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Sample records for combined granulocyte-colony stimulating

  1. Combination of granulocyte colony-stimulating factor and erythropoietin improves outcomes of patients with decompensated cirrhosis.

    PubMed

    Kedarisetty, Chandan Kumar; Anand, Lovkesh; Bhardwaj, Ankit; Bhadoria, Ajeet Singh; Kumar, Guresh; Vyas, Ashish Kumar; David, Paul; Trehanpati, Nirupama; Rastogi, Archana; Bihari, Chhagan; Maiwall, Rakhi; Garg, Hitendra Kumar; Vashishtha, Chitranshu; Kumar, Manoj; Bhatia, Vikram; Sarin, Shiv Kumar

    2015-06-01

    Patients with decompensated cirrhosis have significantly reduced survival without liver transplantation. Granulocyte colony-stimulating factor (G-CSF) has been shown to increase survival in patients with acute-on-chronic liver failure, and erythropoietin promoted hepatic regeneration in animal studies. We performed a double-blind, randomized, placebo-controlled trial to determine whether co-administration of these growth factors improved outcomes for patients with advanced cirrhosis. In a prospective study, consecutive patients with decompensated cirrhosis seen at the Institute of Liver and Biliary Sciences, New Delhi (from May 2011 through June 2012) were randomly assigned to groups given subcutaneous G-CSF (5 μg/kg/d) for 5 days and then every third day (12 total doses), along with subcutaneous darbopoietin α(40 mcg/wk) for 4 weeks (GDP group, n = 29), or only placebos (control group, n = 26). All patients also received standard medical therapy and were followed for 12 months. Histology was performed on liver biopsies. The primary end point was survival at 12 months. Baseline characteristics of patients were comparable; alcohol intake was the most common etiology of cirrhosis. A higher proportion of patients in the GDP group than controls survived until 12 months (68.6% vs 26.9%; P = .003). At 12 months, Child-Turcotte Pugh scores were reduced by 48.6% in the GDP group and 39.1% in the control group, from baseline (P = .001); Model for End Stage Liver Disease scores were reduced by 40.4% and 33%, respectively (P = .03). The need for large-volume paracentesis was significantly reduced in GDP group, compared with controls (P < .05). A lower proportion of patients in the GDP group developed septic shock (6.9%) during follow-up compared with controls (38.5%; P = .005). No major adverse events were observed in either group. In a single-center randomized trial, a significantly larger proportion of patients with decompensated cirrhosis given a combination of G-CSF and

  2. The combination of stem cell factor and granulocyte-colony stimulating factor for chronic stroke treatment in aged animals

    PubMed Central

    2012-01-01

    Background Stroke occurs more frequently in the elderly population and presents the number one leading cause of persistent disability worldwide. Lack of effective treatment to enhance brain repair and improve functional restoration in chronic stroke, the recovery phase of stroke, is a challenging medical problem to be solved in stroke research. Our early study has revealed the therapeutic effects of stem cell factor (SCF) in combination with granulocyte-colony stimulating factor (G-CSF) (SCF+G-CSF) on chronic stroke in young animals. However, whether this treatment is effective and safe to the aged population remains to be determined. Methods Cortical brain ischemia was produced in aged C57BL mice or aged spontaneously hypertensive rats. SCF+G-CSF or equal volume of vehicle solution was subcutaneously injected for 7 days beginning at 3–4 months after induction of cortical brain ischemia. Using the approaches of biochemistry assays, flow cytometry, pathology, and evaluation of functional outcome, several doses of SCF+G-CSF have been examined for their safety and efficiency on chronic stroke in aged animals. Results All tested doses did not show acute or chronic toxicity in the aged animals. Additionally, SCF+G-CSF treatment in chronic stroke of aged animals mobilized bone marrow stem cells and improved functional outcome in a dose-dependent manner. Conclusions SCF+G-CSF treatment is a safe and effective approach to chronic stroke in the aged condition. This study provides important information needed for developing a new therapeutic strategy to improve the health of older adults with chronic stroke. PMID:23254113

  3. Effect of combination therapy with recombinant human granulocyte colony-stimulating factor (rG-CSF) and antibiotics in neutropenic mice unresponsive to antibiotics alone.

    PubMed

    Matsumoto, M; Matsubara, S; Yokota, T

    1991-09-01

    The effect of recombinant human granulocyte colony-stimulating factor (rG-CSF) in enhancing antimicrobial chemotherapy was investigated. Combined treatments of rG-CSF with cefotaxime, cefazolin, fosfomycin, gentamicin or amphotericin B were evaluated in systemic infections with Pseudomonas aeruginosa, Escherichia coli, Serratia marcescens, Staphylococcus aureus and Candida albicans in leucopenic mice induced by pretreatment with cyclophosphamide. Administration of appropriate antibiotics afforded a dose-related inhibition of death from infection in normal mice and mice treated with rG-CSF after cyclophosphamide injection. In cyclophosphamide-treated mice, even larger doses of the antibiotics failed to provide protection against infection with the same inoculum size. These results suggest the possibility that rG-CSF could be of help in treatments with antimicrobial agents against infections in leucopenic patients.

  4. Just-in-time rescue plerixafor in combination with chemotherapy and granulocyte-colony stimulating factor for peripheral blood progenitor cell mobilization

    PubMed Central

    Smith, Veronica R.; Popat, Uday; Ciurea, Stefan; Nieto, Yago; Anderlini, Paolo; Rondon, Gabriela; Alousi, Amin; Qazilbash, Muzaffar; Kebriaei, Partow; Khouri, Issa; de Lima, Marcos; Champlin, Richard; Hosing, Chitra

    2014-01-01

    Plerixafor, a recently approved peripheral blood progenitor cell mobilizing agent, is often added to granulocyte-colony stimulating factor (G-CSF) to mobilize peripheral blood progenitor cells in patients with lymphoma or myeloma who cannot mobilize enough CD34+ cells with G-CSF alone to undergo autologous stem cell transplantation. However, data are lacking regarding the feasibility and efficacy of just-in-time plerixafor in combination with chemotherapy and G-CSF. We reviewed the peripheral blood stem cell collection data of 38 consecutive patients with lymphoma (Hodgkin’s and non-Hodgkin’s) and multiple myeloma who underwent chemomobilization and high-dose G-CSF and just-in-time plerixafor to evaluate the efficacy of this treatment combination. All patients with multiple myeloma and all but 1 patient with lymphoma collected the minimum required number of CD34+ cells to proceed with autologous stem cell transplantation (>2 × 106/kilogram of body weight). The median CD34+ cell dose collected in patients with non-Hodgkin lymphoma was 4.93 × 106/kilogram of body weight. The median CD34+ cell dose collected for patients with multiple myeloma was 8.81 × 106/kilogram of body weight. Plerixafor was well tolerated; no grade 2 or higher non- hematologic toxic effects were observed. PMID:23749720

  5. Just-in-time rescue plerixafor in combination with chemotherapy and granulocyte-colony stimulating factor for peripheral blood progenitor cell mobilization.

    PubMed

    Smith, Veronica R; Popat, Uday; Ciurea, Stefan; Nieto, Yago; Anderlini, Paolo; Rondon, Gabriela; Alousi, Amin; Qazilbash, Muzaffar; Kebriaei, Partow; Khouri, Issa; de Lima, Marcos; Champlin, Richard; Hosing, Chitra

    2013-09-01

    Plerixafor, a recently approved peripheral blood progenitor cell mobilizing agent, is often added to granulocyte-colony stimulating factor (G-CSF) to mobilize peripheral blood progenitor cells in patients with lymphoma or myeloma who cannot mobilize enough CD34+ cells with G-CSF alone to undergo autologous stem cell transplantation. However, data are lacking regarding the feasibility and efficacy of just-in-time plerixafor in combination with chemotherapy and G-CSF. We reviewed the peripheral blood stem cell collection data of 38 consecutive patients with lymphoma (Hodgkin's and non-Hodgkin's) and multiple myeloma who underwent chemomobilization and high-dose G-CSF and just-in-time plerixafor to evaluate the efficacy of this treatment combination. All patients with multiple myeloma and all but one patient with lymphoma collected the minimum required number of CD34+ cells to proceed with autologous stem cell transplantation (>2 × 10(6) /kg of body weight). The median CD34+ cell dose collected in patients with non-Hodgkin lymphoma was 4.93 × 10(6) /kg of body weight. The median CD34+ cell dose collected for patients with multiple myeloma was 8.81 × 10(6) /kg of body weight. Plerixafor was well tolerated; no grade 2 or higher non-hematologic toxic effects were observed.

  6. Evaluating the effects of buffer conditions and extremolytes on thermostability of granulocyte colony-stimulating factor using high-throughput screening combined with design of experiments.

    PubMed

    Ablinger, Elisabeth; Hellweger, Monika; Leitgeb, Stefan; Zimmer, Andreas

    2012-10-15

    In this study, we combined a high-throughput screening method, differential scanning fluorimetry (DSF), with design of experiments (DoE) methodology to evaluate the effects of several formulation components on the thermostability of granulocyte colony stimulating factor (G-CSF). First we performed a primary buffer screening where we tested thermal stability of G-CSF in different buffers, pH values and buffer concentrations. The significance of each factor and the two-way interactions between them were studied by multivariable regression analysis. pH was identified as most critical factor regarding thermal stability. The most stabilizing buffer, sodium glutamate, and sodium acetate were determined for further investigations. Second we tested the effect of 6 naturally occurring extremolytes (trehalose, sucrose, ectoine, hydroxyectoine, sorbitol, mannitol) on the thermal stability of G-CSF, using a central composite circumscribed design. At low pH (3.8) and low buffer concentration (5 mM) all extremolytes led to a significant increase in thermal stability except the addition of ectoine which resulted in a strong destabilization of G-CSF. Increasing pH and buffer concentration led to an increase in thermal stability with all investigated extremolytes. The described systematic approach allowed to create a ranking of stabilizing extremolytes at different buffer conditions. Copyright © 2012. Published by Elsevier B.V.

  7. Case Report: Combination Therapy with Mesenchymal Stem Cells and Granulocyte-Colony Stimulating Factor in a Case of Spinal Cord Injury

    PubMed Central

    Derakhshanrad, Nazi; Saberi, Hooshang; Tayebi Meybodi, Keyvan; Taghvaei, Mohammad; Arjmand, Babak; Aghayan, Hamid Reza; Kohan, Amir Hassan; Haghpanahi, Mohammad; Rahmani, Shahrokh

    2015-01-01

    Introduction: Various neuroregenerative procedures have been recently employed along with neurorehabilitation programs to promote neurological function after Spinal Cord Injury (SCI), and recently most of them have focused on the acute stage of spinal cord injury. In this report, we present a case of acute SCI treated with neuroprotective treatments in conjunction with conventional rehabilitation program. Methods: A case of acute penetrative SCI (gunshot wound), 40 years old, was treated with intrathecal bone marrow derived stem cells and parenteral Granulocyte-Colony Stimulating Factor (G-CSF) along with rehabilitation program. The neurological outcomes as well as safety issues have been reported. Results: Assessment with American Spinal Injury Association (ASIA), showed neurological improvement, meanwhile he reported neuropathic pain, which was amenable to oral medication. Discussion: In the acute setting, combination therapy of G-CSF and intrathecal Mesenchymal Stem Cells (MSCs) was safe in our case as an adjunct to conventional rehabilitation programs. Further controlled studies are needed to find possible side effects, and establish net efficacy. PMID:26649168

  8. Neuroprotective and Angiogenic Effects of Bone Marrow Transplantation Combined With Granulocyte Colony-Stimulating Factor in a Mouse Model of Amyotrophic Lateral Sclerosis

    PubMed Central

    Ohta, Yasuyuki; Nagai, Makiko; Miyazaki, Kazunori; Tanaka, Nobuhito; Kawai, Hiromi; Mimoto, Takafumi; Morimoto, Nobutoshi; Kurata, Tomoko; Ikeda, Yoshio; Matsuura, Tohru; Abe, Koji

    2011-01-01

    Bone marrow (BM) cells from amyotrophic lateral sclerosis (ALS) patients show significantly reduced expression of several neurotrophic factors. Monotherapy with either wild-type (WT) BM transplantation (BMT) or granulocyte colony-stimulating factor (GCSF) has only a small clinical therapeutic effect in an ALS mouse model, due to the phenomenon of neuroprotection. In this study, we investigated the clinical benefits of combination therapy using BMT with WT BM cells, plus GCSF after disease onset in ALS mice [transgenic mice expressing human Cu/Zn superoxide dismutase (SOD1) bearing a G93A mutation]. Combined treatment with BMT and GCSF delayed disease progression and prolonged the survival of G93A mice, whereas BMT or GCSF treatment alone did not. Histological study of the ventral horns of lumbar cords from G93A mice treated with BMT and GCSF showed a reduction in motor neuron loss coupled with induced neuronal precursor cell proliferation, increased expression of neurotrophic factors (glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, vascular endothelial growth factor and angiogenin), and neovascularization compared with controls (vehicle only). Compared with G93A microglial cells, most BM-derived WT cells differentiated into microglial cells and strongly expressed neurotrophic factors, combined BMT and GCSF treatment led to the replacement of G93A microglial cells with BM-derived WT cells. These results indicate combined treatment with BMT and GCSF has potential neuroprotective and angiogenic effects in ALS mice, induced by the replacement of G93A microglial cells with BM-derived WT cells. Furthermore, this is the first report showing the effects of combined BMT and GCSF treatment on blood vessels in ALS. PMID:26998403

  9. Plerixafor on-demand combined with chemotherapy and granulocyte colony-stimulating factor: significant improvement in peripheral blood stem cells mobilization and harvest with no increase in costs.

    PubMed

    Milone, Giuseppe; Martino, Massimo; Spadaro, Andrea; Leotta, Salvatore; Di Marco, Annalia; Scalzulli, Potito; Cupri, Alessandra; Di Martina, Valentina; Schinocca, Elena; Spina, Eleonora; Tripepi, Giovanni

    2014-01-01

    To date, no prospective study on Plerixafor 'on-demand' in combination with chemotherapy and granulocyte colony-stimulating factor (G-CSF) has been reported. We present an interim analysis of the first prospective study in which Plerixafor was administered on-demand in patients affected by multiple myeloma and lymphoma who received high dose cyclophosphamide or DHAP (dexamethasone, cytarabine, cisplatin) plus G-CSF to mobilize peripheral blood stem cells (PBSC). One hundred and two patients were evaluable for response. A cohort of 240 patients receiving the same mobilizing chemotherapy was retrospectively studied. Failure to mobilize CD34(+) cells in peripheral blood was reduced by 'on-demand' strategy compared to conventional mobilization; from 13·0 to 3·0% (P = 0·004). Failure to harvest CD34(+) cells 2 × 10(6) /kg decreased from 20·9 to 4·0% (P = 0·0001). The on-demand Plerixafor strategy also resulted in a lower rate of mobilization failure (P = 0·03) and harvest failure (P = 0·0008) when compared to a 'bias-adjusted set of controls'. Evaluation of economic costs of the two strategies showed that the overall cost of the two treatments were comparable when salvage mobilizations were taken into account. When in combination with cyclophosphamide or DHAP plus G-CSF, the 'on-demand' use of Plerixafor showed, in comparison to conventionally treated patients, a significant improvement in mobilization of PBSC with no increase in overall cost.

  10. Combined therapy with sitagliptin plus granulocyte-colony stimulating factor in patients with acute myocardial infarction - Long-term results of the SITAGRAMI trial.

    PubMed

    Gross, Lisa; Theiss, Hans Diogenes; Grabmaier, Ulrich; Adrion, Christine; Mansmann, Ulrich; Sohn, Hae-Young; Hoffmann, Ellen; Steinbeck, Gerhard; Franz, Wolfgang-Michael; Brenner, Christoph

    2016-07-15

    Autologous progenitor cell therapy comprising granulocyte-colony stimulating factor (G-CSF) for mobilization of bone-marrow derived progenitor cells (BMPCs) into peripheral blood and inhibition of dipeptidylpeptidase-IV by sitagliptin for enhanced myocardial recruitment of circulating BMPCs has been shown to improve survival after acute myocardial infarction (MI) in preclinical studies. In the SITAGRAMI trial we found that during short-term follow-up G-CSF plus sitagliptin (GS) failed to show a beneficial effect on cardiac function and clinical events in patients with acute MI that underwent successful PCI. The objective of the present analysis was to assess the impact of GS versus placebo treatment on long-term clinical outcomes of the SITAGRAMI trial patient population. In the randomized, prospective, double-blind, placebo-controlled SITAGRAMI trial, 174 patients with acute MI were assigned to GS or placebo in a 1:1 ratio. The primary outcome for the present long-term analysis was the composite of death, MI or stroke on long-term follow-up. The median [IQR] follow-up duration was 4.50 [3.56-5.95] years. The primary outcome occurred in 12.8% of patients assigned to placebo and 9.2% assigned to GS (HR 0.69, 95% CI 0.28-1.69; p=0.42). The incidence of the combined cardiovascular outcome was 47.7% in the placebo- and 41.4% in the GS-group (HR 0.75, 95% CI 0.48-1.18; p=0.21). Overall, there was no significant difference in MACCE rates between both treatment groups (p=0.41). These long-term follow-up data indicate that GS therapy does not improve clinical outcomes of patients with acute MI. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Combination Therapy of Human Umbilical Cord Blood Cells and Granulocyte Colony Stimulating Factor Reduces Histopathological and Motor Impairments in an Experimental Model of Chronic Traumatic Brain Injury

    PubMed Central

    Acosta, Sandra A.; Tajiri, Naoki; Shinozuka, Kazutaka; Ishikawa, Hiroto; Sanberg, Paul R.; Sanchez-Ramos, Juan; Song, Shijie; Kaneko, Yuji; Borlongan, Cesar V.

    2014-01-01

    Traumatic brain injury (TBI) is associated with neuro-inflammation, debilitating sensory-motor deficits, and learning and memory impairments. Cell-based therapies are currently being investigated in treating neurotrauma due to their ability to secrete neurotrophic factors and anti-inflammatory cytokines that can regulate the hostile milieu associated with chronic neuroinflammation found in TBI. In tandem, the stimulation and mobilization of endogenous stem/progenitor cells from the bone marrow through granulocyte colony stimulating factor (G-CSF) poses as an attractive therapeutic intervention for chronic TBI. Here, we tested the potential of a combined therapy of human umbilical cord blood cells (hUCB) and G-CSF at the acute stage of TBI to counteract the progressive secondary effects of chronic TBI using the controlled cortical impact model. Four different groups of adult Sprague Dawley rats were treated with saline alone, G-CSF+saline, hUCB+saline or hUCB+G-CSF, 7-days post CCI moderate TBI. Eight weeks after TBI, brains were harvested to analyze hippocampal cell loss, neuroinflammatory response, and neurogenesis by using immunohistochemical techniques. Results revealed that the rats exposed to TBI treated with saline exhibited widespread neuroinflammation, impaired endogenous neurogenesis in DG and SVZ, and severe hippocampal cell loss. hUCB monotherapy suppressed neuroinflammation, nearly normalized the neurogenesis, and reduced hippocampal cell loss compared to saline alone. G-CSF monotherapy produced partial and short-lived benefits characterized by low levels of neuroinflammation in striatum, DG, SVZ, and corpus callosum and fornix, a modest neurogenesis, and a moderate reduction of hippocampal cells loss. On the other hand, combined therapy of hUCB+G-CSF displayed synergistic effects that robustly dampened neuroinflammation, while enhancing endogenous neurogenesis and reducing hippocampal cell loss. Vigorous and long-lasting recovery of motor function

  12. Multimodal Approaches for Regenerative Stroke Therapies: Combination of Granulocyte Colony-Stimulating Factor with Bone Marrow Mesenchymal Stem Cells is Not Superior to G-CSF Alone

    PubMed Central

    Balseanu, Adrian Tudor; Buga, Ana-Maria; Catalin, Bogdan; Wagner, Daniel-Christoph; Boltze, Johannes; Zagrean, Ana-Maria; Reymann, Klaus; Schaebitz, Wolf; Popa-Wagner, Aurel

    2014-01-01

    Attractive therapeutic strategies to enhance post-stroke recovery of aged brains include methods of cellular therapy that can enhance the endogenous restorative mechanisms of the injured brain. Since stroke afflicts mostly the elderly, it is highly desirable to test the efficacy of cell therapy in the microenvironment of aged brains that is generally refractory to regeneration. In particular, stem cells from the bone marrow allow an autologous transplantation approach that can be translated in the near future to the clinical practice. Such a bone marrow-derived therapy includes the grafting of stem cells as well as the delayed induction of endogenous stem cell mobilization and homing by the stem cell mobilizer granulocyte colony-stimulating factor (G-CSF). We tested the hypothesis that grafting of bone marrow-derived pre-differentiated mesenchymal cells (BM-MSCs) in G-CSF-treated animals improves the long-term functional outcome in aged rodents. To this end, G-CSF alone (50 μg/kg) or in combination with a single dose (106 cells) of rat BM MSCs was administered intravenously to Sprague-Dawley rats at 6 h after transient occlusion (90 min) of the middle cerebral artery. Infarct volume was measured by magnetic resonance imaging at 3 and 48 days post-stroke and additionally by immunhistochemistry at day 56. Functional recovery was tested during the entire post-stroke survival period of 56 days. Daily treatment for post-stroke aged rats with G-CSF led to a robust and consistent improvement of neurological function after 28 days. The combination therapy also led to robust angiogenesis in the formerly infarct core and beyond in the “islet of regeneration.” However, G-CSF + BM MSCs may not impact at all on the spatial reference-memory task or infarct volume and therefore did not further improve the post-stroke recovery. We suggest that in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be

  13. Multimodal Approaches for Regenerative Stroke Therapies: Combination of Granulocyte Colony-Stimulating Factor with Bone Marrow Mesenchymal Stem Cells is Not Superior to G-CSF Alone.

    PubMed

    Balseanu, Adrian Tudor; Buga, Ana-Maria; Catalin, Bogdan; Wagner, Daniel-Christoph; Boltze, Johannes; Zagrean, Ana-Maria; Reymann, Klaus; Schaebitz, Wolf; Popa-Wagner, Aurel

    2014-01-01

    Attractive therapeutic strategies to enhance post-stroke recovery of aged brains include methods of cellular therapy that can enhance the endogenous restorative mechanisms of the injured brain. Since stroke afflicts mostly the elderly, it is highly desirable to test the efficacy of cell therapy in the microenvironment of aged brains that is generally refractory to regeneration. In particular, stem cells from the bone marrow allow an autologous transplantation approach that can be translated in the near future to the clinical practice. Such a bone marrow-derived therapy includes the grafting of stem cells as well as the delayed induction of endogenous stem cell mobilization and homing by the stem cell mobilizer granulocyte colony-stimulating factor (G-CSF). We tested the hypothesis that grafting of bone marrow-derived pre-differentiated mesenchymal cells (BM-MSCs) in G-CSF-treated animals improves the long-term functional outcome in aged rodents. To this end, G-CSF alone (50 μg/kg) or in combination with a single dose (10(6) cells) of rat BM MSCs was administered intravenously to Sprague-Dawley rats at 6 h after transient occlusion (90 min) of the middle cerebral artery. Infarct volume was measured by magnetic resonance imaging at 3 and 48 days post-stroke and additionally by immunhistochemistry at day 56. Functional recovery was tested during the entire post-stroke survival period of 56 days. Daily treatment for post-stroke aged rats with G-CSF led to a robust and consistent improvement of neurological function after 28 days. The combination therapy also led to robust angiogenesis in the formerly infarct core and beyond in the "islet of regeneration." However, G-CSF + BM MSCs may not impact at all on the spatial reference-memory task or infarct volume and therefore did not further improve the post-stroke recovery. We suggest that in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be

  14. FDA review summary: Mozobil in combination with granulocyte colony-stimulating factor to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation.

    PubMed

    Brave, Michael; Farrell, Ann; Ching Lin, Sue; Ocheltree, Terrance; Pope Miksinski, Sarah; Lee, Shwu-Luan; Saber, Haleh; Fourie, Jeanne; Tornoe, Christoffer; Booth, Brian; Yuan, Weishi; He, Kun; Justice, Robert; Pazdur, Richard

    2010-01-01

    On December 15, 2008, the US Food and Drug Administration approved plerixafor (Mozobil; Genzyme Corp.), a new small-molecule inhibitor of the CXCR4 chemokine receptor, for use in combination with granulocyte colony-stimulating factor (G-CSF) to mobilize hematopoietic stem cells (HSC) to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). This summary reviews the database supporting this approval. The safety and efficacy of plerixafor were demonstrated by 2 multicenter, randomized, placebo-controlled studies in patients with NHL and MM who were eligible for autologous HSC transplantation. The primary efficacy end points were the collection of > or = 5 x 10(6) CD34+ cells/kg from the peripheral blood in 4 or fewer apheresis sessions in patients with NHL or > or = 6 x 10(6) CD34+ cells/kg from the peripheral blood in 2 or fewer apheresis sessions in patients with MM. The 2 randomized studies combined enrolled 600 patients (298 with NHL and 302 with MM). Fifty-nine percent of patients with NHL who were mobilized with G-CSF and plerixafor had peripheral blood HSC collections of > or = 5 x 10(6) CD34+ cells/kg in 4 or fewer apheresis sessions, compared with 20% of patients with NHL who were mobilized with G-CSF and placebo (p < 0.001). Seventy-two percent of patients with MM who were mobilized with Mozobil and G-CSF had peripheral blood HSC collections of > or = 6 x 10(6) CD34+ cells/kg in 2 or fewer apheresis sessions, compared with 34% of patients with MM who were mobilized with placebo and G-CSF (p < 0.001). Common adverse reactions included diarrhea, nausea, vomiting, flatulence, injection site reactions, fatigue, arthralgia, headache, dizziness, and insomnia. This report describes the Food and Drug Administration review supporting the approval of plerixafor. Copyright 2010 S. Karger AG, Basel.

  15. Granulocyte colony-stimulating factor induces in vitro lymphangiogenesis

    SciTech Connect

    Lee, Ae Sin; Kim, Dal; Wagle, Susbin Raj; Lee, Jung Eun; Jung, Yu Jin; Kang, Kyung Pyo; Lee, Sik; Park, Sung Kwang; Kim, Won

    2013-07-12

    Highlights: •G-CSF induces tube formation, migration and proliferation of lymphatic cells. •G-CSF increases phosphorylation of MAPK and Akt in lymphatic endothelial cells. •MAPK and Akt pathways are linked to G-CSF-induced in vitro lymphangiogenesis. •G-CSF increases sprouting of a lymphatic ring. •G-CSF produces peritoneal lymphangiogenesis. -- Abstract: Granulocyte-colony stimulating factor (G-CSF) is reported to induce differentiation in cells of the monocyte lineage and angiogenesis in vascular endothelial cells, but its effects on lymphangiogenesis is uncertain. Here we examined the effects and the mechanisms of G-CSF-induced lymphangiogenesis using human lymphatic endothelial cells (hLECs). Our results showed that G-CSF induced capillary-like tube formation, migration and proliferation of hLECs in a dose- and time-dependent manner and enhanced sprouting of thoracic duct. G-CSF increased phosphorylation of Akt and ERK1/2 in hLECs. Supporting the observations, specific inhibitors of phosphatidylinositol 3′-kinase and MAPK suppressed the G-CSF-induced in vitro lymphangiogenesis and sprouting. Intraperitoneal administration of G-CSF to mice also stimulated peritoneal lymphangiogenesis. These findings suggest that G-CSF is a lymphangiogenic factor.

  16. Does granulocyte colony-stimulating factor ameliorate the proinflammatory response in human meningococcal septic shock?

    PubMed

    Rojahn, Astrid; Brusletto, Berit; Øvstebø, Reidun; Haug, Kari B F; Kierulf, Peter; Brandtzaeg, Petter

    2008-09-01

    To test the hypothesis that granulocyte colony-stimulating factor acts cooperatively with interleukin-10 in down-regulating monocyte function in severe meningococcal septic shock. 1) We quantified the plasma levels of granulocyte colony-stimulating factor, interleukin-10, Neisseria meningitidis lipopolysaccharide and the number of N. meningitidis DNA copies in 28 patients with systemic meningococcal disease. 2) We studied the inhibitory effect of recombinant human granulocyte colony-stimulating factor on normal human monocytes stimulated with purified meningococcal lipopolysaccaride. 3) We monitored the inhibitory effects of endogenously produced granulocyte colony-stimulating factor and interleukin-10 in meningococcal shock plasmas on monocytes. Comparative, experimental study. University Hospital and laboratory. Twenty-eight patients with systemic meningococcal disease, 13 with persistent shock, 7 died, and 15 without shock. The median levels of granulocyte colony-stimulating factor in shock and nonshock patients were 1.7 x 10(6) and 8.1 x 10(2) pg/mL; interleukin-10, 2.1 x 10(4) and 4 x 10(1) pg/mL; number of N. meningitidis DNA copies, 2.9 x 10(7) and <10(3)/mL; and lipopolysaccharide, 105 and <0.04 endotoxin units/mL, respectively. The plasma levels of granulocyte colony-stimulating factor were reduced by 50% within 4 to 6 hrs after initiation of antibiotic treatment. In model experiments with lipopolysaccharide-stimulated human monocytes, recombinant human granulocyte colony-stimulating factor and interleukin-10 reduced the release of tumor necrosis factor-alpha by mean 30% and 92%, respectively. When plasmas from three shock patients were depleted of native granulocyte colony-stimulating factor or interleukin-10 by immunoprecipitation, no increase in tumor necrosis factor-alpha release occurred after removal of granulocyte colony-stimulating factor, whereas removal of interleukin-10 increased the tumor necrosis factor-alpha release eight-fold. Although

  17. Granulocyte colony-stimulating factor in the treatment of acute radiation syndrome: a concise review.

    PubMed

    Hofer, Michal; Pospíšil, Milan; Komůrková, Denisa; Hoferová, Zuzana

    2014-04-16

    This article concisely summarizes data on the action of one of the principal and best known growth factors, the granulocyte colony-stimulating factor (G-CSF), in a mammalian organism exposed to radiation doses inducing acute radiation syndrome. Highlighted are the topics of its real or anticipated use in radiation accident victims, the timing of its administration, the possibilities of combining G-CSF with other drugs, the ability of other agents to stimulate endogenous G-CSF production, as well as of the capability of this growth factor to ameliorate not only the bone marrow radiation syndrome but also the gastrointestinal radiation syndrome. G-CSF is one of the pivotal drugs in the treatment of radiation accident victims and its employment in this indication can be expected to remain or even grow in the future.

  18. Combination of stem cell factor and granulocyte colony-stimulating factor mobilizes the highest number of primitive haemopoietic progenitors as shown by pre-colony-forming unit (pre-CFU) assay.

    PubMed

    Horsfall, M J; Hui, C H; To, L B; Begley, C G; Basser, R L; Simmons, P J

    2000-06-01

    Fifty-two patients with poor prognosis carcinoma of the breast underwent peripheral blood stem cell (PBSC) mobilization using five different regimens. The yields of primitive haemopoietic progenitors were quantified by a recently described pre-colony-forming unit (pre-CFU) assay using limiting dilution analysis (LDA). Results of days 14 and 35 pre-CFU were also correlated with conventional CD34+ cell enumeration, CFU-GM (granulocyte-macrophage) and long-term culture-initiating cell (LTCIC) assays. The yield of pre-CFUs with the combination of granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) was significantly higher than with G-CSF alone, cyclophosphamide (Cyclo) and granulocyte-monocyte colony-stimulating factor (GM-CSF), interleukin (IL)-3 and GM-CSF, or Cyclo alone. No significant correlation between neutrophil engraftment and pre-CFU could be demonstrated. Furthermore, CFU-GM was shown to bear a stronger correlation with pre-CFU and LTCIC than CD34+ cell measurement; thus, CFU-GM remains a useful biological tool for haemopoietic stem cell assay. We conclude that the combination of G-CSF and SCF mobilizes the highest number of pre-CFUs as measured by functional pre-CFU assay, which provides an alternative measurement of primitive haemopoietic progenitors to the LTCIC assay.

