokohama City University Hospital. From 17 patients, the corresponding normal myometrium was also collected. All samples were analyzed for EPO messenger RNA (mRNA) expression by real-time reverse transcription-polymerase chain reaction. EPO protein expression was determined by an enzyme-linked immunosorbent assay. The relationships between EPO expression and clinicopathological features were retrospectively analyzed using the patients' charts. Blood vessel density and maturity were assessed using hematoxylin-eosin staining and CD34 immunohistochemistry. EPO mRNA expression was detected in 108 of 114, or 95%, of the leiomyomas. The mean EPO mRNA expression in the leiomyoma was higher than the corresponding normal myometrium (3836 ± 4122 vs 1455 ± 2141; P = .025 by Wilcoxon rank test). The EPO mRNA expression in the leiomyomas varied extensively among samples, ranging from undetectable levels to 18-fold above the mean EPO mRNA of normal myometrium. EPO protein production was observed concomitant with mRNA expression. A positive correlation of leiomyoma size and EPO mRNA expression was shown by Spearman rank correlation coefficient (ρ = 0.294; P = .001), suggesting the involvement of EPO in leiomyoma growth. The blood vessel maturity was also significantly increased in EPO-producing leiomyomas (high vessel maturity in high vs low EPO group: 67% vs 20%; P = .013 by Fisher exact test). This report demonstrates that EPO is produced in most of conventional leiomyomas and supports a model in which EPO accelerates tumor growth, possibly by inducing vessel maturity. Our study suggests one possible mechanism by which

A Partnership between English Language Learners and a Team of Rocket Scientists: EPO for the NASA SDO Extreme Ultraviolet Variability Experiment (EVE)

Science.gov (United States)

Buhr, S. M.; McCaffrey, M. S.; Eparvier, F.; Murillo, M.

2008-05-01

Recent immigrant high school students were successfully engaged in learning about Sun-Earth connections through a partnership with the NASA Solar Dynamics Observatory Extreme Ultraviolet Variability Experiment (EVE) project. The students were enrolled in a pilot course as part of the Math, Engineering and Science Achievement (MESA) program. The English Language Learner (ELL) students doubled their achievement on a pre- and post- assessment on the content of the course. Students learned scientific content and vocabulary in English with support in Spanish, attended field trips, hosted scientist speakers, built antenna and deployed space weather monitors as part of the Stanford SOLAR project, and gave final presentations in English, showcasing their new computer skills. Teachers who taught the students in other courses noted gains in the students' willingness to use English in class and noted gains in math skills. The course has been broken into modules for use in shorter after-school environments, or for use by EVE scientists who are outside of the Boulder area. Video footage of "The Making of a Satellite", and "All About EVE" is completed for use in the kits. Other EVE EPO includes upcoming professional development for teachers and content workshops for journalists.

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.

Near Fault Observatories: multidisciplinary research infrastructures, high resolution data and scientific products available through dedicated services implemented within the EPOS-IP project

Science.gov (United States)

Festa, Gaetano; Chiaraluce, Lauro; Ergintav, Semih; Bernard, Pascal; Clinton, John; Marmureanu, Alexandru; Tataru, Dragos; Vogfjord, Kristin

2017-04-01

Near Fault Observatories (NFOs) are innovative research infrastructures based on dense, state of the art networks of multi-parametric sensors that continuously monitor the underlying Earth instability processes over a broad time interval. They aim at understanding the physical/chemical processes responsible for earthquakes and faulting and tracking their evolution over time by enabling advancements in ground shaking prediction. EPOS-IP is aimed at contributing in creating and harmonizing data and products distributors from seven NFOs, operating on different tectonic regimes and different areas of Europe. They include plate boundary systems at South Iceland Seismic Zone, the Marmara Sea and the Corinth rift. In mountain settings, NFOs monitor the Alto Tiberina and Irpinia faults in the Apennine mountain range, the Valais region in the Alps, and the Vrancea fault in the Carpathian Mountains. They monitor diverse faulting mechanisms (strike-slip, normal and thrust), high to low angle faults, shallow and deep faults, as well as regions with fast and slow strain rate accumulation. The focus of the observatories varies, ranging from small- to large-scale seismicity and includes the role of different parameters such as fluid playing in fault initiation, the internal structure of fault systems, site effects and derived processes such as earthquake generated landslides and tsunamis. In response to their specific objectives, the NFOs operate a diverse set of monitoring instrumentation using seismic, deformation, strain, geochemical and electromagnetic equipment. Since NFO methodological approach is based on extremely dense networks and less common instruments deserving multi-parameter data description, a main goal of this group is to build inclusive and harmonised services supporting the installation over the next decade of tens of near-fault observatories monitoring active faults in different tectonic environments in Europe. The NFO Thematic Core Service (TCS) relies on

Profile of peginesatide and its potential for the treatment of anemia in adults with chronic kidney disease who are on dialysis

Directory of Open Access Journals (Sweden)

Mikhail A

2012-05-01

Full Text Available Ashraf MikhailRenal Unit, Morriston Hospital, Swansea University, Wales, UKAbstract: Peginesatide is a synthetic, dimeric peptide that is covalently linked to polyethylene glycol (PEG. The amino acid sequence of peginesatide is unrelated to that of erythropoietin (EPO and is not immunologically cross-reactive with EPO. Peginesatide binds to and activates the human EPO receptor, stimulating the proliferation and differentiation of human red cell precursors in vitro in a manner similar to other EPO-stimulating agents (ESAs. In Phase II and III studies in dialysis and predialysis patients, peginesatide administered once monthly was as effective as epoetin alfa given thrice weekly (dialysis patients or darbepoetin given once weekly (nondialysis patients, in correcting anemia of chronic kidney disease as well as maintaining hemoglobin within the desired target range. In the dialysis population, the reported side-effect profile of peginesatide was comparable to that known with other marketed ESAs. In the nondialysis studies, compared with those treated with darbepoetin, patients treated with peginesatide experienced a higher adverse-effect profile. Peginesatide is likely to be licensed for treatment of renal anemia in dialysis patients and not in nondialysis patients. Despite this limitation, peginesatide is likely to prove valuable in treating dialysis patients because of its infrequent mode of administration, thereby allowing for a reduced number of injections, with associated better compliance, reduced cold storage requirement, and improved stock accountability. PEGylated therapeutic proteins can elicit immunological response to the PEG moiety of the therapeutic complex. Only long-term experience and post-marketing surveillance will address whether this immunological response will have any impact on the clinical efficacy or safety of peginesatide in clinical practice.Keywords: peginesatide, dialysis, chronic kidney disease

Erythropoietin over-expression protects against diet-induced obesity in mice through increased fat oxidation in muscles.

Science.gov (United States)

Hojman, Pernille; Brolin, Camilla; Gissel, Hanne; Brandt, Claus; Zerahn, Bo; Pedersen, Bente Klarlund; Gehl, Julie

2009-06-12

Erythropoietin can be over-expressed in skeletal muscles by gene electrotransfer, resulting in 100-fold increase in serum EPO and significant increases in haemoglobin levels. Earlier studies have suggested that EPO improves several metabolic parameters when administered to chronically ill kidney patients. Thus we applied the EPO over-expression model to investigate the metabolic effect of EPO in vivo.At 12 weeks, EPO expression resulted in a 23% weight reduction (Pincrease in muscle volume and a 25% increase in vascularisation of the EPO transfected muscle. Muscle force and stamina were not affected by EPO expression. PCR array analysis revealed that genes involved in lipid metabolism, thermogenesis and inflammation were increased in muscles in response to EPO expression, while genes involved in glucose metabolism were down-regulated. In addition, muscular fat oxidation was increased 1.8-fold in both the EPO transfected and contralateral muscles.In conclusion, we have shown that EPO when expressed in supra-physiological levels has substantial metabolic effects including protection against diet-induced obesity and normalisation of glucose sensitivity associated with a shift to increased fat metabolism in the muscles.

Somatostatin receptors

DEFF Research Database (Denmark)

Møller, Lars Neisig; Stidsen, Carsten Enggaard; Hartmann, Bolette

2003-01-01

functional units, receptors co-operate. The total receptor apparatus of individual cell types is composed of different-ligand receptors (e.g. SRIF and non-SRIF receptors) and co-expressed receptor subtypes (e.g. sst(2) and sst(5) receptors) in characteristic proportions. In other words, levels of individual......-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...

Erythropoietin over-expression protects against diet-induced obesity in mice through increased fat oxidation in muscles.

Directory of Open Access Journals (Sweden)

Pernille Hojman

Full Text Available Erythropoietin can be over-expressed in skeletal muscles by gene electrotransfer, resulting in 100-fold increase in serum EPO and significant increases in haemoglobin levels. Earlier studies have suggested that EPO improves several metabolic parameters when administered to chronically ill kidney patients. Thus we applied the EPO over-expression model to investigate the metabolic effect of EPO in vivo.At 12 weeks, EPO expression resulted in a 23% weight reduction (P<0.01 in EPO transfected obese mice; thus the mice weighed 21.9+/-0.8 g (control, normal diet, 21.9+/-1.4 g (EPO, normal diet, 35.3+/-3.3 g (control, high-fat diet and 28.8+/-2.6 g (EPO, high-fat diet. Correspondingly, DXA scanning revealed that this was due to a 28% reduction in adipose tissue mass.The decrease in adipose tissue mass was accompanied by a complete normalisation of fasting insulin levels and glucose tolerance in the high-fat fed mice. EPO expression also induced a 14% increase in muscle volume and a 25% increase in vascularisation of the EPO transfected muscle. Muscle force and stamina were not affected by EPO expression. PCR array analysis revealed that genes involved in lipid metabolism, thermogenesis and inflammation were increased in muscles in response to EPO expression, while genes involved in glucose metabolism were down-regulated. In addition, muscular fat oxidation was increased 1.8-fold in both the EPO transfected and contralateral muscles.In conclusion, we have shown that EPO when expressed in supra-physiological levels has substantial metabolic effects including protection against diet-induced obesity and normalisation of glucose sensitivity associated with a shift to increased fat metabolism in the muscles.

The Nasal Route as a Potential Pathway for Delivery of Erythropoietin in the Treatment of Acute Ischemic Stroke in Humans

Directory of Open Access Journals (Sweden)

Julio Cesar García-Rodríguez

2009-01-01

Full Text Available Intranasal delivery provides a practical, noninvasive method of bypassing the blood-brain barrier (BBB in order to deliver therapeutic agents to the brain. This method allows drugs that do not cross the BBB to be delivered to the central nervous system in a few minutes. With this technology, it will be possible to eliminate systemic administration and its potential side effects. Using the intranasal delivery system, researchers have demonstrated neuroprotective effects in different animal models of stroke using erythropoietin (EPO as a neuroprotector or other different types of EPO without erythropoiesis-stimulating activity. These new molecules retain their ability to protect neural tissue against injury and they include Asialoerythropoietin (asialoEPO carbamylated EPO (CEPO, and rHu-EPO with low sialic acid content (Neuro-EPO. Contrary to the other EPO variants, Neuro-EPO is not chemically modified, making it biologically similar to endogenous EPO, with the advantage of less adverse reactions when this molecule is applied chronically. This constitutes a potential benefit of Neuro-EPO over other variants of EPO for the chronic treatment of neurodegenerative illnesses. Nasal administration of EPO is a potential, novel, neurotherapeutic approach. However, it will be necessary to initiate clinical trials in stroke patients using intranasal delivery in order to obtain the clinical evidence of its neuroprotectant capacity in the treatment of patients with acute stroke and other neurodegenerative disorders. This new therapeutic approach could revolutionize the treatment of neurodegenerative disorders in the 21st century.

Erythropoietin reduces the expression of myostatin in mdx dystrophic mice

International Nuclear Information System (INIS)

Feder, D.; Rugollini, M.; Santomauro, A. Jr; Oliveira, L.P.; Lioi, V.P.; Santos, R. dos; Ferreira, L.G.; Nunes, M.T.; Carvalho, M.H.; Delgado, P.O.; Carvalho, A.A.S.; Fonseca, F.L.A.

2014-01-01

Erythropoietin (EPO) has been well characterized as a renal glycoprotein hormone regulating red blood cell production by inhibiting apoptosis of erythrocyte progenitors in hematopoietic tissues. EPO exerts regulatory effects in cardiac and skeletal muscles. Duchenne muscular dystrophy is a lethal degenerative disorder of skeletal and cardiac muscle. In this study, we tested the possible therapeutic beneficial effect of recombinant EPO (rhEPO) in dystrophic muscles in mdx mice. Total strength was measured using a force transducer coupled to a computer. Gene expression for myostatin, transforming growth factor-β1 (TGF-β1), and tumor necrosis factor-α (TNF-α) was determined by quantitative real time polymerase chain reaction. Myostatin expression was significantly decreased in quadriceps from mdx mice treated with rhEPO (rhEPO=0.60±0.11, control=1.07±0.11). On the other hand, rhEPO had no significant effect on the expression of TGF-β1 (rhEPO=0.95±0.14, control=1.05±0.16) and TNF-α (rhEPO=0.73±0.20, control=1.01±0.09). These results may help to clarify some of the direct actions of EPO on skeletal muscle

Erythropoietin reduces the expression of myostatin in mdx dystrophic mice

Energy Technology Data Exchange (ETDEWEB)

Feder, D.; Rugollini, M.; Santomauro, A. Jr; Oliveira, L.P.; Lioi, V.P. [Faculdade de Medicina do ABC, Santo André, SP (Brazil); Santos, R. dos; Ferreira, L.G.; Nunes, M.T.; Carvalho, M.H. [Universidade de São Paulo, Instituto de Ciências Biomédicas, São Paulo, SP (Brazil); Delgado, P.O.; Carvalho, A.A.S. [Faculdade de Medicina do ABC, Santo André, SP (Brazil); Fonseca, F.L.A. [Faculdade de Medicina do ABC, Santo André, SP (Brazil); Universidade Federal de São Paulo, Ambientais e Farmacêuticas, Instituto de Ciências Químicas, Diadema, SP (Brazil)

2014-09-05

Erythropoietin (EPO) has been well characterized as a renal glycoprotein hormone regulating red blood cell production by inhibiting apoptosis of erythrocyte progenitors in hematopoietic tissues. EPO exerts regulatory effects in cardiac and skeletal muscles. Duchenne muscular dystrophy is a lethal degenerative disorder of skeletal and cardiac muscle. In this study, we tested the possible therapeutic beneficial effect of recombinant EPO (rhEPO) in dystrophic muscles in mdx mice. Total strength was measured using a force transducer coupled to a computer. Gene expression for myostatin, transforming growth factor-β1 (TGF-β1), and tumor necrosis factor-α (TNF-α) was determined by quantitative real time polymerase chain reaction. Myostatin expression was significantly decreased in quadriceps from mdx mice treated with rhEPO (rhEPO=0.60±0.11, control=1.07±0.11). On the other hand, rhEPO had no significant effect on the expression of TGF-β1 (rhEPO=0.95±0.14, control=1.05±0.16) and TNF-α (rhEPO=0.73±0.20, control=1.01±0.09). These results may help to clarify some of the direct actions of EPO on skeletal muscle.

NASA GSFC Science Communication Working Group: Addressing Barriers to Scientist and Engineer Participation in Education and Public Outreach Activities

Science.gov (United States)

Bleacher, L.; Hsu, B. C.; Campbell, B. A.; Hess, M.

2011-12-01

The Science Communication Working Group (SCWG) at NASA Goddard Space Flight Center (GSFC) has been in existence since late 2007. The SCWG is comprised of education and public outreach (E/PO) professionals, public affairs specialists, scientists, and engineers. The goals of the SCWG are to identify barriers to scientist and engineer engagement in E/PO activities and to enable those scientists and engineers who wish to contribute to E/PO to be able to do so. SCWG members have held meetings with scientists and engineers across GSFC to determine barriers to their involvement in E/PO. During these meetings, SCWG members presented examples of successful, ongoing E/PO projects, encouraged active research scientists and engineers to talk about their own E/PO efforts and what worked for them, discussed the E/PO working environment, discussed opportunities for getting involved in E/PO (particularly in high-impact efforts that do not take much time), handed out booklets on effective E/PO, and asked scientists and engineers what they need to engage in E/PO. The identified barriers were consistent among scientists in GSFC's four science divisions (Earth science, planetary science, heliophysics, and astrophysics). Common barriers included 1) lack of time, 2) lack of funding support, 3) lack of value placed on doing E/PO by supervisors, 4) lack of training on doing appropriate/effective E/PO for different audiences, 5) lack of awareness and information about opportunities, 6) lack of understanding of what E/PO really is, and 7) level of effort required to do E/PO. Engineers reported similar issues, but the issues of time and funding support were more pronounced due to their highly structured work day and environment. Since the barriers were identified, the SCWG has taken a number of steps to address and rectify them. Steps have included holding various events to introduce scientists and engineers to E/PO staff and opportunities including an E/PO Open House, brown bag seminars on

Perioperative erythropoietin protects the CNS against ischemic lesions in patients after open heart surgery.

Science.gov (United States)

Lakič, Nikola; Mrak, Miha; Šušteršič, Miha; Rakovec, Peter; Bunc, Matjaž

2016-12-01

The aim of this study was to establish erythropoietin as a protective factor against brain ischemia during open heart surgery. A total of 36 consecutive patients scheduled for revascularization heart surgery were included in the study. Of the patients 18 received 3 intravenous doses of recombinant human erythropoietin (rHuEpo, 24,000 IU) and 18 patients received a placebo. Magnetic resonance imaging (MRI) to detect new brain ischemic lesions was performed. Additionally, S100A, S100B, neuron-specific enolase A and B (NSE-A and B) and the concentration of antibodies against N‑methyl-D-aspartate receptors (NMDAR) to identify new neurological complications were determined. Patients who received rHuEpo showed no postoperative ischemic changes in the brain on MRI images. In the control group 5 (27.8 %) new ischemic lesions were found. The NMDAR antibody concentration, S100A, S100B and NSE showed no significant differences between the groups for new cerebral ischemia. High levels of lactate before and after external aortic compression (p = 0.022 and p = 0.048, respectively) and duration of operation could predict new ischemic lesions (p = 0.009). The addition of rHuEpo reduced the formation of lesions detectable by MRI in the brain and could be used clinically as neuroprotection in cardiac surgery.

RECOMBINANT HUMAN MAST-CELL GROWTH-FACTOR SUPPORTS ERYTHROID COLONY FORMATION IN POLYCYTHEMIA-VERA IN THE PRESENCE AND ABSENCE OF ERYTHROPOIETIN AND SERUM

NARCIS (Netherlands)

MULLER, EW; DEWOLF, JTM; HENDRIKS, DW; ESSELINK, MT; HALIE, MR; VELLENGA, E

The effect of mast cell growth factor (MGF) was studied on erythropoietin (Epo)-dependent and Epo-independent (''spontaneous'') erythroid colony formation in patients with polycythemia vera (PV). MGF stimulated both Epo-dependent and Epo-independent erythroid colony formation from PV peripheral

A Partnership between English Language Learners and a Team of Rocket Scientists: EPO for the NASA SDO Extreme-Ultraviolet Variability Experiment (EVE)

Science.gov (United States)

Buhr, S. M.; Eparvier, F.; McCaffrey, M.; Murillo, M.

2007-12-01

Recent immigrant high school students were successfully engaged in learning about Sun-Earth connections through a partnership with the NASA SDO Extreme-Ultraviolet Variability Experiment (EVE) project. The students were enrolled in a pilot course as part of the Math, Engineering and Science Achievement MESA) program. For many of the students, this was the only science option available to them due to language limitations. The English Language Learner (ELL) students doubled their achievement on a pre- and post-assessment on the content of the course. Students learned scientific content and vocabulary in English with support in Spanish, attended field trips, hosted scientist speakers, built and deployed space weather monitors as part of the Stanford SOLAR project, and gave final presentations in English, showcasing their new computer skills. Teachers who taught the students in other courses noted gains in the students' willingness to use English in class and noted gains in math skills. The MESA-EVE course won recognition as a Colorado MESA Program of Excellence and is being offered again in 2007-08. The course has been broken into modules for use in shorter after-school environments, or for use by EVE scientists who are outside of the Boulder area. Other EVE EPO includes professional development for teachers and content workshops for journalists.

Properties of novel bone hemostat prepared using sugar-modified hydroxyapatite, phosphoryl oligosaccharides of calcium and thermoplastic resin

International Nuclear Information System (INIS)

Mimira, Tokio; Umeda, Tomohiro; Itatani, Kiyoshi; Musha, Yoshiro

2013-01-01

A novel hemostatic agent was prepared using phosphoryl oligosaccharides of calcium (POs-Ca), hydroxyapatite (Ca 10 (PO 4 ) 6 (OH) 2 ; HAp) obtained by the hydrolysis of POs-Ca or sugar-containing HAp (s-HAp; 60.3 mass% calcium-deficient HAp and 39.5 mass% organic materials, Ca/P ratio = 1.56) and thermoplastic resin (the mixture of random copolymer of ethylene oxide/propylene oxide (EPO) and polyethylene oxide (EO); EPO : EO : water = 25 : 15 : 60 (mass ratio); 25EPO-15EO). The gel formed by mixing 25EPO-15EO with water (25EPO-15EO/water mass ratio: 0.20) was flash frozen at -80°C, freeze-dried at -50°C for 15 h and then ground using mixer. The consistency conditions of hemostats mixed with POs-Ca or s-HAp were optimized for the practical uses. The mean stanching times of hemostats were: s-HAp/25EPO-15EO (8.2 h; s-HAp/25EPO-15EO = 0.20) > 25EPO-15EO (5.3 h) > POs-Ca/25EPO-15EO (4.7 h; POs-Ca/25EPO-15EO = 0.20). The gentamicin, a typical antibiotic agent, loaded s-HAp/25EPO-15EO composite hemostat showed the steady state releasing in phosphate buffered saline till 10 h immersion at 37.0°C

Properties of novel bone hemostat prepared using sugar-modified hydroxyapatite, phosphoryl oligosaccharides of calcium and thermoplastic resin

Science.gov (United States)

Mimira, Tokio; Umeda, Tomohiro; Musha, Yoshiro; Itatani, Kiyoshi

2013-12-01

A novel hemostatic agent was prepared using phosphoryl oligosaccharides of calcium (POs-Ca), hydroxyapatite (Ca10(PO4)6(OH)2; HAp) obtained by the hydrolysis of POs-Ca or sugar-containing HAp (s-HAp; 60.3 mass% calcium-deficient HAp and 39.5 mass% organic materials, Ca/P ratio = 1.56) and thermoplastic resin (the mixture of random copolymer of ethylene oxide/propylene oxide (EPO) and polyethylene oxide (EO); EPO : EO : water = 25 : 15 : 60 (mass ratio); 25EPO-15EO). The gel formed by mixing 25EPO-15EO with water (25EPO-15EO/water mass ratio: 0.20) was flash frozen at -80°C, freeze-dried at -50°C for 15 h and then ground using mixer. The consistency conditions of hemostats mixed with POs-Ca or s-HAp were optimized for the practical uses. The mean stanching times of hemostats were: s-HAp/25EPO-15EO (8.2 h; s-HAp/25EPO-15EO = 0.20) > 25EPO-15EO (5.3 h) > POs-Ca/25EPO-15EO (4.7 h; POs-Ca/25EPO-15EO = 0.20). The gentamicin, a typical antibiotic agent, loaded s-HAp/25EPO-15EO composite hemostat showed the steady state releasing in phosphate buffered saline till 10 h immersion at 37.0°C.

Mechanisms and mediators of hypertension induced by erythropoietin and related molecules.

Science.gov (United States)

Agarwal, Rajiv

2017-12-08

Hypertension is a common but frequently overlooked adverse effect of erythropoietin (EPO) therapy. Underreporting of hypertension with EPO is likely due to either more aggressively managing hypertension through the prescription of antihypertensive drugs or closer attention to dry weight. The purpose and focus of this review is to critically evaluate the mechanisms of EPO-induced hypertension. Preclinical data are considered first, followed by clinical data where available. Mediated by a variety of molecules, there is an imbalance in the vascular tone favoring net vasoconstriction that mediates EPO-induced hypertension. Animal studies show the primary importance of chronic kidney disease in the genesis of EPO-induced hypertension. Preclinical studies show deranged regulation of the nitric oxide, endothelins and porstanoids and the sympathoadrenal and renin-angiotensin pathways as causes of EPO-induced hypertension. Human studies suggest that EPO administration is also associated with increased responsiveness to catecholamines and angiotensin II on vascular tissue; in addition, hypoxia-induced vasodilation may be impaired in those with EPO-induced hypertension. There is little evidence for EPO as a direct vasoconstrictor or its effect on blood viscosity as a mechanism of EPO-induced hypertension. EPO-induced hypertension, at least in part, appears to be independent of an increase in hemoglobin, because experiments show that hemoglobin may be increased by EPO without an increase in blood pressure (BP) by simply treating the animals with EPO-binding protein and that treatment with EPO in the setting of iron deficiency may not increase hemoglobin but may still increase BP. However, experimental data are not consistent across studies and better mechanistic designs are needed, especially in patients with chronic kidney disease, to dissect the precise mechanism of EPO-induced hypertension. Animal studies suggest that hypoxia-inducible factor stablizers may induce

Erythropoietin protects against rhabdomyolysis-induced acute kidney injury by modulating macrophage polarization

Science.gov (United States)

Wang, Shuo; Zhang, Chao; Li, Jiawei; Niyazi, Sidikejiang; Zheng, Long; Xu, Ming; Rong, Ruiming; Yang, Cheng; Zhu, Tongyu

2017-01-01

Erythropoietin (EPO) is a well-known hormone that is clinically used for the treatment of anemia. Very recently, an increasing body of evidence showed that EPO could still regulate bioactivities of macrophages. However, the details about the immunomodulatory effect of EPO on macrophages are not fully delineated, particularly in the setting of renal damages. Therefore, in the present study, we determined whether EPO could exert an impact on the dynamics of macrophages in a well-established model of rhabdomyolysis-induced acute kidney injury and explored the potential mechanisms. EPO was found to ameliorate kidney injuries by reducing macrophages recruitment and promoting phenotype switch toward M2 macrophages in vivo. It was also confirmed that EPO could directly suppress pro-inflammatory responses of M1 macrophages and promote M2 marker expression in vitro. Data indicated the possible involvement of Jak2/STAT3/STAT6 pathway in the augmentation of EPO on M2 polarization. These results improved the understanding of the immunoregulatory capacity of EPO on macrophages, which might optimize the therapeutic modalities of EPO. PMID:28383559

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

Efectos musculares y hematológicos del uso de rHuEpo en combinación con el entrenamiento físico. Implicaciones de la demospresina y la hipoxia en el dopaje sanguineo. Estudios in vivo e in vitro.