  19. Enhancement of tendon-bone osteointegration of anterior cruciate ligament graft using granulocyte colony-stimulating factor.

    PubMed

    Sasaki, Ken; Kuroda, Ryosuke; Ishida, Kazunari; Kubo, Seiji; Matsumoto, Tomoyuki; Mifune, Yutaka; Kinoshita, Keisuke; Tei, Katsumasa; Akisue, Toshihiro; Tabata, Yasuhiko; Kurosaka, Masahiro

    2008-08-01

    Whereas anterior cruciate ligament rupture usually requires reconstruction, the attachment between the tendon and the bone is the weakest region in the early posttransplantation period. In this process, the acquisition of appropriate vascularity is a key for early bone-tendon healing. Granulocyte colony-stimulating factor has an effect on the maturation of bone-tendon integration of anterior cruciate ligament reconstruction. Controlled laboratory study. Twenty-eight healthy adult beagle dogs underwent bilateral anterior cruciate ligament reconstruction using the ipsilateral flexor digitorum superficialis tendon and were divided into 2 groups. A granulocyte colony-stimulating factor-incorporated gelatin surrounded the graft in the granulocyte colony-stimulating factor group, and the same gelatin without granulocyte colony-stimulating factor was used as the control group. Assessment was done at 2 and 4 weeks. Histological analysis at week 2 demonstrated that, in addition to more Sharpey fibers, microvessels were significantly enhanced in the granulocyte colony-stimulating factor group's grafts. Computed tomography at week 4 showed a significantly smaller tibial bone tunnel in the granulocyte colony-stimulating factor group. Real-time polymerase chain reaction revealed significantly elevated messenger ribonucleic acid expression levels of vascular endothelial growth factor and osteocalcin in the tibial bone tunnel and graft compared with controls. Furthermore, biomechanical testing of force during loading to ultimate failure at week 4 demonstrated a significant increase in strength in the granulocyte colony-stimulating factor group. This study demonstrated that a local application of granulocyte colony-stimulating factor-incorporated gelatin significantly accelerates bone-tendon interface strength via enhanced angiogenesis and osteogenesis. Granulocyte colony-stimulating factor has therapeutic potential in promoting an environment conductive to angiogenesis and

  20. Effect of Granulocyte Colony-Stimulating Factor-Combined Conditioning in Cord Blood Transplantation for Myelodysplastic Syndrome and Secondary Acute Myeloid Leukemia: A Retrospective Study in Japan.

    PubMed

    Konuma, Takaaki; Takahashi, Satoshi; Uchida, Naoyuki; Kuwatsuka, Yachiyo; Yamasaki, Satoshi; Aoki, Jun; Onishi, Yasushi; Aotsuka, Nobuyuki; Ohashi, Kazuteru; Mori, Takehiko; Masuko, Masayoshi; Nakamae, Hirohisa; Miyamura, Kouichi; Kato, Koji; Atsuta, Yoshiko; Kato, Seiko; Asano, Shigetaka; Takami, Akiyoshi; Miyazaki, Yasushi

    2015-09-01

    Granulocyte colony-stimulating factor (G-CSF) increases the susceptibility of dormant malignant or nonmalignant hematopoietic cells to cytarabine arabinoside (Ara-C) through the induction of cell cycle entry. Therefore, G-CSF-combined conditioning before allogeneic stem cell transplantation might positively contribute to decreased incidences of relapse and graft failure without having to increase the dose of cytotoxic drugs. We conducted a retrospective nationwide study of 336 adult patients with myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (sAML) after single-unit cord blood transplantation (CBT) who underwent 4 different kinds of conditioning regimens: total body irradiation (TBI) ≥ 8 Gy + Ara-C/G-CSF + cyclophosphamide (CY) (n = 65), TBI ≥ 8 Gy + Ara-C + CY (n = 119), TBI ≥ 8 Gy + other (n = 104), or TBI < 8 Gy or non-TBI (n = 48). The TBI ≥ 8 Gy + Ara-C/G-CSF + CY regimen showed significantly higher incidence of neutrophil engraftment (hazard ratio, 1.52; 95% confidence interval [CI], 1.10 to 2.08; P = .009) and lower overall mortality (hazard ratio, .46; 95% CI, .26 to .82; P = .008) rates compared with those without a G-CSF regimen. This retrospective study shows that the G-CSF-combined conditioning regimen provides better engraftment and survival results in CBT for adults with MDS and sAML.

  1. Granulocyte colony-stimulating factor-based stem cell mobilization in patients with sickle cell disease.

    PubMed

    Rosenbaum, Cara; Peace, David; Rich, Elizabeth; Van Besien, Koen

    2008-06-01

    Granulocyte colony-stimulating factor (G-CSF) has been reported to exacerbate vaso-occlusive crises in sickle cell disease. It has been recommended to avoid its use for stem cell mobilization in this population, yet autologous transplant is the standard of care and at times a life-saving treatment for patients with various hematologic malignancies such as relapsed aggressive lymphoma or multiple myeloma. We report 5 cases of patients with sickle cell disease and related hemoglobinopathies who underwent granulocyte-colony stimulating factor (G-CSF)-mobilization of peripheral blood stem cells (PBSC). Three of them developed manageable vaso-occlusive pain symptoms requiring parenteral narcotics alone. The 2 others had no complications. These cases demonstrate that stem cell mobilization using G-CSF, although complicated and not without risk, is feasible in patients with sickle cell syndromes.

  2. First-line combination chemotherapy with cisplatin, etoposide and ifosfamide for the treatment of disseminated germ cell cancer: re-evaluation in the granulocyte colony-stimulating factor era.

    PubMed

    Tanaka, Hajime; Yuasa, Takeshi; Fujii, Yasuhisa; Sakura, Mizuaki; Urakami, Shinji; Yamamoto, Shinya; Masuda, Hitoshi; Fukui, Iwao; Yonese, Junji

    2013-01-01

    This study re-evaluated the efficacy and tolerability of cisplatin, etoposide, and ifosfamide (VIP) combination chemotherapy as an alternative first-line regimen for patients with disseminated germ cell cancer (GCC) in this granulocyte colony-stimulating factor (G-CSF) era. The medical records of 91 consecutive patients with previously untreated disseminated GCC who received first-line VIP between 1995 and 2011 were retrospectively reviewed. The 5-year overall survival rates for patients with good (n = 49), intermediate (n = 22) and poor (n = 20) prognoses according to the International Germ Cell Cancer Collaborative Group classification were 100, 79 and 83%, respectively. G-CSF was given to all patients, and no treatment-related deaths due to myelosuppression occurred. The present study is the first to examine the therapeutic outcomes and safety profile of first-line VIP after routine G-CSF use. VIP might be an alternative first-line regimen for patients with disseminated GCC in this G-CSF era. © 2014 S. Karger AG, Basel

  3. Human granulocyte colony stimulating factor (hG-CSF): cloning, overexpression, purification and characterization

    PubMed Central

    Vanz, Ana LS; Renard, Gaby; Palma, Mario S; Chies, Jocelei M; Dalmora, Sérgio L; Basso, Luiz A; Santos, Diógenes S

    2008-01-01

    Background Biopharmaceutical drugs are mainly recombinant proteins produced by biotechnological tools. The patents of many biopharmaceuticals have expired, and biosimilars are thus currently being developed. Human granulocyte colony stimulating factor (hG-CSF) is a hematopoietic cytokine that acts on cells of the neutrophil lineage causing proliferation and differentiation of committed precursor cells and activation of mature neutrophils. Recombinant hG-CSF has been produced in genetically engineered Escherichia coli (Filgrastim) and successfully used to treat cancer patients suffering from chemotherapy-induced neutropenia. Filgrastim is a 175 amino acid protein, containing an extra N-terminal methionine, which is needed for expression in E. coli. Here we describe a simple and low-cost process that is amenable to scaling-up for the production and purification of homogeneous and active recombinant hG-CSF expressed in E. coli cells. Results Here we describe cloning of the human granulocyte colony-stimulating factor coding DNA sequence, protein expression in E. coli BL21(DE3) host cells in the absence of isopropyl-β-D-thiogalactopyranoside (IPTG) induction, efficient isolation and solubilization of inclusion bodies by a multi-step washing procedure, and a purification protocol using a single cationic exchange column. Characterization of homogeneous rhG-CSF by size exclusion and reverse phase chromatography showed similar yields to the standard. The immunoassay and N-terminal sequencing confirmed the identity of rhG-CSF. The biological activity assay, in vivo, showed an equivalent biological effect (109.4%) to the standard reference rhG-CSF. The homogeneous rhG-CSF protein yield was 3.2 mg of bioactive protein per liter of cell culture. Conclusion The recombinant protein expression in the absence of IPTG induction is advantageous since cost is reduced, and the protein purification protocol using a single chromatographic step should reduce cost even further for large

  4. Increasing aclarubicin dosage of the conventional CAG (low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor) regimen is more efficacious as a salvage therapy than CAG for relapsed/refractory acute myeloid leukemia.

    PubMed

    Qu, Qi; Liu, Limin; Zhang, Yanming; Li, Xiaoli; Wu, Depei

    2015-12-01

    The efficacy and safety of a modified CAG (low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor) regimen with an increased aclarubicin dosage [high-dose (HD)-CAG] were observed in 145 patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and compared to the results of 172 patients treated with a conventional CAG regimen. The HD-CAG regimen showed both a higher complete remission (CR) rate (60.7% vs. 46.5%, P=0.013) and overall response (OR) rate (74.5% vs. 63.4%, P=0.039) than CAG. For patients aged <60 years, HD-CAG manifested an efficacy advantage over the CAG regimen (62.6% vs. 47.4%, P=0.015). The 4-year overall survival (OS) rate was 30.3%±13.2% with a median survival time of 19.0±5.4 months for patients re-induced with the HD-CAG regimen, which showed no significant difference compared to the CAG regimen (with a 4-year OS rate of 18.2%±5.3% and a median survival time of 16.0±3.6 months, P=0.485). The main adverse effect was myelosuppression; platelet recovery over 50×10(9)/L was extended by the HD-CAG regimen (15 days vs. 10 days of the CAG regimen, P=0.003), which was tolerable and manageable. HD-CAG can safely improve efficacy compared to the CAG regimen and thus serves as an alternative treatment for R/R AML.

  5. The Granulocyte-colony stimulating factor has a dual role in neuronal and vascular plasticity

    PubMed Central

    Wallner, Stephanie; Peters, Sebastian; Pitzer, Claudia; Resch, Herbert; Bogdahn, Ulrich; Schneider, Armin

    2015-01-01

    Granulocyte-colony stimulating factor (G-CSF) is a growth factor that has originally been identified several decades ago as a hematopoietic factor required mainly for the generation of neutrophilic granulocytes, and is in clinical use for that. More recently, it has been discovered that G-CSF also plays a role in the brain as a growth factor for neurons and neural stem cells, and as a factor involved in the plasticity of the vasculature. We review and discuss these dual properties in view of the neuroregenerative potential of this growth factor. PMID:26301221

  6. Combination treatment of biomechanical support and targeted intra-arterial infusion of peripheral blood stem cells mobilized by granulocyte-colony stimulating factor for the osteonecrosis of the femoral head: a randomized controlled clinical trial.

    PubMed

    Mao, Qiang; Wang, Weidong; Xu, Taotao; Zhang, Shanxing; Xiao, Luwei; Chen, Di; Jin, Hongting; Tong, Peijian

    2015-04-01

    The objective of this study was to determine the benefits of combination treatment with mechanical support and targeted intra-arterial infusion of peripheral blood stem cells (PBSCs) mobilized by granulocyte-colony stimulating factor (G-CSF) via the medial circumflex femoral artery on the progression of osteonecrosis of the femoral head (ONFH). Fifty-five patients (89 hips) with early and intermediate stage ONFH were recruited and randomly assigned to combination treatment or mechanical support treatment (control group). All hips received mechanical support treatment (porous tantalum rod implantation). Then, hips in the combination treatment group were performed targeted intra-arterial infusion of PBSCs. At each follow-up, Harris hip score (HHS) and Association Research Circulation Osseous (ARCO) classification were used to evaluate the symptoms and progression of osteonecrosis. Total hip arthroplasty (THA) was assessed as an endpoint at each follow-up. At 36 months, 9 of the 41 hips (21.95%) in the control group progressed to clinical failure and underwent THA whereas only 3 of the 48 hips (6.25%) in the combination treatment group required THA (p = 0.031). Kaplan-Meier survival analysis showed a significant difference in the survival time between the two groups (log-rank test; p = 0.025). Compared to the control group, combination treatment significantly improved the HHS at 36 months (p = 0.003). At the final follow-up examination, radiological progression was noted in 13 of 41 hips (31.71%) for the control group, but in only 4 of 48 hips (8.33%) for the combination treatment group (p = 0.005). The overall collapse rates were 15.15% (5/33 hips) and 8.11% (3/37 hips) in the control and combination treatment groups, respectively. Targeted intra-arterial infusion of PBSCs is capable of enhancing the efficacy of biomechanical support in the treatment of ONFH. This clinical trial confirmed that the combination treatment might be a safe and feasible

  7. The structure of granulocyte-colony-stimulating factor and its relationship to other growth factors.

    PubMed Central

    Hill, C P; Osslund, T D; Eisenberg, D

    1993-01-01

    We have determined the three-dimensional structure of recombinant human granulocyte-colony-stimulating factor by x-ray crystallography. Phases were initially obtained at 3.0-A resolution by multiple isomorphous replacement and were refined by solvent flattening and by averaging of the electron density of the three molecules in the asymmetric unit. The current R factor is 21.5% for all data between 6.0- and 2.2-A resolution. The structure is predominantly helical, with 104 of the 175 residues forming a four-alpha-helix bundle. The only other secondary structure is also helical. In the loop between the first two long helices a four-residue 3(10)-helix is immediately followed by a 6-residue alpha-helix. Three residues in the short connection between the second and third bundle helices form almost one turn of left-handed helix. The up-up-down-down connectivity with two long crossover connections has been reported previously for five other proteins, which like granulocyte-colony-stimulating factor are all signaling ligands: growth hormone, granulocyte/macrophage-colony-stimulating factor, interferon beta, interleukin 2, and interleukin 4. Structural similarity among these growth factors occurs despite the absence of similarity in their amino acid sequences. Conservation of this tertiary structure suggests that these different growth factors might all bind to their respective sequence-related receptors in an equivalent manner. Images Fig. 2 PMID:7685117

  8. Effect of thrombopoietin and granulocyte colony-stimulating factor on platelets and polymorphonuclear leukocytes.

    PubMed

    Schattner, M; Pozner, R G; Gorostizaga, A B; Lazzari, M A

    2000-07-15

    Thrombopoietin (TPO) and granulocyte colony-stimulating factor (G-CSF) may be administered together in aplastic patients. We evaluated the effect of both cytokines alone or combined on platelets and polymorphonuclear leukocytes (PMN) functional responses. TPO, G-CSF, or the combination of both cytokines, induced neither platelet nor PMN activation. TPO but not G-CSF synergized with threshold ADP concentrations to induce maximal aggregation and ATP release. The synergistic effect of TPO with ADP was not modified by the presence of G-CSF. Flow cytometry studies have shown that thrombin-induced loss of GPIb from platelet surface was significantly increased by pretreatment of platelets with TPO, G-CSF, or both cytokines. P-selectin expression induced by thrombin was augmented by TPO, but not by G-CSF. Coincubation of the cells with TPO and G-CSF did not modify the values obtained with TPO alone. Expression of CD11b on PMN surface was augmented by G-CSF or fMLP. G-CSF-treated PMN increased the effect of fMLP on CD11b expression. TPO did not modify either basal levels of CD11b or the increased expression induced by G-CSF or fMLP. Incubation of PMN with both cytokines showed no differences compared to G-CSF alone. Platelet-PMN aggregates induced by thrombin in whole blood were augmented by TPO. G-CSF alone neither synergized with thrombin nor changed the results observed with TPO. These data show that in vitro functional responses of platelets, or PMN induced by TPO or G-CSF alone, were neither further increased nor inhibited by treatment of the cells with both cytokines.

  9. Review of granulocyte colony-stimulating factors in the treatment of established febrile neutropenia.

    PubMed

    Pérez Velasco, Román

    2011-09-01

    To assess the value of granulocyte colony-stimulating factors (G-CSF) in promoting recovery from established episodes of febrile neutropenia (FN) after chemotherapy in cancer patients. The literature was searched using the MEDLINE, EMBASE, BIOSIS, and IPA databases. Reference lists from the retrieved papers and hand searches of relevant journals complemented the search. Eleven randomized controlled trials were selected for review. G-CSF use in established FN appears to be limited to a small reduction in neutropenia duration, length of hospitalization, and duration of antibiotic use. Overall, there are no significant reductions in time to neutrophil recovery and fever resolution. The cost analyses performed do not show significant cost savings. Granulocyte colony-stimulating factors (G-CSF) are biological agents typically used for prevention of febrile neutropenia (FN) or as adjunctive treatment with antibiotics of established FN. Most clinical guidelines discourage the general use of G-CSF for adjunctive treatment of ongoing neutropenic fever; however, its use in special situations, such as high-risk for infectious complications or adverse prognostic factors, is advised. G-CSF should be reserved for high-risk cancer patients, in accordance with the results of this review. This recommendation needs to be taken with caution in view of the disparities and methodological flaws found among trials. It is necessary to design further trials appropriately, well-powered and focused on high-risk patients. Moreover, it is necessary to perform an appropriate economic evaluation for this setting.

  10. In vivo stimulation of granulopoiesis by recombinant human granulocyte colony-stimulating factor

    SciTech Connect

    Cohen, A.M.; Zsebo, K.M.; Inoue, H.; Hines, D.; Boone, T.C.; Chazin, V.R.; Tsai, L.; Ritch, T.; Souza, L.M.

    1987-04-01

    Osmotic pumps containing Escherichia coli-derived recombinant human granulocyte colony-stimulating factor (rhG-CSF) were attached to indwelling jugular vein catheters and implanted subcutaneously into Golden Syrian hamsters. Within 3 days, peripheral granulocyte counts had increased > 10-fold with a concomitant 4-fold increase in total leukocytes. Microscopic examination of Wright-Giemsa-stained blood smears from rhG-CSF hamsters showed that only the neutrophil subpopulation of granulocytes had increased. After subcutaneous injection at /sup 35/S-labeled rhG-CSF doses of up to 10 ..mu..g x kg/sup -1/ x day/sup -1/ only granulocyte counts were affected. However, at higher dose levels, a transient thrombocytopenia was noted. Erythrocyte and lymphocyte/monocyte counts remained unaffected by rhG-CSF over the entire dose range studied. Total leukocyte counts increased 3-fold within 12 hr after a single s.c. injection of rhG-CSF. This early effect was associated with an increase in the total number of colony-forming cells and the percent of active cycling cells in the marrow. A sustained elevation of peripheral leukocyte and marrow progenitor counts was observed following seven daily s.c. injections of rhG-CSF. The ability of rhG-CSF to increase the production and release of granulocytes from the marrow may underlie the beneficial effect it produced on the restoration of peripheral leukocyte counts in hamsters made leukopenic by treatment with 5-fluorouracil.

  11. Treatment of clozapine- and molindone-induced agranulocytosis with granulocyte colony-stimulating factor.

    PubMed

    Geibig, C B; Marks, L W

    1993-10-01

    To report a case of clozapine- and molindone-induced agranulocytosis and to discuss treatment using filgrastim, a granulocyte colony-stimulating factor. A 64-year-old woman who had been on long-term clozapine therapy for schizophrenia was hospitalized with presumed drug-induced agranulocytosis. She had also been on short-term molindone therapy. A bone marrow biopsy and the initial white blood cell (WBC) count were consistent with drug-induced agranulocytosis. Following seven days of treatment with subcutaneous filgrastim 300 micrograms/d, her absolute neutrophil count was above 500 x 10(6)/L. Reports in the literature discussing antipsychotic drug-induced agranulocytosis are reviewed. A relationship between treatment with filgrastim and WBC response is postulated. Filgrastim may be useful in ameliorating the effects of clozapine- and molindone-induced agranulocytosis.

  12. Expression and purification of canine granulocyte colony-stimulating factor (cG-CSF).

    PubMed

    Yamamoto, Akira; Iwata, Akira; Saito, Toshiki; Watanabe, Fumiko; Ueda, Susumu

    2009-08-15

    Canine granulocyte colony-stimulating factor (cG-CSF) with modification of cysteine at position 17 to serine was expressed in Brevibacillus choshinensis HPD31. cG-CSF secreted into the culture medium was purified by ammonium sulfate precipitation and consecutive column chromatography, using butyl sepharose and DEAE sepharose. Biological activity of the recombinant cG-CSF was 8.0 x 10(6) U/mg protein, as determined by its stimulatory effect on NFS-60 cell proliferation. Purified cG-CSF was subcutaneously administered once a day for two successive days to dogs (1, 5, 25, or 125 microg). Neutrophil count increased the following day in all dogs except those administered the lowest dose (1 microg). No severe side effects were observed in dogs after administration of cG-CSF.

  13. Autopsy of anaplastic carcinoma of the pancreas producing granulocyte colony-stimulating factor.

    PubMed

    Hayashi, Haruna; Eguchi, Noriaki; Sumimoto, Kyoku; Matsumoto, Kenta; Azakami, Takahiro; Sumida, Tomonori; Tamura, Tadamasa; Sumii, Masaharu; Uraoka, Naohiro; Shimamoto, Fumio

    2016-08-01

    A 50-year-old man presented to a nearby hospital with high fever and anorexia. An abdominal tumor was detected, and he was referred to our hospital. A pancreatic tumor was detected by computed tomography and abdominal ultrasonography. He had high fever, leukocytosis, and high serum granulocyte colony-stimulating factor (G-CSF). We performed a tumor biopsy and histological examination revealed anaplastic carcinoma of the pancreas. Based on the diagnosis, we initiated chemotherapy using gemcitabine plus S-1. However, the tumor rapidly progressed and he deteriorated and died 123 days after admission. As immunohistochemical study showed positive staining for G-CSF in the tumor cell, we diagnosed the tumor producing G-CSF during autopsy. Anaplastic carcinoma of the pancreas producing G-CSF is very rare, with 10 cases, including ours, reported in the literature.

  14. Successful mobilization of peripheral blood stem cells in children with cancer using plerixafor (Mozobil) and granulocyte-colony stimulating factor.

    PubMed

    Avramova, Boryana E; Yordanova, Maya N; Konstantinov, Dobrin N; Bobev, Dragan G

    2011-01-01

    This paper describes the successful mobilization of peripheral blood stem cells for autologous transplantation in three children with malignant diseases by using plerixafor (Mozobil; Genzyme Corporation, Cambridge, MA) and granulocyte-colony stimulating factor (G-CSF) after failed previous mobilizations. A median sixfold increase in the number of circulating CD34+ cells after plerixafor treatment as compared with the baseline level was observed. An optimal CD34+ cell count for transplantation with one or two leukapheresis sessions was achieved. Mobilization using plerixafor was found to be safe with no adverse events. Therefore, the combination of G-CSF and plerixafor in children results in effective increases in peripheral CD34+ cell counts and reduces the risk of mobilization failure.

  15. Successful mobilization of peripheral blood stem cells in children with cancer using plerixafor (Mozobil™) and granulocyte-colony stimulating factor

    PubMed Central

    Avramova, Boryana E; Yordanova, Maya N; Konstantinov, Dobrin N; Bobev, Dragan G

    2011-01-01

    This paper describes the successful mobilization of peripheral blood stem cells for autologous transplantation in three children with malignant diseases by using plerixafor (Mozobil™; Genzyme Corporation, Cambridge, MA) and granulocyte-colony stimulating factor (G-CSF) after failed previous mobilizations. A median sixfold increase in the number of circulating CD34+ cells after plerixafor treatment as compared with the baseline level was observed. An optimal CD34+ cell count for transplantation with one or two leukapheresis sessions was achieved. Mobilization using plerixafor was found to be safe with no adverse events. Therefore, the combination of G-CSF and plerixafor in children results in effective increases in peripheral CD34+ cell counts and reduces the risk of mobilization failure. PMID:21966213

  16. Acetylation impacts Fli-1-driven regulation of granulocyte colony stimulating factor.

    PubMed

    Lennard Richard, Mara L; Brandon, Danielle; Lou, Ning; Sato, Shuzo; Caldwell, Tomika; Nowling, Tamara K; Gilkeson, Gary; Zhang, Xian K

    2016-10-01

    Fli-1 has emerged as a critical regulator of inflammatory mediators, including MCP-1, CCL5, and IL-6. The cytokine, granulocyte colony stimulating factor (G-CSF) regulates neutrophil precursor maturation and survival, and activates mature neutrophils. Previously, a significant decrease in neutrophil infiltration into the kidneys of Fli-1(+/-) lupus-prone mice was observed. In this study, a significant decrease in G-CSF protein expression was detected in stimulated murine and human endothelial cells when expression of Fli-1 was inhibited. The murine G-CSF promoter contains numerous putative Fli-1 binding sites and several regions within the proximal promoter are significantly enriched for Fli-1 binding. Transient transfection assays indicate that Fli-1 drives transcription from the G-CSF promoter and mutation of the Fli-1 DNA binding domain resulted in a 94% loss of transcriptional activation. Mutation of a known acetylation site, led to a significant increase in G-CSF promoter activation. The histone acetyltransferases p300/CBP and p300/CBP associated factor (PCAF) significantly decrease Fli-1 specific activation of the G-CSF promoter. Thus, acetylation appears to be an important mechanism behind Fli-1 driven activation of the G-CSF promoter. These results further support the theory that Fli-1 plays a major role in the regulation of several inflammatory mediators, ultimately affecting inflammatory disease pathogenesis.

  17. Requirement of Src kinase Lyn for induction of DNA synthesis by granulocyte colony-stimulating factor.

    PubMed

    Corey, S J; Dombrosky-Ferlan, P M; Zuo, S; Krohn, E; Donnenberg, A D; Zorich, P; Romero, G; Takata, M; Kurosaki, T

    1998-02-06

    Treatment of cells with granulocyte colony-stimulating factor (G-CSF) leads to tyrosine phosphorylation of cellular proteins. G-CSF stimulates both the activation of protein tyrosine kinases Lyn, Jak1, and Jak2 and the association of these enzymes with the G-CSF receptor. Wild-type, lyn-deficient, and syk-deficient chicken B lymphocyte cell lines were transfected with the human G-CSF receptor, and stable transfectants were studied. G-CSF-dependent tyrosyl phosphorylation of Jak1 and Jak2 occurred in all three cell lines. Wild-type and syk-deficient transfectants responded to G-CSF in a dose-responsive fashion with increased thymidine incorporation, but none of the clones of lyn-deficient transfectants did. Ectopic expression of Lyn, but not that of c-Src, in the lyn-deficient cells restored their mitogenic responsiveness to G-CSF. Ectopic expression in wild-type cells of the kinase-inactive form of Lyn, but not of the kinase-inactive form of Jak2, inhibited thymidine incorporation in response to G-CSF. These studies show that the absence of Lyn results in the loss of mitogenic signaling in the G-CSF signaling pathway and that activation of Jak1 or Jak2 is not sufficient to cause mitogenesis.

  18. Treatment of leg ischemia with biodegradable gelatin hydrogel microspheres incorporating granulocyte colony-stimulating factor.

    PubMed

    Kawamura, Itta; Takemura, Genzou; Tsujimoto, Akiko; Watanabe, Takatomo; Kanamori, Hiromitsu; Esaki, Masayasu; Kobayashi, Hiroyuki; Takeyama, Toshiaki; Kawaguchi, Tomonori; Goto, Kazuko; Maruyama, Rumi; Fujiwara, Takako; Fujiwara, Hisayoshi; Tabata, Yasuhiko; Minatoguchi, Shinya

    2011-04-01

    Granulocyte colony-stimulating factor (G-CSF) is a potent angiogenic factor. We hypothesized that G-CSF-immersed gelatin hydrogel microspheres (G-CSF-GHMs) injected into the ischemic legs might continuously release a small amount of G-CSF to locally stimulate angiogenesis without unfavorable systemic effects. Just after ligation of the right femoral artery of BALB/c mice, recombinant human G-CSF (100-μg/kg)-immersed GHM was injected into the right hindlimb muscles; the controls included a saline-injected group, an intramuscularly injected G-CSF group, a subcutaneously injected G-CSG group, and an empty GHM-injected group. Eight weeks later, improvement of blood perfusion to the ischemic limb was significantly augmented in the G-CSF-GHM group compared with any of the control groups. Despite there being no increase in the serum concentration of G-CSF, in peripheral granulocytes, or in circulating endothelial progenitor cells, not only capillary but also arteriolar density was significantly increased in this group. Next, we started treatment with G-CSF-GHM 4 weeks after ligation to examine whether the treatment is effective if performed during the chronic stage of ischemia. The late treatment was also found to effectively improve blood flow in the ischemic leg. In conclusion, G-CSF-GHM administration is suggested to be a promising and readily usable approach to treating peripheral artery disease, applicable even during the chronic stage.

  19. Hematologic improvement in dogs with parvovirus infection treated with recombinant canine granulocyte-colony stimulating factor.

    PubMed

    Duffy, A; Dow, S; Ogilvie, G; Rao, S; Hackett, T

    2010-08-01

    Previously, dogs with canine parvovirus-induced neutropenia have not responded to treatment with recombinant human granulocyte-colony stimulating factor (rhG-CSF). However, recombinant canine G-CSF (rcG-CSF) has not been previously evaluated for treatment of parvovirus-induced neutropenia in dogs. We assessed the effectiveness of rcG-CSF in dogs with parvovirus-induced neutropenia with a prospective, open-label, nonrandomized clinical trial. Endpoints of our study were time to recovery of WBC and neutrophil counts, and duration of hospitalization. 28 dogs with parvovirus and neutropenia were treated with rcG-CSF and outcomes were compared to those of 34 dogs with parvovirus and neutropenia not treated with rcG-CSF. We found that mean WBC and neutrophil counts were significantly higher (P < 0.05) in the 28 dogs treated with rcG-CSF compared to disease-matched dogs not treated with rcG-CSF. In addition, the mean duration of hospitalization was reduced (P = 0.01) in rcG-CSF treated dogs compared to untreated dogs. However, survival times were decreased in dogs treated with rcG-CSF compared to untreated dogs. These results suggest that treatment with rcG-CSF was effective in stimulating neutrophil recovery and shortening the duration of hospitalization in dogs with parvovirus infection, but indicate the need for additional studies to evaluate overall safety of the treatment.

  20. Increasing aclarubicin dose in low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor (CAG regimen) is efficacious as salvage chemotherapy for relapsed/refractory mixed-phenotype acute leukemia.

    PubMed

    Liu, Limin; Qu, Qi; Jiao, Wenjing; Zhang, Yanming; Li, Xiaoli; Ding, Chao; Wu, Depei

    2015-08-01

    We treated 60 relapsed/refractory mixed-phenotype acute leukemia patients (MPAL-1) with increasing the aclarubicin dose in CAG regimen (HD-CAG, cytarabine (10 mg/m(2)/12 h, days 1-14), aclarubicin (5-7 mg/m(2)/day, days 1-14), granulocyte colony-stimulating factor (200 μg/m(2)/day, days 1-14). This was compared to 64 relapsed/refractory MPAL patients (MPAL-2) treated with DOAP regimen (daunorubicin, vincristine/vindesine, cytarabine and prednisone), 113 relapsed/refractory acute myeloid leukemia (AML) patients and 78 acute lymphocytic leukemia (ALL) patients treated with HD-CAG regimen. After one course, complete remission (CR) and overall response [OR, CR+partial remission (PR)] rates for MPAL-1 exceeded MPAL-2 (CR, 61.02% vs. 28.13%, P=0.000; OR, 72.88% vs. 34.38%, P=0.000), but these data were similar to AML and ALL (P>0.05). In MPAL-1 group, CR and OR rates of T-lymphoid+myeloid immunophenotype were higher than B-lymphoid+myeloid immunophenotype (CR, 81.82% vs. 44.12%, P=0.005; OR, 90.91% vs. 58.82%, P=0.009). The overall survival at 3 years in MPAL-1, MPAL-2, AML and ALL groups were 14.2%±6.8%, 14.1%±6.4%, 17.3%±5.0% and 15.0%±5.3% (P>0.05). Side effects were similar between HD-CAG and DOAP (P>0.05). HD-CAG regimen is efficacious for relapsed/refractory MPAL, especially for T+My patients. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Human Granulocyte Colony-Stimulating Factor (hG-CSF) Expression in Plastids of Lactuca sativa

    PubMed Central

    Sharifi Tabar, Mehdi; Habashi, Ali Akbar; Rajabi Memari, Hamid

    2013-01-01

    Background: Human granulocyte colony-stimulating factor (hG-CSF) can serve as valuable biopharmaceutical for research and treatment of the human blood cancer. Transplastomic plants have been emerged as a new and high potential candidate for production of recombinant biopharmaceutical proteins in comparison with transgenic plants due to extremely high level expression, biosafety and many other advantages. Methods: hG-CSF gene was cloned into pCL vector between prrn16S promoter and TpsbA terminator. The recombinant vector was coated on nanogold particles and transformed to lettuce chloroplasts through biolistic method. Callogenesis and regeneration of cotyledonary explants were obtained by Murashige and Skoog media containing 6-benzylaminopurine and 1-naphthaleneacetic acid hormones. The presence of hG-CSF gene in plastome was studied with four specific PCR primers and expression by Western immunoblotting. Results: hG-CSF gene cloning was confirmed by digestion and sequencing. Transplastomic lettuce lines were regenerated and subjected to molecular analysis. The presence of hG-CSF in plastome was confirmed by PCR using specific primers designed from the plastid genome. Western immunoblotting of extracted protein from transplastomic plants showed a 20-kDa band, which verified the expression of recombinant protein in lettuce chloroplasts. Conclusions: This study is the first report that successfully express hG-CSF gene in lettuce chloroplast. The lettuce plastome can provide a cheap and safe expression platform for producing valuable biopharmaceuticals for research and treatment. PMID:23748895

  2. Adjunctive granulocyte colony-stimulating factor for treatment of septic shock due to melioidosis.

    PubMed

    Cheng, Allen C; Stephens, Dianne P; Anstey, Nicholas M; Currie, Bart J

    2004-01-01

    Melioidosis, caused by the intracellular pathogen Burkholderia pseudomallei, is endemic in northern Australia and Southeast Asia. Risk factors for this infection have also been associated with functional neutrophil defects. Because of this, granulocyte colony-stimulating factor (G-CSF) was adopted for use in patients with septic shock due to melioidosis in December 1998. We compared the mortality rates from before and after the introduction of G-CSF therapy at the Royal Darwin Hospital (Darwin, Australia) during the period of 1989-2002. The mortality rate decreased from 95% to 10% after the introduction of G-CSF. Risk factors, the duration of illness before presentation, and the severity of illness were similar in both groups. A smaller decrease in mortality among patients in the intensive care unit who did not have melioidosis was observed, suggesting that other changes in management did not account for the magnitude of the benefit seen. We conclude that G-CSF may have contributed to the reduction in the mortality rate among patients with septic shock due to melioidosis.

  3. Granulocyte colony-stimulating factor increases the platelet volume in peripheral stem cell apheresis donors.

    PubMed

    Ihara, Akihiro; Matsui, Keiko; Minami, Ryouta; Uchida, Shuzou; Ueda, Shuji; Nishiura, Tetsuo

    2008-01-01

    We investigated the short-term influence of granulocyte colony-stimulating factor (G-CSF) administration on platelet counts and platelet indices in 12 donors (8 males and 4 females; median age 34 years, range 16-49) for peripheral stem cell transplantation using an automated blood cell analyzer. On day 3 (D3) compared with D0, 11 donors with normal laboratory and physical findings showed increases in platelet indices (chi(2) = 12.0, p = 0.0025). Furthermore, mean platelet volume (MPV) was significantly increased (p = 0.04). Also, platelet count decreased, and platelet distribution width and platelet-large cell ratio were increased, but these were not significant. On the contrary, 1 donor with abnormal laboratory findings who had large platelets (MPV 11.4 fl) before G-CSF administration showed decreases in platelet indices (MPV 10.3 fl) on D3, although platelet count (18.2 x 10(4)/microl) decreased after G-CSF administration. G-CSF administration induces an inflammatory process with endothelial cell activation. This is probably the reason why platelet volume increases after G-CSF use. This is the first report showing that G-CSF administration immediately induces increases in large platelets in peripheral stem cell transplant donors before harvest.

  4. Sulfasalazine-induced DRESS and severe agranulocytosis successfully treated by granulocyte colony-stimulating factor.

    PubMed

    Fathallah, Neila; Slim, Raoudha; Rached, Salaheddine; Hachfi, Wissem; Letaief, Amel; Ben Salem, Chaker

    2015-08-01

    A drug reaction with eosinophilia and systemic symptom (DRESS) is a severe and rare adverse-drug hypersensitivity syndrome. The evolution of DRESS is unpredictable and haematological abnormalities may occur in 50 % of cases. Sulfasalazine (SSZ) is rarely associated with DRESS. Agranulocytosis is a rare but recognized side-effect to SSZ. Both DRESS and agranulocytosis were not reported previously with SSZ. We report a case of SSZ-induced DRESS followed by severe agranulocytosis occurring in a 25-year-old man. The patient's general condition and laboratory tests gradually improved after the administration of granulocyte colony-stimulating factor (GCSF). In our patient, the co-occurrence of DRESS and agranulocytosis is unlikely to be coincidental. Immunological mechanisms may play an important role in drug associated agranulocytosis in patients presenting DRESS. According to the Naranjo's algorithm the likelihood that our patient's DRESS and agranulocytosis occurred as a result of therapy with SSZ is probable. G-CSF was found to be useful in shortening the duration of granulocyte recovery in drug-induced agranulocytosis. Careful monitoring of neutrophil counts is required on SSZ therapy as well as in the course of DRESS.

  5. Biosimilar granulocyte-colony-stimulating factor for healthy donor stem cell mobilization: need we be afraid?

    PubMed

    Bonig, Halvard; Becker, Petra S; Schwebig, Arnd; Turner, Matthew

    2015-02-01

    Biosimilars are approved biologics with comparable quality, safety, and efficacy to a reference product. Unlike generics, which are chemically manufactured copies of small-molecule drugs with relatively simple chemical structures, the biosimilar designation is applied to drugs that are produced by living organisms, implying much more difficult to control manufacturing and purification procedures. To account for these complexities, the European Medicines Agency (EMA), the US Food and Drug Administration, the Australian Therapeutic Goods Administration, and other regulatory authorities have devised and implemented specific, markedly more demanding pathways for the evaluation and approval of biosimilars. To date, several biosimilars have been approved, including versions of somatropin, erythropoietin, and granulocyte-colony-stimulating factor (G-CSF), and several biosimilar monoclonal antibodies are currently in development. The reference G-CSF product (Neupogen, Amgen) has been used for many years for prevention and treatment of neutropenia and also for mobilization of peripheral blood stem cells (PBSCs). However, concerns have been raised about the safety and efficacy of biosimilar G-CSF during PBSC mobilization procedures, especially in healthy donors. This article reviews the available evidence on the use of biosimilar G-CSF in this setting. Aggregate clinical evidence supports the assessment by the EMA of biosimilar and originator G-CSF as highly biologically similar, with respect to desired and undesired effects.

  6. Granulocyte-colony stimulating factor ameliorates irradiation-induced suppression of hippocampal neurogenesis in adult mice.

    PubMed

    Kim, Joong-Sun; Yang, Miyoung; Jang, Hyosun; Oui, Heejin; Kim, Sung-Ho; Shin, Taekyun; Jang, Won-Suk; Lee, Seung-Sook; Moon, Changjong

    2010-12-03

    Granulocyte-colony stimulating factor (G-csf) is a member of the hematopoietic growth factor family and demonstrates neuroprotective functions in neurodegenerative diseases. This study evaluated the radioprotective effects of G-csf in the suppression of hippocampal neurogenesis in adult mice undergoing irradiation. The radioprotective effects were assessed using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay and immunohistochemical markers of neurogenesis, including the proliferating cell marker Ki-67 and the immature progenitor neuron marker doublecortin (DCX). Acute exposure to cranial irradiation (5Gy γ-rays) induced neural apoptosis and inhibited neurogenesis in the dentate gyrus (DG) of the adult mouse hippocampus. Pretreatment with G-csf (100μg/kg every 12h subcutaneously on three consecutive days) attenuated neural apoptosis and decreased the number of Ki-67- and DCX-positive cells in the DG of the irradiated mouse hippocampus. Therefore, G-csf inhibited the detrimental effects of irradiation on hippocampal neurogenesis, suggesting that G-csf administration has potential therapeutic utility in brain irradiation. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  7. Chronic neutropenia. A new canine model induced by human granulocyte colony-stimulating factor.

    PubMed Central

    Hammond, W P; Csiba, E; Canin, A; Hockman, H; Souza, L M; Layton, J E; Dale, D C

    1991-01-01

    Normal dogs were treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF) at 10 micrograms/kg/day for 30 d, which caused an initial neutrophilia, followed by a prolonged period of chronic neutropenia. A control dog treated with recombinant canine G-CSF (rcG-CSF) showed persistent neutrophilia over 3 mo. Serum from dogs during neutropenia contained an antibody to rhG-CSF, which neutralized the stimulatory effects of both rhG-CSF and rcG-CSF on dog marrow neutrophilic progenitor cell growth and on NFS-60 cell proliferation. 4 mo after discontinuation of rhG-CSF, the dogs' neutrophil counts returned to the normal range. Rechallenge with the rhG-CSF re-induced severe neutropenia in 1 wk. Neutropenia was transferred by plasma infusion from a neutropenic dog to a previously normal dog. These data suggest that human rhG-CSF immunizes normal dogs and thereby induces neutralization of endogenous canine G-CSF and neutropenia. This model system should allow more precise definition of the in vivo role of G-CSF. PMID:1704019

  8. Neuroprotection of Granulocyte Colony-Stimulating Factor for Early Stage Parkinson's Disease.

    PubMed

    Tsai, Sheng-Tzung; Chu, Sung-Chao; Liu, Shu-Hsin; Pang, Cheng-Yoong; Hou, Ting-Wen; Lin, Shinn-Zong; Chen, Shin-Yuan

    2017-03-13

    Parkinson's disease (PD) is a slowly progressive neurodegenerative disease. Both medical and surgical choices provide symptomatic treatment. Granulocyte colony-stimulating factor (G-CSF), a conventional treatment for hematological diseases, has demonstrated its effectiveness in acute and chronic neurological diseases through its anti-inflammatory and antiapoptosis mechanisms. Based on previous in vitro and in vivo studies, we administered a lower dose (3.3 μg/kg) G-CSF injection for 5 days and six courses for 1 year in early-stage PD patients as a phase I trial. The four PD patient's mean unified PD rating scale motor scores in medication off status remained stable from 23 before the first G-CSF injection to 22 during the 2-year follow-up. 3,4-Dihydroxy-6-18F-fluoro-l-phenylalanine (18F-DOPA) positron emission tomography (PET) studies also revealed an annual 3.5% decrease in radiotracer uptake over the caudate nucleus and 7% in the putamen, both slower than those of previous reports of PD. Adverse effects included transient muscular-skeletal pain, nausea, vomiting, and elevated liver enzymes. Based on this preliminary report, G-CSF seems to alleviate disease deterioration for early stage PD patients. The effectiveness of G-CSF was possibly due to its amelioration of progressive dopaminergic neuron degeneration.

  9. Enhanced and Secretory Expression of Human Granulocyte Colony Stimulating Factor by Bacillus subtilis SCK6

    PubMed Central

    Bashir, Shaista; Sadaf, Saima; Ahmad, Sajjad; Akhtar, Muhammad Waheed

    2015-01-01

    This study describes a simplified approach for enhanced expression and secretion of a pharmaceutically important human cytokine, that is, granulocyte colony stimulating factor (GCSF), in the culture supernatant of Bacillus subtilis SCK6 cells. Codon optimized GCSF and pNWPH vector containing SpymwC signal sequence were amplified by prolonged overlap extension PCR to generate multimeric plasmid DNA, which was used directly to transform B. subtilis SCK6 supercompetent cells. Expression of GCSF was monitored in the culture supernatant for 120 hours. The highest expression, which corresponded to 17% of the total secretory protein, was observed at 72 hours of growth. Following ammonium sulphate precipitation, GCSF was purified to near homogeneity by fast protein liquid chromatography on a QFF anion exchange column. Circular dichroism spectroscopic analysis showed that the secondary structure contents of the purified GCSF are similar to the commercially available GCSF. Biological activity, as revealed by the regeneration of neutrophils in mice treated with ifosfamine, was also similar to the commercial preparation of GCSF. This, to our knowledge, is the first study that reports secretory expression of human GCSF in B. subtilis SCK6 with final recovery of up to 96 mg/L of the culture supernatant, without involvement of any chemical inducer. PMID:26881203

  10. Endotoxin down-modulates granulocyte colony-stimulating factor receptor (CD114) on human neutrophils.

    PubMed

    Hollenstein, U; Homoncik, M; Stohlawetz, P J; Marsik, C; Sieder, A; Eichler, H G; Jilma, B

    2000-07-01

    During infection, the development of nonresponsiveness to granulocyte colony-stimulating factor (G-CSF) may be influenced by the down-modulation of G-CSF receptor (G-CSFR) by cytokines. This down-modulation was studied during experimental human endotoxemia. Healthy volunteers received either 2 ng/kg endotoxin (lipopolysaccharide [LPS], n=20) or placebo (n=10) in a randomized, controlled trial. Endotoxin infusion increased the mean fluorescence intensity of the neutrophil activation marker CD11b >300% after 1 h (P<.001 vs. placebo). LPS infusion down-modulated G-CSFR expression in as early as 60 min (-17%; P=.001 vs. placebo). Down-modulation was almost maximal at 90 min and persisted for 6 h (-50% from baseline; P<.0001 vs. placebo). Plasma levels of G-CSF started to increase only after G-CSFR down-modulation had occurred and peaked 37-fold above baseline at 4 h (P<.0001 vs. placebo). In conclusion, LPS down-modulates G-CSFR expression in humans, which may render neutrophils less responsive to the effects of G-CSF and, thereby, compromise host defense mechanisms.

  11. The use of granulocyte-colony-stimulating factor in volunteer unrelated hemopoietic stem cell donors.

    PubMed

    Pamphilon, Derwood; Nacheva, Elisabeth; Navarrete, Cristina; Madrigal, Alejandro; Goldman, John

    2008-07-01

    Granulocyte-colony-stimulating factor (G-CSF) is used for the mobilization of hemopoietic stem cells in healthy donors. It has a number of common side effects such as bone pain, which resolve rapidly after administration is discontinued. Recent publications have raised concern that it might act as a trigger for the development of hematologic malignancy in susceptible individuals, possibly by causing genomic instability, but to date there is no evidence that healthy volunteer donors who receive G-CSF are at any increased risk. Ongoing studies aim to confirm whether or not G-CSF can cause chromosomal abnormalities in healthy donors. In the UK, the British Bone Marrow Registry and Anthony Nolan Trust give G-CSF to donors who have agreed to donate peripheral blood stem cells. It is recommended by the UK Registries at present that all stem cell donors are given updated information explaining the current uncertainties with regard to the use of G-CSF before they give informed consent to its administration. This information is based on a statement agreed by the World Marrow Donor Association for use by individual donor registries. Further, it is our current practice that all donors who have received G-CSF, as well as marrow donors who do not, should be under regular review for at least 10 years to allow the occurrence of any long-term adverse events to be documented.

  12. Long-active granulocyte colony-stimulating factor for peripheral blood hematopoietic progenitor cell mobilization.

    PubMed

    Martino, Massimo; Laszlo, Daniele; Lanza, Francesco

    2014-06-01

    Peg-filgrastim (PEG-FIL), a polyethylene glycol-conjugated form of granulocyte colony-stimulating factor (G-CSF), has been introduced in clinical practice and is effective in shortening the time of neutropenia after cytotoxic chemotherapy. G-CSF has emerged as the preferred cytokine for hematopoietic progenitor cells' (HPC) mobilization. Nevertheless, data on the ability of PEG-FIL in this field have been published. We review publications in the field with the goal of providing an overview of this approach. PEG-FIL may be able to mobilize CD34(+) cells in a more timely fashion than G-CSF, with the advantages of only a single-dose administration, an earlier start and a reduction in the number of apheresis procedures. The main controversies concern the dosage of the drug and the optimal dose. In the context of chemo-mobilization, a single dose of 6 mg PEG-FIL seems effective in terms of HPC's mobilization and there is no increase in this effect if the dose is doubled to 12 mg. Steady-state mobilization requires higher doses of PEG-FIL and this approach is not cost-effective when compared with G-CSF. The experiences with PEG-FIL in the healthy donor setting are very limited.

  13. Prophylactic use of granulocyte colony-stimulating factor after consolidation therapy with high-dose cytarabine for acute myeloid leukemia.

    PubMed

    Shadman, Mazyar; Estey, Elihu H

    2013-04-01

    Prophylactic use of granulocyte colony-stimulating factor after chemotherapy in acute myeloid leukemia patients has become part of the supportive care strategy in some institutions. Despite shortening the neutropenia period and lowering the hospitalization rate, randomized studies have not shown any improvement in the clinical outcomes with this intervention. In their single-institution retrospective study, Bradley et al. reported that granulocyte colony-stimulating factor administration following consolidation therapy with high-dose cytarabine is associated with decreased hospitalization rate and improved survival. This finding is not consistent with the prior knowledge from the randomized studies. Herein, we review some of the explanations for the findings and re-emphasize the limitations of nonrandomized studies in assessing acute myeloid leukemia outcomes, as appreciated by the authors.

  14. Granulocyte colony-stimulating factor in repeated IVF failure, a randomized trial.

    PubMed

    Aleyasin, Ashraf; Abediasl, Zhila; Nazari, Atefeh; Sheikh, Mahdi

    2016-06-01

    Recent studies have revealed key roles for granulocyte colony-stimulating factor (GCSF) in embryo implantation process and maintenance of pregnancy, and some studies showed promising results by using local intrauterine infusion of GCSF in patients undergoing in vitro fertilization (IVF). This multicenter, randomized, controlled trial included 112 infertile women with repeated IVF failure to evaluate the efficacy of systemic single-dose subcutaneous GCSF administration on IVF success in these women. In this study, the Long Protocol of ovarian stimulation was used for all participants. Sealed, numbered envelopes assigned 56 patients to receive subcutaneous 300 µg GCSF before implantation and 56 in the control group. The implantation (number of gestational sacs on the total number of transferred embryos), chemical pregnancy (positive serum β-HCG), and clinical pregnancy (gestational sac and fetal heart) rates were compared between the two groups. This trial is registered at www.irct.ir (IRCT201503119568N11). The successful implantation (18% vs 7.2%, P=0.007), chemical pregnancy (44.6% vs 19.6%, P=0.005), and clinical pregnancy (37.5% vs 14.3%, P=0.005) rates were significantly higher in the intervention group than in the control group. After adjustment for participants' age, endometrial thickness, good-quality oocyte counts, number of transferred embryos, and anti-Mullerian hormone levels, GCSF treatment remained significantly associated with successful implantation (OR=2.63, 95% CI=1.09-6.96), having chemical pregnancy (OR= 2.74, 95% CI=1.11-7.38) and clinical pregnancy (OR=2.94, 95% CI=1.23-8.33). In conclusion, administration of single-dose systemic subcutaneous GCSF before implantation significantly increases the IVF success, implantation, and pregnancy rates in infertile women with repeated IVF failure.

  15. Administration of granulocyte colony-stimulating factor with radiotherapy promotes tumor growth by stimulating vascularization in tumor-bearing mice.

    PubMed

    Kim, Joong Sun; Son, Yeonghoon; Bae, Min Ji; Lee, Minyoung; Lee, Chang Geun; Jo, Wol Soon; Kim, Sung Dae; Yang, Kwangmo

    2015-07-01

    Although granulocyte-colony stimulating factor (G-CSF) is commonly used to support recovery from radiation-induced side-effects, the precise effects of G-CSF on colon cancer under radiotherapy remain poorly understood. In the present study, to investigate the effects of tumor growth following radiotherapy and G-CSF administration in a murine xenograft model of colon cancer, female BALB/c mice were injected with cells of a colon carcinoma cell line (CT26) with irradiation and G-CSF, alone or in combination. Mice received 2 Gy of focal radiation daily for 5 days and intraperitoneal injection of G-CSF (100 µg/kg/day) after irradiation for 7 days. Changes in the levels of myeloperoxidase (MPO), vascular endothelial growth factor (VEGF), matrix metalloproteinase type 9 (MMP-9) and CD31 were assessed in the mouse cancer induced by injection of colon cancer cells. We observed that G-CSF increased the number of circulating neutrophils, but facilitated tumor growth. However, G-CSF treatment did not affect radiation-induced cytotoxicity and cell viability in CT26 cells in vitro. Increased levels of myeloperoxidase, a neutrophil marker and those of vascular endothelial growth factor were observed in tumors with G-CSF supplementation. In addition, we found that increased levels of CD31 and matrix metalloproteinase-9 were correlated with the enhanced tumor growth after G-CSF treatment. Therefore, these data suggest that G-CSF may contribute to tumor growth and decrease the antitumor effect of radiotherapy, possibly by promoting vascularization in cancer lesions.

  16. Molecular Mechanism of Regulation of MTA1 Expression by Granulocyte Colony-stimulating Factor*

    PubMed Central

    Kumar, Arathy S.; Jagadeeshan, Sankar; Subramanian, Anirudh; Chidambaram, Saravana Babu; Surabhi, Rohan Prasad; Singhal, Mahak; Bhoopalan, Hemadev; Sekar, Sathiya; Pitani, Ravi Shankar; Duvuru, Prathiba; Venkatraman, Ganesh; Rayala, Suresh K.

    2016-01-01

    Parkinson disease (PD) is a neurodegenerative disorder with loss of dopaminergic neurons of the brain, which results in insufficient synthesis and action of dopamine. Metastasis-associated protein 1 (MTA1) is an upstream modulator of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, and hence MTA1 plays a significant role in PD pathogenesis. To impart functional and clinical significance to MTA1, we analyzed MTA1 and TH levels in the substantia nigra region of a large cohort of human brain tissue samples by Western blotting, quantitative PCR, and immunohistochemistry. Our results showed that MTA1 and TH levels were significantly down-regulated in PD samples as compared with normal brain tissue. Correspondingly, immunohistochemistry analysis for MTA1 in substantia nigra sections revealed that 74.1% of the samples had a staining intensity of <6 in the PD samples as compared with controls, 25.9%, with an odds ratio of 8.54. Because of the clinical importance of MTA1 established in PD, we looked at agents to modulate MTA1 expression in neuronal cells, and granulocyte colony-stimulating factor (G-CSF) was chosen, due to its clinically proven neurogenic effects. Treatment of the human neuronal cell line KELLY and acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model with G-CSF showed significant induction of MTA1 and TH with rescue of phenotype in the mouse model. Interestingly, the observed induction of TH was compromised on silencing of MTA1. The underlying molecular mechanism of MTA1 induction by G-CSF was proved to be through induction of c-Fos and its recruitment to the MTA1 promoter. PMID:27044752

  17. Granulocyte colony stimulating factor attenuates inflammation in a mouse model of amyotrophic lateral sclerosis

    PubMed Central

    2011-01-01

    Background Granulocyte colony stimulating factor (GCSF) is protective in animal models of various neurodegenerative diseases. We investigated whether pegfilgrastim, GCSF with sustained action, is protective in a mouse model of amyotrophic lateral sclerosis (ALS). ALS is a fatal neurodegenerative disease with manifestations of upper and lower motoneuron death and muscle atrophy accompanied by inflammation in the CNS and periphery. Methods Human mutant G93A superoxide dismutase (SOD1) ALS mice were treated with pegfilgrastim starting at the presymptomatic stage and continued until the end stage. After long-term pegfilgrastim treatment, the inflammation status was defined in the spinal cord and peripheral tissues including hematopoietic organs and muscle. The effect of GCSF on spinal cord neuron survival and microglia, bone marrow and spleen monocyte activation was assessed in vitro. Results Long-term pegfilgrastim treatment prolonged mutant SOD1 mice survival and attenuated both astro- and microgliosis in the spinal cord. Pegfilgrastim in SOD1 mice modulated the inflammatory cell populations in the bone marrow and spleen and reduced the production of pro-inflammatory cytokine in monocytes and microglia. The mobilization of hematopoietic stem cells into the circulation was restored back to basal level after long-term pegfilgrastim treatment in SOD1 mice while the storage of Ly6C expressing monocytes in the bone marrow and spleen remained elevated. After pegfilgrastim treatment, an increased proportion of these cells in the degenerative muscle was detected at the end stage of ALS. Conclusions GCSF attenuated inflammation in the CNS and the periphery in a mouse model of ALS and thereby delayed the progression of the disease. This mechanism of action targeting inflammation provides a new perspective of the usage of GCSF in the treatment of ALS. PMID:21711557

  18. Granulocyte colony-stimulating factor receptor expression on human transitional cell carcinoma of the bladder.

    PubMed Central

    Tachibana, M.; Miyakawa, A.; Uchida, A.; Murai, M.; Eguchi, K.; Nakamura, K.; Kubo, A.; Hata, J. I.

    1997-01-01

    Receptors for granulocyte colony-stimulating factor (G-CSFRs) have been confirmed on the cell surfaces of several non-haematopoietic cell types, including bladder cancer cells. This observation has naturally led to the hypothesis that the expression of G-CSFR on these cells may enhance their growth by G-CSF. In this study, the expression of G-CSFR was determined in both established human bladder cancer cell lines and primary bladder cancers. We studied five different human bladder cancer cell lines (KU-1, KU-7, T-24, NBT-2 and KK) and 26 newly diagnosed bladder tumours. G-CSFR mRNA expressions on cultured cell lines were determined using the reverse transcriptase polymerase chain reaction (RT-PCR) method. Furthermore, the G-CSFR binding experiments on the cultured cell lines were conducted using the Na(125)I-labelled G-CSF ligand-binding assay method. Moreover, the G-CSFR mRNA expressions on primary bladder tumour specimens were assessed using the in situ RT-PCR method. Three out of the five cultured cell lines (KU-1, NBT-2 and KK) exhibited G-CSFR mRNA signals when the RT-PCR method was used. The G-CSFR binding experiments showed an equilibrium dissociation constant (K[d]) of 490 pM for KU-1, 340 pM for NBT-2 and 103 pM for KK cells. With in situ RT-PCR, the tumour cells of 6 out of 26 primary bladder tumour specimens (23.1%) presented positive G-CSFR mRNA signals. Thus, in this study, G-CSFR expression was frequently observed on bladder cancer cells. Therefore, the clinical use of G-CSF for patients with bladder cancer should be selected with great care. Images Figure 1 Figure 3 Figure 4 PMID:9166942

  19. Use of granulocyte colony-stimulating factor during pregnancy in women with chronic neutropenia.

    PubMed

    Boxer, Laurence A; Bolyard, Audrey Anna; Kelley, Merideth L; Marrero, Tracy M; Phan, Lan; Bond, Jordan M; Newburger, Peter E; Dale, David C

    2015-01-01

    To report outcomes associated with the administration of granulocyte colony-stimulating factor (G-CSF) to women with chronic neutropenia during pregnancy. We conducted an observational study of women of childbearing potential with congenital, cyclic, idiopathic, or autoimmune neutropenia enrolled in the Severe Chronic Neutropenia International Registry to determine outcomes of pregnancies, without and with chronic G-CSF therapy, 1999-2014. Treatment decisions were made by the patients' personal physicians. A research nurse conducted telephone interviews of all enrolled U.S. women of childbearing potential using a standard questionnaire. Comparisons used Fisher's exact test analysis and Student's t test. One hundred seven women reported 224 pregnancies, 124 without G-CSF therapy and 100 on chronic G-CSF therapy (median dose 1.0 micrograms/kg per day, range 0.02-8.6 micrograms/kg per day). There were no significant differences in adverse events between the groups considering all pregnancies or individual mothers, for example, spontaneous terminations (all pregnancies: no G-CSF in 27/124, G-CSF in 13/100; P=.11, Fisher's exact test), preterm labors (all pregnancies, no G-CSF in 9/124, G-CSF in 2/100, P=.12). A study with at least 300 per group would be needed to detect a difference in these events with 80% statistical power (α=0.05). Four newborns of mothers with idiopathic or autoimmune neutropenia not on G-CSF (4/101) had life-threatening infections, whereas there were no similar events (0/90) in the treated group, but this difference was also not statistically significant (P=.124). Adverse events in the neonates were similar for the two groups. This observational study showed no significant adverse effects of administration of G-CSF to women with severe chronic neutropenia during pregnancy. III.

  20. The effects of granulocyte colony-stimulating factor in preclinical models of infection and acute inflammation.

    PubMed

    Marshall, John C

    2005-12-01

    The cytokine granulocyte colony-stimulating factor (G-CSF) is a potent endogenous trigger for the release of neutrophils from bone marrow stores and for their activation for enhanced antimicrobial activity. G-CSF has been widely evaluated in preclinical models of acute illness, with generally promising though divergent results. A recombinant G-CSF molecule has recently undergone clinical trials to assess its efficacy as an adjuvant therapy in community-acquired and nosocomial pneumonia, however, these studies failed to provide convincing evidence of benefit. We undertook a systematic review of the published literature reporting the effects of modulation of G-CSF in preclinical in vivo models to determine whether evidence of differential efficacy might explain the disappointing results of human studies and point to disease states that might be more likely to benefit from G-CSF therapy. G-CSF has been evaluated in 86 such studies involving a variety of different models. The strongest evidence of benefit was seen in studies involving intraperitoneal challenge with live organisms; benefit was evident whether the agent was given before or after challenge. G-CSF demonstrates anti-inflammatory activity in models of systemic challenge with viable organisms or endotoxin, but only when the agent is given before challenge; evidence of benefit after challenge was minimal. Preclinical models of intrapulmonary challenge only show efficacy when the cytokine is administered before the infectious challenge, and suggested harm in gram-negative pneumonia resulting from challenge with Escherichia coli or Klebsiella. There is little evidence for therapeutic efficacy in noninfectious models of acute illness. We conclude that the most promising populations for evaluation of G-CSF are neutropenic patients with invasive infection and patients with intra-abdominal infection, particularly those with the syndrome of tertiary, or recurrent, peritonitis. Significant variability in the design

  1. Bacillus cereus brain abscesses occurring in a severely neutropenic patient: successful treatment with antimicrobial agents, granulocyte colony-stimulating factor and surgical drainage.