OpenAIRE

Martínez Bello, Vladimir Essau

2011-01-01

En la presente Tesis Doctoral hemos querido estudiar, en primer lugar, el efecto que tendría el incremento artificial de la capacidad de transporte de oxígeno, a través del tratamiento con rHuEpo, sobre distintos parámetros musculares así como su implicación en la mejora del rendimiento físico. Son muchos los autores que, tanto en el ámbito clínico (Winearls, Oliver y cols. 1986; Bommer, Muller-Buhl y cols. 1987) como en el ámbito deportivo (Berglund y Ekblom 1991; Lundby, Robach y cols. 2008...

Inflammatory cytokine tumor necrosis factor α suppresses neuroprotective endogenous erythropoietin from astrocytes mediated by hypoxia-inducible factor-2α.

Science.gov (United States)

Nagaya, Yoshiaki; Aoyama, Mineyoshi; Tamura, Tetsuya; Kakita, Hiroki; Kato, Shin; Hida, Hideki; Saitoh, Shinji; Asai, Kiyofumi

2014-12-01

Interest in erythropoietin (EPO) as a neuroprotective mediator has grown since it was found that systemically administered EPO is protective in several animal models of disease. However, given that the blood-brain barrier limits EPO entry into the brain, alternative approaches that induce endogenous EPO production in the brain may be more effective clinically and associated with fewer untoward side-effects. Astrocytes are the main source of EPO in the central nervous system. In the present study we investigated the effect of the inflammatory cytokine tumor necrosis factor α (TNFα) on hypoxia-induced upregulation of EPO in rat brain. Hypoxia significantly increased EPO mRNA expression in the brain and kidney, and this increase was suppressed by TNFα in vivo. In cultured astrocytes exposed to hypoxic conditions for 6 and 12 h, TNFα suppressed the hypoxia-induced increase in EPO mRNA expression in a concentration-dependent manner. TNFα inhibition of hypoxia-induced EPO expression was mediated primarily by hypoxia-inducible factor (HIF)-2α rather than HIF-1α. The effects of TNFα in reducing hypoxia-induced upregulation of EPO mRNA expression probably involve destabilization of HIF-2α, which is regulated by the nuclear factor (NF)-κB signaling pathway. TNFα treatment attenuated the protective effects of astrocytes on neurons under hypoxic conditions via EPO signaling. The effective blockade of TNFα signaling may contribute to the maintenance of the neuroprotective effects of EPO even under hypoxic conditions with an inflammatory response. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Online Citizen Science with Clickworkers & MRO HiRISE E/PO

Science.gov (United States)

Gulick, V. C.; Deardorff, G.; Kanefsky, B.; HiRISE Science Team

2010-12-01

The High-Resolution Imaging Science Experiment’s E/PO has fielded several online citizen science projects. Our efforts are guided by HiRISE E/PO’s philosophy of providing innovative opportunities for students and the public to participate in the scientific discovery process. HiRISE Clickworkers, a follow-on to the original Clickworkers crater identification and size diameter marking website, provides an opportunity for the public to identify & mark over a dozen landform feature types in HiRISE images, including dunes, gullies, patterned ground, wind streaks, boulders, craters, layering, volcanoes, etc. In HiRISE Clickworkers, the contributor views several sample images showing variations of different landforms, and simply marks all the landform types they could spot while looking at a small portion of a HiRISE image. Contributors then submit their work & once validated by comparison to the output of other participants, results are then added to geologic feature databases. Scientists & others will eventually be able to query these databases for locations of particular geologic features in the HiRISE images. Participants can also mark other features that they find intriguing for the HiRISE camera to target. The original Clickworkers website pilot study ran from November 2000 until September 2001 (Kanefsky et al., 2001, LPSC XXXII). It was among the first online Citizen Science efforts for planetary science. In its pilot study, we endeavored to answer two questions: 1) Was the public willing & able to help science, & 2) Can the public produce scientifically useful results? Since its inception over 3,500,000 craters have been identified, & over 350,000 of these craters have been classified. Over 2 million of these craters were marked on Viking Orbiter image mosaics, nearly 800,000 craters were marked on Mars Orbiter Camera (MOC) images. Note that these are not counts of distinct craters. For example, each crater in the Viking orbiter images was counted by about 50

Planting local seed for growth to nationwide E/PO efforts

Science.gov (United States)

Fox, N.; Beisser, K.; Mendez, F.; Cockrell, D.; Wilhide, B.

The Johns Hopkins University Applied Physics Laboratory (JHU/APL) is the home to hundreds of scientists and engineers, all involved in research, design and implementation of space missions. Many of these people actively seek out ways to raise awareness and interest in the local community by visiting schools, giving public lectures and supporting events held at the laboratory. During the past few years, APL has begun to foster a number of firm partnerships with organizations to further these community opportunities and provide a test bed for both formal and informal education activities through the Space Department E/PO office One of our ongoing partnerships is with the Maryland Science Center in Baltimore. A continual challenge faced by museums is how to stay current and allow visitors to experience the immediacy and excitement of scientific discovery. To help meet these challenges, the Maryland Science Center houses "SpaceLink", the Nation's first space, science and astronomy update center. Part media center, part discovery room, and part newsroom, the exhibit is a multi-purpose Professional Development Site for educators and a "classroom of the future" for K 12 students. APL scientists and- engineers regularly support SpaceLink's flexible programming, including scientist in residence, monthly credited seminars for educators (Teachers' Thursdays), a menu of Classroom Programs on request, Distance Learning Teacher Presentations, and special Live Events to highlight mission milestones and space-related anniversaries. This allows the guest scientists and engineers to interact directly with the public. These events also compliment the APL exhibits housed at the Science Center. JHU/APL offers an exciting environment for the study of applications in space by hosting the annual Maryland Summer Center for Space Science sponsored by the Maryland State Department of Education. Rising 6t h and 7t h grade students learn to harness the power of technology and keep pace with

Human pluripotent stem cell-derived erythropoietin-producing cells ameliorate renal anemia in mice.

Science.gov (United States)

Hitomi, Hirofumi; Kasahara, Tomoko; Katagiri, Naoko; Hoshina, Azusa; Mae, Shin-Ichi; Kotaka, Maki; Toyohara, Takafumi; Rahman, Asadur; Nakano, Daisuke; Niwa, Akira; Saito, Megumu K; Nakahata, Tatsutoshi; Nishiyama, Akira; Osafune, Kenji

2017-09-27

The production of erythropoietin (EPO) by the kidneys, a principal hormone for the hematopoietic system, is reduced in patients with chronic kidney disease (CKD), eventually resulting in severe anemia. Although recombinant human EPO treatment improves anemia in patients with CKD, returning to full red blood cell production without fluctuations does not always occur. We established a method to generate EPO-producing cells from human induced pluripotent stem cells (hiPSCs) by modifying previously reported hepatic differentiation protocols. These cells showed increased EPO expression and secretion in response to low oxygen conditions, prolyl hydroxylase domain-containing enzyme inhibitors, and insulin-like growth factor 1. The EPO protein secreted from hiPSC-derived EPO-producing (hiPSC-EPO) cells induced the erythropoietic differentiation of human umbilical cord blood progenitor cells in vitro. Furthermore, transplantation of hiPSC-EPO cells into mice with CKD induced by adenine treatment improved renal anemia. Thus, hiPSC-EPO cells may be a useful tool for clarifying the mechanisms of EPO production and may be useful as a therapeutic strategy for treating renal anemia. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Recombinant erythropoietin in humans has a prolonged effect on circulating erythropoietin isoform distribution

DEFF Research Database (Denmark)

Aachmann-Andersen, Niels Jacob; Just Christensen, Søren; Lisbjerg, Kristian

2014-01-01

The membrane-assisted isoform immunoassay (MAIIA) quantitates erythropoietin (EPO) isoforms as percentages of migrated isoforms (PMI). We evaluated the effect of recombinant human EPO (rhEPO) on the distribution of EPO isoforms in plasma in a randomized, placebo-controlled, double-blinded, cross......-over study. 16 healthy subjects received either low-dose Epoetin beta (5000 IU on days 1, 3, 5, 7, 9, 11 and 13); high-dose Epoetin beta (30.000 IU on days 1, 2 and 3 and placebo on days 5, 7, 9, 11 and 13); or placebo on all days. PMI on days 4, 11 and 25 was determined by interaction of N......-acetyl glucosamine with the glycosylation dependent desorption of EPO isoforms. At day 25, plasma-EPO in both rhEPO groups had returned to values not different from the placebo group. PMI with placebo, reflecting the endogenous EPO isoforms, averaged 82.5 (10.3) % (mean (SD)). High-dose Epoetin beta decreased PMI...

Comparison of different hadron production models for the study of π±, K±, protons and antiprotons production in proton-carbon interactions at 90 GeV/c

Science.gov (United States)

Ajaz, M.; Ali, Y.; Ullah, S.; Ali, Q.; Tabassam, U.

2018-05-01

In this research paper, comprehensive results on the double differential yield of π± and K± mesons, protons and antiprotons as a function of laboratory momentum in several polar angle ranges from 0-420 mrad for pions, 0-360 mrad for kaons, proton and antiproton are reported. EPOS 1.99, EPOS-LHC and QGSJETII-04 models are used to perform simulations. The predictions of these models at 90 GeV/c are plotted for comparison, which shows that QGSJETII-04 model gives overall higher yield for π+ mesons in the polar angle interval of 0-40 mrad but for the π‑ the yield is higher only up to 20 mrad. For π+ mesons after 40 mrad, EPOS-LHC predicts higher yield as compared to EPOS 1.99 and QGSJETII-04 while EPOS-LHC and EPOS 1.99 give similar behavior in these two intervals. However, for π‑ mesons EPOS-LHC and EPOS 1.99 give similar behavior in these two intervals. For of K± mesons, QGSJETII-04 model gives higher predictions in all cases from 0-300 mrad, while EPOS 1.99 and EPOS-LHC show similar distributions. In case of protons, all models give similar distribution but this is not true for antiproton. All models are in good agreement for p > 20 GeV/c. EPOS 1.99 produce lower yield compared to the other two models from 60-360 mrad polar angle interval.

The feed-back regulation of erythropoietin production in healthy humans

International Nuclear Information System (INIS)

Klausen, T.

1998-01-01

The proposed oxygen-dependent feed-back loop regulation of EPO (erythropoietin) production is mainly supported by data from studies in animals and cell cultures. The feed-back loop and its dependence on oxygen was therefore challenged by studies in healthy humans: Exposure of humans to different levels of acute and continued altitude hypobaria provided evidence for an oxygen dependence of the EPO response. This response is consistent with the proposed feed-back loop regulation of EPO production; Exposure to continued altitude hypobaria demonstrated that the decline in human EPO production is initiated before an EPO-induced erythopoiesis is detectable, and that this decline is related to a concomitant decrease in the haemoglobin-oxygen affinity. Contrary to the feed-back loop, this time-relation indicate that the feed-back regulation of EPO production during continued hypobaric hypoxia is exerted primarily through a decrease in the haemoglobin-oxygen affinity, rather than by the effects of an EPO-stimulated erythropoiesis; Increased circulating levels of the proinflammatory cytokine IL-6 was found in healthy humans during four days of altitude exposure as compared with sea level. The other proinflammatory cytokines IL-1 beta, and TNF alpha remained unchanged, and the increased serum IL-6 did not induce production of c-reactive protein; Comparable circadian variations in human EPO production were shown in sedentary subjects, athletes, and healthy but hypoxaemic subjects. Human EPO production could not be triggered by one hour of high-intensity exercise, whereas longitudinal changes in exercise showed a trend of relation between human EPO production, serum concentration of free testosterone, and indices of body composition. These results have demonstrated and endogenous, probably hormonal, and oxygen-independent regulation of human EPO production, which is at variance with the oxygen dependent feed-back loop regulation of EPO production. Conclusively, the present

Natural form of noncytolytic flexible human Fc as a long-acting carrier of agonistic ligand, erythropoietin.

Directory of Open Access Journals (Sweden)

Se Jin Im

Full Text Available Human IgG1 Fc has been widely used as a bioconjugate, but exhibits shortcomings, such as antibody- and complement-mediated cytotoxicity as well as decreased bioactivity, when applied to agonistic proteins. Here, we constructed a nonimmunogenic, noncytolytic and flexible hybrid Fc (hyFc consisting of IgD and IgG4, and tested its function using erythropoietin (EPO conjugate, EPO-hyFc. Despite low amino acid homology (20.5% between IgD Fc and IgG4 Fc, EPO-hyFc retained "Y-shaped" structure and repeated intravenous administrations of EPO-hyFc into monkeys did not generate EPO-hyFc-specific antibody responses. Furthermore, EPO-hyFc could not bind to FcγR I and C1q in contrast to EPO-IgG1 Fc. In addition, EPO-hyFc exhibited better in vitro bioactivity and in vivo bioactivity in rats than EPO-IgG1 Fc, presumably due to the high flexibility of IgD. Moreover, the mean serum half-life of EPO-hyFc(H, a high sialic acid content form of EPO-hyFc, was approximately 2-fold longer than that of the heavily glycosylated EPO, darbepoetin alfa, in rats. More importantly, subcutaneous injection of EPO-hyFc(H not only induced a significantly greater elevation of serum hemoglobin levels than darbepoetin alfa in both normal rats and cisplatin-induced anemic rats, but also displayed a delayed time to maximal serum level and twice final area-under-the-curve (AUC(last. Taken together, hyFc might be a more attractive Fc conjugate for agonistic proteins/peptides than IgG1 Fc due to its capability to elongate their half-lives without inducing host effector functions and hindering bioactivity of fused molecules. Additionally, a head-to-head comparison demonstrated that hyFc-fusion strategy more effectively improved the in vivo bioactivity of EPO than the hyperglycosylation approach.

Natural form of noncytolytic flexible human Fc as a long-acting carrier of agonistic ligand, erythropoietin.

Science.gov (United States)

Im, Se Jin; Yang, Sang In; Yang, Se Hwan; Choi, Dong Hoon; Choi, So Young; Kim, Hea Sook; Jang, Do Soo; Jin, Kyeong Sik; Chung, Yo-Kyung; Kim, Seung-Hee; Paik, Sang Hoon; Park, Yoo Chang; Chung, Moon Koo; Kim, Yong Bum; Han, Kang-Hyun; Choi, Kwan Yong; Sung, Young Chul

2011-01-01

Human IgG1 Fc has been widely used as a bioconjugate, but exhibits shortcomings, such as antibody- and complement-mediated cytotoxicity as well as decreased bioactivity, when applied to agonistic proteins. Here, we constructed a nonimmunogenic, noncytolytic and flexible hybrid Fc (hyFc) consisting of IgD and IgG4, and tested its function using erythropoietin (EPO) conjugate, EPO-hyFc. Despite low amino acid homology (20.5%) between IgD Fc and IgG4 Fc, EPO-hyFc retained "Y-shaped" structure and repeated intravenous administrations of EPO-hyFc into monkeys did not generate EPO-hyFc-specific antibody responses. Furthermore, EPO-hyFc could not bind to FcγR I and C1q in contrast to EPO-IgG1 Fc. In addition, EPO-hyFc exhibited better in vitro bioactivity and in vivo bioactivity in rats than EPO-IgG1 Fc, presumably due to the high flexibility of IgD. Moreover, the mean serum half-life of EPO-hyFc(H), a high sialic acid content form of EPO-hyFc, was approximately 2-fold longer than that of the heavily glycosylated EPO, darbepoetin alfa, in rats. More importantly, subcutaneous injection of EPO-hyFc(H) not only induced a significantly greater elevation of serum hemoglobin levels than darbepoetin alfa in both normal rats and cisplatin-induced anemic rats, but also displayed a delayed time to maximal serum level and twice final area-under-the-curve (AUC(last)). Taken together, hyFc might be a more attractive Fc conjugate for agonistic proteins/peptides than IgG1 Fc due to its capability to elongate their half-lives without inducing host effector functions and hindering bioactivity of fused molecules. Additionally, a head-to-head comparison demonstrated that hyFc-fusion strategy more effectively improved the in vivo bioactivity of EPO than the hyperglycosylation approach.

Analysis of human reticulocyte genes reveals altered erythropoiesis: potential use to detect recombinant human erythropoietin doping.

Science.gov (United States)

Varlet-Marie, Emmanuelle; Audran, Michel; Lejeune, Mireille; Bonafoux, Béatrice; Sicart, Marie-Therese; Marti, Jacques; Piquemal, David; Commes, Thérèse

2004-08-01

Enhancement of oxygen delivery to tissues is associated with improved sporting performance. One way of enhancing oxygen delivery is to take recombinant human erythropoietin (rHuEpo), which is an unethical and potentially dangerous practice. However, detection of the use of rHuEpo remains difficult in situations such as: i) several days after the end of treatment ii) when a treatment with low doses is conducted iii) if the rHuEpo effect is increased by other substances. In an attempt to detect rHuEpo abuse, we selected erythroid gene markers from a SAGE library and analyzed the effects of rHuEpo administration on expression of the HBB, FTL and OAZ genes. Ten athletes were assigned to the rHuEpo or placebo group. The rHuEpo group received subcutaneous injections of rHuEpo (50 UI/kg three times a week, 4 weeks; 20 UI/kg three times a week, 2 weeks). HBB, FTL and OAZ gene profiles were monitored by real time-polymerase chain reaction (PCR) quantification during and for 3 weeks after drug administration. The global analysis of these targeted genes detected in whole blood samples showed a characteristic profile of subjects misusing rHuEpo with a increase above the threshold levels. The individual analysis of OAZ mRNA seemed indicative of rHuEpo treatment. The performance-enhancing effect of rHuEpo treatment is greater than the duration of hematologic changes associated with rHuEpo misuse. Although direct electrophoretic methods to detect rHuEpo have been developed, recombinant isoforms of rHuEpo are not detectable some days after the last subcutaneous injection. To overcome these limitations indirect OFF models have been developed. Our data suggest that, in the near future, it will be possible to consolidate results achievable with the OFF models by analyzing selected erythroid gene markers as a supplement to indirect methods.

Damage of tracer erythropoietin results in erroneous estimation of concentration in mouse submaxillary gland.

Science.gov (United States)

Vidal, A; Carcagno, M; Criscuolo, M; Barcelò, A C; Alippi, R M; Leal, T; Bozzini, C E

1993-02-01

It has been previously reported that 1) plasma erythropoietin (Epo) titer during exposure to hypobaria is lower in nephrectomized rats and mice whose submaxillary glands (SMG) were either ablated or atrophied than in nephrectomized controls whose SMG were intact and 2) that the gland shows one of the highest levels of immunoreactive Epo (iEpo) in the body. The latter observation, however, was questioned recently when it was observed that SMG extracts degrade labeled Epo used as tracer antigen in the radioimmunoassay (RIA), thus giving invalid estimates of Epo. Since this interpretation was in turn questioned, the present study was conducted to obtain more information on the subject and make these conflicting points clear. Investigation of the reported/possible degradation of Epo by SMG homogenates was conducted via polyacrylamide gel electrophoresis followed by radioautography or by a RIA in solid phase in which there was no simultaneous incubation of the tracer antigen with the SMG homogenates. It was observed that 125I-labeled rhEpo was degraded when incubated with SMG homogenates. Degradation was rapid, being evident when incubation lasted 30 minutes, and occurred in the presence of a protease inhibitor. It showed a high degree of specificity since it did not occur when Epo was incubated with kidney homogenate or normal mouse serum. SMG homogenate did not degrade labeled thyrotrophic hormone and degraded alpha interferon (IFN-alpha) only partially. When estimates of iEpo in SMG homogenate were performed in conditions of simultaneous (SI-RIA) or nonsimultaneous (NSI-RIA) incubation of the homogenate with tracer Epo, it was observed that while estimates of Epo in plasma were similar in both types of RIA and somewhat higher in kidney homogenate in the SI-RIA than in the NSI-RIA, estimates of Epo in SMG were about 60 times higher in the former than in the latter. Therefore, it could be concluded that most of the Epo detected by standard RIA in SMG homogenate does

CIRCULATING ANTIBODIES TO ERYTHROPOIETIN ARE ASSOCIATED WITH LOWER EFFICACY OF RECOMBINANT EPOETIN TREATMENT IN PATIENTS UNDERGOING HAEMODIALYSIS

Directory of Open Access Journals (Sweden)

V. D. Nazarov

2018-01-01

Full Text Available Biological preparations (BP obtained by gene engineering possess a special characteristic called immunogenicity, i.e. propensity of biological drugs to induce an undesired immune response associated with arising anti-drug antibodies. These antibodies can change BP pharmacokinetics and pharmacodynamics, and therapeutical efficacy. A significant proportion of hemodialysis patients with end-stage renal disease treated by recombinant erythropoietin (rEPO have clinical features of resistance to such therapy. The aim of the study was to investigate whether anti-rEPO antibodies are associated with hemoglobin concentrations (Hb and red blood cells counts (RBC in hemodialysis patients, receiving long-term rEPO therapy. This research was performed at the Research Institute of Nephrology at the First St. Petersburg I.Pavlov State Medical University. Thirty-seven hemodialysis patients (pts with end-stage renal disease and anemia treated with different rEPO formulations were included into the study. The patients were further divided into two groups: those with diminished and normal clinical response to rEPO therapy (DCR, n = 21 vs NCR group, n = 16, respectively. To determine threshold levels of antibodies to rEPO-beta (Roche, Switzerland we tested blood serum samples of 35 healthy blood donors who never received rEPO in the past. Concentration of antibodies was measured by means of dot-blot method. The threshold antibody concentrations were defined by measurement of anti-rEPO concentrations in 2-fold stepwise dilutions (1:10 to 1:200 of blood sera from 35 healthy donors .The threshold value for rEPO-binding antibodies was 20.27 µg/ml (95 CI%±0.43. Antibodies to rEPO were found in 54 % of serum samples in the patients. Anti-rEPO antibodies concentrations correlated with mean values of hemoglobin and erythrocyte counts over a period of 12-months for the entire group of hemodialysis patients (r = -0.368, p = 0.025 and r = -0.336, p = 0.042 respectively

Radio-labelling of long-lasting erythropoietin

International Nuclear Information System (INIS)

Liu Guoxia; Zeng Xianyin; Bao Lun; Xu Xiankun; Chen Zhiyu; Liu Xianyi

2004-01-01

The study is designed to investigate the labelling of LL-EPO, purification of labelled compound, and therefore, to prepare the labelled LL-EPO with high purity and biological activity. LL-EPO was labelled with 125 I by the common used chloramine-T and the modified two-phase chloramine-T method, respectively. The labelled compound was purified by both gel filtration and ultrafiltration method, respectively. The purity of the labelled LL-EPO was determined by both trichloroacetic acid (TCA) and SDS-PAGE method, and the biological activity was determined by the reticulocyte counting method. The results demonstrated that the iodine incorporation and specific radioactivities were 89% and 5.82 x 10 5 Bq·μg -1 for LL-EPO labelled by the modified two-phase chloramine-T method and were 20.65% and 3.62 x 10 5 Bq·μg -1 for LL-EPO labelled by the common used chloramine-T method, respectively. The purity of labelled LL-EPO purified by both gel filtration and ultrafiltration were over 96% with TCA method purification. The labelled LL-EPO showed two bands with Rf of 0.28 and 0.49, respectively, which is identical to that of standard LL-EPO through SDS-PAGE. There was no loss of biological activity of LL-EPO after labelling as determined by reticulocyte counting method

Epoetin in the 'untransfusable' anaemic patient: a retrospective case series and systematic analysis of literature case reports.

Science.gov (United States)

Heh-Foster, A M; Naber, M; Pai, M P; Lesar, T S

2014-08-01

Erythropoiesis stimulating agents [erythropoietin (EPO)] have been recommended to treat anaemic patients who cannot receive or refuse blood tranfusion ('untransfusable' patients). The objective of the study was to quantify the association of EPO use with haemoglobin (Hgb) recovery in anaemic untransfusable hospitalised patients. EPO treated anaemic untransfusable patients were identified through the combination of a retrospective case review and a systematic review of the medical literature. Literature reports of untransfusable patients not treated with any EPO were used as a comparator group. Hgb concentrations before and following EPO use were abstracted and used to determine the rate of Hgb recovery for each case. Multilevel mixed effects modelling was used to determine the association of Hgb recovery with EPO use. A total of 76 EPO treated cases (19 cases from the retrospective hospital case review and 57 from the literature), and 33 non-EPO treated comparator patients from the literature were included in the study. Hgb increased similarly over time in all groups at an overall mean standard error (SE) rate of 0·13 (0·01) g dL(-1)  day(-1) . The Hgb recovery rate was higher in patients with lower baseline Hgb, regardless of EPO use. No association was found between the rate of Hgb recovery and EPO use, dose or therapy duration. In anaemic, 'untransfusable' hospitalised patients, EPO use was not associated with increased Hgb recovery at anytime within 28 days. © 2014 The Authors. Transfusion Medicine © 2014 British Blood Transfusion Society.

Erythropoiesis stimulating agents and techniques: a challenge for doping analysts.

Science.gov (United States)

Jelkmann, W

2009-01-01

Recombinant human erythropoietin (rHuEPO) engineered in Chinese hamster ovary (CHO) cell cultures (Epoetin alfa and Epoetin beta) and its hyperglycosylated analogue Darbepoetin alfa are known to be misused by athletes. The drugs can be detected by isoelectric focusing (IEF) and immunoblotting of urine samples, because "EPO" is in reality a mixture of isoforms and the N-glycans of the recombinant products differ from those of the endogenous hormone. However, there is a plethora of novel erythropoiesis stimulating agents (ESAs). Since the originator Epoetins alfa and beta are no longer protected by patent in the European Union, rHuEPO biosimilars have entered the market. In addition, several companies in Asia, Africa and Latin America produce copied rHuEPOs for clinical purposes. While the amino acid sequence of all Epoetins is identical, the structure of their glycans differs depending on the mode of production. Some products contain more acidic and others more basic EPO isoforms. Epoetin delta is special, as it was engineered by homologous recombination in human fibrosarcoma cells (HT-1080), thus lacking N-glycolylneuraminic acid like native human EPO. ESAs under development include EPO fusion proteins, synthetic erythropoiesis stimulating protein (SEP) and peptidic (Hematide(), CNTO 528) as well as non-peptidic EPO mimetics. Furthermore, preclinical respectively clinical trials have been performed with small orally active drugs that stimulate endogenous EPO production by activating the EPO promoter ("GATA-inhibitors": diazepane derivatives) or enhancer ("HIF-stabilizers": 2-oxoglutarate analogues). The prohibited direct EPO gene transfer may become a problem in sports only in the future.

Erythropoietin in the treatment of carbon monoxide neurotoxicity in rat.

Science.gov (United States)

Moallem, Seyed Adel; Mohamadpour, Amir Hooshang; Abnous, Khalil; Sankian, Mojtaba; Sadeghnia, Hamid Reza; Tsatsakis, Aristidis; Shahsavand, Shabnam

2015-12-01

Erythropoietin (EPO) plays a critical role in the development of the nervous system. In this study, the effects of EPO in carbon monoxide (CO) neurotoxicity were examined. Rats were exposed to 3000 ppm CO for 1 h and then different doses of EPO were administrated intraperitoneally. After 24 h, glial fibrillary acidic protein (GFAP) levels in the serum were determined and water content of brain and the extravasation of a tracer (Evans blue) were measured. Brain lipid peroxidation, myeloperoxidase activity Myelin basic protein (MBP) and BAX/BcL2 protein relative expressions were determined. Cation exchange chromatography was used to evaluate MBP alterations. Seven days after exposure, pathological assessment was performed after Klüver-Barrera staining. EPO reduced malondialdehyde levels at all doses (2500, 5000 and 10,000 u/kg). Lower doses of EPO (625, 1250, 2500 u/kg) significantly decreased the elevated serum levels of GFAP. EPO could not reduce the water content of the edematous poisoned brains. However, at 5000 and 10,000 u/kg it protected the blood brain barrier against integrity loss as a result of CO. EPO could significantly decrease the MPO activity. CO-mediated oxidative stress caused chemical alterations in MBP and EPO could partially prevent these biochemical changes. Fewer vacuoles and demyelinated fibers were found in the EPO-treated animals. EPO (5000 u/kg) could restore the MBP density. CO increased brain BAX/Bcl-2 ratio 38.78%. EPO reduced it 38.86%. These results reveal that EPO could relatively prevent different pathways of neurotoxicity by CO poisoning and thus has the potential to be used as a novel approach to manage this poisoning. Copyright © 2015 Elsevier Ltd. All rights reserved.

Recombinant erythropoietin in humans has a prolonged effect on circulating erythropoietin isoform distribution.

Directory of Open Access Journals (Sweden)

Niels Jacob Aachmann-Andersen

Full Text Available The membrane-assisted isoform immunoassay (MAIIA quantitates erythropoietin (EPO isoforms as percentages of migrated isoforms (PMI. We evaluated the effect of recombinant human EPO (rhEPO on the distribution of EPO isoforms in plasma in a randomized, placebo-controlled, double-blinded, cross-over study. 16 healthy subjects received either low-dose Epoetin beta (5000 IU on days 1, 3, 5, 7, 9, 11 and 13; high-dose Epoetin beta (30.000 IU on days 1, 2 and 3 and placebo on days 5, 7, 9, 11 and 13; or placebo on all days. PMI on days 4, 11 and 25 was determined by interaction of N-acetyl glucosamine with the glycosylation dependent desorption of EPO isoforms. At day 25, plasma-EPO in both rhEPO groups had returned to values not different from the placebo group. PMI with placebo, reflecting the endogenous EPO isoforms, averaged 82.5 (10.3 % (mean (SD. High-dose Epoetin beta decreased PMI on days 4 and 11 to 31.0 (4.2% (p<0.00001 and 45.2 (7.3% (p<0.00001. Low-dose Epoetin beta decreased PMI on days 4 and 11 to 46.0 (12.8% (p<0.00001 and 46.1 (10.4% (p<0.00001. In both rhEPO groups, PMI on day 25 was still decreased (high-dose Epoetin beta: 72.9 (19.4% (p=0.029; low-dose Epoetin beta: 73.1 (17.8% (p=0.039. In conclusion, Epoetin beta leaves a footprint in the plasma-EPO isoform pattern. MAIIA can detect changes in EPO isoform distribution up til at least three weeks after administration of Epoetin beta even though the total EPO concentration has returned to normal.

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.

Recombinant erythropoietin acutely decreases renal perfusion and decouples the renin-angiotensin-aldosterone system

DEFF Research Database (Denmark)

Aachmann-Andersen, Niels J.; Christensen, Soren J.; Lisbjerg, Kristian

2018-01-01

The effect of recombinant erythropoietin (rhEPO) on renal and systemic hemodynamics was evaluated in a randomized double-blinded, cross-over study. Sixteen healthy subjects were tested with placebo, or low-dose rhEPO for 2 weeks, or high-dose rhEPO for 3 days. Subjects refrained from excessive salt...... that seems to decouple the activity of the renin-angiotensin-aldosterone system from changes in renal hemodynamics. This may serve as a negative feed-back mechanism on endogenous synthesis of EPO when circulating levels of EPO are high. These results demonstrates for the first time in humans a direct effect...... of rhEPO on renal hemodynamics and a decoupling of the renin-angiotensin-aldosterone system....

Antibody-based enzyme-linked lectin assay (ABELLA) for the sialylated recombinant human erythropoietin present in culture supernatant.

Science.gov (United States)

Kim, Hyoung Jin; Lee, Seung Jae; Kim, Hong-Jin

2008-11-04

The terminal sialic acid of human erythropoietin (hEPO) is essential for in vivo activity. The current resorcinol and HPLC methods for analyzing alpha2,3-linked sialic acid require more than a microgram of purified rhEPO, and purification takes a great deal of time and labor. In this study, we assessed the use of an antibody-based enzyme-linked lectin assay (ABELLA) for analyzing non-purified recombinant hEPO (rhEPO). The major problem of this method was the high background due to terminal sialylation of components of the assay (antibody and bovine serum albumin) other than rhEPO. To solve this problem, we used a monoclonal antibody (Mab 287) to capture the rhEPO, and oxidized the bovine serum albumin used for blocking with meta-periodate. The sialic acid content of non-purified rhEPO measured by ABELLA was similar to that obtained by the resorcinol method on purified rhEPO. ABELLA has advantages such as adaptability and need for minimal amounts of rhEPO (40 ng/ml). Our observations suggest that ABELLA should reduce the time and labor needed to improve culture conditions so as to increase protein sialylation, and also facilitate the study of sialylation mechanisms.

Fibronectin potentiates topical erythropoietin-induced wound repair in diabetic mice.

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Hamed, Saher; Ullmann, Yehuda; Egozi, Dana; Daod, Essam; Hellou, Elias; Ashkar, Manal; Gilhar, Amos; Teot, Luc

2011-06-01

Diabetes mellitus disrupts all phases of the wound repair cascade and leads to development of chronic wounds. We previously showed that topical erythropoietin (EPO) can promote wound repair in diabetic rats. Fibronectin (FN) has a critical role throughout the process of wound healing, yet it is deficient in wound tissues of diabetic patients. Therefore, we investigated the effect of topical treatment of both EPO and FN (EPO/FN) on wound repair in diabetic mice. Full-thickness excisional skin wounds in diabetic and nondiabetic mice were treated with a cream containing vehicle, EPO, FN, or EPO/FN. We assessed the rate of wound closure, angiogenesis, apoptosis, and expression of inflammatory cytokines, endothelial nitric oxide synthase (eNOS) and β1-integrin, in the wound tissues. We also investigated the effect of EPO, FN, and EPO/FN on human dermal microvascular endothelial cells and fibroblasts cultured on fibrin-coated plates, or in high glucose concentrations. EPO/FN treatment significantly increased the rate of wound closure and this effect was associated with increased angiogenesis, increased eNOS and β1-integrin expression, and reduced expression of inflammatory cytokines and apoptosis. Our findings show that EPO and FN have an additive effect on wound repair in diabetic mice.

Topical erythropoietin promotes wound repair in diabetic rats.

Science.gov (United States)

Hamed, Saher; Ullmann, Yehuda; Masoud, Muhannad; Hellou, Elias; Khamaysi, Ziad; Teot, Luc

2010-01-01

Wound healing in diabetic patients is slower than in healthy individuals. Erythropoietin (EPO) has non-hemopoietic targets in the skin, and systemically administered EPO promotes wound healing in experimental animals. This study investigated the effect of topical EPO treatment on defective wound repair in the skin of diabetic rats. Full-thickness excisional skin wounds were made in 38 rats, of which 30 had diabetes. The wounds were then treated topically with a cream that contained either vehicle, 600 IU ml(-1) EPO (low dose), or 3,000 IU ml(-1) (high dose) EPO. We assessed the rate of wound closure during the 12-day treatment period, and microvascular density (MVD), vascular endothelial growth factor (VEGF), and hydroxyproline (HP) contents, and the extent of apoptosis in wound tissues at the end of the 12-day treatment period. Topical EPO treatment significantly reduced the time to final wound closure. This increased rate of closure of the two EPO-treated wounds in diabetic rats was associated with increased MVD, VEGF, and HP contents, and a reduced extent of apoptosis. In light of our finding that topical EPO treatment promotes skin wound repair in diabetic rats, we propose that topical EPO treatment is a therapeutically beneficial method of treating chronic diabetic wounds.

The LDL receptor.

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Goldstein, Joseph L; Brown, Michael S

2009-04-01

In this article, the history of the LDL receptor is recounted by its codiscoverers. Their early work on the LDL receptor explained a genetic cause of heart attacks and led to new ways of thinking about cholesterol metabolism. The LDL receptor discovery also introduced three general concepts to cell biology: receptor-mediated endocytosis, receptor recycling, and feedback regulation of receptors. The latter concept provides the mechanism by which statins selectively lower plasma LDL, reducing heart attacks and prolonging life.

Recombinant erythropoietin acutely decreases renal perfusion and decouples the renin-angiotensin-aldosterone system.

Science.gov (United States)

Aachmann-Andersen, Niels J; Christensen, Soren J; Lisbjerg, Kristian; Oturai, Peter; Johansson, Pär I; Holstein-Rathlou, Niels-Henrik; Olsen, Niels V

2018-03-01

The effect of recombinant erythropoietin (rhEPO) on renal and systemic hemodynamics was evaluated in a randomized double-blinded, cross-over study. Sixteen healthy subjects were tested with placebo, or low-dose rhEPO for 2 weeks, or high-dose rhEPO for 3 days. Subjects refrained from excessive salt intake, according to instructions from a dietitian. Renal clearance studies were done for measurements of renal plasma flow, glomerular filtration rate (GFR) and the segmentel tubular handling of sodium and water (lithium clearance). rhEPO increased arterial blood pressure, total peripheral resistance, and renal vascular resistance, and decreased renal plasma flow in the high-dose rhEPO intervention and tended to decrease GFR. In spite of the decrease in renal perfusion, rhEPO tended to decrease reabsorption of sodium and water in the proximal tubule and induced a prompt decrease in circulating levels of renin and aldosterone, independent of changes in red blood cell mass, blood volumes, and blood pressure. We also found changes in biomarkers showing evidence that rhEPO induced a prothrombotic state. Our results suggest that rhEPO causes a direct downregulation in proximal tubular reabsorption that seems to decouple the activity of the renin-angiotensin-aldosterone system from changes in renal hemodynamics. This may serve as a negative feed-back mechanism on endogenous synthesis of EPO when circulating levels of EPO are high. These results demonstrates for the first time in humans a direct effect of rhEPO on renal hemodynamics and a decoupling of the renin-angiotensin-aldosterone system. © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

In vitro expression of erythropoietin by transfected human mesenchymal stromal cells.

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Mok, P-L; Cheong, S-K; Leong, C-F; Othman, A

2008-01-01

Mesenchymal stromal cells (MSC) are pluripotent progenitor cells that can be found in human bone marrow (BM). These cells have low immunogenicity and could suppress alloreactive T-cell responses. In the current study, MSC were tested for their capacity to carry and deliver the erythropoietin (EPO) gene in vitro. Expanded BM MSC was transfected with EPO-encoded plasmid pMCV1.2 and EPO-encoded MIDGE (minimalistic immunologically defined gene expression) vector by electroporation. The expressed EPO was used to induce hematopoietic stem cells (HSC) into erythroid colonies. The results showed that the MIDGE vector was more effective and stable than the plasmid (pMCV1.2) in delivering EPO gene into MSC. The supernatants containing EPO obtained from the transfected cell culture were able to induce the differentiation of HSC into erythroid colonies. MSC hold promise as a cell factory for the production of biologic molecules, and MIDGE vector is more effective and stable than the plasmid in nucleofection involving the EPO gene.

β-Adrenergic receptor-mediated suppression of interleukin 2 receptors in human lymphocytes

International Nuclear Information System (INIS)

Feldman, R.D.; Hunninghake, G.W.; McArdle, W.L.

1987-01-01

Adrenergic receptor agonists are know to attenuate the proliferative response of human lymphocytes after activation; however, their mechanism of action is unknown. Since expression of interleukin 2 (IL-2) receptors is a prerequisite for proliferation, the effect of β-adrenergic receptor agonists on lymphocyte IL-2 receptors was studied on both mitogen-stimulated lymphocytes and IL-2-dependent T lymphocyte cell lines. In both cell types the β-adrenergic receptor agonist isoproterenol blocked the expression of IL-2 receptors, as determined with the IL-2 receptor anti-TAC antibody. To determine the effect of β-adrenergic agonists on expression of the high affinity IL-2 receptors, [ 125 I]IL-2 binding studies were performed at concentrations selective for high affinity sites. No significant effect of β-adrenergic agonists on high affinity IL-2 receptor sites could be detected. The data demonstrate that β-adrenergic receptor agonists down-regulate IL-2 receptors primarily affecting low affinity sites

[Blunted erythropoietic response in the anemia of anorexia nervosa].

Science.gov (United States)

Juncà, Jordi; Sorigué, Marc; Rodríguez-Hernández, Inés; Aldea, Marta; Granada, María Luisa; Sánchez-Planell, Lluis

2015-11-20

The cause of the anemia in anorexia nervosa (AN) has not been fully ascertained. Ferritin, folate and cobalamin values are usually within normal ranges. Anemia does not have a relationship with bone marrow changes and erythropoietin (EPO) levels have not been investigated. The objective of this study was to evaluate the EPO response in a small group of AN patients. EPO levels were measured in serum samples of 41 female AN patients (11 with anemia, and 30 with normal blood cell count). The adequacy of EPO response was assessed by comparing the increase observed in a group of normal weight patients with anemia. EPO concentrations in anemic AN patients were higher than in non-anemic: 20.63mU/mL (4.04-28.46) vs 8.7mU/mL (3.9-20.93), P=.0088, but the increase in EPO was lower than expected (27.85mU/mL [17.7-118.9]), P=.014. BMI and the difference between actual and expected EPO were inversely correlated. Inadequate EPO response may partly explain anemia in AN, but further studies are necessary. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Erythropoietin enhances hippocampal long-term potentiation and memory

Directory of Open Access Journals (Sweden)

El-Kordi Ahmed

2008-09-01

Full Text Available Abstract Background Erythropoietin (EPO improves cognition of human subjects in the clinical setting by as yet unknown mechanisms. We developed a mouse model of robust cognitive improvement by EPO to obtain the first clues of how EPO influences cognition, and how it may act on hippocampal neurons to modulate plasticity. Results We show here that a 3-week treatment of young mice with EPO enhances long-term potentiation (LTP, a cellular correlate of learning processes in the CA1 region of the hippocampus. This treatment concomitantly alters short-term synaptic plasticity and synaptic transmission, shifting the balance of excitatory and inhibitory activity. These effects are accompanied by an improvement of hippocampus dependent memory, persisting for 3 weeks after termination of EPO injections, and are independent of changes in hematocrit. Networks of EPO-treated primary hippocampal neurons develop lower overall spiking activity but enhanced bursting in discrete neuronal assemblies. At the level of developing single neurons, EPO treatment reduces the typical increase in excitatory synaptic transmission without changing the number of synaptic boutons, consistent with prolonged functional silencing of synapses. Conclusion We conclude that EPO improves hippocampus dependent memory by modulating plasticity, synaptic connectivity and activity of memory-related neuronal networks. These mechanisms of action of EPO have to be further exploited for treating neuropsychiatric diseases.

Radioimmunoassay for erytropoetin serum level in polycythemia

International Nuclear Information System (INIS)

Nikolova, K.; Vassileva, D.

2003-01-01

Erythropoietin (Epo) is the first well studied hemopoietic growth factor. The pathological levels of its serum concentration show deviations in the specific mechanisms for some diseases such as polycythemia. Objective of this work is the assessment of the diagnostic value of the Epo in the serum for the differentiation of the main form of polycythemia - true and symptomatic. Material and methods: 47 patients are studied (21 women and 26 men), 23 of them are with polycythemia vera and 24 with polycythemia symptomatica. The following has been determined: the serum level of Erythropoietin, hemoglobin, the number of erythrocytes, leukocytes, thrombocytes, myelogram. The serum level of Epo is quantitatively determined b using of radioimmunological method, through Epo-Trac kit. Results: The diagnosis is also confirmed in all patients by other laboratory tests. The normal values of Epo in healthy persons are 17.0±7.0 mU/ml. The average Epo level in patients with polycythemia vera is 20.4±3.0 mU/ml. In one patient the Epo level is supposedly connected with an accompanying kidney disease. Conclusions: The obtained data show that the Epo serum level is an accurate criterion in the diagnosing of true and symptomatic polycythemia. The true polycythemia is connected with an independent erythrocyte production. In the symptomatic polycythemia the tissue hypoxia stimulated the Epo production

Quantitative receptor radioautography in the study of receptor-receptor interactions in the nucleus tractus solitarii

Directory of Open Access Journals (Sweden)

Fior-Chadi D.R.

1998-01-01

Full Text Available The nucleus tractus solitarii (NTS in the dorsomedial medulla comprises a wide range of neuropeptides and biogenic amines. Several of them are related to mechanisms of central blood pressure control. Angiotensin II (Ang II, neuropeptide Y (NPY and noradrenaline (NA are found in the NTS cells, as well as their receptors. Based on this observation we have evaluated the modulatory effect of these peptide receptors on a2-adrenoceptors in the NTS. Using quantitative receptor radioautography, we observed that NPY and Ang II receptors decreased the affinity of a2-adrenoceptors for their agonists in the NTS of the rat. Cardiovascular experiments agreed with the in vitro data. Coinjection of a threshold dose of Ang II or of the NPY agonists together with an ED50 dose of adrenergic agonists such as NA, adrenaline and clonidine counteracted the depressor effect produced by the a2-agonist in the NTS. The results provide evidence for the existence of an antagonistic interaction between Ang II at1 receptors and NPY receptor subtypes with the a2-adrenoceptors in the NTS. This receptor interaction may reduce the transduction over the a2-adrenoceptors which can be important in central cardiovascular regulation and in the development of hypertension

How NASA's Space Science Support Network Can Assist DPS Members in Their Public Engagement Efforts

Science.gov (United States)

Miner, E. D.; Lowes, L. L.

2003-12-01

In her Carl Sagan Medal lecture last year, Heidi Hammel talked of the dos and don'ts of education and public outreach efforts by DPS members. She pointed out a number of misconceptions about what does and does not constitute "good EPO" and encouraged members to consult with "the experts" if they would like to improve their EPO effectiveness and reach. She named the DPS Education and Public Outreach Officer, Larry Lebofsky, his Deputy, Lou Mayo, and the DPS Press Officer, Ellis Miner, who also co-directs NASA's Solar System Exploration EPO Forum with Leslie Lowes. NASA's Space Science Support Network has been in existence for about six years. It has been directed by DPS member Jeff Rosendhal and is now serving as a model for NASA's new Education Enterprise. Members of the Support Network are prepared to assist (and haves been assisting) space scientists throughout the US and abroad in deciding where to spend their EPO efforts most effectively. The service is provided free of cost and includes, among other services, the following: (1) helping to establish partnerships between educators and scientists, (2) helping to link scientists and professional EPO organizations, (3) helping to link scientists to national youth and community groups, (4) providing ready access to EPO electronic and hardcopy products, (5) providing advice and direction in the preparation of EPO proposals to NASA, (6) helping to maintain several national networks of EPO volunteers, (7) encouraging (at home institutions) the broadening of scientist EPO efforts, (8) maintaining self-help websites for scientists interested in EPO.

Use of high-dose erythropoietin for repair after injury: A comparison of outcomes in heart and kidney.

Science.gov (United States)

Gobe, Glenda C; Morais, Christudas; Vesey, David A; Johnson, David W

2013-07-01

There is a need to define the exact benefits and contraindications of use of high-dose recombinant human erythropoietin (EPO) for its non-hematopoietic function as a cytokine that enhances tissue repair after injury. This review compares the outcomes from use of EPO in the injured heart and kidney, two organs that are thought, traditionally, to have intrinsically-different repair mechanisms. Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched. Ongoing work by us on EPO protection of ischemia-reperfusion-injured kidneys indicated, first, that EPO acutely enhanced kidney repair via anti-apoptotic, pro-regenerative mechanisms, and second, that EPO may promote chronic fibrosis in the long term. Work by others on the ischaemia-injured heart has also indicated that EPO promotes repair. Although myocardial infarcts are made up mostly of necrotic tissue, many publications state EPO is anti-apoptotic in the heart, as well as promoting healing via cell differentiation and stimulation of granulation tissue. In the case of the heart, promotion of fibrosis may be advantageous where an infarct has destroyed a zone of cardiomyocytes, but if EPO stimulates progressive fibrosis in the heart, this may promote cardiac failure. A major concern in relation to the use of EPO in a cytoprotective role is its stimulation of long-term inflammation and fibrosis. EPO usage for cytoprotection is undoubtedly advantageous, but it may need to be offset with an anti-inflammatory agent in some organs, like kidney and heart, where progression to chronic fibrosis after acute injury is often recorded.

A comparative study of efficacy and safety of the lyophilized powder alpha-erythropoietin and the liquid form alpha-erythropoietin for hemoglobin maintenance in patients with hemodialysis treatment.

Science.gov (United States)

Satirapoj, Bancha; Supasyndh, Ouppatham; Choovichian, Panbubpa

2014-09-01

Insufficient production oferythropoietin (EPO) is the primary cause ofanemia in patients with chronic kidney disease (CKD). The EPO treatment is an established treatment for renal anemia. The study investigated the therapeutic outcome between lyophilized powder and liquid form of EPO alpha by intravenous (IV) administration in hemoglobin maintenance of anemic treatment for CKD patients receiving hemodialysis. Forty patients were randomly assigned to either lyophilized powder of EPO alpha (treatment, n = 21) or liquidform of EPO alpha (control, n = 19) for 12 weeks by lVadministration. The hemoglobin was maintained within the target range of 10. 0 to 12.0 g/dL by adjusting the dosage of EPO. The clinical and biochemical profiles including transferrin saturation andferritin were measured. Adverse events were documented. The mean hemoglobin ofboth groups at baseline was 11.2±0.6 g/dL. Mean hemoglobin and mean hematocrit levels at baseline, and follow-up data of both groups were not statistically different. The mean weekly dosage of EPO in the treatment and control groups had no statistical significance within the same group and between groups as well. Stable hemoglobin levels were maintained without EPO dosage adjustment in the majority ofpatients in both groups (treatment group, 90.5%, control group, 94.7%). During the 12-week study period, no serious side effect was detected The present study demonstrated that the lyophilizedpowder ofEPO alpha was effective and safe as the standard liquid form of EPO alpha when it was administered by IV route in hemoglobin maintenance of anemia treatment.

Intraoperative Inducibility of Atrial Fibrillation Does Not Predict Early Postoperative Atrial Fibrillation.

Science.gov (United States)

Lanters, Eva A H; Teuwen, Christophe P; Yaksh, Ameeta; Kik, Charles; van der Does, Lisette J M E; Mouws, Elisabeth M J P; Knops, Paul; van Groningen, Nicole J; Hokken, Thijmen; Bogers, Ad J J C; de Groot, Natasja M S

2018-03-10

Early postoperative atrial fibrillation (EPoAF) is associated with thromboembolic events, prolonged hospitalization, and development of late PoAF (LPoAF). It is, however, unknown if EPoAF can be predicted by intraoperative AF inducibility. The aims of this study are therefore to explore (1) the value of intraoperative inducibility of AF for development of both EPoAF and LPoAF and (2) the predictive value of de novo EPoAF for recurrence of LPoAF. Patients (N=496, 75% male) undergoing cardiothoracic surgery for coronary and/or valvular heart disease were included. AF induction was attempted by atrial pacing, before extracorporeal circulation. All patients were on continuous rhythm monitoring until discharge to detect EPoAF. During a follow-up period of 2 years, LPoAF was detected by ECGs and Holter recordings. Sustained AF was inducible in 56% of patients. There was no difference in patients with or without AF before surgery ( P =0.159), or between different types of surgery ( P =0.687). In patients without a history of AF, incidence of EPoAF and LPoAF was 37% and 2%, respectively. EPoAF recurred in 58% patients with preoperative AF, 53% developed LPoAF. There were no correlations between intraoperative inducibility and EPoAF or LPoAF ( P >0.05). EPoAF was not correlated with LPoAF in patients without a history of AF ( P =0.116), in contrast to patients with AF before surgery ( P <0.001). Intraoperative AF inducibility does not predict development of either EPoAF or LPoAF. In patients with AF before surgery, EPoAF is correlated with LPoAF recurrences. This correlation is absent in patients without AF before surgery. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Prospective identification of erythroid elements in cultured peripheral blood.

Science.gov (United States)

Miller, J L; Njoroge, J M; Gubin, A N; Rodgers, G P

1999-04-01

We have developed a prospective approach to identify the generation of erythroid cells derived from cultured peripheral blood mononuclear cells (PBMC) by monitoring the expression of the cell surface protein CD48. Unpurified populations of PBMC obtained from the buffy coats of normal volunteers were grown in suspension culture in the absence or presence of erythropoietin. A profile of surface CD48 expression permitted a flow cytometric identification of erythropoietin responsive populations at various stages of their maturation. In the absence of erythropoietin (EPO) supplemented media, the CD48- cells represented <5% of the total population of PBMC remaining in culture. In cultures supplemented with 1 U/mL EPO, the mean percentage of CD48- cells increased to 34.7 + 14.9% (p < 0.01) after 14 days in culture. Coordinated CD34 and CD71 (transferrin receptor) expression, morphology, gamma-globin transcription, and colony formation in methylcellulose were observed during the 14-day culture period. Flow cytometric monitoring of bulk cultured PBMC provides a simple and reliable means for the prospective or real-time study of human erythropoiesis.

Brain and skin do not contribute to the systemic rise in erythropoietin during acute hypoxia in humans

DEFF Research Database (Denmark)

Rasmussen, Peter; Nordsborg, Nikolai; Taudorf, Sarah

2012-01-01

these findings apply to humans remains unknown. We exposed healthy young subjects to hypoxia (equivalent to 3800 m) and measured EPO in arterial and jugular venous plasma and in cerebrospinal fluid. To examine the role of the skin for EPO production during hypoxia, subjects were exposed to 8 h of hypobaric......Erythropoietin (EPO) preserves arterial oxygen content by controlling red blood cell and plasma volumes. Synthesis of EPO was long thought to relate inversely to renal oxygenation, but in knockout mice, brain and skin have been identified as essential for the acute hypoxic EPO response. Whether...