    PubMed

    Sakai, C; Iuchi, T; Ishii, A; Kumagai, K; Takagi, T

    2001-07-01

    Multiple brain and liver abscesses developed immediately after Bacillus cereus bacteremia in a neutropenic patient with acute lymphoblastic leukemia. After even 8 weeks of antimicrobial chemotherapy together with administration of granulocyte colony-stimulating factor, every infectious process disappeared but the patient's headache has still persisted. Because the wall of one brain abscess became thin and was in danger of rupturing into the ventricle, surgical drainage was performed, resulting in disappearance of headache and resolution of brain abscess. The present case indicates that a combined medical and surgical approach is mandatory to treat patients with brain abscesses.

  2. Follow-up of healthy donors receiving granulocyte colony-stimulating factor for peripheral blood progenitor cell mobilization and collection. Results of the Spanish Donor Registry.

    PubMed

    de la Rubia, Javier; de Arriba, Felipe; Arbona, Cristina; Pascual, María J; Zamora, Concha; Insunza, Andrés; Martínez, Dorleta; Paniagua, Carmen; Díaz, Miguel A; Sanz, Miguel A

    2008-05-01

    Information about the long-term follow-up and safety of granulocyte colony-stimulating factor administration to healthy donors is limited. The aims of this study were to analyze the side effects of granulocyte colony-stimulating factor administration in donors included in a Spanish Registry of hematopoietic stem cell donors and to determine the long-term outcome of these donors. The Spanish National Donor Registry was developed to record the short- and long-term results of granulocyte colony-stimulating factor administration to mobilize peripheral blood progenitor cells in normal donors. To date, 1436 donors (771 males, 665 females) with a median age of 37 years (range, 1 to 74 years) have been registered. Granulocyte colony-stimulating factor was the only cytokine administered. A baseline investigation was performed in every donor before granulocyte colony-stimulating factor administration and follow-up investigations (controls) were planned at 4 weeks and annually thereafter for up to 5 years after the mobilization. At least one of the scheduled controls was performed in 736 donors, while 320 donors have been followed for 2 years or more. The peripheral white blood cell count decreased significantly from 6.8 x 10(9)/L at baseline to 5.9 x 10(9)/L at 4 weeks after leukapheresis (p<0.0001) and remained at values lower than those observed premobilization until 2 years after mobilization. In contrast, hemoglobin concentration and platelet count returned to normal values within 1 year after mobilization. Bone pain (90%) and headache (33%) were the most frequently reported granulocyte colony-stimulating factor-related side effects. Five patients (0.68%) were diagnosed as having solid tumors (lung cancer in two patients and thyroid carcinoma, choroid melanoma, and colon carcinoma in one patient each) between 10 and 64 months after administration of granulocyte colony-stimulating factor. No hematologic malignancies have been reported. The clinical side effects of

  3. Polymorphonuclear leukocytes released from the bone marrow by granulocyte colony-stimulating factor: intravascular behavior.

    PubMed

    Mukae, H; Zamfir, D; English, D; Hogg, J C; van Eeden, S F

    2000-01-01

    Granulocyte-colony stimulating factor (G-CSF) treatment stimulates the bone marrow and releases polymorphonuclear leukocytes (PMN) into the circulation. This study was designed to measure the intravascular margination, demargination and survival of PMN released from the marrow by G-CSF. To trace PMN in the circulation, dividing PMN in the bone marrow of rabbits were labeled with 5'-bromo-2'-deoxyuridine (BrdU) and the effects of a single dose of G-CSF (12.5 microg/kg) on the behavior of these labeled cells in the circulation were measured. The results show that G-CSF induced a granulocytosis that peaked 12 h after treatment. This granulocytosis was associated with stimulation of the bone marrow characterized by shortening of the transit time of PMN through the marrow (97.3+/-2.5 h n=4 control vs 78.9+/-3.6 h n=5 G-CSF) particularly in the post-mitotic pool (P<0.01). Morphometric studies of the lung show a reduced sequestration of BrdU-labeled PMN in lung microvessels in G-CSF-treated animals (P<0.05) and a approximately 14-fold (G-CSF-group) vs a approximately 65-fold (control-group) enrichment of BrdU-labeled PMN in lung tissue if compared to circulating blood. The effect of G-CSF on demargination of PMN was measured by transferring BrdU-labeled PMN from donor animals treated with G-CSF to recipients. G-CSF did not cause demargination of intravascular PMN but delayed the clearance of G-CSF-treated PMN in the circulation. This delayed clearance was associated with inhibition of apoptosis in circulating PMN when measured both by morphology (17.7+/-2.3 vs 7.5+/-1.4%, P<0.01) and flow cytometry (16.2+/-1.1 vs 5+/-1.9%, P<0.01) using a DNA end-labeling method (control vs G-CSF group). We conclude that PMN released from the bone marrow by G-CSF sequestered less in the lung microvessels and have a prolonged intravascular life span.

  4. Using Hydrogen/Deuterium Exchange Mass Spectrometry to Study Conformational Changes in Granulocyte Colony Stimulating Factor upon PEGylation

    NASA Astrophysics Data System (ADS)

    Wei, Hui; Ahn, Joomi; Yu, Ying Qing; Tymiak, Adrienne; Engen, John R.; Chen, Guodong

    2012-03-01

    PEGylation is the covalent attachment of polyethylene glycol to proteins, and it can be used to alter immunogenicity, circulating half life and other properties of therapeutic proteins. To determine the impact of PEGylation on protein conformation, we applied hydrogen/deuterium exchange mass spectrometry (HDX MS) to analyze granulocyte colony stimulating factor (G-CSF) upon PEGylation as a model system. The combined use of HDX automation technology and data analysis software allowed reproducible and robust measurements of the deuterium incorporation levels for peptic peptides of both PEGylated and non-PEGylated G-CSF. The results indicated that significant differences in deuterium incorporation were induced by PEGylation of G-CSF, although the overall changes observed were quite small. PEGylation did not result in gross conformational rearrangement of G-CSF. The data complexity often encountered in HDX MS measurements was greatly reduced through a data processing and presentation format designed to facilitate the comparison process. This study demonstrates the practical utility of HDX MS for comparability studies, process monitoring, and protein therapeutic characterization in the biopharmaceutical industry.

  5. Characterization of Stress-Exposed Granulocyte Colony Stimulating Factor Using ELISA and Hydrogen/Deuterium Exchange Mass Spectrometry

    NASA Astrophysics Data System (ADS)

    Tsuchida, Daisuke; Yamazaki, Katsuyoshi; Akashi, Satoko

    2014-10-01

    Information on the higher-order structure is important in the development of biopharmaceutical drugs. Recently, hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS) has been widely used as a tool to evaluate protein conformation, and unique automated systems for HDX-MS are now commercially available. To investigate the potential of this technique for the prediction of the activity of biopharmaceuticals, granulocyte colony stimulating factor (G-CSF), which had been subjected to three different stress types, was analyzed using HDX-MS and through comparison with receptor-binding activity. It was found that HDX-MS, in combination with ion mobility separation, was able to identify conformational changes in G-CSF induced by stress, and a good correlation with the receptor-binding activity was demonstrated, which cannot be completely determined by conventional peptide mapping alone. The direct evaluation of biological activity using bioassay is absolutely imperative in biopharmaceutical development, but HDX-MS can provide the alternative information in a short time on the extent and location of the structural damage caused by stresses. Furthermore, the present study suggests the possibility of this system being a versatile evaluation method for the preservation stability of biopharmaceuticals.

  6. Plerixafor and granulocyte colony-stimulating factor for first-line steady-state autologous peripheral blood stem cell mobilization in lymphoma and multiple myeloma: results of the prospective PREDICT trial

    PubMed Central

    Russell, Nigel; Douglas, Kenny; Ho, Anthony D.; Mohty, Mohamad; Carlson, Kristina; Ossenkoppele, G.J.; Milone, Giuseppe; Pareja, Macarena Ortiz; Shaheen, Daniel; Willemsen, Arnold; Whitaker, Nicky; Chabannon, Christian

    2013-01-01

    In Europe, the combination of plerixafor + granulocyte colony-stimulating factor is approved for the mobilization of hematopoietic stem cells for autologous transplantation in patients with lymphoma and myeloma whose cells mobilize poorly. The purpose of this study was to further assess the safety and efficacy of plerixafor + granulocyte colony-stimulating factor for front-line mobilization in European patients with lymphoma or myeloma. In this multicenter, open label, single-arm study, patients received granulocyte colony-stimulating factor (10 μg/kg/day) subcutaneously for 4 days; on the evening of day 4 they were given plerixafor (0.24 mg/kg) subcutaneously. Patients underwent apheresis on day 5 after a morning dose of granulocyte colony-stimulating factor. The primary study objective was to confirm the safety of mobilization with plerixafor. Secondary objectives included assessment of efficacy (apheresis yield, time to engraftment). The combination of plerixafor + granulocyte colony-stimulating factor was used to mobilize hematopoietic stem cells in 118 patients (90 with myeloma, 25 with non-Hodgkin's lymphoma, 3 with Hodgkin's disease). Treatment-emergent plerixafor-related adverse events were reported in 24 patients. Most adverse events occurred within 1 hour after injection, were grade 1 or 2 in severity and included gastrointestinal disorders or injection-site reactions. The minimum cell yield (≥2×106 CD34+ cells/kg) was harvested in 98% of patients with myeloma and in 80% of those with non-Hodgkin's lymphoma in a median of one apheresis. The optimum cell dose (≥5×106 CD34+ cells/kg for non-Hodgkin's lymphoma or ≥6×106 CD34+ cells/kg for myeloma) was harvested in 89% of myeloma patients and 48% of non-Hodgkin's lymphoma patients. In this prospective, multicenter European study, mobilization with plerixafor + granulocyte colony-stimulating factor allowed the majority of patients with myeloma or non-Hodgkin's lymphoma to undergo transplantation with

  7. Protective effects of granulocyte colony-stimulating factor on endotoxin shock in mice with retrovirus-induced immunodeficiency syndrome.

    PubMed

    Toki, S; Hiromatsu, K; Aoki, Y; Makino, M; Yoshikai, Y

    1997-10-01

    Mice with retrovirus-induced murine acquired immunodeficiency syndrome (MAIDS) were hypersensitive to lipopolysaccharide (LPS)-induced lethal shock accompanied by marked elevations of systematic interleukin 1beta (IL-beta) and interferon gamma (IFN-gamma) after LPS challenge. Pretreatment with 10 microg of recombinant human granulocyte colony-stimulating factor (rhG-CSF) protected MAIDS mice from hypersensitivity to LPS-induced lethal shock and this protection was concomitant with suppression of IFN-gamma production. Copyright 1997 Academic Press Limited.

  8. Adrenaline administration promotes the efficiency of granulocyte colony stimulating factor-mediated hematopoietic stem and progenitor cell mobilization in mice.

    PubMed

    Chen, Chong; Cao, Jiang; Song, Xuguang; Zeng, Lingyu; Li, Zhenyu; Li, Yong; Xu, Kailin

    2013-01-01

    A high dose of granulocyte colony stimulating factor (G-CSF) is widely used to mobilize hematopoietic stem and progenitor cells (HSPC), but G-CSF is relatively inefficient and may cause adverse effects. Recently, adrenaline has been found to play important roles in HSPC mobilization. In this study, we explored whether adrenaline combined with G-CSF could induce HSPC mobilization in a mouse model. Mice were treated with adrenaline and either a high or low dose of G-CSF alone or in combination. Peripheral blood HSPC counts were evaluated by flow cytometry. Levels of bone marrow SDF-1 were measured by ELISA, the transcription of CXCR4 and SDF-1 was measured by real-time RT-PCR, and CXCR4 protein was detected by Western blot. Our results showed that adrenaline alone fails to mobilize HSPCs into the peripheral blood; however, when G-CSF and adrenaline are combined, the WBC counts and percentages of HSPCs are significantly higher compared to those in mice that received G-CSF alone. The combined use of adrenaline and G-CSF not only accelerated HSPC mobilization, but also enabled the efficient mobilization of HSPCs into the peripheral blood at lower doses of G-CSF. Adrenaline/G-CSF treatment also extensively downregulated levels of SDF-1 and CXCR4 in mouse bone marrow. These results demonstrated that adrenaline combined with G-CSF can induce HSPC mobilization by down-regulating the CXCR4/SDF-1 axis, indicating that the use of adrenaline may enable the use of reduced dosages or durations of G-CSF treatment, minimizing G-CSF-associated complications.

  9. Granulocyte Colony-stimulating Factor Producing Anaplastic Carcinoma of the Pancreas: Case Report and Review of the Literature.

    PubMed

    Vinzens, Sarah; Zindel, Joel; Zweifel, Martin; Rau, Tilman; Gloor, Beat; Wochner, Annette

    2017-01-01

    We report on the case of a 67-year-old man with granulocyte colony-stimulating factor (G-CSF) producing anaplastic carcinoma of the pancreas. Preoperative routine tests revealed an elevated white blood cell (WBC) count of 25.2 G/l, consisting almost exclusively of neutrophilic granulocytes (23.31 G/l) with a predominance of segmented neutrophils (78% of all neutrophilic granulocytes), and elevated levels of C-reactive protein at 87 mg/l. Upon surgery, local tumour infiltration was more extensive than expected from preoperative imaging. However, no peritoneal dissemination was found and curative resection was attempted. Only seven days after the operation, signs of relapse were seen upon computed tomograpy. Histology revealed an undifferentiated anaplastic carcinoma, on the basis of a poorly differentiated ductal adenocarcinoma. Immunohistochemistry demonstrated G-CSF and G-CSF-Receptor expression in some CD68-positive syncytial macrophages. Granulocyte colony-stimulating factor (G-CSF) in serum was elevated at 5.6 pg/ml, which further raised to 43 pg/ml one week after FOLFIRINOX chemotherapy (oxaliplatin, irinotecan, 5-fluorouracil), while WBC decreased from 103.3 G/l to 59.3 G/l. Granulocyte macrophage-colony stimulating factor (GM-CSF) in serum was normal (<0.5 pg/ml). The patient died on postoperative day 34.

  10. Survival enhancement and hemopoietic regeneration following radiation exposure: Therapeutic approach using glucan and granulocyte colony-stimulating factor

    SciTech Connect

    Patchen, M.L.; MacVittie, T.J.; Solberg, B.D.; Souza, L.M. )

    1990-10-01

    C3H/HeN female mice were exposed to whole-body cobalt-60 radiation and administered soluble glucan (5 mg i.v. at 1 h following exposure), recombinant human granulocyte colony-stimulating factor (G-CSF; 2.5 micrograms/day s.c., days 3-12 following exposure), or both agents. Treatments were evaluated for their ability to enhance hemopoietic regeneration, and to increase survival after radiation-induced myelosuppression. Both glucan and G-CSF enhanced hemopoietic regeneration alone; however, greater effects were observed in mice receiving both agents. For example, on day 17 following a sublethal 6.5-Gy radiation exposure, mice treated with saline, G-CSF, glucan, or both agents, respectively, exhibited 36%, 65%, 50%, and 78% of normal bone marrow cellularity, and 84%, 175%, 152%, and 212% of normal splenic cellularity. At this same time, granulocyte-macrophage colony-forming cell (GM-CFC) values in saline, G-CSF, glucan, or combination-treated mice, respectively, were 9%, 46%, 26%, and 57% of normal bone marrow values, and 57%, 937%, 364%, and 1477% of normal splenic values. Endogenous spleen colony formation was also increased in all treatment groups, with combination-treated mice exhibiting the greatest effects. Likewise, although both glucan and G-CSF alone enhanced survival following an 8-Gy radiation exposure, greatest survival was observed in mice treated with both agents. These studies suggest that glucan, a macrophage activator, can synergize with G-CSF to further accelerate hemopoietic regeneration and increase survival following radiation-induced myelosuppression.

  11. The efficiency of granulocyte colony-stimulating factor in hemorrhagic mucositis and febrile neutropenia resulted from methotrexate toxicity.

    PubMed

    Ozkol, Hatice Uce; Toptas, Tayfur; Calka, Omer; Akdeniz, Necmettin

    2015-01-01

    Methotrexate (MTX) remains one of the most frequently used anti-metabolite agents in dermatology. MTX is an analog of folate that competitively and irreversibly inhibits dihydrofolate reductase. Oral mucositis is a common side effect of chemotherapy drugs and is characterized by erythema, pain, poor oral intake, pseudomembranous destruction, open ulceration and hemorrhage of the oral mucosa. In this paper, we report a 32-year-old female with a case of mucositis due to MTX intoxication that resulted from an overdose for rheumatoid arthritis. The patient had abdominal pain, vomiting, and nausea. During follow-up, the patient's white blood cell count was found to be 0.9 × 10(9)/L (4-10 × 10(9)/L). The patient developed fever exceeding 40 °C. The patient was consulted to the hematology service. They suggested using granulocyte colony-stimulating factor for febrile neutropenia. On the fifth day of treatment, the white blood cell count reached 5.3 × 10(9)/L and the patient's fever and mucositis started to resolve. Here, we presented a case of hemorrhagic mucositis and febrile neutropenia resulted from high-dose MTX that responded very well to granulocyte colony-stimulating factor treatment and we reviewed the literature.

  12. Effect of Granulocyte Colony-Stimulating Factor Immobilized by the Electron-Beam Synthesis Nanotechnology on Reparative Regeneration of Spermatogenous Tissue.

    PubMed

    Borovskaya, T G; Dygai, A M; Shchemerova, Yu A; Kamalova, S I; Mashanova, V A; Vychuzhanina, A V; Poluektova, M E; Madonov, P G; Kinsht, D N; Goldberg, V E

    2016-09-01

    Effectiveness of the granulocyte colony-stimulating factor immobilized by using electronbeam synthesis nanotechnology was investigated on the model of experimental testicular failure caused by the toxic effect on stem spermatogonia. Administration of the drug to experimental paclitaxel-treated animals increased the number of sources of the proliferative pool of spermatogenesis and its productivity. The effectiveness of immobilized granulocyte colony-stimulating factor was based on its ability to stimulate reparative regeneration of the spermatogenic tissue, which manifested in a decrease in spermatogenic layer maturity and increase in the number of microenvironment cells. Effectiveness of the immobilized form of the drug was superior to that of non-immobilized form.

  13. Stem cell factor and granulocyte colony-stimulating factor exhibit therapeutic effects in a mouse model of CADASIL.

    PubMed

    Liu, Xiao-Yun; Gonzalez-Toledo, Maria E; Fagan, Austin; Duan, Wei-Ming; Liu, Yanying; Zhang, Siyuan; Li, Bin; Piao, Chun-Shu; Nelson, Lila; Zhao, Li-Ru

    2015-01-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a Notch3 dominant mutation-induced cerebral small vascular disease, is characterized by progressive degeneration of vascular smooth muscle cells (vSMCs) of small arteries in the brain, leading to recurrent ischemic stroke, vascular dementia and death. To date, no treatment can stop or delay the progression of this disease. Herein, we determined the therapeutic effects of stem cell factor (SCF) in combination with granulocyte colony-stimulating factor (G-CSF) (SCF+G-CSF) in a mouse model of CADASIL carrying the human mutant Notch3 gene. SCF+G-CSF was subcutaneously administered for 5 days and repeated 4 times with 1-4 month intervals. We found through water maze testing that SCF+G-CSF treatment improved cognitive function. SCF+G-CSF also attenuated vSMC degeneration in small arteries, increased cerebral blood vascular density, and inhibited apoptosis in CADASIL mice. We also discovered that loss of cerebral capillary endothelial cells and neural stem cells/neural progenitor cells (NSCs/NPCs) occurred in CADASIL mice. SCF+G-CSF treatment inhibited the CADASIL-induced cell loss in the endothelia and NSCs/NPCs and promoted neurogenesis. In an in vitro model of apoptosis, SCF+G-CSF prevented apoptotic cell death in vSMCs through AKT signaling and by inhibiting caspase-3 activity. These data suggest that SCF+G-CSF restricts the pathological progression of CADASIL. This study offers new insights into developing therapeutic strategies for CADASIL.

  14. Phase II Trial of Intravenous Low-Dose Granulocyte Colony-Stimulating Factor in Acute Ischemic Stroke.

    PubMed

    Mizuma, Atsushi; Yamashita, Toru; Kono, Syoichiro; Nakayama, Taira; Baba, Yasuhiko; Itoh, Shinji; Asakura, Kunihiko; Niimi, Yoshiki; Asahi, Takashi; Kanemaru, Kazuya; Mutoh, Tatsuro; Kuroda, Satoshi; Kinouchi, Hiroyuki; Abe, Koji; Takizawa, Shunya

    2016-06-01

    Granulocyte colony-stimulating factor (G-CSF) has shown neuroprotective and neurogenerative activities in experimental studies, and our previous phase I clinical study suggested the safety and potential efficacy of low-dose G-CSF in acute ischemic stroke patients. The present phase II trial is aimed to evaluate the effect of G-CSF administration on neurological function and infarct volume, compared with a placebo group. Forty-nine acute ischemic stroke patients (29 males, 20 females; 71 ± 10 years) within 24 hours after onset were recruited. Eligible patients were randomized 2:2:1 to receive G-CSF 150 µg/body/day, G-CSF 300 µg/body/day, and placebo, respectively. We evaluated clinical outcome in terms of the National Institutes of Health Stroke Scale, the modified Rankin Scale, and the Barthel Index at 90 days after onset, together with changes in infarct volume on magnetic resonance imaging. We found no serious adverse event, including change in leukocyte levels, which remained below 31,000/µL, at 150 and 300 µg G-CSF/body/day. Clinical outcome scores did not show any significant difference among the 3 groups. Chronological changes in infarct volume also showed no significant difference. G-CSF was well-tolerated at 150 and 300 µg/body/day in patients with acute ischemic stroke. However, administration of G-CSF at both 150 and 300 µg/body/day neither contributed to functional recovery nor reduced infarct volume at 3 months after onset, compared with the control group. The apparent lack of effectiveness may have been due to the small sample size. A trial of combination therapy with recombinant tissue plasminogen activator and G-CSF is planned. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  15. MicroRNA126 contributes to granulocyte colony-stimulating factor-induced hematopoietic progenitor cell mobilization by reducing the expression of vascular cell adhesion molecule 1.

    PubMed

    Salvucci, Ombretta; Jiang, Kan; Gasperini, Paola; Maric, Dragan; Zhu, Jinfang; Sakakibara, Shuhei; Espigol-Frigole, Georgina; Wang, Shushang; Tosato, Giovanna

    2012-06-01

    Mobilization of hematopoietic stem/progenitor cells from the bone marrow to the peripheral blood by granulocyte colony-stimulating factor is the primary means to acquire stem cell grafts for hematopoietic cell transplantation. Since hematopoietic stem/progenitor cells represent a minority of all blood cells mobilized by granulocyte colony-stimulating factor, the underlying mechanisms need to be understood in order to develop selective drugs. We analyzed phenotypic, biochemical and genetic changes in bone marrow cell populations from granulocyte colony-stimulating factor-mobilized and control mice, and linked such changes to effective mobilization of hematopoietic stem/progenitor cells. We show that granulocyte colony-stimulating factor indirectly reduces expression of surface vascular cell adhesion molecule 1 on bone marrow hematopoietic stem/progenitor cells, stromal cells and endothelial cells by promoting the accumulation of microRNA-126 (miR126)-containing microvescicles in the bone marrow extracellular compartment. We found that hematopoietic stem/progenitor cells, stromal cells and endothelial cells readily incorporate these miR126-loaded microvescicles, and that miR126 represses vascular cell adhesion molecule 1 expression on bone marrow hematopoietic stem/progenitor cells, stromal cells and endothelial cells. In line with this, miR126-null mice displayed a reduced mobilization response to granulocyte colony-stimulating factor. Our results implicate miR126 in the regulation of hematopoietic stem/progenitor cell trafficking between the bone marrow and peripheral sites, clarify the role of vascular cell adhesion molecule 1 in granulocyte colony-stimulating factor-mediated mobilization, and have important implications for improved approaches to selective mobilization of hematopoietic stem/progenitor cells.

  16. Mobilization of hematopoietic progenitors from normal donors using the combination of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor results in fewer plasmacytoid dendritic cells in the graft and enhanced donor T cell engraftment with Th1 polarization: results from a randomized clinical trial.

    PubMed

    Lonial, Sagar; Akhtari, Mojtaba; Kaufman, Jonathan; Torre, Claire; Lechowicz, Mary J; Flowers, Christopher; Sinha, Rajni; Khoury, Hanna J; Langston, Amelia A; Waller, Edmund K

    2013-03-01

    Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) both mobilize CD34(+) stem cells into the blood when administered before apheresis but have distinct effects on dendritic cell (DC) differentiation. We previously demonstrated that the combination of GM+G-CSF results in fewer plasmacytoid DCs (pDCs) when used to mobilize peripheral blood stem cells for autologous transplantation. To test the hypothesis that the content of pDCs in an allograft can be modulated with the cytokines used for mobilization, we randomized the human leukocyte antigen-matched sibling donors of 50 patients with hematological malignancies to a mobilization regimen of either GM+G-CSF (n = 25) or G-CSF alone (n = 25). Primary and secondary endpoints included the cellular constituents of the mobilized grafts, the kinetics of posttransplantation immune reconstitution, and clinical outcomes of the transplantation recipients. Grafts from donors receiving GM+G-CSF contained equivalent numbers of CD34(+) cells with fewer pDCs and T cells, with a higher fraction of Th1-polarized donor T cells than G-CSF mobilized grafts. Immune recovery was enhanced among recipients of GM+G-CSF. Survival was not significantly different between transplantation recipients in the two arms. The use of GM+G-CSF modulates immune function and recovery after allogeneic transplantation and should be explored in larger studies powered to evaluate clinical outcomes. Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  17. Granulocyte colony-stimulating factor (G-CSF) transiently suppresses mitogen-stimulated T-cell proliferative response

    PubMed Central

    Reyes, E; García-Castro, I; Esquivel, F; Hornedo, J; Cortes-Funes, H; Solovera, J; Alvarez-Mon, M

    1999-01-01

    Granulocyte colony-stimulation factor (G-CSF) is a cytokine that selectively promotes growth and maturation of neutrophils and may modulate the cytokine response to inflammatory stimuli. The purpose of this study was to examine the effect of G-CSF on ex vivo peripheral blood mononuclear cell (PBMC) functions. Ten patients with breast cancer were included in a clinical trial in which r-metHuG-CSF was administrered daily for 5 days to mobilize peripheral blood stem cells. Ten healthy women were also included as controls. Our data show that G-CSF treatment induces an increase in peripheral blood leucocyte, neutrophil, lymphocyte and monocyte counts. We have found a modulation in the percentages of CD19+, CD45+CD14+, CD4+CD45RA+ and CD4+CD45RO+ cells in PBMC fractions during G-CSF treatment. We have also found a significant reduction in the proliferative response of PBMC to mitogenic stimulation that reverted 14 days after the fifth and the last dose of G-CSF. Furthermore, it was not associated with significant changes in the pattern of cytokine production. The mechanism of this immunoregulatory effect is probably indirect since G-CSF receptor has not been found in T lymphocytes. This mechanism and its potential clinical applications remain to be elucidated. © 1999 Cancer Research Campaign PMID:10390001

  18. Granulocyte colony-stimulating factor versus granulocyte-macrophage colony-stimulating factor for collection of peripheral blood progenitor cells from healthy donors.

    PubMed

    Fischmeister, G; Gadner, H

    2000-05-01

    The harvesting of peripheral blood progenitor cells (PBPCs) after granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor stimulation instead of bone marrow in healthy donors has become increasingly popular. Donors, given the choice between bone marrow and PBPC donation, often prefer cytapheresis because of the easier access, no necessity for general anesthesia, and no multiple bone marrow punctures. In addition, accelerated engraftment and immunomodulation by granulocyte colony-stimulating factor-mobilized PBPCs are advantageous for the recipient. However, because of donor inconvenience and poor mobilization, there is a need to develop improved procedures. Aspects such as durability of hematopoietic engraftment, characterization of the earliest stem cell, and composition of PBPCs are not yet well defined, and international donor registration and follow-up must be considered when evaluating long-term safety profiles in healthy donors. This review concentrates on the most significant developments on mobilization of PBPCs published during the past year.

  19. Granulocyte colony stimulating factor treatment of resistant thin endometrium in women with frozen-thawed blastocyst transfer.

    PubMed

    Kunicki, Michał; Łukaszuk, Krzysztof; Liss, Joanna; Skowrońska, Patrycja; Szczyptańska, Joanna

    2017-02-01

    The aim of the study was to assess the granulocyte-colony stimulating factor (G-CSF) effect on unresponsive thin (<7 mm) endometrium in women undergoing frozen-thawed embryo transfer at the blastocyst stage. A total of 62 women with thin unresponsive endometrium were included in the study, of which, 29 received a G-CSF infusion and 33 who opted out of the study served as controls. Patients in both groups had similar endometrial thickness at the time of the initial evaluation: 6.50 mm (5.50-6.80) in the G-CSF and 6.40 mm (5.50-7.0) in the control group. However, after the infusion endometrial thickness increased significantly in the G-CSF group in comparison with the controls (p=0.01), (Δ) 0.5 (0.02-1.2) (p=0.005). In the G-CSF group endometrium expanded to 7.90 mm (6.58-8.70) while in the control group to 6.90 mm (6.0-7.75). Five women in each group conceived. The clinical pregnancy rate was 5/29 (17.24%) in the G-CSF treated group and 5/33 (15.15%) in the control group (p>0.05). The live birth rate was 2/29 (6.89%) in the G-CSF group and 2/33 (6.06%) in the control group (p>0.05). We concluded that G-CSF infusion leads to an improvement in endometrium thickness but not to any improvement in the clinical pregnancy and live birth rates. Until more data is available G-CSF treatment should be considered to be of limited value in increasing pregnancy rate. G-CSF: granulocyte colony-stimulating factor; M-CSF: macrophagecolony-stimulating factor; GM-CSF: granulocyte-macrophage colony-stimulating factor; FET: frozen embryo transfer; IVF: in vitro fertilization.

  20. Survival enhancement and hemopoietic regeneration following radiation exposure: therapeutic approach using glucan and granulocyte colony-stimulating factor

    SciTech Connect

    Patchen, M.L.; MacVittie, T.J.; Solberg, B.D.; Souza, L.M.

    1990-01-01

    C3H/HeN female mice were exposed to whole-body cobalt-60 radiation and administered soluble glucan (5 mg i.v. at 1 h following exposure), recombinant human granulocyte colony-stimulating factor or both agents. Treatments were evaluated for their ability to enhance hemopoietic regeneration, and to increase survival after radiation-induced myelosuppression. Both glucan and G-CSF enhanced hemopoietic regeneration alone; however, greater effects were observed in mice receiving both agents. For example, on day 17 following a sublethal 6.5-Gy radiation exposure, mice treated with saline, G-CSF, glucan, or both agents, respectively, exhibited 36%, 65%, 50%, and 78% of normal bone marrow cellularity, and 84%, 175%, 152%, and 212% of normal splenic cellularity.

  1. Enhanced activation of B cells in a granulocyte colony-stimulating factor-mobilized peripheral blood stem cell graft.

    PubMed

    Tayebi, H; Lapierre, V; Saas, P; Lienard, A; Sutton, L; Milpied, N; Attal, M; Cahn, J Y; Kuentz, M; Blaise, D; Hervé, P; Tiberghien, P; Robinet, E

    2001-09-01

    In a randomized study that compared human leucocyte antigen-identical allogeneic granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cell (PBSC) versus bone marrow (BM) transplantation, the expression of activation markers, CD23, CD25 and CD45RO by B cells, was compared in blood before and after G-CSF mobilization and in PBSC versus BM grafts. The fractions of CD23+ and CD25+ B cells were higher in PBSC than in BM grafts. Moreover, we observed a G-CSF-induced increase in B-cell fractions in blood as well as in PBSC grafts when compared with BM grafts. Such an enhanced B-cell activation could contribute to the accelerated kinetics of immuno-haematological reconstitution, the occurrence of acute haemolysis in the ABO minor incompatibility setting, as well as the increased incidence of chronic graft-versus-host disease observed after PBSC transplantation.