Erythropoietin modulates neural and cognitive processing of emotional information in biomarker models of antidepressant drug action in depressed patients

DEFF Research Database (Denmark)

Miskowiak, Kamilla W; Favaron, Elisa; Hafizi, Sepehr

2010-01-01

Erythropoietin (Epo) has neuroprotective and neurotrophic effects, and may be a novel therapeutic agent in the treatment of psychiatric disorders. We have demonstrated antidepressant-like effects of Epo on the neural and cognitive processing of facial expressions in healthy volunteers. The curren...... study investigates the effects of Epo on the neural and cognitive response to emotional facial expressions in depressed patients.......Erythropoietin (Epo) has neuroprotective and neurotrophic effects, and may be a novel therapeutic agent in the treatment of psychiatric disorders. We have demonstrated antidepressant-like effects of Epo on the neural and cognitive processing of facial expressions in healthy volunteers. The current...

XMRV: usage of receptors and potential co-receptors

Directory of Open Access Journals (Sweden)

Gaddam Durga

2011-09-01

Full Text Available Abstract Background XMRV is a gammaretrovirus first identified in prostate tissues of Prostate Cancer (PC patients and later in the blood cells of patients with Chronic Fatigue Syndrome (CFS. Although XMRV is thought to use XPR1 for cell entry, it infects A549 cells that do not express XPR1, suggesting usage of other receptors or co-receptors. Methods To study the usage of different receptors and co- receptors that could play a role in XMRV infection of lymphoid cells and GHOST (GFP- Human osteosarcoma cells expressing CD4 along with different chemokine receptors including CCR1, CCR2, etc., were infected with XMRV. Culture supernatants and cells were tested for XMRV replication using real time quantitative PCR. Results Infection and replication of XMRV was seen in a variety of GHOST cells, LNCaP, DU145, A549 and Caski cell lines. The levels of XMRV replication varied in different cell lines showing differential replication in different cell lines. However, replication in A549 which lacks XPR1 expression was relatively higher than DU145 but lower than, LNCaP. XMRV replication varied in GHOST cell lines expressing CD4 and each of the co- receptors CCR1-CCR8 and bob. There was significant replication of XMRV in CCR3 and Bonzo although it is much lower when compared to DU145, A549 and LNCaP. Conclusion XMRV replication was observed in GHOST cells that express CD4 and each of the chemokine receptors ranging from CCR1- CCR8 and BOB suggesting that infectivity in hematopoietic cells could be mediated by use of these receptors.

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.

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

The two-state dimer receptor model: a general model for receptor dimers.

Science.gov (United States)

Franco, Rafael; Casadó, Vicent; Mallol, Josefa; Ferrada, Carla; Ferré, Sergi; Fuxe, Kjell; Cortés, Antoni; Ciruela, Francisco; Lluis, Carmen; Canela, Enric I

2006-06-01

Nonlinear Scatchard plots are often found for agonist binding to G-protein-coupled receptors. Because there is clear evidence of receptor dimerization, these nonlinear Scatchard plots can reflect cooperativity on agonist binding to the two binding sites in the dimer. According to this, the "two-state dimer receptor model" has been recently derived. In this article, the performance of the model has been analyzed in fitting data of agonist binding to A(1) adenosine receptors, which are an example of receptor displaying concave downward Scatchard plots. Analysis of agonist/antagonist competition data for dopamine D(1) receptors using the two-state dimer receptor model has also been performed. Although fitting to the two-state dimer receptor model was similar to the fitting to the "two-independent-site receptor model", the former is simpler, and a discrimination test selects the two-state dimer receptor model as the best. This model was also very robust in fitting data of estrogen binding to the estrogen receptor, for which Scatchard plots are concave upward. On the one hand, the model would predict the already demonstrated existence of estrogen receptor dimers. On the other hand, the model would predict that concave upward Scatchard plots reflect positive cooperativity, which can be neither predicted nor explained by assuming the existence of two different affinity states. In summary, the two-state dimer receptor model is good for fitting data of binding to dimeric receptors displaying either linear, concave upward, or concave downward Scatchard plots.

OBJECTIVES AND INCENTIVES AT THE EUROPEAN PATENT OFFICE

DEFF Research Database (Denmark)

Friebel, Guido; Koch, Alexander; Seabright, Paul

This report examines the effectiveness of the current system of incentives within the European Patent Office (EPO) and considers the possible consequences of placing greater emphasis on quantitative measures of productivity in rewarding EPO staff.......This report examines the effectiveness of the current system of incentives within the European Patent Office (EPO) and considers the possible consequences of placing greater emphasis on quantitative measures of productivity in rewarding EPO staff....

Cyclooxygenase-2 and hypoxia-regulated proteins are modulated by basic fibroblast growth factor in acute renal failure

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Sandra Villanueva

2012-01-01

Full Text Available Acute renal failure (ARF can be caused by injuries that induce tissue hypoxia, which in turn can trigger adaptive or inflammatory responses. We previously showed the participation of basic fibroblast growth factor (FGF-2 in renal repair. Based on this, the aim of this study was to analyze the effect of FGF-2 signaling pathway manipulation at hypoxia-induced protein levels, as well as in key proteins from the vasoactive systems of the kidney. We injected rat kidneys with FGF-2 recombinant protein (r-FGF or FGF-2 receptor antisense oligonucleotide (FGFR2-ASO after bilateral ischemia, and evaluated the presence of iNOS, EPO and HO-1, in representation of hypoxia-induced proteins, as well as COX-2, renin, kallikrein, and B2KR, in representation of the vasoactive systems of the kidney. A reduction in iNOS, HO-1, EPO, renin, kallikrein, B2KR, and in renal damage was observed in animals treated with r-FGF. The opposite effect was found with FGF-2 receptor down-regulation. In contrast, COX-2 protein levels were higher in kidneys treated with r-FGF and lower in those that received FGFR2-ASO, as compared to saline treated kidneys. These results suggest that the protective role of FGF-2 in the pathogenesis of ARF induced by I/R is a complex process, through which a differential regulation of metabolic pathways takes place.

Enhanced anti-proliferative efficacy of epothilone B loaded with Escherichia coli Nissle 1917 bacterial ghosts on the HeLa cells by mitochondrial pathway of apoptosis.

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Zhu, Wenxing; Hao, Lujiang; Liu, Xinli; Orlando, Borrás-Hidalgo; Zhang, Yuyu

2018-03-20

Epothilones constitute a new class of microtubule-stabilizing anti-cancer agents with promising preclinical and clinical activity. However, its systemic application still causes some toxic side effects. To reduce these undesired effects, advanced drug delivery systems based on cell targeting carriers are needed currently. In this study, the high quality bacterial ghosts of the probiotic Escherichia coli Nissle 1917 (EcN) were prepared in a large scale and retained fully intact surface structures for specific attachment to mammalian cells. The EcN ghosts could be efficiently loaded with the low hydrophilic drug Epothilone B (Epo B) and the maximal load efficiency was approximately 2.5% (w/w). Cytotoxicity assays revealed that Epo B-ghosts exhibited enhanced anti-proliferative properties on the HeLa cells. The Epo B associated with EcN ghosts was more cytotoxic at least 10 times than the free Epo B at the same concentrations. Apoptosis assays showed that both Epo B-ghosts and free Epo B induced time course-dependent apoptosis and necrosis in HeLa cells, respectively. While the former induced more apoptosis and necrosis than the latter. Furthermore, the cytochrome C release and the activation of caspase-3 were more remarkable after treatment with the Epo B-ghosts compared to the free Epo B, which implied that Epo B-ghosts might more effectively induce the apoptosis mediated by mitochondrial pathway in HeLa cells. Therefore, the higher anti-proliferative effects of the Epo B-ghosts on the HeLa cells were mediated by mitochondrial pathway of apoptosis. The EcN ghosts may provide a useful drug delivery carrier for drug candidates in cancer therapy.

ERYTHROPOIETIN TREATMENT FOR ANEMIA IN CHILDREN WITH CANCER – SINGLE CENTRE EXPERIENCES

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Polona Mali

2004-12-01

Full Text Available Background. Anemia, a common complication during treatment of malignant disease in children, was frequently treated with red blood cell transfusions. Several studies have shown, that the introduction of recombinant human erythropoietin (rh EPO for treating anemia in patients has been effective in reducing the need for transfusions. Variable doses of EPO from 150 to 900 IU/kg body weight have been used usually three times weekly. Recently some studies showed equally effective once weekly administration of EPO with proposed doses for children of 450 to 600 IU/ kg body weight.Efficacy and safety of once weekly EPO therapy was tested in 8/10 children treated in our Unit for solid tumors and nonHodgkin’s lymphoma. In this article we would like to present our one year experience with EPO treatment.Patients and methods. Patients have subcutaneously received the EPO dose of 600 UI/ kg body weight once weekly. Hemoglobin response and transfusion needs before and during treatment with EPO were analyzed.Results. Response was seen in 7/8 of patient, with increased hemoglobin level and lower transfusion needs. Only one patient was poor responder at first, but responded perfect after twice weekly EPO application. No adverse reaction related to EPO therapy was observed.Conclusions. Our experience with treating anemia in pediatric cancer patients who undergo intensive and aggressive chemotherapy treatment regimens are good and promising. Once weekly dosage regimen is child friendly and acceptable way of treating anemia.

Erythropoietin-enhanced endothelial progenitor cell recruitment in peripheral blood and renal vessels during experimental acute kidney injury in rats.

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Cakiroglu, Figen; Enders-Comberg, Sora Maria; Pagel, Horst; Rohwedel, Jürgen; Lehnert, Hendrik; Kramer, Jan

2016-03-01

Beneficial effects of erythropoietin (EPO) have been reported in acute kidney injury (AKI) when administered prior to induction of AKI. We studied the effects of EPO administration on renal function shortly after ischemic AKI. For this purpose, rats were subjected to renal ischemia for 30 min and EPO was administered at a concentration of 500 U/kg either i.v. as a single shot directly after ischemia or with an additional i.p. dose until 3 days after surgery. The results were compared with AKI rats without EPO application and a sham-operated group. Renal function was assessed by measurement of serum biochemical markers, histological grading, and using an isolated perfused kidney (IPK) model. Furthermore, we performed flow cytometry to analyze the concentration of endothelial progenitor cells (EPCs) in the peripheral blood and renal vessels. Following EPO application, there was only a statistically non-significant tendency of serum creatinine and urea to improve, particularly after daily EPO application. Renal vascular resistance and the renal perfusion rate were not significantly altered. In the histological analysis, acute tubular necrosis was only marginally ameliorated following EPO administration. In summary, we could not demonstrate a significant improvement in renal function when EPO was applied after AKI. Interestingly, however, EPO treatment resulted in a highly significant increase in CD133- and CD34-positive EPC both in the peripheral blood and renal vessels. © 2015 International Federation for Cell Biology.

Inhibition of erythropoietin siRNA on corneal neovascularization of rabbit

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Yu-Shun Xue

2017-03-01

Full Text Available AIM: To observe the expression of erythropoietin(EPOon the corneal of rabbit and evaluate the inhibition effect of EPO siRNA on corneal neovascularization(CNV. METHODS: Totally 22 healthy rabbits were randomly divided into 2 groups, which were experimental group and normal control group. Both eyes of rabbits in experimental group were chosen to establish corneal neovascularization model by alkali burn. The morphologic change of corneal was observed with slit lamp microscope and the area of CNV was calculated every day. After alkali burn, the right eye of the experimental group was accepted EPO siRNA injection under the conjunctiva, and the left eye was assigned to be experimental control group. The corneal with CNV was collected for immunohistochemistry at 3d, 7d, 14d, 21d after alkali burn, and the expression of EPO was measured. RESULTS: CNV began growing at the 3d after alkali burn in experimental group, and it was vigorous growing at 7d-14d period. The result of immunohistochemistry shows that the expression of EPO increased after the operation. Compared with experimental group, the rabbits who were treated by EPO siRNA was found with less neovascularization on their corneal, and the expression of EPO decreased. There were statistical significance between the two group at different time(PCONCLUSION: EPO is likely to play an important role on CNV growth, and EPO siRNA can inhibit the growth of CNV by restraining the expression of EPO.

Epothilones Suppress Neointimal Thickening in the Rat Carotid Balloon-Injury Model by Inducing Vascular Smooth Muscle Cell Apoptosis through p53-Dependent Signaling Pathway.

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Son, Dong Ju; Jung, Jae Chul; Hong, Jin Tae

2016-01-01

Microtubule stabilizing agents (MTSA) are known to inhibit vascular smooth muscle cell (VSMC) proliferation and migration, and effectively reduce neointimal hyperplasia and restenosis. Epothilones (EPOs), non-taxane MTSA, have been found to be effective in the inhibition of VSMC proliferation and neointimal formation by cell cycle arrest. However, effect of EPOs on apoptosis in hyper-proliferated VSMCs as a possible way to reduce neointimal formation and its action mechanism related to VSMC viability has not been suited yet. Thus, the purposes of the present study was to investigate whether EPOs are able to inhibit neointimal formation by inducing apoptosis within the region of neointimal hyperplasia in balloon-injured rat carotid artery, as well as underlying action mechanism. Treatment of EPO-B and EPO-D significantly induced apoptotic cell death and mitotic catastrophe in hyper-proliferated VSMCs, resulting in cell growth inhibition. Further, EPOs significantly suppressed VSMC proliferation and induced apoptosis by activation of p53-dependent apoptotic signaling pathway, Bax/cytochrome c/caspase-3. We further demonstrated that the local treatment of carotid arteries with EPOs potently inhibited neointimal lesion formation by induction of apoptosis in rat carotid injury model. Our findings demonstrate a potent anti-neointimal hyperplasia property of EPOs by inducing p53-depedent apoptosis in hyper-proliferated VSMCs.

Receptor oligomerization in family B1 of G-protein-coupled receptors

DEFF Research Database (Denmark)

Roed, Sarah Norklit; Ørgaard, Anne; Jørgensen, Rasmus

2012-01-01

, the glucagon receptor, and the receptors for parathyroid hormone (PTHR1 and PTHR2). The dysregulation of several family B1 receptors is involved in diseases, such as diabetes, chronic inflammation, and osteoporosis which underlines the pathophysiological importance of this GPCR subfamily. In spite of this......, investigation of family B1 receptor oligomerization and especially its pharmacological importance is still at an early stage. Even though GPCR oligomerization is a well-established phenomenon, there is a need for more investigations providing a direct link between these interactions and receptor functionality......The superfamily of the seven transmembrane G-protein-coupled receptors (7TM/GPCRs) is the largest family of membrane-associated receptors. GPCRs are involved in the pathophysiology of numerous human diseases, and they constitute an estimated 30-40% of all drug targets. During the last two decades...

Activation of glucocorticoid receptors increases 5-HT2A receptor levels

DEFF Research Database (Denmark)

Trajkovska, Viktorija; Kirkegaard, Lisbeth; Krey, Gesa

2009-01-01

an effect of GR activation on 5-HT2A levels, mature organotypic hippocampal cultures were exposed to corticosterone with or without GR antagonist mifepristone and mineralocorticoid receptor (MR) antagonist spironolactone. In GR under-expressing mice, hippocampal 5-HT2A receptor protein levels were decreased......Major depression is associated with both dysregulation of the hypothalamic pituitary adrenal axis and serotonergic deficiency, not the least of the 5-HT2A receptor. However, how these phenomena are linked to each other, and whether a low 5-HT2A receptor level is a state or a trait marker...... of depression is unknown. In mice with altered glucocorticoid receptor (GR) expression we investigated 5-HT2A receptor levels by Western blot and 3H-MDL100907 receptor binding. Serotonin fibre density was analyzed by stereological quantification of serotonin transporter immunopositive fibers. To establish...

Effective Practices for Evaluating Education and Public Outreach Programs

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Wilkerson, S.

2013-12-01

Stephanie Baird Wilkerson, PhD Carol Haden EdD Magnolia Consulting,LLC Education and public outreach (EPO) program developers and providers seeking insights regarding effective practices for evaluating EPO activities programs benefit from understanding why evaluation is critical to the success of EPO activities and programs, what data collection methods are appropriate, and how to effectively communicate and report findings. Based on our extensive experience evaluating EPO programs, we will share lessons learned and examples of how these practices play out in actual evaluation studies. EPO program developers, providers, and evaluators must consider several factors that influence which evaluation designs and data collection methods will be most appropriate, given the nature of EPO programs. Effective evaluation practices of EPO programs take into account a program's phase of development, duration, and budget as well as a program's intended outcomes. EPO programs that are just beginning development will have different evaluation needs and priorities than will well-established programs. Effective evaluation practices consider the 'life' of a program with an evaluation design that supports a program's growth through various phases including development, revision and refinement, and completion. It would be premature and inappropriate to expect the attainment of longer-term outcomes of activities during program development phases or early stages of implementation. During program development, EPO providers should clearly define program outcomes that are feasible and appropriate given a program's scope and expected reach. In many respects, this directly relates to the amount of time, or duration, intended audiences participate in EPO programs. As program duration increases so does the likelihood that the program can achieve longer-term outcomes. When choosing which outcomes are reasonable to impact and measure, program duration should be considered. Effective evaluation

Gβ promotes pheromone receptor polarization and yeast chemotropism by inhibiting receptor phosphorylation.

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Ismael, Amber; Tian, Wei; Waszczak, Nicholas; Wang, Xin; Cao, Youfang; Suchkov, Dmitry; Bar, Eli; Metodiev, Metodi V; Liang, Jie; Arkowitz, Robert A; Stone, David E

2016-04-12

Gradient-directed cell migration (chemotaxis) and growth (chemotropism) are processes that are essential to the development and life cycles of all species. Cells use surface receptors to sense the shallow chemical gradients that elicit chemotaxis and chemotropism. Slight asymmetries in receptor activation are amplified by downstream signaling systems, which ultimately induce dynamic reorganization of the cytoskeleton. During the mating response of budding yeast, a model chemotropic system, the pheromone receptors on the plasma membrane polarize to the side of the cell closest to the stimulus. Although receptor polarization occurs before and independently of actin cable-dependent delivery of vesicles to the plasma membrane (directed secretion), it requires receptor internalization. Phosphorylation of pheromone receptors by yeast casein kinase 1 or 2 (Yck1/2) stimulates their internalization. We showed that the pheromone-responsive Gβγ dimer promotes the polarization of the pheromone receptor by interacting with Yck1/2 and locally inhibiting receptor phosphorylation. We also found that receptor phosphorylation is essential for chemotropism, independently of its role in inducing receptor internalization. A mathematical model supports the idea that the interaction between Gβγ and Yck1/2 results in differential phosphorylation and internalization of the pheromone receptor and accounts for its polarization before the initiation of directed secretion. Copyright © 2016, American Association for the Advancement of Science.

Glucocorticoid receptor modulators.

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Meijer, Onno C; Koorneef, Lisa L; Kroon, Jan

2018-06-01

The glucocorticoid hormone cortisol acts throughout the body to support circadian processes and adaptation to stress. The glucocorticoid receptor is the target of cortisol and of synthetic glucocorticoids, which are used widely in the clinic. Both agonism and antagonism of the glucocorticoid receptor may be beneficial in disease, but given the wide expression of the receptor and involvement in various processes, beneficial effects are often accompanied by unwanted side effects. Selective glucocorticoid receptor modulators are ligands that induce a receptor conformation that allows activation of only a subset of downstream signaling pathways. Such molecules thereby combine agonistic and antagonistic properties. Here we discuss the mechanisms underlying selective receptor modulation and their promise in treating diseases in several organ systems where cortisol signaling plays a role. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Preliminary Results from a Survey of DPS Scientist’s Attitudes, Activities and Needs in Education and Public Outreach

Science.gov (United States)

Grier, Jennifer A.; Buxner, Sanlyn; Schneider, Nick

2014-11-01

The NASA SMD Planetary Sciences Forum, in partnership with the AAS DPS Education officer has conducted a semi-structured series of interviews with two-dozen DPS members to ascertain: the nature E/PO activities pursued by scientists, what resources and professional development opportunities are needed by scientists, how to increase the impact of scientists’ E/PO efforts, scientists’ concerns and questions regarding E/PO, and what we can do to identify opportunities to address these issues, both from the SMD and DPS perspectives. Members were contacted by phone, and responded to a loose script of questions over a time span of 20 to 90 minutes, depending on the individual. Members were chosen to represent a variety of career experience, home institutions and affiliations, and level of involvement with E/PO. Questions included: What is your level of involvement in E/PO? What sort of professional development or resources would you like to have to increase the efficiency of your E/PO efforts? What barriers to E/PO involvement have you encountered? How do you use social media in your E/PO efforts, if at all? What are your motivations for involvement in E/PO? etc. Our results are consistent with previous research conducted regarding this issue, but they do offer insight specific to the nature of DPS members and their views about E/PO. We will present a subset of these results, the opportunities they present, and the responses of both the PS Forum and the DPS. Based on this survey, the SMD PS Forum was able to identify specific new resources needed by scientists, and therefore developed the brief-one page guides, “The Quick Introduction to Education and Public Outreach,” and “Making the Most of Your E/PO Time - Increasing Your Efficiency and Impact.” Further resources and professional development opportunities will be developed as the data continue to be reviewed. This data collection effort is ongoing. If you would like to become involved, contact Jennifer

Elevated endogenous erythropoietin concentrations are associated with increased risk of brain damage in extremely preterm neonates.

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Steven J Korzeniewski

Full Text Available We sought to determine, in very preterm infants, whether elevated perinatal erythropoietin (EPO concentrations are associated with increased risks of indicators of brain damage, and whether this risk differs by the co-occurrence or absence of intermittent or sustained systemic inflammation (ISSI.Protein concentrations were measured in blood collected from 786 infants born before the 28th week of gestation. EPO was measured on postnatal day 14, and 25 inflammation-related proteins were measured weekly during the first 2 postnatal weeks. We defined ISSI as a concentration in the top quartile of each of 25 inflammation-related proteins on two separate days a week apart. Hypererythropoietinemia (hyperEPO was defined as the highest quartile for gestational age on postnatal day 14. Using logistic regression and multinomial logistic regression models, we compared risks of brain damage among neonates with hyperEPO only, ISSI only, and hyperEPO+ISSI, to those who had neither hyperEPO nor ISSI, adjusting for gestational age.Newborns with hyperEPO, regardless of ISSI, were more than twice as likely as those without to have very low (< 55 Mental (OR 2.3; 95% CI 1.5-3.5 and/or Psychomotor (OR 2.4; 95% CI 1.6-3.7 Development Indices (MDI, PDI, and microcephaly at age two years (OR 2.4; 95%CI 1.5-3.8. Newborns with both hyperEPO and ISSI had significantly increased risks of ventriculomegaly, hemiparetic cerebral palsy, microcephaly, and MDI and PDI < 55 (ORs ranged from 2.2-6.3, but not hypoechoic lesions or other forms of cerebral palsy, relative to newborns with neither hyperEPO nor ISSI.hyperEPO, regardless of ISSI, is associated with elevated risks of very low MDI and PDI, and microcephaly, but not with any form of cerebral palsy. Children with both hyperEPO and ISSI are at higher risk than others of very low MDI and PDI, ventriculomegaly, hemiparetic cerebral palsy, and microcephaly.

Generation of a transplantable erythropoietin-producer derived from human mesenchymal stem cells.

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Yokoo, Takashi; Fukui, Akira; Matsumoto, Kei; Ohashi, Toya; Sado, Yoshikazu; Suzuki, Hideaki; Kawamura, Tetsuya; Okabe, Masataka; Hosoya, Tatsuo; Kobayashi, Eiji

2008-06-15

Differentiation of autologous stem cells into functional transplantable tissue for organ regeneration is a promising regenerative therapeutic approach for cancer, diabetes, and many human diseases. Yet to be established, however, is differentiation into tissue capable of producing erythropoietin (EPO), which has a critical function in anemia. We report a novel EPO-producing organ-like structure (organoid) derived from human mesenchymal stem cells. Using our previously established relay culture system, a human mesenchymal stem cell-derived, human EPO-competent organoid was established in rat omentum. The organoid-derived levels of human EPO increased in response to anemia induced by rapid blood withdrawal. In addition, the presence of an organoid in rats suppressed for native (rat) EPO production enhanced recovery from anemia when compared with control animals lacking the organoid. Together these results confirmed the generation of a stem cell-derived organoid that is capable of producing EPO and sensitive to physiological regulation.

Erythropoietin augments the cytokine response to acute endotoxin-induced inflammation in humans

DEFF Research Database (Denmark)

Hojman, Pernille; Taudorf, Sarah; Lundby, Carsten

2009-01-01

in a human in vivo model of acute systemic low-grade inflammation, we measured circulating inflammatory mediators after intravenous administration of Escherichia coli endotoxin (LPS) bolus injection (0.1 ng/kg of body weight) in young healthy male subjects. The subjects were divided into three groups...... receiving either (1) LPS alone, (2) EPO alone (15,000 IE of rHuEPO) or (3) EPO and LPS. Endotoxin administration alone induced a 3-, 12- and 5-fold increase in plasma concentrations of TNF-alpha, IL-6 and IL-10, respectively, 3h after LPS challenge. When EPO was given prior to a bolus injection...... with endotoxin, the levels of TNF-alpha and IL-6 were enhanced by 5- and 40-fold, respectively, whereas the endotoxin-induced increase in IL-10 response was not influenced by EPO. In contrast to our hypothesis, we find that EPO augments the acute inflammatory effect....

Hepatic erythropoietin response in cirrhosis

DEFF Research Database (Denmark)

Risør, Louise M; Fenger, Mogens; Olsen, Niels Vidiendal

2016-01-01

The main function of erythropoietin (EPO) is to maintain red blood cell mass, but in recent years, increasing evidence has suggested a wider biological role not solely related to erythropoiesis, e.g. angiogenesis and tissue protection. EPO is produced in the liver during fetal life, but the main...... production shifts to the kidney after birth. The liver maintains a production capacity of up to 10% of the total EPO synthesis in healthy controls, but can be up-regulated to 90-100%. However, the hepatic EPO synthesis has been shown not to be adequate for correction of anemia in the absence of renal......, which lead to arterial hypotension, hepatic nephropathy and anemia. An increase in EPO due to renal hypoperfusion, hypoxia and anemia or an EPO-mediated hepato-protective and regenerative mechanism is plausible. However, poor hepatic synthesis capacity, a decreasing co-factor level and inflammatory...

[Effects of benazepril and valsartan on erythropoietin levels in patients with essential hypertension].

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Guo, Lin-lin; Li, Min; Wang, Ai-hong

2011-10-01

To compare effects of valsartan and benazepril on erythropoietin (EPO) levels in essential hypertensive patients with normal renal function. Sixty essential hypertensive patients were randomly divided into valsartan group (n=30, valsartan 80 mg/day) and benazepril group (n=30, benazepril 10 mg/day). Plasma EPO and hemoglobin (Hb) levels were measured at the start of and at 4 and 8 weeks during the treatments. EPO and Hb levels were all in normal range in the two groups. Valsartan decreased EPO levels from 14.179∓3.214 U/L (baseline) to 12.138∓2.926 U/L (PBenazepril treatment did not resulted in any obvious changes in EPO or Hb levels (P>0.05). Valsartan may lower EPO and Hb levels in patients with essential hypertension, while benazepril does not have such effects. The safety of valsartan in anemic hypertensive patients should be further investigated.