  2. Granulocyte colony-stimulating factors in the prevention of febrile neutropenia: review of cost-effectiveness models.

    PubMed

    Fust, Kelly; Parthan, Anju; Maschio, Michael; Gu, Qing; Li, Xiaoyan; Lyman, Gary H; Tzivelekis, Spiros; Villa, Guillermo; Weinstein, Milton C

    2017-02-01

    We reviewed the evolution of the methods used in cost-effectiveness analyses of granulocyte colony-stimulating factors (G-CSFs) in the primary and secondary prevention of febrile neutropenia (FN) in patients receiving myelosuppressive cancer chemotherapy. Areas covered: FN is a side effect of myelosuppressive chemotherapy associated with significant morbidity, mortality, and costs. The risk of FN may depend on the drugs used within a chemotherapy regimen, and an FN event may cause chemotherapy dose reductions or delays in subsequent cycles. Expert commentary: More recent pharmacoeconomic models have reflected these clinical observations by modeling sequential chemotherapy regimens to account for FN risk on a per-cycle basis, and by accounting for chemotherapy dose reductions and consequent survival losses.

  3. Weekly CODE chemotherapy with recombinant human granulocyte colony-stimulating factor for relapsed or refractory small cell lung cancer.

    PubMed

    Sato, K; Tsuchiya, S; Minato, K; Sunaga, N; Ishihara, S I; Makimoto, T; Naruse, I; Hoshino, H; Watanabe, S; Saitoh, R; Mori, M

    2000-01-01

    We used cisplatin, vincristine, doxorubicin, and etoposide (CODE) plus recombinant human granulocyte colony-stimulating factor (rhG-CSF) weekly for salvage chemotherapy in relapsed or refractory small cell lung cancer (SCLC). We reviewed the medical charts of patients between January 1993 and December 1996 at the National Nishi-Gunma Hospital. Twenty patients were treated with salvage chemotherapy. The overall response rate was 55.0%. The median survival time of extensive disease patients from the start of CODE therapy was 23 weeks and the 1-year survival rate was 21.0%. Toxicities were severe, especially in myelosuppression. CODE could be selected as a salvage therapy for chemotherapy- relapsed SCLC cases.

  4. Chronic recurrent multifocal osteomyelitis with Crohn's disease exacerbation and vasculitis after granulocyte colony-stimulating factor therapy.

    PubMed

    Manners, P; Robbins, P

    2000-10-01

    Chronic recurrent multifocal osteomyelitis (CRMO), of unknown etiology, is characterized by recurring non-suppurative lesions of bone in multiple sites, and has been considered to be self-limiting. Reported therapies include prolonged antibiotics, corticosteroids and anti-inflammatory medications. This case is presented to illustrate the following: 1) CRMO may be severe, on-going, and unresponsive to treatment; 2) it may be associated with Crohns' disease; 3) the use of granulocyte colony-stimulating factor (G-CSF) may be associated with severe gastrointestinal vasculitis. A male was treated from ages 11-20 years for CRMO (manifesting as multiple bone lesions), with therapies of variable efficacy (anti-inflammatories, antibiotics, corticosteroids, gammaglobulin and methotrexate). With increasing disruption to his life, a 10-day course of granulocyte colony-stimulating factor (G-CSF) was given with benefit seen on magnetic resonance imaging (MRI). With exacerbation of symptoms one month later, G-CSF was re-commenced but ceased after 3 weeks because of abdominal pain, rectal blood loss, and progression of bone lesions with subsequent removal of portions of ileum, colon and appendix, which showed vasculitis. Months later, a colonoscopy revealed perianastomotic ulcers and continuing gastroenterological ulceration not unlike Crohn's disease. With azathioprine, gut and bone symptoms improved. We conclude that 1) CRMO may adversely affect life for years; 2) proven treatments are unavailable; 3) gastroenterological vasculitis/ Crohn's may be associated with CRMO; 4) MRI is useful for monitoring CRMO; 5) In this patient, G-CSF seemed beneficial initially, but later, vasculitis (possibly Crohn's) manifested, leading to bowel resection; 6) Crohn's disease may have been present for years, masked by corticosteroid, and unmasked by reduction of steroids and use of G-CSF.

  5. Predicting erythroid response to recombinant erythropoietin plus granulocyte colony-stimulating factor therapy following a single subcutaneous bolus in patients with myelodysplasia.

    PubMed

    Bowen, David; Hyslop, Ann; Keenan, Norene; Groves, Michael; Culligan, Dominic; Johnson, Peter; Shaw, Ann; Geddes, Fiona; Evans, Patricia; Porter, John; Cavill, Ivor

    2006-05-01

    We randomized 21 patients with low-risk myelodysplastic syndromes (MDS) to receive a single subcutaneous bolus of recombinant erythropoietin (epoietin) +/- granulocyte-colony stimulating factor (G-CSF), or placebo and monitored erythropoietic response over 7 days. In this small study, the reticulocyte response at day 7 was highly predictive of subsequent response to a therapeutic trial of epoietin + G-CSF.

  6. Porcine granulocyte-colony stimulating factor (G-CSF) delivered via replication-defective adenovirus induces a sustained increase in circulating peripheral blood neutrophils

    USDA-ARS?s Scientific Manuscript database

    The use of immunomodulators is a promising area for biotherapeutic, prophylactic, and metaphylactic use to prevent and combat infectious disease, particularly during periods of peak disease incidence. Cytokines, including granulocyte colony-stimulating factor (G-CSF), are one class of compounds that...

  7. Administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) for the intracranial hemorrhage in two dogs: a case report

    PubMed Central

    Kang, M. H.; Park, H. M.

    2016-01-01

    Two dogs with generalized seizures were evaluated. The dogs were diagnosed with traumatic intracranial hemorrhages based on the history, neurological examinations, and magnetic resonance imaging (MRI) of the brain. Treatment was started with oxygen, prednisolone and anticonvulsant agents. No further seizure activity was observed after treatment in both dogs, however cushing reflex was detected in case 1 and a left-sided hemi-paresis was detected in case 2. Further supportive treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF) was attempted. No abnormal signs were noted in either of the dogs and no recurrence was noted 16 and 14 months later, in case 1 and 2, respectively. These cases indicate that a combination of rhG-CSF treatment with previous therapy could be used in dogs with traumatic brain injury. PMID:27656233

  8. Activation of adenosine A(3) receptors supports hematopoiesis-stimulating effects of granulocyte colony-stimulating factor in sublethally irradiated mice.

    PubMed

    Hofer, Michal; Pospísil, Milan; Sefc, Ludek; Dusek, Ladislav; Vacek, Antonín; Holá, Jirina; Hoferová, Zuzana; Streitová, Denisa

    2010-08-01

    Research areas of 'post-exposure treatment' and 'cytokines and growth factors' have top priority among studies aimed at radiological nuclear threat countermeasures. The experiments were aimed at testing the ability of N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA), an adenosine A(3) receptor agonist, to modulate hematopoiesis in sublethally irradiated mice, when administered alone or in a combination with granulocyte colony-stimulating factor (G-CSF) in a two-day post-irradiation treatment regimen. A complete analysis of hematopoiesis including determination of numbers of bone marrow hematopoietic progenitor and precursor cells, as well as of numbers of peripheral blood cells, was performed. The outcomes of the treatment were assessed at days 3 to 22 after irradiation. IB-MECA alone has been found to induce a significant elevation of numbers of bone marrow granulocyte-macrophage progenitor cells (GM-CFC) and peripheral blood neutrophils. IB-MECA given concomitantly with G-CSF increased significantly bone marrow GM-CFC and erythroid progenitor cells (BFU-E) in comparison with the controls and with animals administered each of the drugs alone. The findings suggest the ability of IB-MECA to stimulate hematopoiesis and to support the hematopoiesis-stimulating effects of G-CSF in sublethally irradiated mice.

  9. Effects of a granulocyte colony stimulating factor, Neulasta, in mini pigs exposed to total body proton irradiation

    PubMed Central

    Sanzari, Jenine K.; Krigsfeld, Gabriel S.; Shuman, Anne L.; Diener, Antonia K.; Lin, Liyong; Mai, Wilfried; Kennedy, Ann R.

    2015-01-01

    Astronauts could be exposed to solar particle event (SPE) radiation, which is comprised mostly of proton radiation. Proton radiation is also a treatment option for certain cancers. Both astronauts and clinical patients exposed to ionizing radiation are at risk for white blood cell (WBC) loss, which are the body’s main defense against infection. In this report, the effect of Neulasta treatment, a granulocyte colony stimulating factor, after proton radiation exposure is discussed. Mini pigs exposed to total body proton irradiation at a dose of 2 Gy received 4 treatments of either Neulasta or saline injections. Peripheral blood cell counts and thromboelastography parameters were recorded up to 30 days post-irradiation. Neulasta significantly improved white blood cell (WBC), specifically neutrophil, loss in irradiated animals by approximately 60% three days after the first injection, compared to the saline treated irradiated animals. Blood cell counts quickly decreased after the last Neulasta injection, suggesting a transient effect on WBC stimulation. Statistically significant changes in hemostasis parameters were observed after proton radiation exposure in both the saline and Neulasta treated irradiated groups, as well internal organ complications such as pulmonary changes. In conclusion, Neulasta treatment temporarily alleviates proton radiation-induced WBC loss, but has no effect on altered hemostatic responses. PMID:25909052

  10. Efficacy of Intrauterine infusion of granulocyte colony stimulating factor on patients with history of implantation failure: A randomized control trial

    PubMed Central

    Eftekhar, Maryam; Miraj, Sepideh; Farid Mojtahedi, Maryam; Neghab, Nosrat

    2016-01-01

    Background: Although pregnancy rate in in vitro fertilization-embryo transfer (IVF-ET) cycles has been increased over the preceding years, but the majority of IVF-ET cycles still fail. Granulocyte colony stimulating factor (GCSF) is a glycoprotein that stimulates cytokine growth factor and induces immune system which may improve pregnancy rate in women with history of implantation failure. Objective: The aim of this study was to evaluate GCSF ability to improve pregnancy rate in women with history of implantation failure Materials and Methods: 0.5 ml (300 µg/ml) GCSF was infused intrauterine in intervention group. Pregnancy outcomes were assessed based on clinical pregnancy. Results: The mean age of participants was 31.95±4.71 years old. There were no significant differences between demographic characteristics in two groups (p>0.05). The pregnancy outcome in GCSF group was improved significantly (p=0.043). Conclusion: GCSF can improve pregnancy outcome in patients with history of implantation failure. PMID:27981253

  11. Simplified Large-Scale Refolding, Purification, and Characterization of Recombinant Human Granulocyte-Colony Stimulating Factor in Escherichia coli

    PubMed Central

    Kim, Chang Kyu; Lee, Chi Ho; Lee, Seung-Bae; Oh, Jae-Wook

    2013-01-01

    Granulocyte-colony stimulating factor (G-CSF) is a pleiotropic cytokine that stimulates the development of committed hematopoietic progenitor cells and enhances the functional activity of mature cells. Here, we report a simplified method for fed-batch culture as well as the purification of recombinant human (rh) G-CSF. The new system for rhG-CSF purification was performed using not only temperature shift strategy without isopropyl-l-thio-β-d-galactoside (IPTG) induction but also the purification method by a single step of prep-HPLC after the pH precipitation of the refolded samples. Through these processes, the final cell density and overall yield of homogenous rhG-CSF were obtained 42.8 g as dry cell weights, 1.75 g as purified active proteins, from 1 L culture broth, respectively. The purity of rhG-CSF was finally 99% since the isoforms of rhG-CSF could be separated through the prep-HPLC step. The result of biological activity indicated that purified rhG-CSF has a similar profile to the World Health Organization (WHO) 2nd International Standard for G-CSF. Taken together, our results demonstrate that the simple purification through a single step of prep-HPLC may be valuable for the industrial-scale production of biologically active proteins. PMID:24224041

  12. Effects of a granulocyte colony stimulating factor, Neulasta, in mini pigs exposed to total body proton irradiation

    NASA Astrophysics Data System (ADS)

    Sanzari, Jenine K.; Krigsfeld, Gabriel S.; Shuman, Anne L.; Diener, Antonia K.; Lin, Liyong; Mai, Wilfried; Kennedy, Ann R.

    2015-04-01

    Astronauts could be exposed to solar particle event (SPE) radiation, which is comprised mostly of proton radiation. Proton radiation is also a treatment option for certain cancers. Both astronauts and clinical patients exposed to ionizing radiation are at risk for loss of white blood cells (WBCs), which are the body's main defense against infection. In this report, the effect of Neulasta treatment, a granulocyte colony stimulating factor, after proton radiation exposure is discussed. Mini pigs exposed to total body proton irradiation at a dose of 2 Gy received 4 treatments of either Neulasta or saline injections. Peripheral blood cell counts and thromboelastography parameters were recorded up to 30 days post-irradiation. Neulasta significantly improved WBC loss, specifically neutrophils, in irradiated animals by approximately 60% three days after the first injection, compared to the saline treated, irradiated animals. Blood cell counts quickly decreased after the last Neulasta injection, suggesting a transient effect on WBC stimulation. Statistically significant changes in hemostasis parameters were observed after proton radiation exposure in both the saline and Neulasta treated irradiated groups, as well as internal organ complications such as pulmonary changes. In conclusion, Neulasta treatment temporarily alleviates proton radiation-induced WBC loss, but has no effect on altered hemostatic responses.

  13. Analytical characterization of in vitro refolding in the quality by design paradigm: Refolding of recombinant human granulocyte colony stimulating factor.

    PubMed

    Pathak, Mili; Dixit, Shruti; Muthukumar, S; Rathore, Anurag S

    2016-07-15

    Protein based therapeutics dominate most pharmaceutical pipelines today. For a therapeutic product to be effective, it is important that it is in its native form as slight modifications have been known to result in significantly different performance in the clinic. When expressed in hosts such as Escherichia coli, formation of inactive insoluble aggregates of proteins popularly known as inclusion bodies occurs in most cases. This necessitates the need for in vitro refolding to generate the native (and active) form of the therapeutic protein. This paper aims to provide an approach to generate a deeper understanding of refolding of a therapeutic protein and then to use it for its optimal production commercially. Recombinant human granulocyte colony stimulating factor has been chosen as the model protein. Seven orthogonal analytical tools have been used to elucidate the refolding process. By strategically using these tools protein refolding has been segregated into a series of well-defined sequence of events, starting from the unfolded random coil and ending with the uniquely folded metastable state. The study also suggests the choice of tools that can be used to monitor each event. We believe that this paper successfully demonstrates an approach to generate deeper understanding of the protein refolding process as per the expectations laid out in the Quality by Design paradigm. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Granulocyte colony-stimulating factor (G-CSF) plays an important role in immune complex-mediated arthritis.

    PubMed

    Christensen, Anne D; Haase, Claus; Cook, Andrew D; Hamilton, John A

    2016-05-01

    Neutrophils are an abundant cell type in many chronic inflammatory diseases such as rheumatoid arthritis (RA); however, their contribution to the pathology of RA has not been widely studied. A key cytokine involved in neutrophil development and function is granulocyte-colony stimulating factor (G-CSF). In this study we used the K/BxN serum-transfer arthritis (STA) model, mimicking the effector phase of RA, to investigate the importance of G-CSF in arthritis development and its relation to neutrophils. Here, we show for the first time in this model that G-CSF levels are increased both in the serum and in inflamed paws of arthritic mice and importantly that G-CSF blockade leads to a profound reduction in arthritis severity, as well as reduced numbers of neutrophils in blood. Moreover, CXCL1 and CXCL2 levels in the arthritic joints were also lowered. Our data demonstrate that G-CSF is a pivotal driver of the disease progression in the K/BxN STA model and possibly acts in part by regulating neutrophil numbers in the circulation. Therefore, our findings suggest that G-CSF might be a suitable target in RA, and perhaps in other immune complex-driven pathologies. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Radiation promotes invasiveness of non-small-cell lung cancer cells through granulocyte-colony-stimulating factor.

    PubMed

    Cui, Y-H; Suh, Y; Lee, H-J; Yoo, K-C; Uddin, N; Jeong, Y-J; Lee, J-S; Hwang, S-G; Nam, S-Y; Kim, M-J; Lee, S-J

    2015-10-16

    Despite ionizing radiation (IR) is being widely used as a standard treatment for lung cancer, many evidences suggest that IR paradoxically promotes cancer malignancy. However, its molecular mechanisms underlying radiation-induced cancer progression remain obscure. Here, we report that exposure to fractionated radiation (2 Gy per day for 3 days) induces the secretion of granulocyte-colony-stimulating factor (G-CSF) that has been commonly used in cancer therapies to ameliorate neutropenia. Intriguingly, radiation-induced G-CSF promoted the migratory and invasive properties by triggering the epithelial-mesenchymal cell transition (EMT) in non-small-cell lung cancer cells (NSCLCs). By irradiation, G-CSF was upregulated transcriptionally by β-catenin/TCF4 complex that binds to the promoter region of G-CSF as a transcription factor. Importantly, irradiation increased the stability of β-catenin through the activation of PI3K/AKT (phosphatidylinositol 3-kinase/AKT), thereby upregulating the expression of G-CSF. Radiation-induced G-CSF is recognized by G-CSFR and transduced its intracellular signaling JAK/STAT3 (Janus kinase/signal transducers and activators of transcription), thereby triggering EMT program in NSCLCs. Taken together, our findings suggest that the application of G-CSF in cancer therapies to ameliorate neutropenia should be reconsidered owing to its effect on cancer progression, and G-CSF could be a novel therapeutic target to mitigate the harmful effect of radiotherapy for the treatment of NSCLC.

  16. Kinetics of Neutrophils in Mice Exposed to Radiation and/or Granulocyte Colony-Stimulating Factor Treatment

    PubMed Central

    Romero-Weaver, A. L.; Wan, X. S.; Diffenderfer, E. S.; Lin, L.; Kennedy, A. R.

    2014-01-01

    Astronauts have the potential to develop the hematopoietic syndrome as a result of exposure to radiation from a solar particle event (SPE) during exploration class missions. This syndrome is characterized by a reduction in the number of circulating blood cells (cytopenias). In the present study the effects of SPE-like proton and γ radiation on the kinetics of circulating neutrophils were evaluated during a one-month time period using mice as a model system. The results revealed that exposure to a 2 Gy dose of either SPE-like proton or γ radiation significantly decreased the number of circulating neutrophils, with two nadirs observed on day 4 and day 16 postirradiation. Low circulating neutrophil count (neutropenia) is particularly important because it can increase the risk of astronauts developing infections, which can compromise the success of the mission. Thus, two granulocyte colony-stimulating factors (G-CSFs), filgrastim and pegfilgrastim were evaluated as countermeasures for this endpoint. Both forms of G-CSF significantly increased neutrophil counts in irradiated mice, however, the effect of pegfilgrastim was more potent and lasted longer than filgrastim. Using the expression of CD11b, CD18 and the production of reactive oxygen species (ROS) as markers of neutrophil activation, it was determined that the neutrophils in the irradiated mice treated with pegfilgrastim were physiologically active. Thus, these results suggest that pegfilgrastim could be a potential countermeasure for the reduced number of circulating neutrophils in irradiated animals. PMID:23829559

  17. Phenotypic features of first-generation transgenic goats for human granulocyte-colony stimulation factor production in milk.

    PubMed

    Batista, Ribrio I T P; Melo, Carlos H S; Souza-Fabjan, Joanna M G; Teixeira, Dárcio I A; Melo, Luciana M; Freitas, Vicente J F

    2014-11-01

    Human granulocyte-colony stimulating factor (hG-CSF) is a hematopoietic growth factor used in neutropenic patients. It is produced in transgenic bacteria or cultured mammalian cells. As an alternative, we now show that hG-CSF can be expressed in the mammary gland of first-generation (F1) transgenic goats during induced lactation. Despite lower milk production, transgenic females presented a similar milk composition (fat, protein and lactose) when compared to non-transgenic (p > 0.05) ones. The mean concentration (±SD) of recombinant hG-CSF in milk during lactation was 360 ± 178 µg ml(-1). All clinical parameters, as well as kidney and liver function, indicated that F1 transgenic goats were healthy. Additionally, no ectopic hG-CSF expression was detected in studied tissues of F1 transgenic males. Thus, F1 hG-CSF-transgenic goats can express the recombinant protein in milk at quantities compatible with their use as bioreactors in a commercial-scale protein-production program.

  18. Use of granulocyte colony-stimulating factor (G-CSF) and outcome in patients with non-chemotherapy agranulocytosis.

    PubMed

    Ibáñez, L; Sabaté, M; Ballarín, E; Puig, R; Vidal, X; Laporte, J-R

    2008-03-01

    The use of granulocyte colony-stimulating factor (G-CSF) in the treatment of non-chemotherapy drug- induced agranulocytosis is controversial. We aimed at assessing the effect of G-CSF on the duration of agranulocytosis. To assess the effect of G-CSF on the duration of agranulocytosis, a Cox proportional hazard model with an estimated propensity score covariate adjusting for several prognostic factors was used. One hundred and forty-five episodes of agranulocytosis were prospectively collected from January 1994 to December 2000 in Barcelona (Spain). No differences were found in the case-fatality rate between treated (9 of 101, 8.9%) and not treated (5 of 44, 11.4%) patients. The median time to reach a neutrophil count > or =1.0 x 10(9)/L was 5 days (95%CI 5-6) in patients treated with G-CSF compared to 7 days (95%CI 6-8) in those not treated, with a hazard ratio of 1.58 (95% CI 1.1-2.3). G-CSF shortens time to recovery in patients with agranulocytosis. However, as an effect on case-fatality has not been recorded, and data on cost-effectiveness are lacking, it would be wise to restrict its use to high-risk patients. Copyright 2008 John Wiley & Sons, Ltd.

  19. Granulocyte-colony stimulating factor administration among hemoglobin S trait donors: A single center experience from the Eastern Mediterranean region.

    PubMed

    Gereklioglu, Cigdem; Asma, Suheyl; Korur, Aslı; Tepebası, Songul; Aytan, Pelin; Yeral, Mahmut; Kozanoglu, Ilknur; Boga, Can; Ozdogu, Hakan

    2017-07-12

    Assessment of Hemoglobin S trait donors has gained importance together with the increased allogeneic peripheral stem cell transplant activity for sickle cell disease in the regions where the disease is prevalent. Outcomes of Granulocyte-Colony Stimulating Factor (G-CSF) administration are obscure for hemoglobin S trait donors. This study aims at investigating the incidence of hemoglobin S carrier status and outcomes of G-CSF administration among donors who live in Eastern Mediterranean region. The cross-sectional, single-center cohort study was performed with 147 donors between January 2013 and March 2017. Prevalence of hemoglobin S trait was estimated and subjects with or without Hemogobin S trait were compared with regard to stem cell characteristics, early and late clinical outcomes after G-CSF administration. Eleven out of 147 donors (7.48%) were found as hemoglobin S trait. G-CSF administration was successfully completed and yielded good harvesting results in hemoglobin S trait donors. No statistically significant difference was found between groups with regard to early and late side effects, stem cell characteristics. Blood pressures and QTc values were within normal ranges in both groups. Groups were similar with regard to CD34 values. G-CSF seems safe in hemoglobin S trait donors. Their being eligible as donors would increase the chance of the patients for allogeneic stem cell transplantation in high prevalence regions. Further studies are required to reveal the safety profile of G-SCF in hemoglobin S carriers in different regions. © 2017 Wiley Periodicals, Inc.

  20. Soluble complement receptor 1 is increased in patients with leukemia and after administration of granulocyte colony-stimulating factor.

    PubMed

    Sadallah, S; Lach, E; Schwarz, S; Gratwohl, A; Spertini, O; Schifferli, J A

    1999-01-01

    Complement receptor type 1 is expressed by erythrocytes and most leukocytes. A soluble form is shed from the leukocytes and found in plasma (sCR1). sCR1 is a powerful inhibitor of complement. We report an increased sCR1 in the plasma of leukemia patients, up to levels producing measurable complement inhibition. Half of the 180 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL) had sCR1 levels above the normal range. The highest levels were observed in T-ALL (17 patients). The complement function of a T-ALL serum was improved by blocking sCR1 with a specific mAb (3D9). Measurements in 16 peripheral stein cell donors before and after granulocyte colony-stimulating factor (G-CSF) administration showed an increase in sCR1 (before, 43.8+/-15.4; at day 5, 118.3+/-44.7 ng/mL; P < 0.0001). This increase paralleled the increase in total leukocyte counts and was concomitant with de novo leukocyte mRNA CR1 expression in all three individuals tested. Whether pharmacological intervention may be used to up-regulate sCR1 so as to inhibit complement in vivo should be further investigated.

  1. Effects of Granulocyte Colony-Stimulating Factor (GCSF) on Persistent Thin Endometrium in Frozen Embryo Transfer (FET) Cycles.

    PubMed

    Mishra, Vineet V; Choudhary, Sumesh; Sharma, Urmila; Aggarwal, Rohina; Agarwal, Ritu; Gandhi, Khushali; Goraniya, Nilesh

    2016-10-01

    To predict the effectiveness of granulocyte colony-stimulating factor (GCSF) in the treatment of persistent thin endometrium resistant to other treatments in frozen embryo transfer (FET) cycles. This is a hospital-based prospective study. Thirty-five women with persistent thin endometrium (<7 mm) resistant to standard treatments were involved in this study. Intrauterine infusion of GCSF (300 mcg/1 ml) was done in patients with thin endometrium on day 14 of FET cycles, and their endometrial thicknesses were measured after 48 h of infusion. The primary outcome was an increase in endometrial thickness and the secondary outcome measures were chemical and clinical pregnancies. The endometrial thickness increased from 5.86 ± 0.58 to 6.58 ± 0.84 mm after GCSF infusion. In 19 of the 35 participants (54.28 %) endometrial thickness increased to ≥7 mm and they subsequently underwent embryo transfer. Of these, 3 (15.78 %) patients had chemical pregnancy, but there was no clinical pregnancy. In 16 participants, embryo transfer was canceled in view of insufficient endometrial thickness (<7 mm). GCSF caused a small increase in endometrial thickness in women with persistent thin endometrium, but there was no improvement in their pregnancy rates.

  2. Granulocyte colony-stimulating factor administration for infertile women with thin endometrium in frozen embryo transfer program.

    PubMed

    Li, Yu; Pan, Ping; Chen, Xiaoli; Li, Lin; Li, Yi; Yang, Dongzi

    2014-03-01

    We aimed to evaluate the effectiveness of granulocyte colony-stimulating factor (G-CSF) administration for infertile women with thin endometrium in frozen embryo transfer program. Among 59 infertile patients with thin endometrium (≤7 mm), 34 patients received uterine infusion of recombinant human G-CSF (100 μg/0.6 mL) on the day of ovulation or administration of progesterone or human chorionic gonadotropin, with 40 cycles defined as G-CSF group and 49 previous cycles as self-controlled group, and 25 patients refused, with 80 cycles defined as the control group. Higher proportion of induced cycles and lower proportion of natural cycles were observed in the G-CSF group, when compared to the self-controlled group or control group (P < .05). The cycle cancellation rate was, in descending order, 69.39% in self-controlled group, 48.75% in control group, and 17.50% in G-CSF group, with significant difference (P < .05). The implantation rate and clinical pregnancy rate per embryo transfer were similar in all the groups (P > .05). Our study fails to demonstrate that G-CSF has the potential to improve embryo implantation and clinical pregnancy rate of the infertile women with thin endometrium.

  3. Intranasal Delivery of Granulocyte Colony-Stimulating Factor Enhances Its Neuroprotective Effects Against Ischemic Brain Injury in Rats.

    PubMed

    Sun, Bao-liang; He, Mei-qing; Han, Xiang-yu; Sun, Jing-yi; Yang, Ming-feng; Yuan, Hui; Fan, Cun-dong; Zhang, Shuai; Mao, Lei-lei; Li, Da-wei; Zhang, Zong-yong; Zheng, Cheng-bi; Yang, Xiao-yi; Li, Yang V; Stetler, R Anne; Chen, Jun; Zhang, Feng

    2016-01-01

    Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor with strong neuroprotective properties. However, it has limited capacity to cross the blood-brain barrier and thus potentially limiting its protective capacity. Recent studies demonstrated that intranasal drug administration is a promising way in delivering neuroprotective agents to the central nervous system. The current study therefore aimed at determining whether intranasal administration of G-CSF increases its delivery to the brain and its neuroprotective effect against ischemic brain injury. Transient focal cerebral ischemia in rat was induced with middle cerebral artery occlusion. Our resulted showed that intranasal administration is 8-12 times more effective than subcutaneous injection in delivering G-CSF to cerebrospinal fluid and brain parenchyma. Intranasal delivery enhanced the protective effects of G-CSF against ischemic injury in rats, indicated by decreased infarct volume and increased recovery of neurological function. The neuroprotective mechanisms of G-CSF involved enhanced upregulation of HO-1 and reduced calcium overload following ischemia. Intranasal G-CSF application also promoted angiogenesis and neurogenesis following brain ischemia. Taken together, G-CSF is a legitimate neuroprotective agent and intranasal administration of G-CSF is more effective in delivery and neuroprotection and could be a practical approach in clinic.