Exercise aggravates cardiovascular risks and mortality in rats with disrupted nitric oxide pathway and treated with recombinant human erythropoietin.

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Meziri, Fayçal; Binda, Delphine; Touati, Sabeur; Pellegrin, Maxime; Berthelot, Alain; Touyz, Rhian M; Laurant, Pascal

2011-08-01

Chronic administration of recombinant human erythropoietin (rHuEPO) can generate serious cardiovascular side effects such as arterial hypertension (HTA) in clinical and sport fields. It is hypothesized that nitric oxide (NO) can protect from noxious cardiovascular effects induced by chronic administration of rHuEPO. On this base, we studied the cardiovascular effects of chronic administration of rHuEPO in exercise-trained rats treated with an inhibitor of NO synthesis (L-NAME). Rats were treated or not with rHuEPO and/or L-NAME during 6 weeks. During the same period, rats were subjected to treadmill exercise. The blood pressure was measured weekly. Endothelial function of isolated aorta and small mesenteric arteries were studied and the morphology of the latter was investigated. L-NAME induced hypertension (197 ± 6 mmHg, at the end of the protocol). Exercise prevented the rise in blood pressure induced by L-NAME (170 ± 5 mmHg). However, exercise-trained rats treated with both rHuEPO and L-NAME developed severe hypertension (228 ± 9 mmHg). Furthermore, in these exercise-trained rats treated with rHuEPO/L-NAME, the acetylcholine-induced relaxation was markedly impaired in isolated aorta (60% of maximal relaxation) and small mesenteric arteries (53%). L-NAME hypertension induced an internal remodeling of small mesenteric arteries that was not modified by exercise, rHuEPO or both. Vascular ET-1 production was not increased in rHuEPO/L-NAME/training hypertensive rats. Furthermore, we observed that rHuEPO/L-NAME/training hypertensive rats died during the exercise or the recovery period (mortality 51%). Our findings suggest that the use of rHuEPO in sport, in order to improve physical performance, represents a high and fatal risk factor, especially with pre-existing cardiovascular risk.

Protective effect of bone marrow mesenchymal stem cells combined with erythropoietin therapy on spinal cord injury rat model

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Peng Xie

2016-01-01

Full Text Available Objective: To study the protective effect of bone marrow mesenchymal stem cells combined with erythropoietin therapy on spinal cord injury rat model. Methods: SD rats were selected as experimental animals, spinal cord injury rat model was built by striking spinal cord with Hatteras Instruments PCI3000, and model rats were divided into control group, bone marrow mesenchymal stem cells (BMSCs group, erythropoietin (EPO group and BMSCs combined with EPO group according to different treatment methods. Then number of apoptotic cells in spinal cord tissue, contents of neural markers and neurotrophic factors as well as expression of apoptosis and injury molecules was detected. Results: Number of apoptotic cells as well as mRNA contents of Caspase-3 and c-fos of BMSCs group, EPO group and BMSCs+EPO group was lower than those of control group, and number of apoptotic cells as well as mRNA contents of Caspase-3 and c-fos of BMSCs+EPO group were lower than those of BMSCs group and EPO group; mRNA contents of NF-200 and MBP as well as protein contents of NGF and BDNF in spinal cord tissue of BMSCs group, EPO group and BMSCs+EPO group were higher than those of control group, and mRNA contents of NF-200 and MBP as well as protein contents of NGF and BDNF in spinal cord tissue of BMSCs+EPO group were higher than those of BMSCs group and EPO group. Conclusions: Bone marrow mesenchymal stem cells combined with erythropoietin therapy can inhibit cell apoptosis in the injured spinal cord tissue, increase neurotrophic factor levels and inhibit apoptosis and injury molecule expression; it has protective effect on spinal cord injury.

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 striki...

Polycythemia is associated with bone loss and reduced osteoblast activity in mice.

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Oikonomidou, P R; Casu, C; Yang, Z; Crielaard, B; Shim, J H; Rivella, S; Vogiatzi, M G

2016-04-01

Increased fragility has been described in humans with polycythemia vera (PV). Herein, we describe an osteoporotic phenotype associated with decreased osteoblast activity in a mouse model of PV and another mouse of polycythemia and elevated circulating erythropoietin (EPO). Our results are important for patients with PV or those treated with recombinant EPO (rEPO). PV and other myeloproliferative syndromes have been recently associated with an increased risk for fractures. However, the presence of osteoporosis in these patients has not been well documented. EPO, a hormone primarily known to stimulate erythropoiesis, has been shown recently to regulate bone homeostasis in mice. The aim of this study was to examine the bone phenotype of a mouse model of PV and compare it to that of animals with polycythemia caused by elevated circulating EPO. Bone mass and remodeling were evaluated by micro-computed tomography and histomorphometry. The JAK2(V617F) knock-in mouse, a model of human PV, manifests polycythemia and low circulating EPO levels. Results from this mouse were compared to wild type (wt) controls and the tg6 transgenic mouse that shows polycythemia caused by increased constitutive expression of EPO. Compared to wt, both JAK2(V617F) and tg6 mice had a decrease in trabecular bone mass. Tg6 mice showed an additional modest decrease in cortical thickness and cortical bone volume per tissue volume (P Polycythemia caused by chronically elevated circulating EPO also results in bone loss, and implications on patients treated with rEPO should be evaluated.

Plasma erythropoietin by high-detectability immunoradiometric assay in untreated and treated patients with polycythaemia vera and essential thrombocythaemia

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Carneskog, J.; Kutti, J.; Wadenvik, H. [Univ. of Goeteborg, Sahlgrenska Univ. Hospital, Dept. of Medicine, Haematology Section (Sweden); Lundberg, P.A.; Lindstedt, G. [Univ. of Goeteborg, Sahlgrenska Univ. Hospital, Dept. of Clinical Chemistry and Transfusion Medicine (Sweden)

1998-12-31

By using an immunoradiometric method with a stated detection limit of {<=}1 IU/l (stated normal reference limit in adults 3.7-16 IU/l) we determined EDTA-plasma erythropoietin (EPO) in 58 patients with polycythaemia vera (PV) and 49 patients with essential thrombocythaemia (ET). At the time of blood sampling, 20 of the PV patients were newly diagnosed and untreated, 23 were treated by phlebotomy only, and 30 also received myelosuppressive treatment (with 32P, hydroxyurea of alpha-interferon). Of the ET patients 24 were untreated and 28 received myelosuppressive therapy. For comparison plasma EPO was also determined in 10 patients with pseudopolycythaemia (PP). In this latter group the results for plasma EPO agreed well with the cited normal reference limits. The majority of untreated PV patients (12/20) had undetectable plasma EPO concentration, and the remainder all had values below the lower normal reference limit. Plasma EPO in PV was not significantly influenced by phlebotomy therapy. Twelve of the 24 untreated ET patients (50%) had plasma EPO values below the reference interval (undetectable in 2 patients). The mean EPO concentration was significantly lower in PV patients receiving phlebotomy therapy than in patients with untreated ET. In the total material of PV and ET treated with myelosuppressive agents the PV patients showed significantly lower values for EPO concentration than did patients with ET. The present results support the view that EPO measurements by high-detectability methods are diagnostically useful and should be included in the panel of new criteria for the diagnosis of PV. (au) 20 refs.

The combined effect of erythropoietin and granulocyte macrophage colony stimulating factor on liver regeneration after major hepatectomy in rats

Directory of Open Access Journals (Sweden)

Frangou Matrona

2010-07-01

Full Text Available Abstract Background The liver presents a remarkable capacity for regeneration after hepatectomy but the exact mechanisms and mediators involved are not yet fully clarified. Erythropoietin (EPO and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF have been shown to promote liver regeneration after major hepatectomy. Aim of this experimental study is to compare the impact of exogenous administration of EPO, GM-CSF, as well as their combination on the promotion of liver regeneration after major hepatectomy. Methods Wistar rats were submitted to 70% major hepatectomy. The animals were assigned to 4 experimental groups: a control group (n = 21 that received normal saline, an EPO group (n = 21, that received EPO 500 IU/kg, a GM-CSF group (n = 21 that received 20 mcg/kg of GM-CSF and a EPO+GMCSF group (n = 21 which received a combination of the above. Seven animals of each group were killed on the 1st, 3rd and 7th postoperative day and their remnant liver was removed to evaluate liver regeneration by immunochemistry for PCNA and Ki 67. Results Our data suggest that EPO and GM-CSF increases liver regeneration following major hepatectomy when administered perioperatively. EPO has a more significant effect than GM-CSF (p Conclusion EPO, GM-CSF and their combination enhance liver regeneration after hepatectomy in rats when administered perioperatively. However their combination has a weaker effect on liver regeneration compared to EPO alone. Further investigation is needed to assess the exact mechanisms that mediate this finding.

Radioimmunoassay of erythropoietin and its potential in the diagnosis of fetal hypoxia

International Nuclear Information System (INIS)

Fingerova, H.

1993-01-01

Radioimmunoassay (RIA) for erythropoietin (EPO) in the serum and amniotic fluid was set up, based on donated rabbit antibody and a commercial tracer. EPO levels obtained by means of the RIA correlated well with the results obtained by means of ELISA or a commercial RIA kit. Retrospective evaluations of EPO levels in umbilical cord serum and amniotic fluid samples obtained during 171 vaginal or Cesarean section deliveries have shown that already in the course of spontaneous vaginal delivery a moderate increase of EPO in umbilical cord serum can be detected. The marked increase of EPO levels in both cord serum and amniotic fluid was always observed in relation to a severe fetal distress. (author) 3 figs., 3 refs

Treatment of anemia of nephrotic syndrome with recombinant erythropoietin

NARCIS (Netherlands)

Gansevoort, RT; Vaziri, ND; deJong, PE

Nephrotic syndrome has been recently shown to cause erythropoietin (EPO) deficiency in humans and experimental models. However, efficacy and safety of recombinant EPO (rEPO) in the treatment of the associated anemia has not been previously investigated. We report a patient with nephrotic syndrome

[Recombinant human erythropoietin in neonates: guidelines for clinical practice from the French Society of Neonatology].

Science.gov (United States)

Lopez, E; Beuchée, A; Truffert, P; Pouvreau, N; Patkai, J; Baud, O; Boubred, F; Flamant, C; Jarreau, P-H

2015-10-01

1/To assess the effectiveness and safety of EPO in reducing red blood cell (RBC) transfusions in preterm infants. 2/To provide guidelines for clinical practice in France. 1/This systematic evidence review is based on PubMed search, Cochrane library. 2/Using French National Authority for Health methods concerning guidelines for clinical practice. Early EPO reduced the risk of RBC transfusions, donor exposure, and the number of transfusions in very preterm infants (LE2). Late EPO reduced the risk of RBC transfusions and the number of transfusions in very preterm infants (LE2). There is no difference between the effectiveness of early and late EPO (LE2). There is no difference between high-dose and low-dose EPO (LE2). The level of evidence is too low to recommend the intravenous route. EPO has no impact on the rate of bronchopulmonary dysplasia, necrotizing enterocolitis (LE3), and retinopathy of prematurity (LE2). The level of evidence is too low to recommend EPO for neuroprotection in very preterm or term infants. EPO to reduce RBC transfusion in very preterm infants is recommended (Level A). The optimal time to start therapy is unknown (Level B). The recommended dose is 750IU/kg/week via three subcutaneous injections for 6weeks (Level B). Copyright © 2015 Elsevier Masson SAS. All rights reserved.

A search for presynaptic inhibitory histamine receptors in guinea-pig tissues: Further H3 receptors but no evidence for H4 receptors.

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Petri, Doris; Schlicker, Eberhard

2016-07-01

The histamine H4 receptor is coupled to Gi/o proteins and expressed on inflammatory cells and lymphoid tissues; it was suggested that this receptor also occurs in the brain or on peripheral neurones. Since many Gi/o protein-coupled receptors, including the H3 receptor, serve as presynaptic inhibitory receptors, we studied whether the sympathetic neurones supplying four peripheral tissues and the cholinergic neurones in the hippocampus from the guinea-pig are equipped with release-modulating H4 and H3 receptors. For this purpose, we preincubated tissue pieces from the aorta, atrium, renal cortex and vas deferens with (3)H-noradrenaline and hippocampal slices with (3)H-choline and determined the electrically evoked tritium overflow. The stimulation-evoked overflow in the five superfused tissues was inhibited by the muscarinic receptor agonist oxotremorine, which served as a positive control, but not affected by the H4 receptor agonist 4-methylhistamine. The H3 receptor agonist R-α-methylhistamine inhibited noradrenaline release in the peripheral tissues without affecting acetylcholine release in the hippocampal slices. Thioperamide shifted the concentration-response curve of histamine in the aorta and the renal cortex to the right, yielding apparent pA2 values of 8.0 and 8.1, respectively, which are close to its affinity at other H3 receptors but higher by one log unit than its pKi at the H4 receptor of the guinea-pig. In conclusion, histamine H4 receptors could not be identified in five experimental models of the guinea-pig that are suited for the detection of presynaptic inhibitory receptors whereas H3 receptors could be shown in the peripheral tissues but not in the hippocampus. This article is part of the Special Issue entitled 'Histamine Receptors'. Copyright © 2015 Elsevier Ltd. All rights reserved.

Antioxidant and antigenotoxic role of recombinant human erythropoeitin against alkylating agents: cisplatin and mitomycin C in cultured Vero cells.

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Rjiba-Touati, Karima; Ayed-Boussema, Imen; Soualeh, Nidhal; Achour, Abdellatif; Bacha, Hassen; Abid, Salwa

2013-08-01

Cisplatin (CDDP) and mitomycin C (MMC), two alkylating agents used against various solid tumours, are a common source of acute kidney injury. Thus, strategies for minimizing CDDP and MMC toxicity are of a clinical interest. In this study, we aimed to investigate the protective role of recombinant human erythropoietin (rhEPO) against oxidative stress and genotoxicity induced by CDDP and MMC in cultured Vero cells. Three types of treatments were performed: (i) cells were treated with rhEPO 24 h before exposure to CDDP/MMC (pre-treatment), (ii) cells were treated with rhEPO and CDDP/MMC simultaneously (co-treatment), (iii) cells were treated with rhEPO 24 h after exposure to CDDP/MMC (post-treatment). Our results showed that rhEPO decreased the reactive oxygen species levels, the malondialdehyde levels and ameliorated glutathione (reduced and oxidized glutathione) modulation induced by CDDP and MMC in cultured Vero cells. Furthermore, rhEPO administration prevented alkylating agents-induced DNA damage accessed by comet test. Altogether, our results suggested a protective role of rhEPO, against CDDP- and MMC-induced oxidative stress and genotoxicity, especially in pre-treatment condition.

How bio-questionable are the different recombinant human erythropoietin copy products in Thailand?

Science.gov (United States)

Halim, Liem Andhyk; Brinks, Vera; Jiskoot, Wim; Romeijn, Stefan; Praditpornsilpa, Kearkiat; Assawamakin, Anunchai; Schellekens, Huub

2014-05-01

The high prevalence of pure red cell aplasia in Thailand has been associated with the sharp increase in number of recombinant human erythropoietin (rhEPO) copy products, based on a classical generic regulatory pathway, which have entered the market. This study aims to assess the quality of rhEPO copy products being used in Thailand. Twelve rhEPO copy products were purchased from pharmacies in Thailand, shipped under controlled cold chain conditions to the Netherlands and characterized using (1) high performance size-exclusion chromatography, (2) asymmetrical flow field-flow fractionation, (3) sodium dodecyl sulfate polyacrylamide gel electrophoresis in combination with (4) Western blotting and additionally tested for (5) host cell protein impurities as well as (6) endotoxin contamination. Some of the tested rhEPO copy products showed high aggregate levels and contained a substantial amount of protein fragments. Also, one of rhEPO copy products had a high endotoxin level, exceeding the FDA limit. Our observations show that some of the tested copy products on the Thai market differ significantly from the originator rhEPO product, Epogen®. This comparison study supports a link between the quality attributes of copy rhEPO products and their immunogenicity.

Erythropoietin abuse and erythropoietin gene doping: detection strategies in the genomic era.

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Diamanti-Kandarakis, Evanthia; Konstantinopoulos, Panagiotis A; Papailiou, Joanna; Kandarakis, Stylianos A; Andreopoulos, Anastasios; Sykiotis, Gerasimos P

2005-01-01

The administration of recombinant human erythropoietin (rhEPO) increases the maximum oxygen consumption capacity, and is therefore abused as a doping method in endurance sports. The detection of erythropoietin (EPO) abuse is based on direct pharmacological and indirect haematological approaches, both of which have several limitations. In addition, current detection methods cannot cope with the emerging doping strategies of EPO mimicry, analogues and gene doping, and thus novel detection strategies are urgently needed. Direct detection methods for EPO misuse can be either pharmacological approaches that identify exogenous substances based on their physicochemical properties, or molecular methods that recognise EPO transgenes or gene transfer vectors. Since direct detection with molecular methods requires invasive procedures, it is not appropriate for routine screening of large numbers of athletes. In contrast, novel indirect methods based on haematological and/or molecular profiling could be better suited as screening tools, and athletes who are suspect of doping would then be submitted to direct pharmacological and molecular tests. This article reviews the current state of the EPO doping field, discusses available detection methods and their shortcomings, outlines emerging pharmaceutical and genetic technologies in EPO misuse, and proposes potential directions for the development of novel detection strategies.

Neuronal erythropoietin overexpression protects mice against age-related hearing loss (presbycusis).

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Monge Naldi, Arianne; Belfrage, Celina; Jain, Neha; Wei, Eric T; Canto Martorell, Belén; Gassmann, Max; Vogel, Johannes

2015-12-01

So far, typical causes of presbycusis such as degeneration of hair cells and/or primary auditory (spiral ganglion) neurons cannot be treated. Because erythropoietin's (Epo) neuroprotective potential has been shown previously, we determined hearing thresholds of juvenile and aged mice overexpressing Epo in neuronal tissues. Behavioral audiometry revealed in contrast to 5 months of age, that 11-month-old Epo-transgenic mice had up to 35 dB lower hearing thresholds between 1.4 and 32 kHz, and at the highest frequencies (50-80 kHz), thresholds could be obtained in aged Epo-transgenic only but not anymore in old C57BL6 control mice. Click-evoked auditory brainstem response showed similar results. Numbers of spiral ganglion neurons in aged C57BL6 but not Epo-transgenic mice were dramatically reduced mainly in the basal turn, the location of high frequencies. In addition, there was a tendency to better preservation of inner and outer hair cells in Epo-transgenic mice. Hence, Epo's known neuroprotective action effectively suppresses the loss of spiral ganglion cells and probably also hair cells and, thus, development of presbycusis in mice. Copyright © 2015 Elsevier Inc. All rights reserved.

Radioimmunoassay of erythropoietin: analytical performance and clinical use in hematology.

Science.gov (United States)

Schlageter, M H; Toubert, M E; Podgorniak, M P; Najean, Y

1990-10-01

We report here the performance of a recently commercialized radioimmunoassay kit for determining erythropoietin (EPO) in serum or plasma. The lower detection limit of the method was 3 U/L. Precision, analyzed by the variation coefficients between different assay runs and in the same experiment, was always less than 10%; accuracy was assessed by recovery and dilution tests. In anemic patients (hematocrit 18-39%), the concentration of EPO was logarithmically related to hematocrit. A relatively large dispersion of the results was noted, as reported by others with various RIAs. Patients with severe renal failure demonstrated a very low EPO value, whatever the degree of their anemia. In some chronic anemias resulting from malignancy, EPO concentrations were also relatively low. In the polycythemia vera group, the EPO mean was below normal for greater than 95% of the patients, whatever their clinical stage (first evaluation, relapse, or remission). In contrast, 91% of the patients with pure erythrocytosis had a normal or increased EPO value, even when the etiology was unknown. Measurement of EPO concentration may be useful for the clinical differentiation of myeloproliferative disorders and, subsequently, for their prognosis and choice of treatment.

Influence de l'érythropoïétine recombinante humaine sur les fonctions cardiovasculaire et rénale chez le rat présentant une dysfonction endothéliale : effets des interactions avec l'exercice chronique

OpenAIRE

Meziri , Fayçal

2011-01-01

The chronic administration of rHuEPO can engender side effects. An increase of the hematocritinduced by rHuEPO, by increasing the erythrocytosis, the blood viscosity and the shear stress onvascular surface, can be responsible of arterial high blood pressure and arterial thrombosis. Thepresence of a normal endothelial function and nitric oxide (NO) can counter the noxious effectsof rHuEPO. On these bases, we studied the cardiovascular effects of a chronic administration ofrHuEPO in various fra...

Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo

DEFF Research Database (Denmark)

Erbayraktar, Serhat; Grasso, Giovanni; Sfacteria, Alessandra

2003-01-01

Erythropoietin (EPO) is a tissue-protective cytokine preventing vascular spasm, apoptosis, and inflammatory responses. Although best known for its role in hematopoietic lineages, EPO also affects other tissues, including those of the nervous system. Enthusiasm for recombinant human erythropoietin...... importantly, asialoEPO exhibits a broad spectrum of neuroprotective activities, as demonstrated in models of cerebral ischemia, spinal cord compression, and sciatic nerve crush. These data suggest that nonerythropoietic variants of rhEPO can cross the blood-brain barrier and provide neuroprotection....

Real-Time G-Protein-Coupled Receptor Imaging to Understand and Quantify Receptor Dynamics

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María S. Aymerich

2011-01-01

Full Text Available Understanding the trafficking of G-protein-coupled receptors (GPCRs and their regulation by agonists and antagonists is fundamental to develop more effective drugs. Optical methods using fluorescent-tagged receptors and spinning disk confocal microscopy are useful tools to investigate membrane receptor dynamics in living cells. The aim of this study was to develop a method to characterize receptor dynamics using this system which offers the advantage of very fast image acquisition with minimal cell perturbation. However, in short-term assays photobleaching was still a problem. Thus, we developed a procedure to perform a photobleaching-corrected image analysis. A study of short-term dynamics of the long isoform of the dopamine type 2 receptor revealed an agonist-induced increase in the mobile fraction of receptors with a rate of movement of 0.08 μm/s For long-term assays, the ratio between the relative fluorescence intensity at the cell surface versus that in the intracellular compartment indicated that receptor internalization only occurred in cells co-expressing G protein-coupled receptor kinase 2. These results indicate that the lateral movement of receptors and receptor internalization are not directly coupled. Thus, we believe that live imaging of GPCRs using spinning disk confocal image analysis constitutes a powerful tool to study of receptor dynamics.

Knock-In Mice with NOP-eGFP Receptors Identify Receptor Cellular and Regional Localization.

Science.gov (United States)

Ozawa, Akihiko; Brunori, Gloria; Mercatelli, Daniela; Wu, Jinhua; Cippitelli, Andrea; Zou, Bende; Xie, Xinmin Simon; Williams, Melissa; Zaveri, Nurulain T; Low, Sarah; Scherrer, Grégory; Kieffer, Brigitte L; Toll, Lawrence

2015-08-19

The nociceptin/orphanin FQ (NOP) receptor, the fourth member of the opioid receptor family, is involved in many processes common to the opioid receptors including pain and drug abuse. To better characterize receptor location and trafficking, knock-in mice were created by inserting the gene encoding enhanced green fluorescent protein (eGFP) into the NOP receptor gene (Oprl1) and producing mice expressing a functional NOP-eGFP C-terminal fusion in place of the native NOP receptor. The NOP-eGFP receptor was present in brain of homozygous knock-in animals in concentrations somewhat higher than in wild-type mice and was functional when tested for stimulation of [(35)S]GTPγS binding in vitro and in patch-clamp electrophysiology in dorsal root ganglia (DRG) neurons and hippocampal slices. Inhibition of morphine analgesia was equivalent when tested in knock-in and wild-type mice. Imaging revealed detailed neuroanatomy in brain, spinal cord, and DRG and was generally consistent with in vitro autoradiographic imaging of receptor location. Multicolor immunohistochemistry identified cells coexpressing various spinal cord and DRG cellular markers, as well as coexpression with μ-opioid receptors in DRG and brain regions. Both in tissue slices and primary cultures, the NOP-eGFP receptors appear throughout the cell body and in processes. These knock-in mice have NOP receptors that function both in vitro and in vivo and appear to be an exceptional tool to study receptor neuroanatomy and correlate with NOP receptor function. The NOP receptor, the fourth member of the opioid receptor family, is involved in pain, drug abuse, and a number of other CNS processes. The regional and cellular distribution has been difficult to determine due to lack of validated antibodies for immunohistochemical analysis. To provide a new tool for the investigation of receptor localization, we have produced knock-in mice with a fluorescent-tagged NOP receptor in place of the native NOP receptor. These

Receptor assay

Energy Technology Data Exchange (ETDEWEB)

Kato, K; Ibayashi, H [Kyushu Univ., Fukuoka (Japan). Faculty of Medicine

1975-05-01

This paper summarized present status and problems of analysis of hormone receptor and a few considerations on clinical significance of receptor abnormalities. It was pointed that in future clinical field quantitative and qualitative analysis of receptor did not remain only in the etiological discussion, but that it was an epoch-making field of investigation which contained the possiblity of artificial change of sensitivity of living body on drugs and the development connected directly with treatment of various diseases.

Increased red cell 2,3-diphosphoglycerate levels in haemodialysis patients treated with erythropoietin.

Science.gov (United States)

Horina, J H; Schwaberger, G; Brussee, H; Sauseng-Fellegger, G; Holzer, H; Krejs, G J

1993-01-01

The efficacy of recombinant human erythropoietin (rHuEpo) for the treatment of renal anaemia is well established. To assess the effect of rHuEpo treatment on physical performance we evaluated physical working capacity, oxygen uptake and red cell 2,3-diphosphoglycerate (DPG) values at rest and during and after exercise on a bicycle spiroergometer in eight chronically haemodialysed patients. Follow-up examination was carried out after a mean of 14 weeks (range 9-19 weeks), when mean haemoglobin had increased from 7.8 to a stable value of 13.0 g/dl in response to rHuEpo treatment (P level without rHuEpo treatment than after correction of anaemia. Therefore rHuEpo treatment results both in better oxygen transport capacity and reduced intraerythrocytic oxygen affinity, which is followed by improved oxygen delivery to tissues per unit of haemoglobin. These effects may explain the improvement of exercise capacity observed in dialysis patients after rHuEpo treatment.

Diurnal variations of serum erythropoietin at sea level and altitude

DEFF Research Database (Denmark)

Klausen, T; Poulsen, T D; Fogh-Andersen, N

1996-01-01

in 2, 3 diphosphoglycerate. After 64 h at altitude, six of the nine subjects had down-regulated their serum-EPO concentrations so that median values were three times above those at sea level. These six subjects had significant diurnal variations of serum-EPO concentration at sea level; the nadir......This study tested the hypothesis that the diurnal variations of serum-erythropoietin concentration (serum-EPO) observed in normoxia also exist in hypoxia. The study also attempted to investigate the regulation of EPO production during sustained hypoxia. Nine subjects were investigated at sea level...... and during 4 days at an altitude of 4350 m. Median sea level serum-EPO concentration was 6 (range 6-13) U.l-1. Serum-EPO concentration increased after 18 and 42 h at altitude, [58 (range 39-240) and 54 (range 36-340) U.l-1, respectively], and then decreased after 64 and 88 h at altitude [34 (range 18...

Targeting higher ferritin concentrations with intravenous iron dextran lowers erythropoietin requirement in hemodialysis patients.

Science.gov (United States)

DeVita, M V; Frumkin, D; Mittal, S; Kamran, A; Fishbane, S; Michelis, M F

2003-11-01

Although clinical use of recombinant human erythropoietin (rHuEPO) since 1989 has improved anemia in most end-stage renal disease patients, there are still many hemodialysis patients unable to maintain an adequate hematocrit (HCT) without large doses of rHuEPO. This suggests that anemia is not solely a consequence of rHuEPO deficiency, but may be due to other factors including functional iron deficiency. Since the optimal prescription for iron replacement is not yet known, we evaluated the effect of intravenous iron dextran (IVFe) infusion on serum ferritin (SFer) concentration and rHuEPO dose. Our objective was to raise and maintain serum ferritin concentrations to 2 different levels above the National Kidney Foundation Dialysis Outcome Quality Initiative standard of 100 ng/ml to determine whether, and by what degree rHuEPO dose could be lowered. HD patients on i.v. rHuEPO with a SFer concentration > or = 70 ng/ml and an HCT of requirements.

Calcitonin and calcitonin receptor-like receptors: common themes with family B GPCRs?

Science.gov (United States)

Barwell, James; Gingell, Joseph J; Watkins, Harriet A; Archbold, Julia K; Poyner, David R; Hay, Debbie L

2012-05-01

The calcitonin receptor (CTR) and calcitonin receptor-like receptor (CLR) are two of the 15 human family B (or Secretin-like) GPCRs. CTR and CLR are of considerable biological interest as their pharmacology is moulded by interactions with receptor activity-modifying proteins. They also have therapeutic relevance for many conditions, such as osteoporosis, diabetes, obesity, lymphatic insufficiency, migraine and cardiovascular disease. In light of recent advances in understanding ligand docking and receptor activation in both the family as a whole and in CLR and CTR specifically, this review reflects how applicable general family B GPCR themes are to these two idiosyncratic receptors. We review the main functional domains of the receptors; the N-terminal extracellular domain, the juxtamembrane domain and ligand interface, the transmembrane domain and the intracellular C-terminal domain. Structural and functional findings from the CLR and CTR along with other family B GPCRs are critically appraised to gain insight into how these domains may function. The ability for CTR and CLR to interact with receptor activity-modifying proteins adds another level of sophistication to these receptor systems but means careful consideration is needed when trying to apply generic GPCR principles. This review encapsulates current thinking in the realm of family B GPCR research by highlighting both conflicting and recurring themes and how such findings relate to two unusual but important receptors, CTR and CLR. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Development of a VHH-Based Erythropoietin Quantification Assay

DEFF Research Database (Denmark)

Kol, Stefan; Beuchert Kallehauge, Thomas; Adema, Simon

2015-01-01

Erythropoietin (EPO) quantification during cell line selection and bioreactor cultivation has traditionally been performed with ELISA or HPLC. As these techniques suffer from several drawbacks, we developed a novel EPO quantification assay. A camelid single-domain antibody fragment directed against...... human EPO was evaluated as a capturing antibody in a label-free biolayer interferometry-based quantification assay. Human recombinant EPO can be specifically detected in Chinese hamster ovary cell supernatants in a sensitive and pH-dependent manner. This method enables rapid and robust quantification...

Chronic erythropoietin treatment improves diet-induced glucose intolerance in rats

DEFF Research Database (Denmark)

Caillaud, Corinne; Mechta, Mie; Ainge, Heidi

2015-01-01

Erythropoietin (EPO) ameliorates glucose metabolism through mechanisms not fully understood. In this study, we investigated the effect of EPO on glucose metabolism and insulin signaling in skeletal muscle. A 2-week EPO treatment of rats fed with a high-fat diet (HFD) improved fasting glucose levels...... and glucose tolerance, without altering total body weight or retroperitoneal fat mass. Concomitantly, EPO partially rescued insulin-stimulated AKT activation, reduced markers of oxidative stress, and restored heat-shock protein 72 expression in soleus muscles from HFD-fed rats. Incubation of skeletal muscle...... not directly activate the phosphorylation of AKT in muscle cells. We propose that the reduced systemic inflammation or oxidative stress that we observed after treatment with EPO could contribute to the improvement of whole-body glucose metabolism....

Sensitive and comprehensive analysis of O-glycosylation in biotherapeutics: a case study of novel erythropoiesis stimulating protein.

Science.gov (United States)

Kim, Unyong; Oh, Myung Jin; Seo, Youngsuk; Jeon, Yinae; Eom, Joon-Ho; An, Hyun Joo

2017-09-01

Glycosylation of recombinant human erythropoietins (rhEPOs) is significantly associated with drug's quality and potency. Thus, comprehensive characterization of glycosylation is vital to assess the biotherapeutic quality and establish the equivalency of biosimilar rhEPOs. However, current glycan analysis mainly focuses on the N-glycans due to the absence of analytical tools to liberate O-glycans with high sensitivity. We developed selective and sensitive method to profile native O-glycans on rhEPOs. O-glycosylation on rhEPO including O-acetylation on a sialic acid was comprehensively characterized. Details such as O-glycan structure and O-acetyl-modification site were obtained from tandem MS. This method may be applied to QC and batch analysis of not only rhEPOs but also other biotherapeutics bearing multiple O-glycosylations.

Erythropoietin suppresses epithelial to mesenchymal transition and intercepts Smad signal transduction through a MEK-dependent mechanism in pig kidney (LLC-PK1) cell lines

International Nuclear Information System (INIS)

Chen, Chien-Liang; Chou, Kang-Ju; Lee, Po-Tsang; Chen, Ying-Shou; Chang, Tsu-Yuan; Hsu, Chih-Yang; Huang, Wei-Chieh; Chung, Hsiao-Min; Fang, Hua-Chang

2010-01-01

Purpose: Tumor growth factor-β1 (TGF-β1) plays a pivotal role in processes like kidney epithelial-mesenchymal transition (EMT) and interstitial fibrosis, which correlate well with progression of renal disease. Little is known about underlying mechanisms that regulate EMT. Based on the anatomical relationship between erythropoietin (EPO)-producing interstitial fibroblasts and adjacent tubular cells, we investigated the role of EPO in TGF-β1-mediated EMT and fibrosis in kidney injury. Methods: We examined apoptosis and EMT in TGF-β1-treated LLC-PK1 cells in the presence or absence of EPO. We examined the effect of EPO on TGF-β1-mediated Smad signaling. Apoptosis and cell proliferation were assessed with flow cytometry and hemocytometry. We used Western blotting and indirect immunofluorescence to evaluate expression levels of TGF-β1 signal pathway proteins and EMT markers. Results: We demonstrated that ZVAD-FMK (a caspase inhibitor) inhibited TGF-β1-induced apoptosis but did not inhibit EMT. In contrast, EPO reversed TGF-β1-mediated apoptosis and also partially inhibited TGF-β1-mediated EMT. We showed that EPO treatment suppressed TGF-β1-mediated signaling by inhibiting the phosphorylation and nuclear translocation of Smad 3. Inhibition of mitogen-activated protein kinase kinase 1 (MEK 1) either directly with PD98059 or with MEK 1 siRNA resulted in inhibition of EPO-mediated suppression of EMT and Smad signal transduction in TGF-β1-treated cells. Conclusions: EPO inhibited apoptosis and EMT in TGF-β1-treated LLC-PK1 cells. This effect of EPO was partially mediated by a mitogen-activated protein kinase-dependent inhibition of Smad signal transduction.

Molecular recognition of epothilones by microtubules and tubulin dimers revealed by biochemical and NMR approaches.

Science.gov (United States)

Canales, Angeles; Nieto, Lidia; Rodríguez-Salarichs, Javier; Sánchez-Murcia, Pedro A; Coderch, Claire; Cortés-Cabrera, Alvaro; Paterson, Ian; Carlomagno, Teresa; Gago, Federico; Andreu, José M; Altmann, Karl-Heinz; Jiménez-Barbero, Jesús; Díaz, J Fernando

2014-04-18

The binding of epothilones to dimeric tubulin and to microtubules has been studied by means of biochemical and NMR techniques. We have determined the binding constants of epothilone A (EpoA) and B (EpoB) to dimeric tubulin, which are 4 orders of magnitude lower than those for microtubules, and we have elucidated the conformation and binding epitopes of EpoA and EpoB when bound to tubulin dimers and microtubules in solution. The determined conformation of epothilones when bound to dimeric tubulin is similar to that found by X-ray crystallographic techniques for the binding of EpoA to the Tubulin/RB3/TTL complex; it is markedly different from that reported for EpoA bound to zinc-induced sheets obtained by electron crystallography. Likewise, only the X-ray structure of EpoA bound to the Tubulin/RB3/TTL complex at the luminal site, but not the electron crystallography structure, is compatible with the results obtained by STD on the binding epitope of EpoA bound to dimeric tubulin, thus confirming that the allosteric change (structuring of the M-loop) is the biochemical mechanism of induction of tubulin assembly by epothilones. TR-NOESY signals of EpoA bound to microtubules have been obtained, supporting the interaction with a transient binding site with a fast exchange rate (pore site), consistent with the notion that epothilones access the luminal site through the pore site, as has also been observed for taxanes. Finally, the differences in the tubulin binding affinities of a series of epothilone analogues has been quantitatively explained using the newly determined binding pose and the COMBINE methodology.

Molecular modeling of ligand-receptor interactions in the OR5 olfactory receptor.

Science.gov (United States)

Singer, M S; Shepherd, G M

1994-06-02

Olfactory receptors belong to the superfamily of seven transmembrane domain, G protein-coupled receptors. In order to begin analysis of mechanisms of receptor activation, a computer model of the OR5 olfactory receptor has been constructed and compared with other members of this superfamily. We have tested docking of the odor molecule lyral, which is known to activate the OR5 receptor. The results point to specific ligand-binding residues on helices III through VII that form a binding pocket in the receptor. Some of these residues occupy sequence positions identical to ligand-binding residues conserved among other superfamily members. The results provide new insights into possible molecular mechanisms of odor recognition and suggest hypotheses to guide future experimental studies using site-directed mutagenesis.

Role of JAK-STAT signaling in the pathogenesis of myeloproliferative disorders.

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Levine, Ross L; Wernig, Gerlinde

2006-01-01

The identification of JAK2V617F mutations in polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis (MF) represents an important advance in our understanding of these myeloproliferative disorders (MPD). Most, if not all, patients with PV and a significant number of patients with ET and MF are JAK2V617F positive, and the mutation likely arises in the hematopoietic stem cell compartment. JAK2V617F is a constitutively active tyrosine kinase that is able to activate JAK-STAT signaling most efficiently when co-expressed with the erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte colony-stimulating factor receptor (GCSFR). Data from murine models supports the central role of JAK2V617F in the pathogenesis of MPD, as expression of JAK2V617F in a bone marrow transplantation assay results in polycythemia and myelofibrosis in recipient mice. Activation of JAK-STAT signaling by JAK2V617F in some, but not all MPD patients with ET and MF led to the identification of the constitutively active MPLW515L allele in ET and MF. Small molecule inhibitors of JAK-STAT signaling are currently being developed, which offer potential for molecularly targeted therapy for patients with PV, ET, and MF. Despite these advances, many questions remain regarding the role of a single disease allele in three phenotypically distinct MPD, the potential clinical efficacy of JAK2 inhibitors, and the identity of oncogenic alleles in JAK2V617F/MPLW515-negative MPD.

An integrative 'omics' solution to the detection of recombinant human erythropoietin and blood doping.

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Pitsiladis, Yannis P; Durussel, Jérôme; Rabin, Olivier

2014-05-01

Administration of recombinant human erythropoietin (rHumanEPO) improves sporting performance and hence is frequently subject to abuse by athletes, although rHumanEPO is prohibited by the WADA. Approaches to detect rHumanEPO doping have improved significantly in recent years but remain imperfect. A new transcriptomic-based longitudinal screening approach is being developed that has the potential to improve the analytical performance of current detection methods. In particular, studies are being funded by WADA to identify a 'molecular signature' of rHumanEPO doping and preliminary results are promising. In the first systematic study to be conducted, the expression of hundreds of genes were found to be altered by rHumanEPO with numerous gene transcripts being differentially expressed after the first injection and further transcripts profoundly upregulated during and subsequently downregulated up to 4 weeks postadministration of the drug; with the same transcriptomic pattern observed in all participants. The identification of a blood 'molecular signature' of rHumanEPO administration is the strongest evidence to date that gene biomarkers have the potential to substantially improve the analytical performance of current antidoping methods such as the Athlete Biological Passport for rHumanEPO detection. Given the early promise of transcriptomics, research using an 'omics'-based approach involving genomics, transcriptomics, proteomics and metabolomics should be intensified in order to achieve improved detection of rHumanEPO and other doping substances and methods difficult to detect such a recombinant human growth hormone and blood transfusions.

Receptor downregulation and desensitization enhance the information processing ability of signalling receptors

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Resat Haluk

2007-11-01

Full Text Available Abstract Background In addition to initiating signaling events, the activation of cell surface receptors also triggers regulatory processes that restrict the duration of signaling. Acute attenuation of signaling can be accomplished either via ligand-induced internalization of receptors (endocytic downregulation or via ligand-induced receptor desensitization. These phenomena have traditionally been viewed in the context of adaptation wherein the receptor system enters a refractory state in the presence of sustained ligand stimuli and thereby prevents the cell from over-responding to the ligand. Here we use the epidermal growth factor receptor (EGFR and G-protein coupled receptors (GPCR as model systems to respectively examine the effects of downregulation and desensitization on the ability of signaling receptors to decode time-varying ligand stimuli. Results Using a mathematical model, we show that downregulation and desensitization mechanisms can lead to tight and efficient input-output coupling thereby ensuring synchronous processing of ligand inputs. Frequency response analysis indicates that upstream elements of the EGFR and GPCR networks behave like low-pass filters with the system being able to faithfully transduce inputs below a critical frequency. Receptor downregulation and desensitization increase the filter bandwidth thereby enabling the receptor systems to decode inputs in a wider frequency range. Further, system-theoretic analysis reveals that the receptor systems are analogous to classical mechanical over-damped systems. This analogy enables us to metaphorically describe downregulation and desensitization as phenomena that make the systems more resilient in responding to ligand perturbations thereby improving the stability of the system resting state. Conclusion Our findings suggest that in addition to serving as mechanisms for adaptation, receptor downregulation and desensitization can play a critical role in temporal information

Modulating Estrogen Receptor-related Receptor-α Activity Inhibits Cell Proliferation*

OpenAIRE

Bianco, Stéphanie; Lanvin, Olivia; Tribollet, Violaine; Macari, Claire; North, Sophie; Vanacker, Jean-Marc

2009-01-01

High expression of the estrogen receptor-related receptor (ERR)-α in human tumors is correlated to a poor prognosis, suggesting an involvement of the receptor in cell proliferation. In this study, we show that a synthetic compound (XCT790) that modulates the activity of ERRα reduces the proliferation of various cell lines and blocks the G1/S transition of the cell cycle in an ERR...

Receptor binding properties and antinociceptive effects of chimeric peptides consisting of a micro-opioid receptor agonist and an ORL1 receptor antagonist.

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Kawano, Susumu; Ito, Risa; Nishiyama, Miharu; Kubo, Mai; Matsushima, Tomoko; Minamisawa, Motoko; Ambo, Akihiro; Sasaki, Yusuke

2007-07-01

Receptor binding properties and antinociceptive activities of chimeric peptides linked by spacers were investigated. The peptides consisted of the micro-opioid receptor ligand dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH(2)) or its analog YRFB (Tyr-D-Arg-Phe-betaAla-NH(2)) linked to the ORL1 receptor ligand Ac-Arg-Tyr-Tyr-Arg-Ile-Lys-NH(2) (Ac-RYYRIK-NH(2)). All chimeric peptides were found to possess high receptor binding affinities for both micro-opioid and ORL1 receptors in mouse brain membranes although their binding affinities for both receptors in spinal membranes were significantly lower. Among them, chimeric peptide 2, which consists of dermorphin and Ac-RYYRIK-NH(2) connected by a long spacer, had the highest binding affinity towards both receptors. In the tail-flick test following intrathecal (i.t.) administration to mice, all chimeric peptides showed potent and dose-dependent antinociceptive activities with an ED(50) of 1.34-4.51 (pmol/mouse), nearly comparable to dermorphin alone (ED(50); 1.08 pmol/mouse). In contrast to their micro-opioid receptor binding profiles, intracerebroventricular (i.c.v.) administration of the chimeric peptides resulted in much less potent antinociceptive activity (ED(50) 5.55-100peptides, and the regulation of mu-opioid receptor-mediated antinociception in brain. The present chimeric peptides may be useful as pharmacological tools for studies on micro-opioid receptor/ORL1 receptor heterodimers.

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...

The Intersection of NASA Astrophysics Education and Public Outreach and Higher Education: A Special Interest Group Meeting

Science.gov (United States)

Sharma, M.; Smith, D.; Schultz, G.; Bianchi, L.; Blair, W.

2011-09-01

This paper presents highlights from a group discussion on how the NASA Science Mission Directorate (SMD) education and public outreach (EPO) community could better support undergraduate astronomy education through EPO products and resources - current and future - targeted at the college level. The discussion was organized by the SMD Astrophysics EPO Forum through a Special Interest Group Meeting at the 2010 ASP Annual Meeting in Boulder. Our session took advantage of the simultaneous presence of EPO professionals and the Cosmos in the Classroom participants to seek out diverse perspectives on and experiences in higher education.

Cocaine Inhibits Dopamine D2 Receptor Signaling via Sigma-1-D2 Receptor Heteromers

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Navarro, Gemma; Moreno, Estefania; Bonaventura, Jordi; Brugarolas, Marc; Farré, Daniel; Aguinaga, David; Mallol, Josefa; Cortés, Antoni; Casadó, Vicent; Lluís, Carmen; Ferre, Sergi

2013-01-01

Under normal conditions the brain maintains a delicate balance between inputs of reward seeking controlled by neurons containing the D1-like family of dopamine receptors and inputs of aversion coming from neurons containing the D2-like family of dopamine receptors. Cocaine is able to subvert these balanced inputs by altering the cell signaling of these two pathways such that D1 reward seeking pathway dominates. Here, we provide an explanation at the cellular and biochemical level how cocaine may achieve this. Exploring the effect of cocaine on dopamine D2 receptors function, we present evidence of σ1 receptor molecular and functional interaction with dopamine D2 receptors. Using biophysical, biochemical, and cell biology approaches, we discovered that D2 receptors (the long isoform of the D2 receptor) can complex with σ1 receptors, a result that is specific to D2 receptors, as D3 and D4 receptors did not form heteromers. We demonstrate that the σ1-D2 receptor heteromers consist of higher order oligomers, are found in mouse striatum and that cocaine, by binding to σ1 -D2 receptor heteromers, inhibits downstream signaling in both cultured cells and in mouse striatum. In contrast, in striatum from σ1 knockout animals these complexes are not found and this inhibition is not seen. Taken together, these data illuminate the mechanism by which the initial exposure to cocaine can inhibit signaling via D2 receptor containing neurons, destabilizing the delicate signaling balance influencing drug seeking that emanates from the D1 and D2 receptor containing neurons in the brain. PMID:23637801

Science Education and Public Outreach Forums (SEPOF): Providing Coordination and Support for NASA's Science Mission Directorate Education and Outreach Programs

Science.gov (United States)

Mendez, B. J.; Smith, D.; Shipp, S. S.; Schwerin, T. G.; Stockman, S. A.; Cooper, L. P.; Peticolas, L. M.

2009-12-01

NASA is working with four newly-formed Science Education and Public Outreach Forums (SEPOFs) to increase the overall coherence of the Science Mission Directorate (SMD) Education and Public Outreach (E/PO) program. SEPOFs support the astrophysics, heliophysics, planetary and Earth science divisions of NASA SMD in three core areas: * E/PO Community Engagement and Development * E/PO Product and Project Activity Analysis * Science Education and Public Outreach Forum Coordination Committee Service. SEPOFs are collaborating with NASA and external science and education and outreach communities in E/PO on multiple levels ranging from the mission and non-mission E/PO project activity managers, project activity partners, and scientists and researchers, to front line agents such as naturalists/interpreters, teachers, and higher education faculty, to high level agents such as leadership at state education offices, local schools, higher education institutions, and professional societies. The overall goal for the SEPOFs is increased awareness, knowledge, and understanding of scientists, researchers, engineers, technologists, educators, product developers, and dissemination agents of best practices, existing NASA resources, and community expertise applicable to E/PO. By coordinating and supporting the NASA E/PO Community, the NASA/SEPOF partnerships will lead to more effective, sustainable, and efficient utilization of NASA science discoveries and learning experiences.

Hepcidin-25 in diabetic chronic kidney disease is predictive for mortality and progression to end stage renal disease.

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Martin Wagner

Full Text Available Anemia is common and is associated with impaired clinical outcomes in diabetic chronic kidney disease (CKD. It may be explained by reduced erythropoietin (EPO synthesis, but recent data suggest that EPO-resistance and diminished iron availability due to inflammation contribute significantly. In this cohort study, we evaluated the impact of hepcidin-25--the key hormone of iron-metabolism--on clinical outcomes in diabetic patients with CKD along with endogenous EPO levels.249 diabetic patients with CKD of any stage, excluding end-stage renal disease (ESRD, were enrolled (2003-2005, if they were not on EPO-stimulating agent and iron therapy. Hepcidin-25 levels were measured by radioimmunoassay. The association of hepcidin-25 at baseline with clinical variables was investigated using linear regression models. All-cause mortality and a composite endpoint of CKD progression (ESRD or doubling of serum creatinine were analyzed by Cox proportional hazards models.Patients (age 67 yrs, 53% male, GFR 51 ml/min, hemoglobin 131 g/L, EPO 13.5 U/L, hepcidin-25 62.0 ng/ml were followed for a median time of 4.2 yrs. Forty-nine patients died (19.7% and forty (16.1% patients reached the composite endpoint. Elevated hepcidin levels were independently associated with higher ferritin-levels, lower EPO-levels and impaired kidney function (all p<0.05. Hepcidin was related to mortality, along with its interaction with EPO, older age, greater proteinuria and elevated CRP (all p<0.05. Hepcidin was also predictive for progression of CKD, aside from baseline GFR, proteinuria, low albumin- and hemoglobin-levels and a history of CVD (all p<0.05.We found hepcidin-25 to be associated with EPO and impaired kidney function in diabetic CKD. Elevated hepcidin-25 and EPO-levels were independent predictors of mortality, while hepcidin-25 was also predictive for progression of CKD. Both hepcidin-25 and EPO may represent important prognostic factors of clinical outcome and have the

Function of the cytoplasmic tail of human calcitonin receptor-like receptor in complex with receptor activity-modifying protein 2

Energy Technology Data Exchange (ETDEWEB)

Kuwasako, Kenji, E-mail: kuwasako@fc.miyazaki-u.ac.jp [Frontier Science Research Center, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692 (Japan); Kitamura, Kazuo; Nagata, Sayaka; Hikosaka, Tomomi [Division of Circulation and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692 (Japan); Kato, Johji [Frontier Science Research Center, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692 (Japan)

2010-02-12

Receptor activity-modifying protein 2 (RAMP2) enables calcitonin receptor-like receptor (CRLR) to form an adrenomedullin (AM)-specific receptor. Here we investigated the function of the cytoplasmic C-terminal tail (C-tail) of human (h)CRLR by co-transfecting its C-terminal mutants into HEK-293 cells stably expressing hRAMP2. Deleting the C-tail from CRLR disrupted AM-evoked cAMP production or receptor internalization, but did not affect [{sup 125}I]AM binding. We found that CRLR residues 428-439 are required for AM-evoked cAMP production, though deleting this region had little effect on receptor internalization. Moreover, pretreatment with pertussis toxin (100 ng/mL) led to significant increases in AM-induced cAMP production via wild-type CRLR/RAMP2 complexes. This effect was canceled by deleting CRLR residues 454-457, suggesting Gi couples to this region. Flow cytometric analysis revealed that CRLR truncation mutants lacking residues in the Ser/Thr-rich region extending from Ser{sup 449} to Ser{sup 467} were unable to undergo AM-induced receptor internalization and, in contrast to the effect on wild-type CRLR, overexpression of GPCR kinases-2, -3 and -4 failed to promote internalization of CRLR mutants lacking residues 449-467. Thus, the hCRLR C-tail is crucial for AM-evoked cAMP production and internalization of the CRLR/RAMP2, while the receptor internalization is dependent on the aforementioned GPCR kinases, but not Gs coupling.

Prostaglandin Receptor Signaling in Disease

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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.

Receptor Autoradiography Protocol for the Localized Visualization of Angiotensin II Receptors.

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Linares, Andrea; Couling, Leena E; Carrera, Eduardo J; Speth, Robert C

2016-06-07

This protocol describes receptor binding patterns for Angiotensin II (Ang II) in the rat brain using a radioligand specific for Ang II receptors to perform receptor autoradiographic mapping. Tissue specimens are harvested and stored at -80 °C. A cryostat is used to coronally section the tissue (brain) and thaw-mount the sections onto charged slides. The slide-mounted tissue sections are incubated in (125)I-SI-Ang II to radiolabel Ang II receptors. Adjacent slides are separated into two sets: 'non-specific binding' (NSP) in the presence of a receptor saturating concentration of non-radiolabeled Ang II, or an AT1 Ang II receptor subtype (AT1R) selective Ang II receptor antagonist, and 'total binding' with no AT1R antagonist. A saturating concentration of AT2 Ang II receptor subtype (AT2R) antagonist (PD123319, 10 µM) is also present in the incubation buffer to limit (125)I-SI-Ang II binding to the AT1R subtype. During a 30 min pre-incubation at ~22 °C, NSP slides are exposed to 10 µM PD123319 and losartan, while 'total binding' slides are exposed to 10 µM PD123319. Slides are then incubated with (125)I-SI-Ang II in the presence of PD123319 for 'total binding', and PD123319 and losartan for NSP in assay buffer, followed by several 'washes' in buffer, and water to remove salt and non-specifically bound radioligand. The slides are dried using blow-dryers, then exposed to autoradiography film using a specialized film and cassette. The film is developed and the images are scanned into a computer for visual and quantitative densitometry using a proprietary imaging system and a spreadsheet. An additional set of slides are thionin-stained for histological comparisons. The advantage of using receptor autoradiography is the ability to visualize Ang II receptors in situ, within a section of a tissue specimen, and anatomically identify the region of the tissue by comparing it to an adjacent histological reference section.