  4. Effect of granulocyte colony stimulating factor (G-CSF) on IVF outcomes in infertile women: An RCT

    PubMed Central

    Eftekhar, Maryam; Hosseinisadat, Robabe; Baradaran, Ramesh; Naghshineh, Elham

    2016-01-01

    Background: Despite major advances in assisted reproductive techniques, the implantation rates remain relatively low. Some studies have demonstrated that intrauterine infusion of granulocyte colony stimulating factor (G-CSF) improves implantation in infertile women. Objective: To assess the G-CSF effects on IVF outcomes in women with normal endometrial thickness. Materials and methods: In this randomized controlled clinical trial, 100 infertile women with normal endometrial thickness who were candidate for IVF were evaluated in two groups. Exclusion criteria were positive history of repeated implantation failure (RIF), endocrine disorders, severe endometriosis, congenital or acquired uterine anomaly and contraindication for G-CSF (renal disease, sickle cell disease, or malignancy). In G-CSF group (n=50), 300 µg trans cervical intrauterine of G-CSF was administered at the oocyte retrieval day. Controls (n=50) were treated with standard protocol. Chemical, clinical and ongoing pregnancy rates, implantation rate, and miscarriage rate were compared between groups. Results: Number of total and mature oocytes (MII), two pronuclei (2PN), total embryos, transferred embryos, quality of transferred embryos, and fertilization rate did not differ significantly between two groups. So there were no significant differences between groups in chemical, clinical and ongoing pregnancy rate, implantation rate, and miscarriage rate Conclusion: our result showed in normal IVF patients with normal endometrial thickness, the intrauterine infusion of G-CSF did not improve pregnancy outcomes. PMID:27326420

  5. Expression of CD163 prevents apoptosis through the production of granulocyte colony-stimulating factor in meningioma

    PubMed Central

    Kanno, Hiromi; Nishihara, Hiroshi; Wang, Lei; Yuzawa, Sayaka; Kobayashi, Hiroyuki; Tsuda, Masumi; Kimura, Taichi; Tanino, Mishie; Terasaka, Shunsuke; Tanaka, Shinya

    2013-01-01

    Background CD163 is a 130-kDa transmembrane protein expressed in human monocytes and macrophages, and the aberrant expression of CD163 in breast and colorectal cancer associated with patients' poor prognosis was reported. Here, we analyzed the expression of CD163 in meningioma, a common intracranial tumor, and its molecular mechanism in association with meningioma progression. Methods First, we performed immunohistochemical analysis using 50 human meningioma specimens. Next, we established CD163-overexpressing human meningioma cell lines and investigated its roles in tumor progression in vitro and in vivo. Results Immunohistochemically, 26 of 50 human meningioma specimens (52.0%) were positive for CD163 in tumor cells, including benign grade I (48.5%) and grade II (71.4%) cases. Furthermore, CD163 expression was correlated with histological atypical parameters that directly predict the prognosis of meningioma. CD163-overexpressing meningioma cells showed significant suppression of apoptosis and accelerated tumor growth in nude mice. In addition, unexpected splenomegaly affiliated with the xenograft predicted tumor-derived granulocyte colony-stimulating factor (G-CSF) production, which was confirmed by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Conclusions To our knowledge, this is the first report that demonstrates CD163 expression in meningioma not only by immunohistochemistry but also by reverse-transcription polymerase chain reaction, using primary culture cells, and provides the novel molecular function of CD163 to prevent apoptosis through the production of G-CSF in meningioma. PMID:23539121

  6. Expression of CD163 prevents apoptosis through the production of granulocyte colony-stimulating factor in meningioma.

    PubMed

    Kanno, Hiromi; Nishihara, Hiroshi; Wang, Lei; Yuzawa, Sayaka; Kobayashi, Hiroyuki; Tsuda, Masumi; Kimura, Taichi; Tanino, Mishie; Terasaka, Shunsuke; Tanaka, Shinya

    2013-07-01

    CD163 is a 130-kDa transmembrane protein expressed in human monocytes and macrophages, and the aberrant expression of CD163 in breast and colorectal cancer associated with patients' poor prognosis was reported. Here, we analyzed the expression of CD163 in meningioma, a common intracranial tumor, and its molecular mechanism in association with meningioma progression. First, we performed immunohistochemical analysis using 50 human meningioma specimens. Next, we established CD163-overexpressing human meningioma cell lines and investigated its roles in tumor progression in vitro and in vivo. Immunohistochemically, 26 of 50 human meningioma specimens (52.0%) were positive for CD163 in tumor cells, including benign grade I (48.5%) and grade II (71.4%) cases. Furthermore, CD163 expression was correlated with histological atypical parameters that directly predict the prognosis of meningioma. CD163-overexpressing meningioma cells showed significant suppression of apoptosis and accelerated tumor growth in nude mice. In addition, unexpected splenomegaly affiliated with the xenograft predicted tumor-derived granulocyte colony-stimulating factor (G-CSF) production, which was confirmed by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay. To our knowledge, this is the first report that demonstrates CD163 expression in meningioma not only by immunohistochemistry but also by reverse-transcription polymerase chain reaction, using primary culture cells, and provides the novel molecular function of CD163 to prevent apoptosis through the production of G-CSF in meningioma.

  7. Design Rationale and Development Approach for Pegfilgrastim as a Long-Acting Granulocyte Colony-Stimulating Factor.

    PubMed

    Arvedson, Tara; O'Kelly, James; Yang, Bing-Bing

    2015-06-01

    Filgrastim, a recombinant methionyl human granulocyte colony-stimulating factor (G-CSF) (r-metHuG-CSF), is efficacious in stimulating neutrophil production and maturation to prevent febrile neutropenia (FN) in response to chemotherapy. Because of its relatively short circulating half-life, daily filgrastim injections are required to stimulate neutrophil recovery. In an effort to develop a long-acting form of filgrastim that was as safe and efficacious as filgrastim but had a longer in vivo residence time, a number of strategies were considered. Ultimately, fusion of filgrastim to polyethylene glycol (PEG) was selected. Following extensive analysis of conjugation chemistries as well as in vitro and in vivo characterization of a panel of PEGylated proteins, a construct containing a 20 kDa PEG moiety covalently conjugated to the N-terminus of filgrastim was chosen for advancement as pegfilgrastim. Pegfilgrastim is primarily cleared by neutrophils and neutrophil precursors (rather than the kidneys), meaning that clearance from the circulation is self-regulating and pegfilgrastim is eliminated only after neutrophils start to recover. Importantly, addition of PEG did not alter the mechanism of action and safety profile compared to filgrastim. Clinical evaluation revealed that a single 6 mg dose effectively reduces the duration of neutropenia and risk of FN in patients receiving chemotherapy. This work demonstrates the benefit of using PEGylation to generate pegfilgrastim, which allows for once-per-chemotherapy cycle administration while maintaining similar safety and efficacy profiles as those for multiple daily administration of filgrastim. Approaches that may provide advances for therapeutic agonists of G-CSF receptor are also discussed.

  8. Development of Aggressive Pancreatic Ductal Adenocarcinomas Depends on Granulocyte Colony Stimulating Factor Secretion in Carcinoma Cells.

    PubMed

    Pickup, Michael W; Owens, Philip; Gorska, Agnieszka E; Chytil, Anna; Ye, Fei; Shi, Chanjuan; Weaver, Valerie M; Kalluri, Raghu; Moses, Harold L; Novitskiy, Sergey V

    2017-09-01

    The survival rate for pancreatic ductal adenocarcinoma (PDAC) remains low. More therapeutic options to treat this disease are needed, for the current standard of care is ineffective. Using an animal model of aggressive PDAC (Kras/p48(TGFβRIIKO)), we discovered an effect of TGFβ signaling in regulation of G-CSF secretion in pancreatic epithelium. Elevated concentrations of G-CSF in PDAC promoted differentiation of Ly6G(+) cells from progenitors, stimulated IL10 secretion from myeloid cells, and decreased T-cell proliferation via upregulation of Arg, iNOS, VEGF, IL6, and IL1b from CD11b(+) cells. Deletion of csf3 in PDAC cells or use of a G-CSF-blocking antibody decreased tumor growth. Anti-G-CSF treatment in combination with the DNA synthesis inhibitor gemcitabine reduced tumor size, increased the number of infiltrating T cells, and decreased the number of Ly6G(+) cells more effectively than gemcitabine alone. Human analysis of human datasets from The Cancer Genome Atlas and tissue microarrays correlated with observations from our mouse model experiments, especially in patients with grade 1, stage II disease. We propose that in aggressive PDAC, elevated G-CSF contributes to tumor progression through promoting increases in infiltration of neutrophil-like cells with high immunosuppressive activity. Such a mechanism provides an avenue for a neoadjuvant therapeutic approach for this devastating disease. Cancer Immunol Res; 5(9); 718-29. ©2017 AACR. ©2017 American Association for Cancer Research.

  9. Controlled Release of Granulocyte Colony-Stimulating Factor Enhances Osteoconductive and Biodegradable Properties of Beta-Tricalcium Phosphate in a Rat Calvarial Defect Model

    PubMed Central

    Minagawa, Tomohiro; Tabata, Yasuhiko; Oyama, Akihiko; Furukawa, Hiroshi; Yamao, Takeshi; Yamamoto, Yuhei

    2014-01-01

    Autologous bone grafts remain the gold standard for the treatment of congenital craniofacial disorders; however, there are potential problems including donor site morbidity and limitations to the amount of bone that can be harvested. Recent studies suggest that granulocyte colony-stimulating factor (G-CSF) promotes fracture healing or osteogenesis. The purpose of the present study was to investigate whether topically applied G-CSF can stimulate the osteoconductive properties of beta-tricalcium phosphate (β-TCP) in a rat calvarial defect model. A total of 27 calvarial defects 5 mm in diameter were randomly divided into nine groups, which were treated with various combinations of a β-TCP disc and G-CSF in solution form or controlled release system using gelatin hydrogel. Histologic and histomorphometric analyses were performed at eight weeks postoperatively. The controlled release of low-dose (1 μg and 5 μg) G-CSF significantly enhanced new bone formation when combined with a β-TCP disc. Moreover, administration of 5 μg G-CSF using a controlled release system significantly promoted the biodegradable properties of β-TCP. In conclusion, the controlled release of 5 μg G-CSF significantly enhanced the osteoconductive and biodegradable properties of β-TCP. The combination of G-CSF slow-release and β-TCP is a novel and promising approach for treating pediatric craniofacial bone defects. PMID:24829581

  10. Efficient Process Development of Recombinant Human Granulocyte Colony-Stimulating Factor (rh-GCSF) Production in Escherichia coli

    PubMed Central

    Babaeipour, Valiollah; Khanchezar, Sirwan; Mofid, Mohammad Reza; Pesaran Hagi Abbas, Mahdi

    2015-01-01

    Background: The protein hormone granulocyte colony-stimulating factor (GCSF) stimulates the production of white blood cells and plays an important role in medical treatment of cancer patients. Methods: An efficient process was developed for heterologous expression of the human GCSF in E. coli BL21 (DE3). The feeding rate was adjusted to achieve the maximum attainable specific growth rate under critical value. In this method, specific growth rate was maintained at the maximum value of 0.55 h-1 at the beginning of feeding to 0.4 h-1 at the induction time. Recombinant human GCSF (rh-GCSF) was produced as inclusion body. At first, inclusion bodies were released by cell disruption and then washed, solubilized and refolded. Finally, the rh-GCSF was purified by cation exchange chromatography. Results: Obviouly, higher specific growth rate decreases process time and consequently increases productivity. The final concentration of biomass and GCSF was achieved 126 g DCW.l-1 and 32.1 g.l-1. Also, the final specific yield (YP/X) and total productivity of rh-GCSF were obtained 254 mg.g-1 DCW and 1.83 g.l-1.h-1, respectively. According to the available data, this is one of the highest YP/X and productivity that has been reported for any human protein which is expressed in E. coli. Recovery yield of purification process was %40 and purity of recombinant protein was over than 99%. The circular dichroism spectra of purified rh-GCSF, Neupogen® and PD-Grastim showed that all proteins have a similar secondary structure. Conclusion: Modified exponential feeding strategy for fed-batch cultivation of recombinant E. coli, results in minimum fed-batch duration and maximum productivity. PMID:25864815

  11. Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta-analysis

    PubMed Central

    2011-01-01

    Background Febrile neutropenia (FN) occurs following myelosuppressive chemotherapy and is associated with morbidity, mortality, costs, and chemotherapy reductions and delays. Granulocyte colony-stimulating factors (G-CSFs) stimulate neutrophil production and may reduce FN incidence when given prophylactically following chemotherapy. Methods A systematic review and meta-analysis assessed the effectiveness of G-CSFs (pegfilgrastim, filgrastim or lenograstim) in reducing FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. G-CSFs were compared with no primary G-CSF prophylaxis and with one another. Nine databases were searched in December 2009. Meta-analysis used a random effects model due to heterogeneity. Results Twenty studies compared primary G-CSF prophylaxis with no primary G-CSF prophylaxis: five studies of pegfilgrastim; ten of filgrastim; and five of lenograstim. All three G-CSFs significantly reduced FN incidence, with relative risks of 0.30 (95% CI: 0.14 to 0.65) for pegfilgrastim, 0.57 (95% CI: 0.48 to 0.69) for filgrastim, and 0.62 (95% CI: 0.44 to 0.88) for lenograstim. Overall, the relative risk of FN for any primary G-CSF prophylaxis versus no primary G-CSF prophylaxis was 0.51 (95% CI: 0.41 to 0.62). In terms of comparisons between different G-CSFs, five studies compared pegfilgrastim with filgrastim. FN incidence was significantly lower for pegfilgrastim than filgrastim, with a relative risk of 0.66 (95% CI: 0.44 to 0.98). Conclusions Primary prophylaxis with G-CSFs significantly reduces FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. Pegfilgrastim reduces FN incidence to a significantly greater extent than filgrastim. PMID:21943360

  12. Myeloid Engraftment in Humanized Mice: Impact of Granulocyte-Colony Stimulating Factor Treatment and Transgenic Mouse Strain.

    PubMed

    Coughlan, Alice M; Harmon, Cathal; Whelan, Sarah; O'Brien, Eóin C; O'Reilly, Vincent P; Crotty, Paul; Kelly, Pamela; Ryan, Michelle; Hickey, Fionnuala B; O'Farrelly, Cliona; Little, Mark A

    2016-04-01

    Poor myeloid engraftment remains a barrier to experimental use of humanized mice. Focusing primarily on peripheral blood cells, we compared the engraftment profile of NOD-scid-IL2Rγc(-/-) (NSG) mice with that of NSG mice transgenic for human membrane stem cell factor (hu-mSCF mice), NSG mice transgenic for human interleukin (IL)-3, granulocyte-macrophage-colony stimulating factor (GM-CSF), and stem cell factor (SGM3 mice). hu-mSCF and SGM3 mice showed enhanced engraftment of human leukocytes compared to NSG mice, and this was reflected in the number of human neutrophils and monocytes present in these strains. Importantly, discrete classical, intermediate, and nonclassical monocyte populations were identifiable in the blood of NSG and hu-mSCF mice, while the nonclassical population was absent in the blood of SGM3 mice. Granulocyte-colony stimulating factor (GCSF) treatment increased the number of blood monocytes in NSG and hu-mSCF mice, and neutrophils in NSG and SGM3 mice; however, this effect appeared to be at least partially dependent on the stem cell donor used to engraft the mice. Furthermore, GCSF treatment resulted in a preferential expansion of nonclassical monocytes in both NSG and hu-mSCF mice. Human tubulointerstitial CD11c(+) cells were present in the kidneys of hu-mSCF mice, while monocytes and neutrophils were identified in the liver of all strains. Bone marrow-derived macrophages prepared from NSG mice were most effective at phagocytosing polystyrene beads. In conclusion, hu-mSCF mice provide the best environment for the generation of human myeloid cells, with GCSF treatment further enhancing peripheral blood human monocyte cell numbers in this strain.

  13. Granulocyte-colony-stimulating factor (G-CSF) signaling in spinal microglia drives visceral sensitization following colitis.

    PubMed

    Basso, Lilian; Lapointe, Tamia K; Iftinca, Mircea; Marsters, Candace; Hollenberg, Morley D; Kurrasch, Deborah M; Altier, Christophe

    2017-10-02

    Pain is a main symptom of inflammatory diseases and often persists beyond clinical remission. Although we have a good understanding of the mechanisms of sensitization at the periphery during inflammation, little is known about the mediators that drive central sensitization. Recent reports have identified hematopoietic colony-stimulating factors as important regulators of tumor- and nerve injury-associated pain. Using a mouse model of colitis, we identify the proinflammatory cytokine granulocyte-colony-stimulating factor (G-CSF or Csf-3) as a key mediator of visceral sensitization. We report that G-CSF is specifically up-regulated in the thoracolumbar spinal cord of colitis-affected mice. Our results show that resident spinal microglia express the G-CSF receptor and that G-CSF signaling mediates microglial activation following colitis. Furthermore, healthy mice subjected to intrathecal injection of G-CSF exhibit pronounced visceral hypersensitivity, an effect that is abolished by microglial depletion. Mechanistically, we demonstrate that G-CSF injection increases Cathepsin S activity in spinal cord tissues. When cocultured with microglia BV-2 cells exposed to G-CSF, dorsal root ganglion (DRG) nociceptors become hyperexcitable. Blocking CX3CR1 or nitric oxide production during G-CSF treatment reduces excitability and G-CSF-induced visceral pain in vivo. Finally, administration of G-CSF-neutralizing antibody can prevent the establishment of persistent visceral pain postcolitis. Overall, our work uncovers a DRG neuron-microglia interaction that responds to G-CSF by engaging Cathepsin S-CX3CR1-inducible NOS signaling. This interaction represents a central step in visceral sensitization following colonic inflammation, thereby identifying spinal G-CSF as a target for treating chronic abdominal pain.

  14. Identification and characterization of receptors for granulocyte colony-stimulating factor on human placenta and trophoblastic cells

    SciTech Connect

    Uzumaki, Hiroya; Okabe, Tetsuro; Sasaki, Norio; Hagiwara, Koichi; Takaku, Fumimaro; Tobita, Masahito; Yasukawa, Kaoru ); Ito, Seiga ); Umezawa, Yoshimi )

    1989-12-01

    Since radioiodination of human granulocyte colony-stimulating factor (G-CSF) is difficult, the authors synthesized a mutein of human G-CSF that retains full biological activity and receptor-binding capacity for at least 2 weeks after radioiodination. Receptors for human G-CSF were characterized in the plasma membrane fraction from the human term placenta (human placental membranes) and trophoblastic cells by using the {sup 125}I-labeled mutein of human G-CSF (KW-2228). The specific binding of {sup 125}I-labeled KW-2228 to placental membranes was pH-dependent, with maximal specific binding at pH 7.8; it increased linearly with protein to 3.7 mg of protein per ml and was both time- and temperature-dependent, with maximal binding at 4{degree}C after a 24-hr incubation. When the authors examined the ability of hematopoietic growth factors to inhibit {sup 125}I-labeled KW-2228 binding, they found that KW-2228 and intact human G-CSF ihibited {sup 125}I-labeled KW-2228 binding, whereas erythropoietin or granulocyte-macrophage colony-stimulating factor did not. Scatchard analysis revealed a single receptor type. The human G-CSF receptors on human placental membranes were shown to consist of two molecular species that could be specifically cross-linked to {sup 125}I-labeled KW-2228. Human trophoblastic cells, T3M-3, also possessed a single receptor for G-CSF. They have identified the receptor for human G-CSF on human placental membranes and trophoblastic cells.

  15. Efficient process development of recombinant human granulocyte colony-stimulating factor (rh-GCSF) production in Escherichia coli.

    PubMed

    Babaeipour, Valiollah; Khanchezar, Sirwan; Mofid, Mohammad Reza; Pesaran Hagi Abbas, Mahdi

    2015-01-01

    The protein hormone granulocyte colony-stimulating factor (GCSF) stimulates the production of white blood cells and plays an important role in medical treatment of cancer patients. An efficient process was developed for heterologous expression of the human GCSF in E. coli BL21 (DE3). The feeding rate was adjusted to achieve the maximum attainable specific growth rate under critical value. In this method, specific growth rate was maintained at the maximum value of 0.55 h⁻¹ at the beginning of feeding to 0.4 h-1 at the induction time. Recombinant human GCSF (rh-GCSF) was produced as inclusion body. At first, inclusion bodies were released by cell disruption and then washed, solubilized and refolded. Finally, the rh-GCSF was purified by cation exchange chromatography. Obviouly, higher specific growth rate decreases process time and consequently increases productivity. The final concentration of biomass and GCSF was achieved 126 g DCW.l⁻¹ and 32.1 g.l⁻¹. Also, the final specific yield (YP/X) and total productivity of rh-GCSF were obtained 254 mg.g⁻¹ DCW and 1.83 g.l⁻¹.h⁻¹, respectively. According to the available data, this is one of the highest YP/X and productivity that has been reported for any human protein which is expressed in E. coli. Recovery yield of purification process was %40 and purity of recombinant protein was over than 99%. The circular dichroism spectra of purified rh-GCSF, Neupogen and PD-Grastim showed that all proteins have a similar secondary structure. Modified exponential feeding strategy for fed-batch cultivation of recombinant E. coli, results in minimum fed-batch duration and maximum productivity.

  16. A Novel Combinatorial Therapy With Pulp Stem Cells and Granulocyte Colony-Stimulating Factor for Total Pulp Regeneration

    PubMed Central

    Iohara, Koichiro; Murakami, Masashi; Takeuchi, Norio; Osako, Yohei; Ito, Masataka; Ishizaka, Ryo; Utunomiya, Shinji; Nakamura, Hiroshi; Matsushita, Kenji

    2013-01-01

    Treatment of deep caries with pulpitis is a major challenge in dentistry. Stem cell therapy represents a potential strategy to regenerate the dentin-pulp complex, enabling conservation and restoration of teeth. The objective of this study was to assess the efficacy and safety of pulp stem cell transplantation as a prelude for the impending clinical trials. Clinical-grade pulp stem cells were isolated and expanded according to good manufacturing practice conditions. The absence of contamination, abnormalities/aberrations in karyotype, and tumor formation after transplantation in an immunodeficient mouse ensured excellent quality control. After autologous transplantation of pulp stem cells with granulocyte-colony stimulating factor (G-CSF) in a dog pulpectomized tooth, regenerated pulp tissue including vasculature and innervation completely filled in the root canal, and regenerated dentin was formed in the coronal part and prevented microleakage up to day 180. Transplantation of pulp stem cells with G-CSF yielded a significantly larger amount of regenerated dentin-pulp complex compared with transplantation of G-CSF or stem cells alone. Also noteworthy was the reduction in the number of inflammatory cells and apoptotic cells and the significant increase in neurite outgrowth compared with results without G-CSF. The transplanted stem cells expressed angiogenic/neurotrophic factors. It is significant that G-CSF together with conditioned medium of pulp stem cells stimulated cell migration and neurite outgrowth, prevented cell death, and promoted immunosuppression in vitro. Furthermore, there was no evidence of toxicity or adverse events. In conclusion, the combinatorial trophic effects of pulp stem cells and G-CSF are of immediate utility for pulp/dentin regeneration, demonstrating the prerequisites of safety and efficacy critical for clinical applications. PMID:23761108

  17. Pharmacological properties of granulocytic colony-stimulating factor pegylated using electron beam synthesis nanotechnologies.

    PubMed

    Dygai, A M; Zyuz'kov, G N; Zhdanov, V V; Madonov, P G; Udut, E V; Miroshnichenko, L A; Khrichkova, T Yu; Simanina, E V; Stavrova, L A; Artamonov, A V; Bekarev, A A; Kinsht, D N; Chaikovskiy, A V; Markova, T S; Gurto, R V

    2011-11-01

    Granulocytic CSF pegylated using electron-beam synthesis nanotechnology exhibits pronounced granulomonocytopoiesis-stimulating and SC-mobilizing activity. More potent stimulation of committed precursors against the background of less pronounced activation of polypotent hemopoietic cells is a peculiarity of hemostimulating action of pegylated using electron-beam synthesis nanotechnology granulocytic CSF in comparison with its non-modified analog. The mobilizing effect of pegylated using electron-beam synthesis nanotechnology granulocytic CSF on early progenitor elements surpasses that of non-conjugated cytokine.

  18. Granulocyte colony-stimulating factor improves survival of patients with decompensated cirrhosis: a randomized-controlled trial.

    PubMed

    Prajapati, Ritesh; Arora, Anil; Sharma, Praveen; Bansal, Naresh; Singla, Vikas; Kumar, Ashish

    2017-04-01

    Liver transplantation is the only curative option for patients with decompensated cirrhosis; however, many patients die while awaiting transplantation. Granulocyte colony-stimulating factor (GCSF) has shown promising results in improving outcomes in patients with advanced liver disease. We evaluated the efficacy of GCSF in patients with decompensated cirrhosis in an open-labeled randomized-controlled trial. Consecutive patients with decompensated cirrhosis were randomized to receive either GCSF 300 μg twice daily for 5 days plus standard medical therapy (SMT) (GCSF+SMT group) or SMT alone (SMT alone group). Outcomes were assessed at 6 months from randomization. A total of 126 patients [median age: 53 (range: 31-76) years, 85% men] received GCSF+SMT and 127 patients received SMT alone. Baseline characteristics were similar in both the groups. The 5-day GCSF therapy did not lead to any significant adverse effects. At 6 months, in the GCSF+SMT group, 17 patients had died and nine were lost to follow-up, whereas in the SMT-alone group, 30 patients had died and 11 were lost to follow-up. By intention-to-treat analysis, cumulative survival was significantly higher in the GCSF+SMT group (79 vs. 68%; P=0.025). Also, significantly more patients (66%) showed improvement or stability in the Child-Turcotte-Pugh score at 6 months in the GCSF+SMT group compared with the SMT-alone group (51%, P=0.021). GCSF therapy improves survival and clinical outcome in patients with decompensated cirrhosis. It may be useful in patients awaiting transplantation to prevent worsening during the waiting period. Further studies are needed to explore whether repeated periodic GCSF courses can further increase the survival and decrease the need for liver transplantation.Clinical trial registered at https://clinicaltrials.gov vide NCT02642003.

  19. Development and calibration of a standard for the protein content of granulocyte colony-stimulating factor products.

    PubMed

    Gao, Kai; Rao, Chunming; Tao, Lei; Han, Chunmei; Shi, Xinchang; Wang, Lan; Fan, Wenhong; Yu, Lei; Wang, Junzhi

    2012-03-01

    This collaborative study characterizes a homogeneous standard for the protein content determination of granulocyte colony-stimulating factor (G-CSF) products with traceability of the measurement. The Kjeldahl method was used to determine the average protein content of G-CSF bulk as 2.505 mg/ml (95% C.I: 2.467-2.543 mg/ml, GCV 4.0%). Using G-CSF bulk as a traceability benchmark, the protein content of the final freeze-dried standard using reverse phase HPLC (RP-HPLC) was 215.4 μg protein per ampoule (95% C.I: 212.407-218.486 μg/ampoule, GCV 3.4%). A comparative study showed that there was no difference between using Filgrastim CRS (European Pharmacopeia G-CSF reference standard) and freeze-dried homogeneous standard when quantifying G-CSF protein content by RP-HPLC (P > 0.05). However, there were significant differences in the G-CSF protein content obtained using a serum albumin standard by Lowry assay and a G-CSF standard with RP-HPLC. Therefore, use of RP-HPLC with a freeze-dried homogeneous standard would eliminate the systematic errors introduced when using a serum albumin standard because of the differences in protein composition between the standard and the sample. It would also be helpful to use this method to compare the quality of G-CSF biosimilar products in situations where the protein content has been calibrated using various standards.

  20. Cost-benefit analysis of prophylactic granulocyte colony-stimulating factor during CHOP antineoplastic therapy for non-Hodgkin's lymphoma.

    PubMed

    Dranitsaris, G; Altmayer, C; Quirt, I

    1997-06-01

    Several randomised comparative trials have shown that granulocyte colony-stimulating factor (G-CSF) reduces the duration of neutropenia, hospitalisation and intravenous antibacterial use in patients with cancer who are receiving high-dosage antineoplastic therapy. However, one area that has received less attention is the role of G-CSF in standard-dosage antineoplastic regimens. One such treatment that is considered to have a low potential for inducing fever and neutropenia is the CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) for non-Hodgkin's lymphoma. We conducted a cost-benefit analysis from a societal perspective in order to estimate the net cost or benefit of prophylactic G-CSF in this patient population. This included direct costs for hospitalisation with antibacterial support, as well as indirect societal costs, such as time off work and antineoplastic therapy delays secondary to neutropenia. The findings were then tested by a comprehensive sensitivity analysis. The administration of G-CSF at a dosage of 5 micrograms/kg/day for 11 doses following CHOP resulted in an overall net cost of $Can1257. In the sensitivity analysis, lowering the G-CSF dosage to 2 micrograms/kg/day generated a net benefit of $Can6564, indicating a situation that was cost saving to society. The results of the current study suggest that the use of G-CSF in patients receiving CHOP antineoplastic therapy produces a situation that is close to achieving cost neutrality. However, low-dosage (2 micrograms/kg/day) G-CSF is an economically attractive treatment strategy because it may result in overall savings to society.

  1. Annual patient and caregiver burden of oncology clinic visits for granulocyte-colony stimulating factor therapy in the US.

    PubMed

    Stephens, J Mark; Li, Xiaoyan; Reiner, Maureen; Tzivelekis, Spiros

    2016-01-01

    Prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs) is indicated for chemotherapy patients with a significant risk of febrile neutropenia. This study estimates the annual economic burden on patients and caregivers of clinic visits for prophylactic G-CSF injections in the US. Annual clinic visits for prophylactic G-CSF injections (all cancers) were estimated from national cancer incidence, chemotherapy treatment and G-CSF utilization data, and G-CSF sales and pricing information. Patient travel times, plus time spent in the clinic, were estimated from patient survey responses collected during a large prospective cohort study (the Prospective Study of the Relationship between Chemotherapy Dose Intensity and Mortality in Early-Stage (I-III) Breast Cancer Patients). Economic models were created to estimate travel costs, patient co-pays and the economic value of time spent by patients and caregivers in G-CSF clinic visits. Estimated total clinic visits for prophylactic G-CSF injections in the US were 1.713 million for 2015. Mean (SD) travel time per visit was 62 (50) min; mean (SD) time in the clinic was 41 (68) min. Total annual time for travel to and from the clinic, plus time at the clinic, is estimated at 4.9 million hours, with patient and caregiver time valued at $91.8 million ($228 per patient). The estimated cumulative annual travel distance for G-CSF visits is 60.2 million miles, with a total transportation cost of $28.9 million ($72 per patient). Estimated patient co-pays were $61.1 million, ∼$36 per visit, $152 per patient. The total yearly economic impact on patients and caregivers is $182 million, ∼$450 per patient. Data to support model parameters were limited. Study estimates are sensitive to the assumptions used. The burden of clinic visits for G-CSF therapy is a significant addition to the total economic burden borne by cancer patients and their families.

  2. Levels of recombinant human granulocyte colony-stimulating factor in serum are inversely correlated with circulating neutrophil counts.

    PubMed Central

    Takatani, H; Soda, H; Fukuda, M; Watanabe, M; Kinoshita, A; Nakamura, T; Oka, M

    1996-01-01

    Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is effective in countering chemotherapy-induced neutropenia. However, serum rhG-CSF levels cannot be maintained throughout the course of rhG-CSF therapy. The drop in serum rhG-CSF levels may vary with the duration of rhG-CSF administration or with the circulating neutrophil counts. We investigated the relationship between serum G-CSF levels and circulating neutrophil counts and the pharmacokinetics of rhG-CSF for patients with lung cancer who had been treated with myelosuppressive chemotherapy and then with subcutaneous rhG-CSF (lenograstim, 2 micrograms per kg of body weight per day). Twelve patients were randomly assigned to four groups with different rhG-CSF therapy schedules. Serum G-CSF levels were measured by an enzyme immunoassay method. Serum G-CSF levels during the rhG-CSF therapy greatly exceeded endogenous G-CSF levels and were mainly due to the presence of exogenous rhG-CSF rather than increased levels of endogenous G-CSF. Despite the duration of rhG-CSF administration, serum G-CSF levels during rhG-CSF therapy were inversely correlated with circulating neutrophil counts (r2 = 0.73, P < 0.0001). The value for the area under the concentration-time curve of rhG-CSF on the day of neutrophilia was lower than that on the day of neutropenia (P < 0.05). Our results suggest that the fall in serum G-CSF levels during rhG-CSF therapy may result from increased clearance and/or decreased absorption of rhG-CSF, two processes related to circulating neutrophil counts. PMID:8849265

  3. Granulocyte colony-stimulating factor-producing pancreatic anaplastic carcinoma in ascitic fluid at initial diagnosis: A case report.

    PubMed

    Kubota, Nao; Naito, Yoshiki; Kawahara, Akihiko; Taira, Tomoki; Yamaguchi, Tomohiko; Yoshida, Tomoko; Abe, Hideyuki; Takase, Yorihiko; Fukumitsu, Chihiro; Murata, Kazuya; Ishida, Yusuke; Okabe, Yoshinobu; Kimura, Yoshizo; Tanigawa, Masahiko; Mihara, Yutaro; Nakayama, Masamichi; Yamaguchi, Rin; Akiba, Jun; Yano, Hirohisa

    2017-02-10

    Granulocyte colony-stimulating factor (G-CSF)-producing pancreatic tumors are extremely rare. These tumors have an aggressive clinical course and no established treatment. Here, we report an autopsy case of G-CSF-production in pancreatic anaplastic carcinoma (PAC). A 72-year-old woman presented with a large pancreatic head mass and multiple liver metastases. Laboratory data showed leukocytosis (leukocyte count 113.3 × 10(3) /µL) and high serum G-CSF levels (441 pg/mL; normal range: <39.0 pg/mL). The ascitic fluid was submitted to our pathology laboratory at initial diagnosis. Cytopathology showed that smears from the ascitic fluid were highly cellular and contained numerous malignant cells, mainly in loose groupings. Occasional pseudoglandular formations and giant cells were also present. The malignant cells were round, and no spindle-shaped cells were visible. The nuclei were round to ovoid with coarsely granular chromatin and large prominent nucleoli. Upon immunocytochemistry, tumor cells were positive for G-CSF and vimentin; there was no E-cadherin expression. Histopathological examination of the tumor showed a mixed composition of adenocarcinomatous and sarcomatous regions. Upon immunohistochemistry, both components were positive for G-CSF. Few CD34-positive myeloblasts were observed in the bone marrow. Thus, we diagnosed this as a case of G-CSF production in PAC with leukocytosis. To the best of our knowledge, this is the first report on G-CSF expression immunocytochemically confirmed in PAC. Diagn. Cytopathol. © 2017 Wiley Periodicals, Inc.