Expression of GABAergic receptors in mouse taste receptor cells.

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Margaret R Starostik

Full Text Available BACKGROUND: Multiple excitatory neurotransmitters have been identified in the mammalian taste transduction, with few studies focused on inhibitory neurotransmitters. Since the synthetic enzyme glutamate decarboxylase (GAD for gamma-aminobutyric acid (GABA is expressed in a subset of mouse taste cells, we hypothesized that other components of the GABA signaling pathway are likely expressed in this system. GABA signaling is initiated by the activation of either ionotropic receptors (GABA(A and GABA(C or metabotropic receptors (GABA(B while it is terminated by the re-uptake of GABA through transporters (GATs. METHODOLOGY/PRINCIPAL FINDINGS: Using reverse transcriptase-PCR (RT-PCR analysis, we investigated the expression of different GABA signaling molecules in the mouse taste system. Taste receptor cells (TRCs in the circumvallate papillae express multiple subunits of the GABA(A and GABA(B receptors as well as multiple GATs. Immunocytochemical analyses examined the distribution of the GABA machinery in the circumvallate papillae. Both GABA(A-and GABA(B- immunoreactivity were detected in the peripheral taste receptor cells. We also used transgenic mice that express green fluorescent protein (GFP in either the Type II taste cells, which can respond to bitter, sweet or umami taste stimuli, or in the Type III GAD67 expressing taste cells. Thus, we were able to identify that GABAergic receptors are expressed in some Type II and Type III taste cells. Mouse GAT4 labeling was concentrated in the cells surrounding the taste buds with a few positively labeled TRCs at the margins of the taste buds. CONCLUSIONS/SIGNIFICANCE: The presence of GABAergic receptors localized on Type II and Type III taste cells suggests that GABA is likely modulating evoked taste responses in the mouse taste bud.

Erythropoietin and vascular endothelial growth factor as risk markers for severe hypoglycaemia in type 1 diabetes

DEFF Research Database (Denmark)

Kristensen, P L; Pedersen-Bjergaard, U; Schalkwijk, C

2010-01-01

OBJECTIVE: Circulating erythropoietin (EPO) and vascular endothelial growth factor (VEGF) increase during hypoglycaemia and may represent protective hormonal counter-regulatory responses. We tested the hypothesis that low levels of EPO and VEGF are associated with a higher frequency of severe....... Plasma EPO and serum VEGF levels were measured at baseline with ELISA. Events of severe hypoglycaemia defined by third party assistance were recorded and validated in telephone interviews within 24 h. RESULTS: Totally 235 episodes of severe hypoglycaemia (1.1 episodes per patient-year) were reported...... mass index, HbAlc, C-peptide level or hypoglycaemia awareness status. The levels of VEGF were positively associated with age and female sex. CONCLUSIONS: Although several studies suggest that VEGF and EPO may affect brain function during hypoglycaemia, this study does not support random VEGF or EPO...

Erythropoietin over-expression protects against diet-induced obesity in mice through increased fat oxidation in muscles

DEFF Research Database (Denmark)

Hojman, Pernille; Brolin, Camilla; Gissel, Hanne

2009-01-01

patients. Thus we applied the EPO over-expression model to investigate the metabolic effect of EPO in vivo.At 12 weeks, EPO expression resulted in a 23% weight reduction (Pobese mice; thus the mice weighed 21.9+/-0.8 g (control, normal diet,) 21.9+/-1.4 g (EPO, normal diet), 35.......3+/-3.3 g (control, high-fat diet) and 28.8+/-2.6 g (EPO, high-fat diet). Correspondingly, DXA scanning revealed that this was due to a 28% reduction in adipose tissue mass.The decrease in adipose tissue mass was accompanied by a complete normalisation of fasting insulin levels and glucose tolerance......-physiological levels has substantial metabolic effects including protection against diet-induced obesity and normalisation of glucose sensitivity associated with a shift to increased fat metabolism in the muscles....

Erythropoietin modulates neural and cognitive processing of emotional information in biomarker models of antidepressant drug action in depressed patients

DEFF Research Database (Denmark)

Miskowiak, Kamilla W; Favaron, Elisa; Hafizi, Sepehr

2010-01-01

. The current study investigates the effects of Epo on the neural and cognitive response to emotional facial expressions in depressed patients. METHOD: Nineteen acutely depressed patients were randomized to receive Epo (40,000 IU) or saline intravenously in a double-blind, parallel-group design. On day 3, we......OBJECTIVE: Erythropoietin (Epo) has neuroprotective and neurotrophic effects, and may be a novel therapeutic agent in the treatment of psychiatric disorders. We have demonstrated antidepressant-like effects of Epo on the neural and cognitive processing of facial expressions in healthy volunteers...... assessed neuronal responses to fearful and happy faces using functional magnetic resonance imaging and measured facial expression recognition after the scan. RESULTS: Epo reduced neural response to fearful vs. happy faces in the amygdala and hippocampus, and to fearful faces vs. baseline in superior...

Neonatal erythropoiesis and subsequent anemia in HIV-positive and HIV-negative Zimbabwean babies during the first year of life: a longitudinal study

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Malaba Lucie C

2006-01-01

Full Text Available Abstract Background Anemia is common in HIV infection and independently associated with disease progression and mortality. The pathophysiology of HIV-related anemia is not well understood especially in infancy. Methods We conducted a longitudinal cohort study nested within the Zimbabwe Vitamin A for Mothers and Babies Project. We measured hemoglobin, erythropoietin (EPO, serum transferrin receptor (TfR and serum ferritin at 6 weeks, 3 and 6 months of age and hemoglobin at 9 and 12 months in 3 groups of randomly selected infants: 136 born to HIV-negative mothers, and 99 born to HIV-positive mothers and who were infected themselves by 6 weeks of age, and 324 born to HIV-positive mothers but who did not become infected in the 6 months following birth. Results At one year of age, HIV-positive infants were 5.26 (adjusted odds ratio, P Conclusion HIV strongly increases anemia risk and confounds interpretation of hematologic indicators in infants. Among HIV-infected infants, the EPO response to anemia is attenuated near the time of infection in the first weeks of life, but normalizes by 6 months.

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 in the f......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...... in the formation of memory. Hence, ligands affecting AMPARs are highly important for the study of the structure and function of this receptor, and in this regard polyamine-based ligands, particularly polyamine toxins, are unique as they selectively block Ca2+ -permeable AMPARs. Indeed, endogenous intracellular...

A2A-D2 receptor-receptor interaction modulates gliotransmitter release from striatal astrocyte processes.

Science.gov (United States)

Cervetto, Chiara; Venturini, Arianna; Passalacqua, Mario; Guidolin, Diego; Genedani, Susanna; Fuxe, Kjell; Borroto-Esquela, Dasiel O; Cortelli, Pietro; Woods, Amina; Maura, Guido; Marcoli, Manuela; Agnati, Luigi F

2017-01-01

Evidence for striatal A2A-D2 heterodimers has led to a new perspective on molecular mechanisms involved in schizophrenia and Parkinson's disease. Despite the increasing recognition of astrocytes' participation in neuropsychiatric disease vulnerability, involvement of striatal astrocytes in A2A and D2 receptor signal transmission has never been explored. Here, we investigated the presence of D2 and A2A receptors in isolated astrocyte processes prepared from adult rat striatum by confocal imaging; the effects of receptor activation were measured on the 4-aminopyridine-evoked release of glutamate from the processes. Confocal analysis showed that A2A and D2 receptors were co-expressed on the same astrocyte processes. Evidence for A2A-D2 receptor-receptor interactions was obtained by measuring the release of the gliotransmitter glutamate: D2 receptors inhibited the glutamate release, while activation of A2A receptors, per se ineffective, abolished the effect of D2 receptor activation. The synthetic D2 peptide VLRRRRKRVN corresponding to the receptor region involved in electrostatic interaction underlying A2A-D2 heteromerization abolished the ability of the A2A receptor to antagonize the D2 receptor-mediated effect. Together, the findings are consistent with heteromerization of native striatal astrocytic A2A-D2 receptors that via allosteric receptor-receptor interactions could play a role in the control of striatal glutamatergic transmission. These new findings suggest possible new pathogenic mechanisms and/or therapeutic approaches to neuropsychiatric disorders. © 2016 International Society for Neurochemistry.

Blood leptin levels and erythropoietin requirement in Iranian hemodialysis patients

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Rahimi A

2008-12-01

Full Text Available "nBackground: Anemia is a common complication accompanied by high morbidity and mortality in hemodialysis patients. Considering the fact that the reduction of erythropoietin (EPO synthesis is the main cause of uremic anemia, receiving recombinant human erythropoietin (rHuEPO can improve the condition in these patients. Some of these hemodialysis patients, however, have acceptable hemoglobin levels without any need to EPO. Higher BMI, higher albumin and leptin plasma levels and longer durations of hemodialysis are possible factors contributing to the reduced need for rHuEPO in these patients. The present study is designed to asses the relationship between the plasma levels of leptin and the reduced EPO need. "nMethods: Fifty eligible hemodialysis patients with hemoglobin levels higher than 11 mg/dl were enrolled in the cross-sectional study. The information on age, sex, hemodialysis duration and the cause of renal dysfunction were extracted from the files. The baseline plasma levels of Leptin and albumin were measured. The patients BMI and the weekly need for rHuEPO were also calculated. "nResults: There was no correlation between the weekly need for rHuEPO and sex, BMI, the cause of renal dysfunction and the plasma levels of albumin and leptin; it, however, was related with age and the duration of dialysis. While age negatively influences the weekly need, the duration of dialysis has a positive effect on the need. "nConclusion: The plasma levels of leptin are not directly correlated with the required amounts of rHuEPO, indicating that leptin is not an effective factor in erythropoiesis. Conversely, older age and shorter hemodialysis durations are accompanied by reduced need for rHuEPO.

Erythropoietin inhibits HIF-1α expression via upregulation of PHD-2 transcription and translation in an in-vitro model of hypoxia ischemia

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Souvenir, Rhonda; Flores, Jerry J.; Ostrowski, Robert P.; Manaenko, Anatol; Duris, Kamil; Tang, Jiping

2014-01-01

Hypoxia inducible factor (HIF)-1α is the central transcriptional factor for the regulation of oxygen-associated genes in response to hypoxia. Erythropoietin (EPO), a hematopoietic growth factor, increases oxygen availability during hypoxia/ischemia and is associated with neuroprotection following hypoxia ischemia in laboratory models of stroke. However, EPO has failed to translate in a clinical setting. Thus it is critical to elucidate the key players in EPO-induced neuroprotection. Our preliminary studies have shown that EPO, as a downstream gene of hypoxia inducible factor (HIF), inhibits HIF-1α in a dose-dependent manner in an in-vitro model of hypoxia ischemia. This study is designed to elucidate the primary mediator of EPO-induced HIF-1α inhibition and subsequent cell survival/neuroprotection. Oxygen and glucose deprivation (OGD) of nerve growth factor (NGF) differentiated rat pheochromocytoma (PC-12) cells were used to model hypoxia ischemia in an in vitro environment. The profile of HIF-1α, HIF-2α and PHD-2 expression, HIF-1α and prolyl hydroxylase (PHD-2) mRNA levels, MMP-9 and cell death was evaluated in the presence and absence of either EPO or PHD-2 inhibitor during OGD. Our findings showed that EPO treatment resulted in an increase in PHD-2 transcription and translation, inhibition of HIF-1α expression, reactive oxygen species (ROS) formation and matrix metalloproteinase (MMP)-9 activity, resulting in increased cell survival after OGD. We also observed that EPO-induced cell survival/neuroprotection was reversed by siRNA silencing of PHD-2. This led to the conclusion that PHD-2 is a key mediator of EPO-induced HIF-1α inhibition and subsequent neuroprotection in an in vitro model of hypoxia ischemia. PMID:24323731

Erythropoietin inhibits HIF-1α expression via upregulation of PHD-2 transcription and translation in an in vitro model of hypoxia-ischemia.

Science.gov (United States)

Souvenir, Rhonda; Flores, Jerry J; Ostrowski, Robert P; Manaenko, Anatol; Duris, Kamil; Tang, Jiping

2014-02-01

Hypoxia inducible factor (HIF)-1α is the central transcriptional factor for the regulation of oxygen-associated genes in response to hypoxia. Erythropoietin (EPO), a hematopoietic growth factor, increases oxygen availability during hypoxia/ischemia and is associated with neuroprotection following hypoxia-ischemia in laboratory models of stroke. However, EPO has failed to translate in a clinical setting. Thus, it is critical to elucidate the key players in EPO-induced neuroprotection. Our preliminary studies have shown that EPO, as a downstream gene of HIF, inhibits HIF-1α in a dose-dependent manner in an in vitro model of hypoxia-ischemia. This study is designed to elucidate the primary mediator of EPO-induced HIF-1α inhibition and subsequent cell survival/neuroprotection. Oxygen and glucose deprivation (OGD) of nerve growth factor-differentiated rat pheochromocytoma (PC-12) cells were used to model hypoxia-ischemia in an in vitro environment. The profile of HIF-1α, HIF-2α and prolyl hydroxylase domain 2 (PHD-2) expression; HIF-1α and prolyl hydroxylase (PHD-2) mRNA levels; matrix metalloproteinase (MMP)-9; and cell death was evaluated in the presence and absence of either EPO or PHD-2 inhibitor during OGD. Our findings showed that EPO treatment resulted in an increase in PHD-2 transcription and translation, inhibition of HIF-1α expression, reactive oxygen species formation, and MMP-9 activity, resulting in increased cell survival after OGD. We also observed that EPO-induced cell survival/neuroprotection was reversed by siRNA silencing of PHD-2. This led to the conclusion that PHD-2 is a key mediator of EPO-induced HIF-1α inhibition and subsequent neuroprotection in an in vitro model of hypoxia-ischemia.

Twelve Years of Education and Public Outreach with the Fermi Gamma-ray Space Telescope

Science.gov (United States)

Cominsky, Lynn R.; McLin, K. M.; Simonnet, A.; Fermi E/PO Team

2013-04-01

During the past twelve years, NASA's Fermi Gamma-ray Space Telescope has supported a wide range of Education and Public Outreach (E/PO) activities, targeting K-14 students and the general public. The purpose of the Fermi E/PO program is to increase student and public understanding of the science of the high-energy Universe, through inspiring, engaging and educational activities linked to the mission’s science objectives. The E/PO program has additional more general goals, including increasing the diversity of students in the Science, Technology, Engineering and Mathematics (STEM) pipeline, and increasing public awareness and understanding of Fermi science and technology. Fermi's multi-faceted E/PO program includes elements in each major outcome category: ● Higher Education: Fermi E/PO promotes STEM careers through the use of NASA data including research experiences for students and teachers (Global Telescope Network), education through STEM curriculum development projects (Cosmology curriculum) and through enrichment activities (Large Area Telescope simulator). ● Elementary and Secondary education: Fermi E/PO links the science objectives of the Fermi mission to well-tested, customer-focused and NASA-approved standards-aligned classroom materials (Black Hole Resources, Active Galaxy Education Unit and Pop-up book, TOPS guides, Supernova Education Unit). These materials have been distributed through (Educator Ambassador and on-line) teacher training workshops and through programs involving under-represented students (after-school clubs and Astro 4 Girls). ● Informal education and public outreach: Fermi E/PO engages the public in sharing the experience of exploration and discovery through high-leverage multi-media experiences (Black Holes planetarium and PBS NOVA shows), through popular websites (Gamma-ray Burst Skymap, Epo's Chronicles), social media (Facebook, MySpace), interactive web-based activities (Space Mysteries, Einstein@Home) and activities by

First-in-man-proof of concept study with molidustat: a novel selective oral HIF-prolyl hydroxylase inhibitor for the treatment of renal anaemia.

Science.gov (United States)

Böttcher, M; Lentini, S; Arens, E R; Kaiser, A; van der Mey, D; Thuss, U; Kubitza, D; Wensing, G

2018-07-01

Insufficient erythropoietin (EPO) synthesis is a relevant cause of renal anaemia in patients with chronic kidney disease. Molidustat, a selective hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, increases endogenous EPO levels dose dependently in preclinical models. We examined the pharmacokinetics, safety, tolerability and effect on EPO levels of single oral doses of molidustat in healthy male volunteers. This was a single-centre, randomized, single-blind, placebo-controlled, group-comparison, dose-escalation study. Molidustat was administered at doses of 5, 12.5, 25, 37.5 or 50 mg as a polyethylene glycol-based solution. In total, 45 volunteers received molidustat and 14 received placebo. Molidustat was absorbed rapidly, and the mean maximum plasma concentration and area under the concentration-time curve increased dose dependently. The mean terminal half-life was 4.64-10.40 h. A significant increase in endogenous EPO was observed following single oral doses of molidustat of 12.5 mg and above. Geometric mean peak EPO levels were 14.8 IU l -1 (90% confidence interval 13.0, 16.9) for volunteers who received placebo and 39.8 IU l -1 (90% confidence interval: 29.4, 53.8) for those who received molidustat 50 mg. The time course of EPO levels resembled the normal diurnal variation in EPO. Maximum EPO levels were observed approximately 12 h postdose and returned to baseline after approximately 24-48 h. All doses of molidustat were well tolerated and there were no significant changes in vital signs or laboratory safety parameters. Oral administration of molidustat to healthy volunteers elicited a dose-dependent increase in endogenous EPO. These results support the ongoing development of molidustat as a potential new treatment for patients with renal anaemia. © 2018 The British Pharmacological Society.

Long-term cadmium exposure induces anemia in rats through hypoinduction of erythropoietin in the kidneys

Energy Technology Data Exchange (ETDEWEB)

Horiguchi, Hyogo [Department of Public Health, Fukushima Medical College, Fukushima (Japan); Sato, Masao [Department of Biomolecular Sciences, Institute of Biomedical Sciences, Fukushima Medical College, Fukushima (Japan); Konno, Nobuhiro [Department of Public Health, Fukushima Medical College, Fukushima (Japan); Fukushima, Masaaki [Department of Public Health, Fukushima Medical College, Fukushima (Japan)

1996-11-01

Cadmium (Cd), a highly toxic heavy metal, is distributed widely in the general environment of today. The characteristic clinical manifestations of chronic Cd intoxication include renal proximal tubular dysfunction, general osteomalacia with severe pains, and anemia. We have recently reported that the serum level of erythropoietin (EPO) remained low despite the severe anemia in patients with Itai-itai disease, the most severe form of chronic Cd intoxication. In order to prove that the anemia observed in chronic Cd intoxication arises from low production of EPO in the kidneys following the renal injury, we administered Cd to rats for a long period and performed the analysis of EPO mRNA inducibility in the kidneys. The rats administered Cd for 6 and 9 months showed anemia with low levels of plasma EPO as well as biochemical and histological renal tubular damage, and also hypoinduction of EPO mRNA in the kidneys. The results indicate that chronic Cd intoxication causes anemia by disturbing the EPO-production capacity of renal cells. (orig.). With 4 figs., 4 tabs.

N-glycosylation of the β2 adrenergic receptor regulates receptor function by modulating dimerization.

Science.gov (United States)

Li, Xiaona; Zhou, Mang; Huang, Wei; Yang, Huaiyu

2017-07-01

N-glycosylation is a common post-translational modification of G-protein-coupled receptors (GPCRs). However, it remains unknown how N-glycosylation affects GPCR signaling. β 2 adrenergic receptor (β 2 AR) has three N-glycosylation sites: Asn6, Asn15 at the N-terminus, and Asn187 at the second extracellular loop (ECL2). Here, we show that deletion of the N-glycan did not affect receptor expression and ligand binding. Deletion of the N-glycan at the N-terminus rather than Asn187 showed decreased effects on isoproterenol-promoted G-protein-dependent signaling, β-arrestin2 recruitment, and receptor internalization. Both N6Q and N15Q showed decreased receptor dimerization, while N187Q did not influence receptor dimerization. As decreased β 2 AR homodimer accompanied with reduced efficiency for receptor function, we proposed that the N-glycosylation of β 2 AR regulated receptor function by influencing receptor dimerization. To verify this hypothesis, we further paid attention to the residues at the dimerization interface. Studies of Lys60 and Glu338, two residues at the receptor dimerization interface, exhibited that the K60A/E338A showed decreased β 2 AR dimerization and its effects on receptor signaling were similar to N6Q and N15Q, which further supported the importance of receptor dimerization for receptor function. This work provides new insights into the relationship among glycosylation, dimerization, and function of GPCRs. Peptide-N-glycosidase F (PNGase F, EC 3.2.2.11); endo-β-N-acetylglucosaminidase A (Endo-A, EC 3.2.1.96). © 2017 Federation of European Biochemical Societies.

Prognostic Value of Estrogen Receptor alpha and Progesterone Receptor Conversion in Distant Breast Cancer Metastases

NARCIS (Netherlands)

Hoefnagel, Laurien D. C.; Moelans, Cathy B.; Meijer, S. L.; van Slooten, Henk-Jan; Wesseling, Pieter; Wesseling, Jelle; Westenend, Pieter J.; Bart, Joost; Seldenrijk, Cornelis A.; Nagtegaal, Iris D.; Oudejans, Joost; van der Valk, Paul; van Gils, Carla H.; van der Wall, Elsken; van Diest, Paul J.

2012-01-01

BACKGROUND: Changes in the receptor profile of primary breast cancers to their metastases (receptor conversion) have been described for the estrogen receptor alpha (ER alpha) and progesterone receptor (PR). The purpose of this study was to evaluate the impact of receptor conversion for ER alpha and

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

CLINICAL APPLICATION OF RECOMBINANT ERYTHROPOIETIN IN BETA-THALASSAEMIA INTERMEDIA.

Science.gov (United States)

Asadov, Ch; Alimirzoyeva, Z; Hasanova, M; Mammadova, T; Shirinova, A

2016-06-01

Research objective is to study the efficacy of recombinant erythropoietin (epoetin alfa) as alternative method of treatment beta-thalassemia intermedia. Study involved 58 patients with beta-thalassemia intermedia (23 women and 35 men). In all observed patients was defined levels of hemoglobin (Hb), red blood cells (RBC), erythrocyte indexes (MCV, MCH, MCHC), hemoglobin fractions (HbA, HbA2, HbF), serum ferritin, serum erythropoietin before and after administrated rEPO. All patients received rEPO during 6 month at the dose - 10000 IU subcutaneously. The majority of patients - 39 (67%) had a good response to rEPO (increase in hemoglobin level more than 20 g/l); 16 patients (28%) had a mean response (increase in Hb 10 - 20 g/l); in 3 (5%) patients occurred poor response to rEPO therapy (increase in Hb intermedia patients there was a statistically significant change in the number of RBC, levels of HbF and sEPO. The evaluation of interdependence between the indices of the baseline sEPO and increased Hb values in patients after rEPO treatment revealed the presence of the reverse direct relationship (r=-0.67). Based on the results, it can be concluded that the use of rEPO in complex therapy of beta-thalassemia intermedia leads to increased levels of Hb and consequently reducing the need for blood transfusions, and accordingly expected to prevent severe complications of blood transfusion (alloimmunization, hypersplenism, iron overload, contamination transmissible infections) facilitating normal growth and development, and a better quality of life.

Immuno-magnetic beads-based extraction-capillary zone electrophoresis-deep UV laser-induced fluorescence analysis of erythropoietin.

Science.gov (United States)

Wang, Heye; Dou, Peng; Lü, Chenchen; Liu, Zhen

2012-07-13

Erythropoietin (EPO) is an important glycoprotein hormone. Recombinant human EPO (rhEPO) is an important therapeutic drug and can be also used as doping reagent in sports. The analysis of EPO glycoforms in pharmaceutical and sports areas greatly challenges analytical scientists from several aspects, among which sensitive detection and effective and facile sample preparation are two essential issues. Herein, we investigated new possibilities for these two aspects. Deep UV laser-induced fluorescence detection (deep UV-LIF) was established to detect the intrinsic fluorescence of EPO while an immuno-magnetic beads-based extraction (IMBE) was developed to specifically extract EPO glycoforms. Combined with capillary zone electrophoresis (CZE), CZE-deep UV-LIF allows high resolution glycoform profiling with improved sensitivity. The detection sensitivity was improved by one order of magnitude as compared with UV absorbance detection. An additional advantage is that the original glycoform distribution can be completely preserved because no fluorescent labeling is needed. By combining IMBE with CZE-deep UV-LIF, the overall detection sensitivity was 1.5 × 10⁻⁸ mol/L, which was enhanced by two orders of magnitude relative to conventional CZE with UV absorbance detection. It is applicable to the analysis of pharmaceutical preparations of EPO, but the sensitivity is insufficient for the anti-doping analysis of EPO in blood and urine. IMBE can be straightforward and effective approach for sample preparation. However, antibodies with high specificity were the key for application to urine samples because some urinary proteins can severely interfere the immuno-extraction. Copyright © 2012 Elsevier B.V. All rights reserved.

The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor

Energy Technology Data Exchange (ETDEWEB)

Zhou, X. Edward; Suino-Powell, Kelly M.; Xu, Yong; Chan, Cee-Wah; Tanabe, Osamu; Kruse, Schoen W.; Reynolds, Ross; Engel, James Douglas; Xu, H. Eric (Michigan-Med); (Van Andel)

2015-11-30

Testicular receptors 2 and 4 (TR2/4) constitute a subgroup of orphan nuclear receptors that play important roles in spermatogenesis, lipid and lipoprotein regulation, and the development of the central nervous system. Currently, little is known about the structural features and the ligand regulation of these receptors. Here we report the crystal structure of the ligand-free TR4 ligand binding domain, which reveals an autorepressed conformation. The ligand binding pocket of TR4 is filled by the C-terminal half of helix 10, and the cofactor binding site is occupied by the AF-2 helix, thus preventing ligand-independent activation of the receptor. However, TR4 exhibits constitutive transcriptional activity on multiple promoters, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, or ligand binding substantially reduce the transcriptional activity of this receptor. Importantly, both retinol and retinoic acid are able to promote TR4 to recruit coactivators and to activate a TR4-regulated reporter. These findings demonstrate that TR4 is a ligand-regulated nuclear receptor and suggest that retinoids might have a much wider regulatory role via activation of orphan receptors such as TR4.