  4. Granulocyte-Colony Stimulating Factor (G-CSF) for stroke: an individual patient data meta-analysis

    PubMed Central

    England, Timothy J.; Sprigg, Nikola; Alasheev, Andrey M.; Belkin, Andrey A.; Kumar, Amit; Prasad, Kameshwar; Bath, Philip M.

    2016-01-01

    Granulocyte colony stimulating factor (G-CSF) may enhance recovery from stroke through neuroprotective mechanisms if administered early, or neurorepair if given later. Several small trials suggest administration is safe but effects on efficacy are unclear. We searched for randomised controlled trials (RCT) assessing G-CSF in patients with hyperacute, acute, subacute or chronic stroke, and asked Investigators to share individual patient data on baseline characteristics, stroke severity and type, end-of-trial modified Rankin Scale (mRS), Barthel Index, haematological parameters, serious adverse events and death. Multiple variable analyses were adjusted for age, sex, baseline severity and time-to-treatment. Individual patient data were obtained for 6 of 10 RCTs comprising 196 stroke patients (116 G-CSF, 80 placebo), mean age 67.1 (SD 12.9), 92% ischaemic, median NIHSS 10 (IQR 5–15), randomised 11 days (interquartile range IQR 4–238) post ictus; data from three commercial trials were not shared. G-CSF did not improve mRS (ordinal regression), odds ratio OR 1.12 (95% confidence interval 0.64 to 1.96, p = 0.62). There were more patients with a serious adverse event in the G-CSF group (29.6% versus 7.5%, p = 0.07) with no significant difference in all-cause mortality (G-CSF 11.2%, placebo 7.6%, p = 0.4). Overall, G-CSF did not improve stroke outcome in this individual patient data meta-analysis. PMID:27845349

  5. Two protocols to treat thin endometrium with granulocyte colony-stimulating factor during frozen embryo transfer cycles.

    PubMed

    Xu, Bin; Zhang, Qiong; Hao, Jie; Xu, Dabao; Li, Yanping

    2015-04-01

    The efficacy of two granulocyte colony-stimulating factor (G-CSF) protocols for thin endometrium were investigated. Eighty-two patients were diagnosed with thin endometrium (<7 mm). Thirty patients with previously cancelled embryo transfers received intrauterine G-CSF in subsequent frozen embryo transfer (FET) cycles. Patients were divided into the G-CSF only and G-CSF with endometrial scratch subgroups. Compared with previous cycles, endometrial thickness increased from 5.7 ± 0.7 mm to 8.1 ± 2.1 mm after G-CSF treatment (P < 0.001). Endometrial thickness increases were not significantly different between the two subgroups. The G-CSF with endometrial scratch subgroup established nominally higher though non-significant clinical pregnancy and live birth rates than the G-CSF only subgroup (53.8 % versus 42.9% and 38.5% versus 28.6%, respectively). Fifty-two patients underwent FET despite edometrial thickness less than 7 mm, and were included as controls. Significantly higher embryo implantation and clinical pregnancy rates were observed in the G-CSF group compared with the control group (31.5% versus 13.9%; P < 0.01; 48.1% versus 25.0%; P = 0.038, respectively). Endometrial scracth did not impair G-CSF treatment for thin endometrium and favoured pregnancy and live birth rates. For patients with thin endometrium, embryo transfer cancellation and G-CSF treatment in subsequent FET cycles is beneficial. Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  6. Contribution of granulocyte colony-stimulating factor to the acute mobilization of endothelial precursor cells by vascular disrupting agents.

    PubMed

    Shaked, Yuval; Tang, Terence; Woloszynek, Jill; Daenen, Laura G; Man, Shan; Xu, Ping; Cai, Shi-Rong; Arbeit, Jeffrey M; Voest, Emile E; Chaplin, David J; Smythe, Jon; Harris, Adrian; Nathan, Paul; Judson, Ian; Rustin, Gordon; Bertolini, Francesco; Link, Daniel C; Kerbel, Robert S

    2009-10-01

    Vascular disrupting agents (VDA) cause acute shutdown of abnormal established tumor vasculature, followed by massive intratumoral hypoxia and necrosis. However, a viable rim of tumor tissue invariably remains from which tumor regrowth rapidly resumes. We have recently shown that an acute systemic mobilization and homing of bone marrow-derived circulating endothelial precursor (CEP) cells could promote tumor regrowth following treatment with either a VDA or certain chemotherapy drugs. The molecular mediators of this systemic reactive host process are unknown. Here, we show that following treatment of mice with OXi-4503, a second-generation potent prodrug derivative of combretastatin-A4 phosphate, rapid increases in circulating plasma vascular endothelial growth factor, stromal derived factor-1 (SDF-1), and granulocyte colony-stimulating factor (G-CSF) levels are detected. With the aim of determining whether G-CSF is involved in VDA-induced CEP mobilization, mutant G-CSF-R(-/-) mice were treated with OXi-4503. We found that as opposed to wild-type controls, G-CSF-R(-/-) mice failed to mobilize CEPs or show induction of SDF-1 plasma levels. Furthermore, Lewis lung carcinomas grown in such mice treated with OXi-4503 showed greater levels of necrosis compared with tumors treated in wild-type mice. Evidence for rapid elevations in circulating plasma G-CSF, vascular endothelial growth factor, and SDF-1 were also observed in patients with VDA (combretastatin-A4 phosphate)-treated cancer. These results highlight the possible effect of drug-induced G-CSF on tumor regrowth following certain cytotoxic drug therapies, in this case using a VDA, and hence G-CSF as a possible therapeutic target.

  7. Granulocyte colony-stimulating factor (G-CSF) production in hemorrhagic shock requires both the ischemic and resuscitation phase.

    PubMed

    Hierholzer, C; Kelly, E; Billiar, T R; Tweardy, D J

    1997-01-01

    Granulocyte colony-stimulating factor (G-CSF) is the cytokine that is critical for polymorphonuclear neutrophilic granulocyte (PMN) production as well as being a potent agonist of PMN activation. We have recently reported that in the lung and the liver of rats resuscitated after hemorrhagic shock (HS) G-CSF mRNA expression is induced. It is not known if both phases of HS, the ischemic and the reperfusion phase, are required for G-CSF mRNA induction. The present study was designed to test the hypothesis that the upregulation of G-CSF mRNA expression is the consequence of HS followed by resuscitation and that ischemia alone is insufficient to induce G-CSF mRNA expression in the affected organs. Male Sprague-Dawley rats were subjected to resuscitated and unresuscitated shock protocols of varying severity. Control animals were subjected to anesthesia and all surgical preparations except for hemorrhage. Lungs and livers were isolated and their RNA extracted. Using semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we demonstrated that G-CSF mRNA was induced in the lung and liver of shock animals above the level observed in control animals. Upregulation of G-CSF mRNA relative to controls occurred only in animals undergoing resuscitated HS and not in ones subjected to unresuscitated HS. These results indicate that G-CSF production specific for the hemorrhage component of shock is dependent on resuscitation. As a consequence, the production of this cytokine may be decreased through modifications in the resuscitation protocols.

  8. Granulocyte-colony stimulating factor for acute-on-chronic liver failure: systematic review and meta-analysis.

    PubMed

    Chavez-Tapia, Norberto C; Mendiola-Pastrana, Indira; Ornelas-Arroyo, Victoria J; Noreña-Herrera, Camilo; Vidaña-Perez, Desiree; Delgado-Sanchez, Guadalupe; Uribe, Misael; Barrientos-Gutierrez, Tonatiuh

    2015-01-01

    Acute-on-chronic liver failure (ACLF) is associated with increased short and long-term mortality. Animal models of liver failure have demonstrated that granulocyte-colony stimulating factor (G-CSF) accelerates the liver regeneration process and improves survival. However, clinical evidence regarding the use of G-CSF in ACLF remains scarce. The aim of this study was to assess the benefits and harms of G-CSF in patients with acute-on-chronic liver failure. An electronic search was made in The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and LILACS up to November 2013. Randomized clinical trials comparing the use of any regimen of G-CSF against placebo or no intervention in patients with ACLF were included. Primary outcomes included overal mortality, mortality due multi-organ failure, and adverse events. Relative risk (RR) and mean difference (MD) were used. Two trials involving 102 patients were included. A significant reduction in short-term overall mortality was observed in patients receiving G-CSF compared to controls (RR 0.56; 95%CI 0.39,0.80). G-CSF failed to reduce mortality secondary to gastrointestinal bleeding (RR 1.45; 95%CI 0.50, 4.27). Adverse effects reported included: fever, rash, herpes zoster, headache and nausea. In conclusion, the use of G-CSF for the treatment of patients with ACLF significantly reduced short-term mortality. While the evidence is still limited, the apparent benefit observed on short-term mortality, mild adverse effects and lack of an alternative therapy make the use of G-CSF in ACLF patients a reasonable alternative when liver transplantation is contraindicated or unavailable.

  9. Granulocyte colony-stimulating factor-producing ascending colon cancer as indicated by histopathological findings: report of a case.

    PubMed

    Fujiwara, Yushi; Yamazaki, Osamu; Takatsuka, Satoshi; Kaizaki, Ryoji; Inoue, Takeshi

    2011-12-01

    Various types of granulocyte colony-stimulating factor (G-CSF)-producing malignant tumors have been reported. However, a G-CSF-producing colorectal cancer is rare. We present a case of G-CSF-producing ascending colon cancer. An 81-year-old man was referred to our hospital with right lower abdominal pain. A colon fiberscopy revealed an ascending colon tumor, and histological examination revealed tubular adenocarcinoma. He was admitted due to worsening abdominal pain. Although laboratory data showed an elevated white blood cell (WBC) count of 17000/mm3 with 77.8% neutrophils, elevated C-reaction protein (CRP) was insignificant (1.06 mg/dL), and he was afebrile. Because computed tomography indicated that the tumor penetrated into surrounding tissue, a semi-urgent ileocecal resection was performed. An abscess was not located. The tumor was staged as T3N2aM0 and as stage IIB according to the TNM classification. Microscopically, significant neutrophil infiltration between cancer cells was observed, suggesting the presence of a G-CSF-producing tumor. Immunohistochemical staining using a G-CSF antibody revealed cytoplasmic staining in cancer cells. The serum concentration of G-CSF upon admission was 334 pg/mL. After surgical resection, the WBC count decreased to within a normal range. These findings confirmed the diagnosis of G-CSF-producing ascending colon cancer. The prognosis of G-CSF-producing tumors is considered to be poor. Early diagnosis and surgical treatment are needed for patients with G-CSF-producing tumors, and continuous careful follow-up is required.

  10. Herbal medicine "sho-saiko-to" induces in vitro granulocyte colony-stimulating factor production on peripheral blood mononuclear cells.

    PubMed

    Yamashiki, M; Asakawa, M; Kayaba, Y; Kosaka, Y; Nishimura, A

    1992-01-01

    The herbal medicine "Sho-saiko-to (Xiao-Chai-Hu-Tang)" has been used in China for about 3000 years for the treatment of pyretic diseases. This medicine is now available as one of the prescribing drugs approved by the Ministry of Health and Welfare of Japan, and has also been widely used for patients with chronic viral liver disease as one of biological response modifiers in the field of Japan's Western Medicine. However, its mode of action has not been fully described. In the present in vitro study, we added "Sho-saiko-to" (TJ-9, Tsumura, Tokyo) to the culture of peripheral blood mononuclear cells (PBMC) obtained from healthy volunteers, and observed a dose-dependent increase in the production of granulocyte colony-stimulating factor (G-CSF). The same experiment was conducted using other herbal medicines "Dai-saiko-to" (TJ-8) and "Saiko-keishi-to" (TJ-10) which showed similar effects, or "Sho-seiryu-to" (TJ-19) which consists of very different compounds and shows different efficacy. The increases of G-CSF production were similar when "Sho-saiko-to" (TJ-9) or one of the 2 reference drugs (TJ-8 and 10) was added, whereas the increase when the control drug "Sho-seiryu-to" (TJ-19) was added, was quite small. This result shows that G-CSF induction is not a common effect of herbal medicines, but a specific effect of TJ-8, 9, and 10. Among these 3 drugs the increase produced by "Sho-saiko-to" was the largest. Based on this result, we conclude that administration of "Sho-saiko-to" may be useful not only for the treatment of chronic liver disease, but also for malignant diseases and acute infectious diseases where G-CSF is efficacious.

  11. High-dosage granulocyte colony stimulating factor treatment alters monocyte trafficking to the brain after experimental stroke.

    PubMed

    Weise, Gesa; Pösel, Claudia; Möller, Karoline; Kranz, Alexander; Didwischus, Nadine; Boltze, Johannes; Wagner, Daniel-Christoph

    2017-02-01

    Ischemic stroke elicits a prompt inflammatory response that is characterized by a well-timed recruitment of peripheral immune cells to the brain. Among these, monocytes play a particularly important, but multifaceted role and have been increasingly recognized to affect stroke outcome. Granulocyte colony stimulating factor (GCSF) is known for its immunosuppressive actions on mononuclear cells, but previous studies in the stroke field were mainly confined to its neuroprotective actions. Herein, we investigated whether GCSF affects post-stroke inflammation in a mouse model of focal brain ischemia by modulating monocyte responses. Treatment with GCSF was controlled by vehicle injection, sham surgery and naive animals. Despite a significant monocytosis, high-dosage GCSF reduced the number of brain-infiltrating monocytes/macrophages four days after stroke. Lower numbers of mononuclear phagocytes in the brain were associated with smaller cerebral edema and improved motor outcome after stroke. GCSF treatment over 72h, but not 24h diminished integrin expression on circulating Ly6C+ inflammatory monocytes. In vitro experiments further revealed that GCSF strongly promotes interleukin (IL)-10 secretion by activated mononuclear cells. Blockade of the IL-10 receptor partly reversed GCSF-induced downregulation of integrin surface expression. Overall, our results suggest that high-dosage GCSF mitigates monocyte infiltration after stroke, likely by attenuating integrin-mediated adhesion to the brain endothelium in an IL-10-dependent manner. Lower amounts of mononuclear cells in the brain translate to less severe brain edema and functional impairment and thus support a harmful role of Ly6C+ inflammatory monocytes in the acute stage of stroke. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Biweekly docetaxel and vinorelbine with granulocyte colony-stimulating factor support for patients with anthracycline-resistant metastatic breast cancer.

    PubMed

    Gómez-Bernal, Amalia; Cruz, Juan Jesús; Olaverri, Amaya; Arizcun, Alberto; Martín, Teresa; Rodríguez, Cesar A; Martín, Germán; Fonseca, Emilio; Sánchez, Pedro

    2005-01-01

    This phase II trial evaluated the efficacy and toxicity of vinorelbine 25 mg/m2 plus docetaxel 60 mg2/m administered on day 1, every 2 weeks with granulocyte colony-stimulating factor support (G-CSF, 5 microg/kg/day, days 3-7) as primary prophylaxis in patients with histologically confirmed metastatic breast cancer (MBC) and previously treated with anthracyclines in the adjuvant or in the first-line setting. A total of 48 patients received 352 cycles (median 8, range 2-10). All patients were included in the efficacy and safety evaluation on an intent-to-treat analysis. Eight patients (17%) showed a complete response and 14 patients (29%) showed a partial response. Overall response rate was 46% [95% confidence interval (CI) 33-60]. The median duration of response was 10.0 months. With a median follow-up of 18.0 months, the median time to progression was 11.9 months and the median overall survival was 27.1 months. The most frequently reported grade 3/4 hematological toxicity was neutropenia (19% of patients, 4% of cycles). Febrile neutropenia was reported in six patients (13%) and 7 cycles (2%), but no toxic deaths were reported. The most common grade 3/4 non-hematological toxicity was asthenia (17% of patients, 6% of cycles) and nail toxicity (15% of patients, 3% of cycles). In conclusion, biweekly docetaxel plus vinorelbine with G-CSF support is active and well tolerated as chemotherapy for patients with MBC resistant to anthracyclines. G-CSF support is recommended for lowering the incidence and severity of neutropenia and febrile neutropenia.

  13. Granulocyte-colony stimulating factor improves Parkinson's disease associated with co-morbid depression: An experimental exploratory study

    PubMed Central

    Prakash, Ajay; Chopra, Kanwaljit; Medhi, Bikash

    2013-01-01

    Introduction: The present study was designed to evaluate the effect of granulocyte-colony stimulating factor (G-CSF) in the treatment of Parkinson's disease (PD), the second most common neurodegenerative disease characterized by muscle and movement disorder, often associated with depression. PD is very difficult to treat. Hence, the present study was aimed to evaluate the effect of G-CSF in PD associated with depression. Materials and Methods: Adult Wistar male rats weighing about 180-250 g were selected and divided into five groups in parallel designed method namely; control group (n = 5); sham operated group (n = 5); Vehicle group (n = 5); G-CSF group (70 μg/kg, s.c.) (n = 5) and L-DOPA group (n = 5). The rats were treated with 6-hydroxydopamine (6-OHDA) on day 0 and then treatment was continued for 14 day of L-DOPA/carbidopa, whereas G-CSF (70 μg/kg, s.c.) was given from day 1 to 6. Thereafter, adhesive removal and forced swim tests were conducted to evaluate the behavioral outcome of G-CSF treatment. The finding was correlated and analyzed with Nissl staining findings for the final conclusion. Results: The behavioral parameters were assessed and found to be ameliorate the symptoms of Parkinson's and reduced the depression like behavior in PD. The histological findings were supported the behavioral findings and showed pathological improvement. Conclusion: As a preliminary work, the present study first time suggested that G-CSF have a potential role in PD and associated depression. PMID:24347771

  14. Phase I study of intravenous low-dose granulocyte colony-stimulating factor in acute and subacute ischemic stroke.

    PubMed

    Moriya, Yusuke; Mizuma, Atsushi; Uesugi, Tsuyoshi; Ohnuki, Yoichi; Nagata, Eiichiro; Takahashi, Wakoh; Kobayashi, Hiroyuki; Kawada, Hiroshi; Ando, Kiyoshi; Takagi, Shigeharu; Takizawa, Shunya

    2013-10-01

    Granulocyte colony-stimulating factor (G-CSF; filgrastim) may be useful for the treatment of acute ischemic stroke because of its neuroprotective and neurogenesis-promoting properties, but an excessive increase of neutrophils may lead to brain injury. We examined the safety and tolerability of low-dose G-CSF and investigated the effectiveness of G-CSF given intravenously in the acute phase (at 24 hours) or subacute phase (at 7 days) of ischemic stroke. Three intravenous dose regimens (150, 300, or 450 μg/body/day, divided into 2 doses for 5 days) of G-CSF were examined in 18 patients with magnetic resonance imaging (MRI)-confirmed infarct in the territory of the middle cerebral artery. Nine patients received the first dose at 24 hours poststroke (acute group) and 9 patients received the first dose on day 7 poststroke (subacute group; n = 3 at each dose in each group). A scheduled administration of G-CSF was skipped if the patient's leukocyte count exceeded 40,000/μL. Patients received neurologic and MRI examinations. We found neither serious adverse event, drug-related platelet reduction nor splenomegaly. Leukocyte levels remained below 40,000/μL at 150 and 300 μg G-CSF/body/day, but rose above 40,000/μL at 450 μg G-CSF/body/day. Neurologic function improvement between baseline and day 90 was more marked after treatment in the acute phase versus the subacute phase (Barthel index 49.4 ± 28.1 v 15.0 ± 22.0; P < .01). Low-dose G-CSF (150 and 300 μg/body/day) was safe and well tolerated in ischemic stroke patients, and leukocyte levels remained below 40,000/μL. Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  15. Myelodysplastic syndrome and acute myeloid leukemia following adjuvant chemotherapy with and without granulocyte colony-stimulating factors for breast cancer

    PubMed Central

    Calip, Gregory S.; Malmgren, Judith A.; Lee, Wan-Ju; Schwartz, Stephen M.; Kaplan, Henry G.

    2015-01-01

    Purpose Risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) post-breast cancer treatment with adjuvant chemotherapy and granulocyte colony-stimulating factors (G-CSF) is not fully characterized. Our objective was to estimate MDS/AML risk associated with specific breast cancer treatments. Methods We conducted a retrospective cohort study of women ages ≥66 years with stage I-III breast cancer between 2001 and 2009 using the Surveillance, Epidemiology and End Results-Medicare database. Women were classified as receiving treatment with radiation, chemotherapy and/or G-CSF. We used multivariable Cox proportional hazards models to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for MDS/AML risk. Results Among 56,251 breast cancer cases, 1.2% developed MDS/AML during median follow-up of 3.2 years. 47.1% of women received radiation and 14.3% received chemotherapy. Compared to breast cancer cases treated with surgery alone, those treated with chemotherapy (HR=1.38, 95%-CI: 0.98–1.93) and chemotherapy/radiation (HR=1.77, 95%-CI: 1.25–2.51) had increased risk of MDS/AML; but not radiation alone (HR=1.08, 95% CI: 0.86–1.36). Among chemotherapy regimens and G-CSF, MDS/AML risk was differentially associated with anthracycline/cyclophosphamide-containing regimens (HR=1.86, 95%-CI: 1.33–2.61) and filgrastim (HR=1.47, 95%-CI: 1.05–2.06), but not pegfilgrastim (HR=1.10, 95%-CI: 0.73–1.66). Conclusions We observed increased MDS/AML risk among older breast cancer survivors treated with anthracycline/cyclophosphamide chemotherapy that was enhanced by G-CSF. Although small, this risk warrants consideration when determining adjuvant chemotherapy and neutropenia prophylaxis for breast cancer patients. PMID:26450505

  16. Drugs elevating extracellular adenosine promote regeneration of haematopoietic progenitor cells in severely myelosuppressed mice: their comparison and joint effects with the granulocyte colony-stimulating factor.

    PubMed

    Hofer, Michal; Pospísil, Milan; Znojil, Vladimír; Vacek, Antonín; Weiterova, Lenka; Holá, Jirina; Vácha, Jirí

    2002-01-01

    We tested capabilities of drugs elevating extracellular adenosine and of granulocyte colony-stimulating factor (G-CSF) given alone or in combination to modulate regeneration from severe myelosuppression resulting from combined exposure of mice to ionizing radiation and carboplatin. Elevation of extracellular adenosine was induced by joint administration of dipyridamole (DP), a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate (AMP), serving as an adenosine prodrug. DP+AMP, G-CSF or all these drugs in combination were administered in a 4-d treatment regimen starting on day 3 after induction of myelosuppression. Comparable enhancements of haematopoietic regeneration due to elevation of extracellular adenosine or to action of G-CSF were demonstrated as shown by elevated numbers of haematopoietic progenitor cells for granulocytes/macrophages (GM-CFC) and erythrocytes (BFU-E) in the bone marrow and spleen in early time intervals after termination of the drug treatment, i.e. on days 7 and 10 after induction of myelosuppression. Coadministration of all the drugs further potentiated the restoration of progenitor cell pools in the haematopoietic organs. The effects of the drug treatments on progenitor cells were reflected in the peripheral blood in later time intervals of days 15 and 20 after induction of myelosuppression, especially as significantly elevated numbers of granulocytes and less pronounced elevation of lymphocytes and erythrocytes. The results substantiate the potential of drugs elevating extracellular adenosine for clinical utilization in myelosuppressive states, e.g. those accompanying oncological radio- and chemotherapy.

  17. Functional characterization of recombinant human granulocyte colony stimulating factor (hGMCSF) immobilized onto silica nanoparticles.

    PubMed

    Vanitha, Selvarajan; Goswami, Upashi; Chaubey, Nidhi; Ghosh, Siddhartha S; Sanpui, Pallab

    2016-02-01

    Granulocyte macrophage colony stimulating factor (GMCSF), an important therapeutic cytokine, was immobilized onto silica nanoparticles. Maintenance of structural integrity and biological performance in immobilized cytokine was assessed to augment its applicability in possible biomedical implications. Following its cloning and expression in E. coli, the recombinant human GMCSF (hGMCSF) was purified as a GST-tagged protein corresponding to a 42 kDa band on SDS-PAGE. The purified cytokine was immobilized onto biocompatible silica nanoparticles (~129.4 nm) by adsorption and the binding was confirmed by dynamic light scattering and infrared spectroscopy. Maximum binding of hGMCSF was at 6.4 µg mg(-1) silica nanoparticles. Efficient release of the cytokine from the nanoparticles with its structural integrity intact was deduced from circular dichroism spectroscopy. hGMCSF-immobilized silica nanoparticles efficiently increased the proliferation of RAW 264.7 macrophage cells with 50 % increase in proliferation at 600 ng hGMCSF µg(-1) silica nanoparticles. Silica nanoparticles successfully immobilized hGMCSF maintaining its structural integrity. The release of the immobilized cytokine from silica nanoparticles resulted in the increased proliferation of macrophages indicating the potential of the system in future applications.

  18. Evaluation of a biosimilar granulocyte colony-stimulating factor (filgrastim XM02) for peripheral blood stem cell mobilization and transplantation: a single center experience in Japan

    PubMed Central

    Yoshimura, Hideaki; Hotta, Masaaki; Nakanishi, Takahisa; Fujita, Shinya; Nakaya, Aya; Satake, Atsushi; Ito, Tomoki; Ishii, Kazuyoshi; Nomura, Shosaku

    2017-01-01

    Background Biosimilar granulocyte colony-stimulating factor (G-CSF) has recently been introduced into clinical practice. G-CSFs are used to mobilize CD34+ cells and accelerate engraftment after transplantation. However, in Asia, particularly in Japan, data for peripheral blood stem cell (PBSC) mobilization by this biosimilar G-CSF are currently lacking. Therefore, the clinical efficacy and safety of biosimilar G-CSF for hematopoietic stem cell transplantation needs to be evaluated in a Japanese context. Materials and methods The subjects included two groups of patients with malignant lymphoma and multiple myeloma. All patients received chemotherapy priming for the mobilization of PBSCs. All patients were treated with chemotherapy followed by the administration of either the biosimilar G-CSF, filgrastim XM02 (FBNK), or the originators, filgrastim, or lenograstim. Results There were no significant differences among FBNK, filgrastim, and lenograstim treatments in the numbers of CD34+ cells in harvested PBSCs, the scores for granulocyte/macrophage colony forming units, or for malignant lymphoma and multiple myeloma patients evaluated as separate or combined cohorts. In addition, there were no significant differences in safety, side effects, complications, or the time to engraftment after autologous hematopoietic stem cell transplantation. Conclusion Biosimilar FBNK shows the same efficacy and safety as originator G-CSFs for facilitating bone marrow recovery in Japanese malignant lymphoma and multiple myeloma patients undergoing stem cell transplantation. In addition, it is less expensive than the originators, reducing hospitalization costs. PMID:28182150

  19. Pretransplant mobilization with granulocyte colony-stimulating factor improves B-cell reconstitution by lentiviral vector gene therapy in SCID-X1 mice.

    PubMed

    Huston, Marshall W; Riegman, Adriaan R A; Yadak, Rana; van Helsdingen, Yvette; de Boer, Helen; van Til, Niek P; Wagemaker, Gerard

    2014-10-01

    Hematopoietic stem cell (HSC) gene therapy is a demonstrated effective treatment for X-linked severe combined immunodeficiency (SCID-X1), but B-cell reconstitution and function has been deficient in many of the gene therapy treated patients. Cytoreductive preconditioning is known to improve HSC engraftment, but in general it is not considered for SCID-X1 since the poor health of most of these patients at diagnosis and the risk of toxicity preclude the conditioning used in standard bone marrow stem cell transplantation. We hypothesized that mobilization of HSC by granulocyte colony-stimulating factor (G-CSF) should create temporary space in bone marrow niches to improve engraftment and thereby B-cell reconstitution. In the present pilot study supplementing our earlier preclinical evaluation (Huston et al., 2011), Il2rg(-/-) mice pretreated with G-CSF were transplanted with wild-type lineage negative (Lin(-)) cells or Il2rg(-/-) Lin(-) cells transduced with therapeutic IL2RG lentiviral vectors. Mice were monitored for reconstitution of lymphocyte populations, level of donor cell chimerism, and antibody responses as compared to 2 Gy total body irradiation (TBI), previously found effective in promoting B-cell reconstitution. The results demonstrate that G-CSF promotes B-cell reconstitution similar to low-dose TBI and provides proof of principle for an alternative approach to improve efficacy of gene therapy in SCID patients without adverse effects associated with cytoreductive conditioning.

  20. Administration of granulocyte colony stimulating factor after liver transplantation leads to an increased incidence and severity of ischemic biliary lesions in the rat model

    PubMed Central

    Dirsch, Olaf; Chi, Haidong; Ji, Yuan; Gu, Yan Li; Broelsch, Christoph E; Dahmen, Uta

    2006-01-01

    AIM: Recently it has been reported that granulocyte colony stimulating factor (G-CSF) can induce hypercoagulability in healthy bone marrow donors. It is conceivable that the induction of a prothrombotic state in a recipient of an organ graft with already impaired perfusion might cause further deterioration in the transplanted organ. This study evaluated whether G-CSF treatment worsens liver perfusion following liver transplantation in the rat model. METHODS: A non-arterialized rat liver transplantation model was employed to evaluate the effect of G-CSF treatment on the liver in a syngeneic and allogeneic strain combination. Study outcomes included survival time and liver damage as investigated by liver enzymes and liver histology. Observation times were 1 d, 1 wk and 12 wk. RESULTS: Rats treated with G-CSF had increased incidence and severity of biliary damage following liver transplantation. In these animals, hepatocellular necrosis was accentuated in the centrilobular region. These lesions are indicative of impaired perfusion in G-CSF treated animals. CONCLUSION: G-CSF should be used with caution in recipients of liver transplantation, as treatment might enhance preexisting, undetected perfusion problems and ultimately lead to ischemia induced biliary complications. PMID:16937499

  1. High pH solubilization and chromatography-based renaturation and purification of recombinant human granulocyte colony-stimulating factor from inclusion bodies.

    PubMed

    Li, Ming; Fan, Hua; Liu, Jiahua; Wang, Minhong; Wang, Lili; Wang, Chaozhan

    2012-03-01

    Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is a very efficient therapeutic protein drug which has been widely used in human clinics to treat cancer patients suffering from chemotherapy-induced neutropenia. In this study, rhG-CSF was solubilized from inclusion bodies by using a high-pH solution containing low concentration of urea. It was found that solubilization of the rhG-CSF inclusion bodies greatly depended on the buffer pH employed; alkalic pH significantly favored the solubilization. In addition, when small amount of urea was added to the solution at high pH, the solubilization was further enhanced. After solubilization, the rhG-CSF was renatured with simultaneous purification by using weak anion exchange, strong anion exchange, and hydrophobic interaction chromatography, separately. The results indicated that the rhG-CSF solubilized by the high-pH solution containing low concentration of urea had much higher mass recovery than the one solubilized by 8 M urea when using anyone of the three refolding methods employed in this work. In the case of weak anion exchange chromatography, the high pH solubilized rhG-CSF could get a mass recovery of 73%. The strategy of combining solubilization of inclusion bodies at high pH with refolding of protein using liquid chromatography may become a routine method for protein production from inclusion bodies.