Soman- or kainic acid-induced convulsions decrease muscarinic receptors but not benzodiazepine receptors

International Nuclear Information System (INIS)

Churchill, L.; Pazdernik, T.L.; Cross, R.S.; Nelson, S.R.; Samson, F.E.

1990-01-01

[3H]Quinuclidinyl benzilate (QNB) binding to muscarinic receptors decreased in the rat forebrain after convulsions induced by a single dose of either soman, a potent inhibitor of acetylcholinesterase, or kainic acid, an excitotoxin. A Rosenthal plot revealed that the receptors decreased in number rather than affinity. When the soman-induced convulsions were blocked, the decrease in muscarinic receptors at 3 days was less extensive than when convulsions occurred and at 10 days they approached control levels in most of the brain areas. The most prominent decrements in QNB binding were in the piriform cortex where the decline in QNB binding is probably related to the extensive convulsion-associated neuropathology. The decrements in QNB binding after convulsions suggest that the convulsive state leads to a down-regulation of muscarinic receptors in some brain areas. In contrast to the decrease in QNB binding after convulsions, [3H]flunitrazepam binding to benzodiazepine receptors did not change even in the piriform cortex where the loss in muscarinic receptors was most prominent. Thus, it appears that those neuronal processes that bear muscarinic receptors are more vulnerable to convulsion-induced change than those with benzodiazepine receptors

Cooperative ethylene receptor signaling

OpenAIRE

Liu, Qian; Wen, Chi-Kuang

2012-01-01

The gaseous plant hormone ethylene is perceived by a family of five ethylene receptor members in the dicotyledonous model plant Arabidopsis. Genetic and biochemical studies suggest that the ethylene response is suppressed by ethylene receptor complexes, but the biochemical nature of the receptor signal is unknown. Without appropriate biochemical measures to trace the ethylene receptor signal and quantify the signal strength, the biological significance of the modulation of ethylene responses ...

Radiolabelled GLP-1 receptor antagonist binds to GLP-1 receptor-expressing human tissues

International Nuclear Information System (INIS)

Waser, Beatrice; Reubi, Jean Claude

2014-01-01

Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. For the somatostatin receptor targeting of tumours, however, it was recently reported that antagonist tracers were superior to agonist tracers. The present study therefore evaluated various forms of the 125 iodinated-Bolton-Hunter (BH)-exendin(9-39) antagonist tracer for the in vitro visualization of GLP-1 receptor-expressing tissues in rats and humans and compared it with the agonist tracer 125 I-GLP-1(7-36)amide. Receptor autoradiography studies with 125 I-GLP-1(7-36)amide agonist or 125 I-BH-exendin(9-39) antagonist radioligands were performed in human and rat tissues. The antagonist 125 I-BH-exendin(9-39) labelled at lysine 19 identifies all human and rat GLP-1 target tissues and GLP-1 receptor-expressing tumours. Binding is of high affinity and is comparable in all tested tissues in its binding properties with the agonist tracer 125 I-GLP-1(7-36)amide. For comparison, 125 I-BH-exendin(9-39) with the BH labelled at lysine 4 did identify the GLP-1 receptor in rat tissues but not in human tissues. The GLP-1 receptor antagonist exendin(9-39) labelled with 125 I-BH at lysine 19 is an excellent GLP-1 radioligand that identifies human and rat GLP-1 receptors in normal and tumoural tissues. It may therefore be the molecular basis to develop suitable GLP-1 receptor antagonist radioligands for in vivo imaging of GLP-1 receptor-expressing tissues in patients. (orig.)

Nonalcoholic fatty liver disease (NAFLD)--is it a new marker of hyporesponsiveness to recombinant human erythropoietin in patients that are on chronic hemodialysis?

Science.gov (United States)

Orlic, L; Mikolasevic, I; Lukenda, V; Racki, S; Stimac, D; Milic, S

2014-12-01

Anemia is a major consequence of chronic kidney disease (CKD) that develops early in the course of illness and affects most patients who exhibit some degree of reduced renal function. Erythropoietin (EPO) deficiency is considered the most important cause of anemia in CKD. Renal anemia has serious clinical consequence. In addition to reducing patient physical capacity and quality of life, anemia induces adaptive cardiovascular mechanisms that increase the risk of cardiovascular disease and death. Thus, treatment of anemia in CKD is very important. While EPO is effective in correcting anemia in most cases, up to 10% of patients however, have an inadequate response to therapy. The two most common and important reasons why patients become relatively unresponsive to EPO therapy are the development of true iron deficiency and the onset of an inflammatory state that impairs the response to EPO. Indeed, the role of inflammation and pro-inflammatory cytokines in resistance to EPO therapy is gaining increasing recognition. On the other hand, the main organ for C-reactive protein (CRP) synthesis is the liver and it is well known that the synthesis of an acute-phase proteins by the liver is up regulated by inflammation. The main consequence of nonalcoholic fatty liver disease (NAFLD) is sub-chronic liver inflammation that leads and contributes to dyslipidemia, inflammation, enhanced oxidative stress and endothelial dysfunction. Considering the recent data about high prevalence of NAFLD in CKD patients, probably due to shared metabolic risk factors, we hypothesized that end-stage renal disease (ESRD) patients with NAFLD will need a much higher dose of EPO to achieve the target hemoglobin levels in comparison with ESRD patients without NAFLD. The possible underlying mechanism is sub-chronic liver inflammation in NAFLD patients that leads and contributes to poor response to EPO. Therefore, we believe that NAFLD could be a new clinical marker of poor response to EPO therapy in

Effect of neoadjuvant chemotherapy on low-density lipoprotein (LDL) receptor and LDL receptor-related protein 1 (LRP-1) receptor in locally advanced breast cancer

International Nuclear Information System (INIS)

Pires, L.A.; Hegg, R.; Freitas, F.R.; Tavares, E.R.; Almeida, C.P.; Baracat, E.C.; Maranhão, R.C.

2012-01-01

Low-density lipoprotein (LDL) receptors are overexpressed in most neoplastic cell lines and provide a mechanism for the internalization and concentration of drug-laden nanoemulsions that bind to these receptors. The aim of the present study was to determine whether the administration of standard chemotherapeutic schemes can alter the expression of LDL and LDL receptor-related protein 1 (LRP-1) receptors in breast carcinoma. Fragments of tumoral and normal breast tissue from 16 consecutive volunteer women with breast cancer in stage II or III were obtained from biopsies before the beginning of neoadjuvant chemotherapy and after chemotherapy, from fragments excised during mastectomy. Tissues were analyzed by immunohistochemistry for both receptors. Because complete response to treatment was achieved in 4 patients, only the tumors from 12 were analyzed. Before chemotherapy, there was overexpression of LDL receptor in the tumoral tissue compared to normal breast tissue in 8 of these patients. LRP-1 receptor overexpression was observed in tumors of 4 patients. After chemotherapy, expression of both receptors decreased in the tumors of 6 patients, increased in 4 and was unchanged in 2. Nonetheless, even when chemotherapy reduced receptors expression, the expression was still above normal. The fact that chemotherapy does not impair LDL receptors expression supports the use of drug carrier systems that target neoplastic cells by the LDL receptor endocytic pathway in patients on conventional chemotherapy

Influence of erythropoietin on cognitive performance during experimental hypoglycemia in patients with type 1 diabetes mellitus: a randomized cross-over trial.

Directory of Open Access Journals (Sweden)

Peter Lommer Kristensen

Full Text Available The incidence of severe hypoglycemia in type 1 diabetes has not decreased over the past decades. New treatment modalities minimizing the risk of hypoglycemic episodes and attenuating hypoglycemic cognitive dysfunction are needed. We studied if treatment with the neuroprotective hormone erythropoietin (EPO enhances cognitive function during hypoglycemia.Eleven patients with type 1 diabetes, hypoglycemia unawareness and recurrent severe hypoglycemia completed the study. In a double-blind, randomized, balanced, cross-over study using clamped hypoglycemia they were treated with 40,000 IU of EPO or placebo administered intravenously six days before the two experiments. Cognitive function (primary endpoint, hypoglycemic symptoms, and counter-regulatory hormonal response were recorded.Compared with placebo, EPO treatment was associated with a significant reduction in errors in the most complex reaction time task (-4.7 (-8.1 to -1.3, p = 0.01 and a less reaction time prolongation (-66 (-117 to -16 msec, p = 0.02. EPO treatment did not change performance in other measures of cognition. Hypoglycemic symptoms, EEG-changes, and counter-regulatory hormone concentrations did not differ between EPO and placebo treatment.In patients with type 1 diabetes and hypoglycemia unawareness, treatment with EPO is associated with a beneficial effect on cognitive function in a complex reaction time task assessing sustained attention/working memory. Hypoglycemic symptoms and hormonal responses were not changed by EPO treatment.ClinicalTrials.gov NCT00615368.

Antioxidants may Attenuate Plasma Erythropoietin Decline after Hyperbaric Oxygen Diving.

Science.gov (United States)

Mutzbauer, T S; Schneider, M; Neubauer, B; Weiss, M; Tetzlaff, K

2015-11-01

According to previous studies, plasma erythropoietin (EPO) may decrease after hyperbaric oxygen exposure due to oxidative stress. It is hypothesized that the decrease of EPO can be attenuated by oxygen free radical scavengers.The aim of the present study was to evaluate whether EPO plasma levels can be influenced by oral application of vitamin C and E before repeated hyperbaric oxygen exposure during diving. 16 healthy male police task force divers performed 3 morning dives on oxygen within a regular diving schedule on 3 consecutive days. They were randomized into either the placebo group or the vitamin group, receiving 1 g ascorbic acid and 600 IU D-α-tocopherol orally 60 min before the dive. Blood samples for EPO measurement were taken on days 1, 2, and 3 at T1, T3 and T5 60 min before and at T2, T4 and T6 60 min after each dive, respectively. A moderate decrease of EPO was observed beginning at T3 until T6 in the placebo group. The EPO concentrations in the vitamin group did not show relevant variations compared to baseline. Radical scavenging vitamins C and D may counteract hyperbaric oxygen related mechanisms reducing EPO production in hyperbaric oxygen exposure during diving. © Georg Thieme Verlag KG Stuttgart · New York.

Serum erythropoietin levels by radioimmunoassay in polycythaemia

Energy Technology Data Exchange (ETDEWEB)

Birgegaard, G.; Miller, O.; Caro, J.; Erslev, A. (Cardeza Foundation for Hematological Research, Jefferson University, Philadelphia, Pa.)

1982-01-01

A radioimmunoassay (RIA) method for erythropoietin (Epo) was developed and validated against the polycythaemic mouse assay. The correlation was good, with a r=0.94. Several other criteria of specificity were also filled by the RIA, which had a lower detection limit of 5 mU/ml. The mean serum-Epo level in 6 patients with secondary polycythaemia, 50.2 +- 26.2 mU/ml, was significantly higher than in a group of 11 normal subjects, 28.7 +- 7.2 mU/ml (P<0.0002). However, the Epo level in 31 polycythaemia vera (PV) patients, M = 21.9 +- 6.6 mU/ml, was not significantly different from normal (P = 0.006). Since previous studies with bioassay of heat-treated and concentrated plasma samples have shown a decreased serum-Epo level in PV, Epo levels were measured before and after heat treatment and concentration of samples from normals and polycythaemics. It was found that the levels of immunoreactive material increased after heat treatment and 40 times concentration in samples from normals and patients with secondary polycythaemias, but decreased in PV. We conclude that the Epo levels in serum in the low range measured by our and previous RIA:s probably are not true Epo levels but are partly due to an unspecific serum effect, that was removed by heat treatment.

Erythropoietin improves the survival of fat tissue after its transplantation in nude mice.

Science.gov (United States)

Hamed, Saher; Egozi, Dana; Kruchevsky, Danny; Teot, Luc; Gilhar, Amos; Ullmann, Yehuda

2010-11-15

Autologous transplanted fat has a high resorption rate, providing a clinical challenge for the means to reduce it. Erythropoietin (EPO) has non-hematopoietic targets, and we hypothesized that EPO may improve long-term fat graft survival because it has both pro-angiogenic and anti-apoptotic properties. We aimed to determine the effect of EPO on the survival of human fat tissue after its transplantation in nude mice. Human fat tissue was injected subcutaneously into immunologically-compromised nude mice, and the grafts were then treated with either 20 IU or 100 IU EPO. At the end of the 15-week study period, the extent of angiogenesis, apoptosis, and histology were assessed in the fat grafts. The results were compared to vascular endothelial growth factor (VEGF)-treated and phosphate-buffered saline (PBS)-treated fat grafts. The weight and volume of the EPO-treated grafts were higher than those of the PBS-treated grafts, whose weights and volumes were not different from those of the VEGF-treated grafts. EPO treatment also increased the expression of angiogenic factors and microvascular density, and reduced inflammation and apoptosis in a dose-dependent manner in the fat grafts. Our data suggest that stimulation of angiogenesis by a cluster of angiogenic factors and decreased fat cell apoptosis account for potential mechanisms that underlie the improved long-term survival of fat transplants following EPO treatment.

Protective Effects of Erythropoietin and N-Acetylcysteine on Methotrexate-Induced Lung Injury in Rats

Directory of Open Access Journals (Sweden)

Hasan Kahraman

2013-03-01

Full Text Available Objective: Methotrexate (MTX is known to have deleterious side effects on lung tissue. We aimed to investigate the effects of erythropoietin (EPO and N-acetyl-cysteine (NAC on MTX-induced lung injury in rats. Study Design: Animal experiment. Material and Methods: Twenty-six female Sprague-Dawley rats were divided into 4 groups. Sham group, 0.3 mL saline; MTX group, 5 mg/kg MTX; EPO group, 5mg/kg MTX and 2000 IU/kg EPO; NAC group, 5 mg/kg MTX and 200 mg/kg NAC were administered once daily for 4 consecutive days. Malondialdehyde (MDA, superoxide dismutase (SOD, catalase (CAT and inflammation and congestion scores in lung tissues were evaluated. Results: In MTX group MDA were significantly higher, CAT and SOD were significantly lower than in sham, EPO and NAC groups (p0.005. In group MTX both scores were significantly higher than in sham (p<0.005. The congestion score of group MTX was significantly higher than those of group EPO and NAC (p<0.005. Conclusion: EPO and NAC have significant preventive effects on MTX-induced lung injury in rats. Decreased antioxidant capacity and increased MDA level may cause the oxidative damage in MTX group. Also, higher antioxidant capacity and lower MDA level may be a response to oxidative stress in EPO and NAC groups.

General anesthetics inhibit erythropoietin induction under hypoxic conditions in the mouse brain.

Directory of Open Access Journals (Sweden)

Tomoharu Tanaka

Full Text Available Erythropoietin (EPO, originally identified as a hematopoietic growth factor produced in the kidney and fetal liver, is also endogenously expressed in the central nervous system (CNS. EPO in the CNS, mainly produced in astrocytes, is induced under hypoxic conditions in a hypoxia-inducible factor (HIF-dependent manner and plays a dominant role in neuroprotection and neurogenesis. We investigated the effect of general anesthetics on EPO expression in the mouse brain and primary cultured astrocytes.BALB/c mice were exposed to 10% oxygen with isoflurane at various concentrations (0.10-1.0%. Expression of EPO mRNA in the brain was studied, and the effects of sevoflurane, halothane, nitrous oxide, pentobarbital, ketamine, and propofol were investigated. In addition, expression of HIF-2α protein was studied by immunoblotting. Hypoxia-induced EPO mRNA expression in the brain was significantly suppressed by isoflurane in a concentration-dependent manner. A similar effect was confirmed for all other general anesthetics. Hypoxia-inducible expression of HIF-2α protein was also significantly suppressed with isoflurane. In the experiments using primary cultured astrocytes, isoflurane, pentobarbital, and ketamine suppressed hypoxia-inducible expression of HIF-2α protein and EPO mRNA.Taken together, our results indicate that general anesthetics suppress activation of HIF-2 and inhibit hypoxia-induced EPO upregulation in the mouse brain through a direct effect on astrocytes.

Epothilone B induces extrinsic pathway of apoptosis in human SKOV-3 ovarian cancer cells.

Science.gov (United States)

Rogalska, Aneta; Gajek, Arkadiusz; Marczak, Agnieszka

2014-06-01

The molecular mechanisms underlying epothilone B (EpoB) induced apoptosis were investigated in SKOV-3 human ovarian cancer cells. The aim of this research was to compare EpoB's, which belongs to the new class of anticancer drugs, with paclitaxel's (PTX) ability to induce apoptosis. The mode of cell death was assessed colorimetrically, fluorimetrically and by immunoblot analyses through measuring DNA fragmentation, the level of intracellular calcium, the level of cytochrome c, TRAIL, the cleavage of poly(ADP-ribose) polymerase (PARP) and the activation of caspase-9, -8 and -3. EpoB leads to an increase of the cytosolic level of cytochrome c after 4 h of cell treatment. After 24 and 48 h of cell treatment the level of intracellular calcium also increased by about 21% and 24% respectively. Moreover, EpoB, similarly to PTX, promoted the expression of TRAIL in lymphocytes, although high TRAIL expression on tumor cells was detected only after adding EpoB to SKOV-3 cells. EpoB mediates caspases-8 and -3 activation, which is independent of the reduction in the amount of caspase-9. Epitope-specific monoclonal and polyclonal antibodies revealed characteristic apoptotic changes that included cleavage of the 116 kDa PARP polypeptide to 25 kDa fragments. The results of our study show that EpoB induces mainly the extrinsic pathway. Copyright © 2014 Elsevier Ltd. All rights reserved.

Opportunities and Resources for Scientist Participation in Education and Public Outreach

Science.gov (United States)

Buxner, Sanlyn; CoBabe-Ammann, E.; Shipp, S.; Hsu, B.

2012-10-01

Active engagement of scientists in Education and Public Outreach (E/PO) activities results in benefits for both the audience and scientists. Most scientists are trained in research but have little formal training in education. The Planetary Science Education and Public Outreach (E/PO) Forum helps the Science Mission Directorate support scientists currently involved in E/PO and to help scientists who are interested in becoming involved in E/PO efforts find ways to do so through a variety of avenues. We will present current and future opportunities and resources for scientists to become engaged in education and public outreach. These include upcoming NASA SMD E/PO funding opportunities, professional development resources for writing NASA SMD E/PO proposals (webinars and other online tools), toolkits for scientists interested in best practices in E/PO (online guides for K-12 education and public outreach), EarthSpace (a community web space where instructors can find and share about teaching space and earth sciences in the undergraduate classroom, including class materials news and funding opportunities, and the latest education research), thematic resources for teaching about the solar system (archived resources from Year of the Solar System), and an online database of scientists interested in connecting with education programs. Learn more about the Forum and find resources at http://smdepo.org/.

Regular endurance training reduces the exercise induced HIF-1alpha and HIF-2alpha mRNA expression in human skeletal muscle in normoxic conditions

DEFF Research Database (Denmark)

Lundby, Carsten; Gassmann, Max; Pilegaard, Henriette

2005-01-01

and 2 (HIFs) are clearly related heterodimeric transcription factors that consist of an oxygen-depended alpha-subunit and a constitutive beta-subunit. With hypoxic exposure, HIF-1alpha and HIF-2alpha protein are stabilized. Upon heterodimerization, HIFs induce the transcription of a variety of genes......Regular exercise induces a variety of adaptive responses that enhance the oxidative and metabolic capacity of human skeletal muscle. Although the physiological adjustments of regular exercise have been known for decades, the underlying mechanisms are still unclear. The hypoxia inducible factors 1...... including erythropoietin (EPO), transferrin and its receptor, as well as vascular endothelial growth factor (VEGF) and its receptor. Considering that several of these genes are also induced with exercise, we tested the hypothesis that the mRNA level of HIF-1alpha and HIF-2alpha subunits increases...

Determining level of endogenous serum erythropoietin for differential diagnosis of polycythemia vera and symptomatic polycythemia

Directory of Open Access Journals (Sweden)

Kostyukevych O.M.

2013-06-01

Full Text Available The article deals with determining possibility of the assessment of the level of endogenous serum erythropoietin (EPO for differential diagnosis of polycythemia vera (PV and secondary erythrocytosis (SE. The determination of subnormal level of this cytokine for the diagnosis of PV has been detected. The relation between the level of endogenous erythropoietin and iron metabolism also has been analyzed. The study involved 88 patients with PV and 119 patients with SE. Statistically significant decrease in EPO concentration level has been detected in PV patients. The mean EPO level was equal to 6.38 ± 0.84 mIU/mL and 17.98 ±2.48 mIU/mL in PV and SE patients respectively. In control group of individuals EPO concentration was equal to 9,81 ±0,58 mIU/mL, the significant difference was found between all studied groups (р<0.01. According to our data, EPO was increased in 28 SE patients (23.53%, it was not observed in control group and in group of PV patients (φ*emp = 4.355, р<0.01. The decrease of EPO level in PV patients has been detected more often than in SE patients (84.09% versus 11.76% , φ*emp = 5.218, р<0.01, it has not been observed in control group. Only 14 (15.91% PV patients had normal EPO level, in contrast 77 (64.71% SE patients demonstrated normal EPO level (φ*emp = 4.578, р<0.01. The average level of ferritin was equal to 57.41 ± 9.74 ng/mL in PV patients and 199.77 ± 14.32 ng/mL in SE patients (р<0.01. Significantly more patients with PV demonstrated decrease of ferritin level (31.81% versus 7.56%, φ*emp = 4.438, р<0.01. Patients with SE more often had raised level of EPO than PV patients (15.12% versus 4.54%, φ*emp = 2.453, р<0.01. The sensitivity of test with detecting of the reduced level of EPO for the diagnosis of PV was 84.1%, specificity - 87.4%, positive predictive value - 83.1%, negative predictive value - 88.1%. Normal range of EPO significantly (rs = 0,5494 correlated with decreased levels of serum ferritin in

Radiolabelled GLP-1 receptor antagonist binds to GLP-1 receptor-expressing human tissues

Energy Technology Data Exchange (ETDEWEB)

Waser, Beatrice; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, PO Box 62, Berne (Switzerland)

2014-06-15

Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. For the somatostatin receptor targeting of tumours, however, it was recently reported that antagonist tracers were superior to agonist tracers. The present study therefore evaluated various forms of the {sup 125}iodinated-Bolton-Hunter (BH)-exendin(9-39) antagonist tracer for the in vitro visualization of GLP-1 receptor-expressing tissues in rats and humans and compared it with the agonist tracer {sup 125}I-GLP-1(7-36)amide. Receptor autoradiography studies with {sup 125}I-GLP-1(7-36)amide agonist or {sup 125}I-BH-exendin(9-39) antagonist radioligands were performed in human and rat tissues. The antagonist {sup 125}I-BH-exendin(9-39) labelled at lysine 19 identifies all human and rat GLP-1 target tissues and GLP-1 receptor-expressing tumours. Binding is of high affinity and is comparable in all tested tissues in its binding properties with the agonist tracer {sup 125}I-GLP-1(7-36)amide. For comparison, {sup 125}I-BH-exendin(9-39) with the BH labelled at lysine 4 did identify the GLP-1 receptor in rat tissues but not in human tissues. The GLP-1 receptor antagonist exendin(9-39) labelled with {sup 125}I-BH at lysine 19 is an excellent GLP-1 radioligand that identifies human and rat GLP-1 receptors in normal and tumoural tissues. It may therefore be the molecular basis to develop suitable GLP-1 receptor antagonist radioligands for in vivo imaging of GLP-1 receptor-expressing tissues in patients. (orig.)

Dark Sky Education | CTIO

Science.gov (United States)

Calendar Activities NOAO-S EPO Programs CADIAS Astro Chile Hugo E. Schwarz Telescope Dark Sky Education ‹› You are here CTIO Home » Outreach » NOAO-S EPO Programs » Dark Sky Education Dark Sky Education Dark Sky Education (in progress) Is an EPO Program. It runs Globe at Night, an annual program to

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...

Repeated blockade of mineralocorticoid receptors, but not of glucocorticoid receptors impairs food rewarded spatial learning

NARCIS (Netherlands)

Douma, B. R.; Korte, S. M.; Buwalda, B.; La Fleur, S. E.; Bohus, B.; Luiten, P. G.

1998-01-01

Corticosteroids from the adrenal cortex influence a variety of behaviours including cognition, learning and memory. These hormones act via two intracellular receptors, the mineralo-corticoid receptor (MR) and the glucocorticoid receptor (GR). These two receptor types display a high concentration and

Repeated blockade of mineralocorticoid receptors, but not of glucocorticoid receptors impairs food rewarded spatial learning

NARCIS (Netherlands)

Douma, BRK; Korte, SM; Buwalda, B; la Fleur, SE; Bohus, B; Luiten, PGM

Corticosteroids from the adrenal cortex influence a variety of behaviours including cognition, learning and memory. These hormones act via two intracellular receptors, the mineralo-corticoid receptor (MR) and the glucocorticoid receptor (GR). These two receptor types display a high concentration and

Use of UV-vis-NIR spectroscopy to monitor label-free interaction between molecular recognition elements and erythropoietin on a gold-coated polycarbonate platform.

Science.gov (United States)

Citartan, Marimuthu; Gopinath, Subash C B; Tominaga, Junji; Chen, Yeng; Tang, Thean-Hock

2014-08-01

Label-free-based detection is pivotal for real-time monitoring of biomolecular interactions and to eliminate the need for labeling with tags that can occupy important binding sites of biomolecules. One simplest form of label-free-based detection is ultraviolet-visible-near-infrared (UV-vis-NIR) spectroscopy, which measure changes in reflectivity as a means to monitor immobilization and interaction of biomolecules with their corresponding partners. In biosensor development, the platform used for the biomolecular interaction should be suitable for different molecular recognition elements. In this study, gold (Au)-coated polycarbonate was used as a platform and as a proof-of-concept, erythropoietin (EPO), a doping substance widely abused by the athletes was used as the target. The interaction of EPO with its corresponding molecular recognition elements (anti-EPO monoclonal antibody and anti-EPO DNA aptamer) is monitored by UV-vis-NIR spectroscopy. Prior to this, to show that UV-vis-NIR spectroscopy is a suitable method for measuring biomolecular interaction, the interaction between biotin and streptavidin was demonstrated via this strategy and reflectivity of this interaction decreased by 25%. Subsequent to this, interaction of the EPO with anti-EPO monoclonal antibody and anti-EPO DNA aptamer resulted in the decrease of reflectivity by 5% and 10%, respectively. The results indicated that Au-coated polycarbonate could be an ideal biosensor platform for monitoring biomolecular interactions using UV-vis-NIR spectroscopy. A smaller version of the Au-coated polycarbonate substrates can be derived from the recent set-up, to be applied towards detecting EPO abuse among atheletes. Copyright © 2014 Elsevier B.V. All rights reserved.

Neuroprotective effect of erythropoietin against pressure ulcer in a mouse model of small fiber neuropathy.