  2. Tyrosine residues in the granulocyte colony-stimulating factor (G-CSF) receptor mediate G-CSF-induced differentiation of murine myeloid leukemic (M1) cells.

    PubMed

    Nicholson, S E; Starr, R; Novak, U; Hilton, D J; Layton, J E

    1996-10-25

    The cytoplasmic tyrosine residues of many growth factor receptors have been shown to be important for receptor signal transduction via the recruitment of proteins containing phosphotyrosine-binding domains. This study demonstrates the importance of specific tyrosine residues in the granulocyte colony-stimulating factor (G-CSF) receptor cytoplasmic domain in G-CSF-induced macrophage cell differentiation. Site-directed mutagenesis was used to generate a series of G-CSF receptor (G-CSF-R) mutants in which the tyrosine residues were replaced with phenylalanine either singly or in combination. The mouse myeloid leukemic cell line (M1) transfected with G-CSF-R cDNA can be induced to differentiate into macrophages in response to G-CSF. The effect of the tyrosine mutations on this differentiation response was assessed by examining cell morphology and differentiation in soft agar colony assays. Although three of the four cytoplasmic tyrosine residues appeared to contribute to the differentiation response, mutation of a single residue (Tyr744) significantly reduced the ability of the M1 cells to differentiate. The STAT family of signaling molecules (Stat1, Stat3, and Stat5) were activated by G-CSF in M1 cells expressing those G-CSF-R tyrosine mutants unable to mediate G-CSF-induced differentiation. Furthermore, activation of STAT proteins was shown to occur in the absence of all four cytoplasmic tyrosine residues, suggesting an alternative mechanism for STAT activation other than direct interaction with receptor phosphotyrosines.

  3. Tachyplesin III and granulocyte-colony stimulating factor enhance the efficacy of tazobactam/piperacillin in a neutropenic mouse model of polymicrobial peritonitis.

    PubMed

    Cirioni, Oscar; Ghiselli, Roberto; Kamysz, Wojciech; Orlando, Fiorenza; Silvestri, Carmela; Mocchegiani, Federico; Di Matteo, Fabio; Kamysz, Elzbieta; Riva, Alessandra; Rocchi, Marco; Saba, Vittorio; Scalise, Giorgio; Giacometti, Andrea

    2008-01-01

    We investigated the efficacy of tazobactam/piperacillin (TZP), tachyplesin III and granulocyte-colony stimulating factor (G-CSF) in an experimental murine neutropenic intraabdominal infection. BALB/c male mice were rendered neutropenic by intraperitoneal administration of cyclophosphamide on days -4 and -2 pre-infection. Septic shock was induced by cecal ligation and puncture. Animals received intravenously isotonic sodium chloride solution (control group C1), 1mg/kg of tachyplesin III, 120 mg/kg of TZP, 0.1mg/kg of G-CSF, tachyplesin III plus TZP, G-CSF plus TZP and finally tachyplesin III plus G-CSF plus TZP, respectively. Lethality, bacterial growth in blood, peritoneum, spleen, liver, and mesenteric lymph nodes, endotoxin, IL-6 and TNF-alpha concentrations in plasma were evaluated. All compounds reduced the lethality when compared to controls. Endotoxin and cytokine plasma levels were significantly higher in TZP-treated animals compared to tachyplesin III-treated animals. Finally, all drug combinations showed to be the most effective treatment in reducing all variables measured. Interestingly, the strongest results concerning the bacterial growth inhibition, lethality and endotoxemia were obtained when the three compounds were contemporaneously administered. The presence of their positive interaction makes tachyplesin III and G-CSF potentially valuable as an adjuvant for antimicrobial chemotherapy of sepsis.

  4. Pretransplant Mobilization with Granulocyte Colony-Stimulating Factor Improves B-Cell Reconstitution by Lentiviral Vector Gene Therapy in SCID-X1 Mice

    PubMed Central

    Huston, Marshall W.; Riegman, Adriaan R.A.; Yadak, Rana; van Helsdingen, Yvette; de Boer, Helen; van Til, Niek P.

    2014-01-01

    Abstract Hematopoietic stem cell (HSC) gene therapy is a demonstrated effective treatment for X-linked severe combined immunodeficiency (SCID-X1), but B-cell reconstitution and function has been deficient in many of the gene therapy treated patients. Cytoreductive preconditioning is known to improve HSC engraftment, but in general it is not considered for SCID-X1 since the poor health of most of these patients at diagnosis and the risk of toxicity preclude the conditioning used in standard bone marrow stem cell transplantation. We hypothesized that mobilization of HSC by granulocyte colony-stimulating factor (G-CSF) should create temporary space in bone marrow niches to improve engraftment and thereby B-cell reconstitution. In the present pilot study supplementing our earlier preclinical evaluation (Huston et al., 2011), Il2rg−/− mice pretreated with G-CSF were transplanted with wild-type lineage negative (Lin−) cells or Il2rg−/− Lin− cells transduced with therapeutic IL2RG lentiviral vectors. Mice were monitored for reconstitution of lymphocyte populations, level of donor cell chimerism, and antibody responses as compared to 2 Gy total body irradiation (TBI), previously found effective in promoting B-cell reconstitution. The results demonstrate that G-CSF promotes B-cell reconstitution similar to low-dose TBI and provides proof of principle for an alternative approach to improve efficacy of gene therapy in SCID patients without adverse effects associated with cytoreductive conditioning. PMID:25222508

  5. Production of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor by carcinomas in a dog and a cat with paraneoplastic leukocytosis.

    PubMed

    Sharkey, L C; Rosol, T J; Gröne, A; Ward, H; Steinmeyer, C

    1996-01-01

    A dog with a pulmonary papillary carcinoma and a cat with a dermal tubular adenocarcinoma had profound paraneoplastic neutrophilic leukocytosis with no clinically detectable inflammatory foci. To investigate the mechanism of the leukocytosis, oligonucleotide primers were designed from the cDNA sequences of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) of dogs. Reverse transcription polymerase chain reaction was performed on tumor tissues, and specific amplification of G-CSF and GM-CSF was obtained with the tumor RNA in the dog. The tumor RNA in the cat demonstrated specific amplification of G-CSF but not GM-CSF. These findings are consistent with the production of G-CSF and/or GM-CSF by neoplasms as a mechanism for paraneoplastic leukocytosis in small animals.

  6. Sustained in vivo activity of recombinant bovine granulocyte colony stimulating factor (rbG-CSF) using HEPES buffer.

    PubMed

    Kasraian, K; Kuzniar, A; Earley, D; Kamicker, B J; Wilson, G; Manion, T; Hong, J; Reiber, C; Canning, P

    2001-08-01

    The purpose of this study was to develop a long-acting injectable formulation of bG-CSF for veterinary use. However, in order to achieve sustained in vivo activity it was first necessary to stabilize the protein at the injection site. Preformulation studies, as well as literature, suggest that bG-CSF aggregates at neutral pH ranges (i.e., pH 6-8) and at temperatures of approximately 40 degrees C. Therefore, bG-CSF will not retain its activity for an extended period of time at the injection site. During this study we determined that HEPES buffer has a very significant impact on protein stability as well as on biological performance. Recombinant bovine granulocyte colony stimulating factor (rbG-CSF) was formulated in 1 M HEPES buffer for subcutaneous injection into cows. bG-CSF formulated in 1 M HEPES buffer resulted in sustained in vivo activity of bG-CSF compared to the "control" formulation (control formulation: 5% mannitol, 10 mM acetate buffer, 0.004% tween-80, pH 4). White blood cell (WBC) count was used as a marker to evaluate in vivo activity of the formulation. WBC numbers remained above a threshold value for only 24-30 h for the control formula. However, when bG-CSF was formulated in 1 M HEPES, the WBC remained above threshold for 3 days or 72 h. Formulating bG-CSF in 1 M HEPES at pH 7.5 also resulted in greater solution stability. This was surprising since bG-CSF is intrinsically not stable at neutral pH. The effect of 1 M HEPES on the T(M) (temperature at maximum heat flow on calorimetry scan) of bG-CSF was determined by microcalorimetry. In the absence of 1 M HEPES buffer the T(M) was 48 degrees C (onset approximately 40 degrees C), while bG-CSF formulated in 1 M HEPES buffer has a T(M) of 59 degrees C (onset approximately 50 degrees C). Similar organic buffers, such as MOPS, HEPPS, TES, and tricine, also resulted in improved solution stability as well as in sustained in vivo activity. The dramatic effect of these buffers on stability and biological

  7. Anti-Obesity Effects of Granulocyte-Colony Stimulating Factor in Otsuka-Long-Evans-Tokushima Fatty Rats

    PubMed Central

    Fang, Cheng-Hu; So, Byung-Im; Park, Jun-Young; Joo, Hyun-Woo; Park, In-Hwa; Shen, Guang-Yin; Shin, Jeong-Hun; Kim, Hyuck; Ahn, You-Heon; Kim, Kyung-Soo

    2014-01-01

    Granulocyte-colony stimulating factor (G-CSF) has molecular structures and intracellular signaling pathways that are similar to those of leptin and ciliary neurotropic factor (CNTF). It also has immune-modulatory properties. Given that leptin and CNTF play important roles in energy homeostasis and that obesity is an inflammatory condition in adipose tissue, we hypothesized that G-CSF could also play a role in energy homeostasis. We treated 12 38-week-old male Otsuka-Long-Evans-Tokushima fatty rats (OLETF, diabetic) and 12 age-matched male Long-Evans-Tokushima rats (LETO, healthy) with 200 µg/day G-CSF or saline for 5 consecutive days. Body weight reduction was greater in G-CSF-treated OLETF (G-CSF/OLETF) than saline-treated OLETF (saline/OLETF) following 8 weeks of treatment (−6.9±1.6% vs. −3.1±2.2%, p<0.05). G-CSF treatment had no effect on body weight in LETO or on food intake in either OLETF or LETO. Body fat in G-CSF/OLETF was more reduced than in saline/OLETF (−32.2±3.1% vs. −20.8±6.2%, p<0.05). Energy expenditure was higher in G-CSF/OLETF from 4 weeks after the treatments than in saline/OLETF. Serum levels of cholesterol, triglyceride, interleukin-6 and tumor necrosis factor-α were lower in G-CSF/OLETF than in saline/OLETF. Uncoupling protein-1 (UCP-1) expression in brown adipose tissue (BAT) was higher in G-CSF/OLETF than in saline/OLETF, but was unaffected in LETO. Immunofluorescence staining and PCR results revealed that G-CSF receptors were expressed in BAT. In vitro experiments using brown adipocyte primary culture revealed that G-CSF enhanced UCP-1 expression from mature brown adipocytes via p38 mitogen-activated protein kinase pathway. In conclusion, G-CSF treatment reduced body weight and increased energy expenditure in a diabetic model, and enhanced UCP-1 expression and decreased inflammatory cytokine levels may be associated with the effects of G-CSF treatment. PMID:25144367

  8. Myelodysplastic syndrome and acute myeloid leukemia following adjuvant chemotherapy with and without granulocyte colony-stimulating factors for breast cancer.

    PubMed

    Calip, Gregory S; Malmgren, Judith A; Lee, Wan-Ju; Schwartz, Stephen M; Kaplan, Henry G

    2015-11-01

    Risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) post-breast cancer treatment with adjuvant chemotherapy and granulocyte colony-stimulating factors (G-CSF) is not fully characterized. Our objective was to estimate MDS/AML risk associated with specific breast cancer treatments. We conducted a retrospective cohort study of women aged ≥66 years with stage I-III breast cancer between 2001 and 2009 using the Surveillance, Epidemiology, and End Results-Medicare database. Women were classified as receiving treatment with radiation, chemotherapy, and/or G-CSF. We used multivariable Cox proportional hazards models to estimate adjusted hazard ratios (HR) and 95 % confidence intervals (CI) for MDS/AML risk. Among 56,251 breast cancer cases, 1.2 % developed MDS/AML during median follow-up of 3.2 years. 47.1 % of women received radiation and 14.3 % received chemotherapy. Compared to breast cancer cases treated with surgery alone, those treated with chemotherapy (HR = 1.38, 95 %-CI 0.98-1.93) and chemotherapy/radiation (HR = 1.77, 95 %-CI 1.25-2.51) had increased risk of MDS/AML, but not radiation alone (HR = 1.08, 95 % CI 0.86-1.36). Among chemotherapy regimens and G-CSF, MDS/AML risk was differentially associated with anthracycline/cyclophosphamide-containing regimens (HR = 1.86, 95 %-CI 1.33-2.61) and filgrastim (HR = 1.47, 95 %-CI 1.05-2.06), but not pegfilgrastim (HR = 1.10, 95 %-CI 0.73-1.66). We observed increased MDS/AML risk among older breast cancer survivors treated with anthracycline/cyclophosphamide chemotherapy that was enhanced by G-CSF. Although small, this risk warrants consideration when determining adjuvant chemotherapy and neutropenia prophylaxis for breast cancer patients.

  9. Pegylated granulocyte colony-stimulating factor conveys long-term neuroprotection and improves functional outcome in a model of Parkinson's disease.

    PubMed

    Frank, Tobias; Klinker, Florian; Falkenburger, Björn H; Laage, Rico; Lühder, Fred; Göricke, Bettina; Schneider, Armin; Neurath, Hartmud; Desel, Herbert; Liebetanz, David; Bähr, Mathias; Weishaupt, Jochen H

    2012-06-01

    Recent proof-of-principle data showed that the haematopoietic growth factor granulocyte colony-stimulating factor (filgrastim) mediates neuroprotection in rodent models of Parkinson's disease. In preparation for future clinical trials, we performed a preclinical characterization of a pegylated derivative of granulocyte colony-stimulating factor (pegfilgrastim) in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. We determined serum and cerebrospinal fluid drug levels after subcutaneous injection. A single injection of pegfilgrastim was shown to achieve stable levels of granulocyte colony-stimulating factor in both serum and cerebrospinal fluid with substantially higher levels compared to repetitive filgrastim injections. Leucocyte blood counts were only transiently increased after repeated injections. We demonstrated substantial dose-dependent long-term neuroprotection by pegfilgrastim in both young and aged mice, using bodyweight-adjusted doses that are applicable in clinical settings. Importantly, we found evidence for the functionally relevant preservation of nigrostriatal projections by pegfilgrastim in our model of Parkinson's disease, which resulted in improved motor performance. The more stable levels of pegylated neuroprotective proteins in serum and cerebrospinal fluid may represent a general advantage in the treatment of chronic neurodegenerative diseases and the resulting longer injection intervals are likely to improve patient compliance. In summary, we found that pegylation of a neuroprotective growth factor improved its pharmacokinetic profile over its non-modified counterpart in an in vivo model of Parkinson's disease. As the clinical safety profile of pegfilgrastim is already established, these data suggest that evaluation of pegfilgrastim in further Parkinson's disease models and ultimately clinical feasibility studies are warranted.

  10. Tumor-Derived Granulocyte-Macrophage Colony-Stimulating Factor and Granulocyte Colony-Stimulating Factor Prolong the Survival of Neutrophils Infiltrating Bronchoalveolar Subtype Pulmonary Adenocarcinoma

    PubMed Central

    Wislez, Marie; Fleury-Feith, Jocelyne; Rabbe, Nathalie; Moreau, Joelle; Cesari, Danielle; Milleron, Bernard; Mayaud, Charles; Antoine, Martine; Soler, Paul; Cadranel, Jacques

    2001-01-01

    We evaluated the role of the tumor environment in the regulation of apoptosis of tumor-infiltrating neutrophils, the number of which correlates negatively with outcome, in patients with adenocarcinoma of the bronchioloalveolar (BAC) subtype. We examined three different parameters of apoptosis, namely morphological aspect, annexin-V expression, and DNA fragmentation. Bronchoalveolar lavage fluid (BALF) supernatants from patients with BAC significantly inhibited the 24-hour spontaneous apoptosis of normal peripheral blood neutrophils in vitro compared to BALF supernatants from control patients (64 ± 4% versus 90 ± 2% measured by annexin-V flow cytometry, P = 0.04). The alveolar neutrophil count correlated positively with the granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) concentrations in the patient’s BALF. Furthermore, neutralizing antibodies (Abs) against GM-CSF and G-CSF significantly inhibited BALF anti-apoptotic activity (15 to 40% and 34 to 63% inhibition, respectively), whereas neutralizing Abs against interleukin (IL)-8, IL-6, IL-1β and tumor necrosis factor-α had no significant effect. In an attempt to identify the cell origin of anti-apoptotic cytokines, we tested in vitro the effect of BAC cells (A549 cell line and primary culture derived from a patient’s BAC tumor) on the apoptosis of peripheral blood neutrophils. Cell-free supernatants from tumor cells did not inhibit neutrophil apoptosis. In contrast, cell-free supernatants from tumor cells previously exposed to conditioned media from peripheral blood mononuclear cells and alveolar macrophages significantly inhibited spontaneous neutrophil apoptosis. This inhibition was partially lifted when conditioned media from mononuclear cells were previously treated with Abs against IL-1β and tumor necrosis factor-α. As in vivo, neutralizing Abs against GM-CSF significantly inhibited the anti-apoptotic activity of cell culture supernatants

  11. Lipopolysaccharide-binding protein (LBP) blockade augments the protective effect of granulocyte colony-stimulating factor (G-CSF) in a rat sepsis model.

    PubMed

    Liu, Anding; Weiss, Stefanie; Fang, Haoshu; Claus, Ralf A; Rödel, Jürgen; Dirsch, Olaf; Dahmen, Uta

    2015-05-01

    The effect of granulocyte colony-stimulating factor (G-CSF) on sepsis is discussed controversially in clinical studies. We previously demonstrated that G-CSF treatment induced lipopolysaccharide (LPS) sensitization via up-regulation of LPS-binding protein (LBP). We hypothesized that the futile effect of G-CSF-treatment in sepsis might be due to its ability to up-regulate LBP. Therefore, blockade of LBP may attenuate the G-CSF-induced LPS sensitization and protect animals from polymicrobial sepsis. Endogenous LBP levels were up-regulated by pretreatment with G-CSF, and the LBP protein was blocked by administration of a specific blocking peptide-LBPK95A. Polymicrobial sepsis was induced by intraperitoneal injection of feces slurry. Rats were monitored every 3 up to 72 h to observe the survival rate. Tissue injury, bacterial infiltration, local inflammatory response, and neutrophil infiltration at 0, 2, and 12 h after the septic insult were analyzed. The survival benefit of G-CSF pretreatment was improved when combined with LBPK95A treatment (control vs. G-CSF vs. combi: 36% vs. 56% vs. 93%; P < 0.05). Combined treatment of G-CSF and LBPK95A was associated with the minimal tissue damage. Treatment with LBPK95A significantly inhibited the neutrophil infiltration without interfering with the bacterial clearance. The G-CSF-induced inflammatory sensitization effect was inhibited by LBPK95A, indicated by the decrease of cytokines expression, and the activation of nuclear factor kappa B and signal transducer and activator of transcription 3 signaling pathway. In conclusion, these results suggested that the effect of prophylactic augmentation of the host's response via G-CSF pretreatment was further enhanced by inhibition of the up-regulation of LBP.

  12. Platelet lysate and granulocyte-colony stimulating factor serve safe and accelerated expansion of human bone marrow stromal cells for stroke therapy.

    PubMed

    Yamauchi, Tomohiro; Saito, Hisayasu; Ito, Masaki; Shichinohe, Hideo; Houkin, Kiyohiro; Kuroda, Satoshi

    2014-12-01

    Autologous human bone marrow stromal cells (hBMSCs) should be expanded in the animal serum-free condition within clinically relevant periods in order to secure safe and effective cell therapy for ischemic stroke. This study was aimed to assess whether the hBMSCs enhance their proliferation capacity and provide beneficial effect in the infarct brain when cultured with platelet lysate (PL) and granulocyte-colony stimulating factor (G-CSF). The hBMSCs were cultured in the fetal calf serum (FCS)-, PL-, or PL/G-CSF-containing medium. Cell growth kinetics was analyzed. The hBMSCs-PL, hBMSC-PL/G-CSF, or vehicle was stereotactically transplanted into the ipsilateral striatum of the rats subjected to permanent middle cerebral artery occlusion 7 days after the insult. Motor function was assessed for 8 weeks, and the fate of transplanted hBMSCs was examined using immunohistochemistry. As the results, the hBMSCs-PL/G-CSF showed more enhanced proliferation than the hBMSCs-FCS and hBMSCs-PL. Transplantation of hBMSCs expanded with the PL- or PL/G-CSF-containing medium equally promoted functional recovery compared with the vehicle group. Histological analysis revealed that there were no significant differences in their migration, survival, and neural differentiation in the infarct brain between the hBMSCs-PL and hBMSCs-PL/G-CSF. These findings strongly suggest that the combination of PL and G-CSF may accelerate hBMSC expansion and serve safe cell therapy for patients with ischemic stroke at clinically relevant timing.

  13. Stem cell mobilisation by granulocyte-colony stimulating factor in patients with acute myocardial infarction. Long-term results of the REVIVAL-2 trial.

    PubMed

    Steppich, Birgit; Hadamitzky, Martin; Ibrahim, Tareq; Groha, Philip; Schunkert, Heribert; Laugwitz, Karl-Ludwig; Kastrati, Adnan; Ott, Ilka

    2016-04-01

    Treatment with granulocyte-colony stimulating factor (G-CSF) mobilises cells from the bone marrow to the peripheral blood. Previous preclinical and early clinical trials may suggest that treatment with G-CSF leads to improved myocardial perfusion and function in acute or chronic ischaemic heart disease. In the REVIVAL-2 study we found that stem cell mobilisation by G-CSF does not influence infarct size, left ventricular function and coronary restenosis in patients with acute myocardial infarction (MI) that underwent successful percutaneous coronary intervention. The objective of the present analysis was to assess the impact of G-CSF treatment on seven-year clinical outcomes from the REVIVAL-2 trial. In the randomized, double-blind, placebo-controlled REVIVAL-2 study, 114 patients with the diagnosis of acute myocardial infarction were enrolled five days after successful reperfusion by percutaneous coronary intervention. Patients were assigned to receive 10 µg/kg G-CSF (n=56) or placebo (n=58) for five days. The primary endpoint for this long-term outcome analysis was the composite of death, myocardial infarction or stroke seven years after randomisation. The endpoint occurred in 14.3 % of patients in the G-CSF group versus 17.2 % assigned to placebo (p=0.67). The combined incidence of death or myocardial infarction occurred in 14.3 % of the patients assigned to G-CSF and 15.5 % of the patients assigned to placebo (p=0.85). In conclusion, these long-term follow-up data show that G-CSF does not improve clinical outcomes of patients with acute myocardial infarction.

  14. Primary granulocyte colony-stimulating factor prophylaxis during the first two cycles only or throughout all chemotherapy cycles in patients with breast cancer at risk for febrile neutropenia.

    PubMed

    Aarts, Maureen J; Peters, Frank P; Mandigers, Caroline M; Dercksen, M Wouter; Stouthard, Jacqueline M; Nortier, Hans J; van Laarhoven, Hanneke W; van Warmerdam, Laurence J; van de Wouw, Agnes J; Jacobs, Esther M; Mattijssen, Vera; van der Rijt, Carin C; Smilde, Tineke J; van der Velden, Annette W; Temizkan, Mehmet; Batman, Erdogan; Muller, Erik W; van Gastel, Saskia M; Borm, George F; Tjan-Heijnen, Vivianne C G

    2013-12-01

    Early breast cancer is commonly treated with anthracyclines and taxanes. However, combining these drugs increases the risk of myelotoxicity and may require granulocyte colony-stimulating factor (G-CSF) support. The highest incidence of febrile neutropenia (FN) and largest benefit of G-CSF during the first cycles of chemotherapy lead to questions about the effectiveness of continued use of G-CSF throughout later cycles of chemotherapy. In a multicenter study, patients with breast cancer who were considered fit enough to receive 3-weekly polychemotherapy, but also had > 20% risk for FN, were randomly assigned to primary G-CSF prophylaxis during the first two chemotherapy cycles only (experimental arm) or to primary G-CSF prophylaxis throughout all chemotherapy cycles (standard arm). The noninferiority hypothesis was that the incidence of FN would be maximally 7.5% higher in the experimental compared with the standard arm. After inclusion of 167 eligible patients, the independent data monitoring committee advised premature study closure. Of 84 patients randomly assigned to G-CSF throughout all chemotherapy cycles, eight (10%) experienced an episode of FN. In contrast, of 83 patients randomly assigned to G-CSF during the first two cycles only, 30 (36%) had an FN episode (95% CI, 0.13 to 0.54), with a peak incidence of 24% in the third cycle (ie, first cycle without G-CSF prophylaxis). In patients with early breast cancer at high risk for FN, continued use of primary G-CSF prophylaxis during all chemotherapy cycles is of clinical relevance and thus cannot be abandoned.

  15. Granulocyte-Colony Stimulating Factor (G-CSF) Accelerates Wound Healing in Hemorrhagic Shock Rats by Enhancing Angiogenesis and Attenuating Apoptosis

    PubMed Central

    Huang, Hong; Zhang, Qi; Liu, Jiejie; Hao, Haojie; Jiang, Chaoguang; Han, Weidong

    2017-01-01

    Background Following severe trauma, treatment of cutaneous injuries is often delayed by inadequate blood supply. The aim of the present study was to determine whether granulocyte-colony stimulating factor (G-CSF) protects endothelial cells (ECs) and enhances angiogenesis in a rat model of hemorrhagic shock (HS) combined with cutaneous injury after resuscitation. Material/Methods The HS rats with full-thickness defects were resuscitated and randomly divided into a G-CSF group (200 μg/kg body weight), a normal saline group, and a blank control group. Histological staining was to used estimate the recovery and apoptosis of skin. Apoptosis- and angiogenesis-related factors were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot (WB). Scratch assay, tube formation, and WB experiments were performed to verify the functional effects of G-CSF on HUVECs in vitro. Results H&E staining and Masson trichrome staining showed earlier inflammation resolution and collagen synthesis in the G-CSF-treated group. Angiogenesis-related factors were elevated at mRNA and protein levels. TUNEL staining suggested fewer apoptotic cells in the G-CSF group. The apoptotic-related factors were down-regulated and anti-apoptotic factors were up-regulated in the G-CSF-treated group. Scratch assay and tube formation experiments revealed that G-CSF facilitated migration ability and angiogenic potential of HUVECs. The angiogenic and anti-apoptotic effects were also enhanced in vitro. Conclusions Our results suggest that G-CSF after resuscitation attenuates local apoptosis and accelerates angiogenesis. These findings hold great promise for improving therapy for cutaneous injury in severe trauma and ischemia diseases. PMID:28559534

  16. NF-κB is involved in brain repair by stem cell factor and granulocyte-colony stimulating factor in chronic stroke.

    PubMed

    Cui, Lili; Duchamp, Nicolas S; Boston, Dakota J; Ren, Xuefang; Zhang, Xiangjian; Hu, Heng; Zhao, Li-Ru

    2015-01-01

    Chronic stroke is the phase of brain recovery and repair generally beginning 3 months after stroke onset. No pharmaceutical approach is currently available to enhance brain repair in chronic stroke. We have previously determined the therapeutic effects of stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF) alone or in combination (SCF+G-CSF) in an animal model of chronic stroke and demonstrated that only SCF+G-CSF induces long-term functional recovery. However, the mechanism underlying the SCF+G-CSF-induced brain repair in chronic stroke remains largely elusive. In the present study, we determined the role of nuclear factor-kappa B (NF-κB) in neurovascular network remodeling and motor function improvement by SCF+G-CSF treatment in chronic stroke. SCF+G-CSF was subcutaneously administered for 7 days beginning 17 weeks after induction of experimental stroke. To inhibit NF-κB activation, NF-κB inhibitor was infused into the brain before SCF+G-CSF treatment. We observed that NF-κB inhibitor abolished the SCF+G-CSF-induced axonal sprouting, synaptogenesis and angiogenesis in the ipsilesional somatosensorimotor cortex. In addition, blockage of NF-κB activation resulted in elimination of the SCF+G-CSF-induced motor functional restoration in chronic stroke. These data suggest that NF-κB is required for the SCF+G-CSF-induced neuron-vascular network remodeling in the ipsilesional somatosensorimotor cortex and motor functional recovery in chronic stroke. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Mobilization and collection of CD34+ cells for autologous transplantation of peripheral blood hematopoietic progenitor cells in children: analysis of two different granulocyte-colony stimulating factor doses

    PubMed Central

    Eid, Kátia Aparecida de Brito; Miranda, Eliana Cristina Martins; Aguiar, Simone dos Santos

    2015-01-01

    Introduction The use of peripheral hematopoietic progenitor cells (HPCs) is the cell choice in autologous transplantation. The classic dose of granulocyte-colony stimulating factor (G-CSF) for mobilization is a single daily dose of 10 μg/kg of patient body weight. There is a theory that higher doses of granulocyte-colony stimulating factor applied twice daily could increase the number of CD34+ cells collected in fewer leukapheresis procedures. Objective The aim of this study was to compare a fractionated dose of 15 μg G-CSF/kg of body weight and the conventional dose of granulocyte-colony stimulating factor in respect to the number of leukapheresis procedures required to achieve a minimum collection of 3 × 106 CD34+ cells/kg body weight. Methods Patients were divided into two groups: Group 10 – patients who received a single daily dose of 10 μg G-CSF/kg body weight and Group 15 – patients who received a fractioned dose of 15 μg G-CSF/kg body weight daily. The leukapheresis procedure was carried out in an automated cell separator. The autologous transplantation was carried out when a minimum number of 3 × 106 CD34+ cells/kg body weight was achieved. Results Group 10 comprised 39 patients and Group 15 comprised 26 patients. A total of 146 apheresis procedures were performed: 110 (75.3%) for Group 10 and 36 (24.7%) for Group 15. For Group 10, a median of three (range: 1–7) leukapheresis procedures and a mean of 8.89 × 106 CD34+ cells/kg body weight (±9.59) were collected whereas for Group 15 the corresponding values were one (range: 1–3) and 5.29 × 106 cells/kg body weight (±4.95). A statistically significant difference was found in relation to the number of apheresis procedures (p-value <0.0001). Conclusions To collect a minimum target of 3 × 106 CD34+ cells/kg body weight, the administration of a fractionated dose of 15 μg G-CSF/kg body weight significantly decreased the number of leukapheresis procedures performed. PMID:26041417

  18. Granulocyte-Colony-Stimulating Factor Stimulation of Bone Marrow Mesenchymal Stromal Cells Promotes CD34+ Cell Migration Via a Matrix Metalloproteinase-2-Dependent Mechanism

    PubMed Central

    Ponte, Adriana López; Ribeiro-Fleury, Tatiana; Chabot, Valérie; Gouilleux, Fabrice; Langonné, Alain; Hérault, Olivier; Charbord, Pierre

    2012-01-01

    Human hematopoietic stem/progenitor cells (HSPCs) can be mobilized into the circulation using granulocyte-colony stimulating factor (G-CSF), for graft collection in view of hematopoietic transplantation. This process has been related to bone marrow (BM) release of serine proteases and of the matrix metalloproteinase-9 (MMP-9). Yet, the role of these mediators in HSC egress from their niches remains questionable, because they are produced by nonstromal cells (mainly neutrophils and monocytes/macrophages) that are not a part of the niche. We show here that the G-CSF receptor (G-CSFR) is expressed by human BM mesenchymal stromal/stem cells (MSCs), and that G-CSF prestimulation of MSCs enhances the in vitro trans-stromal migration of CD34+ cells. Zymography analysis indicates that pro-MMP-2 (but not pro-MMP-9) is expressed in MSCs, and that G-CSF treatment increases its expression and induces its activation at the cell membrane. We further demonstrate that G-CSF-stimulated migration depends on G-CSFR expression and is mediated by a mechanism that involves MMPs. These results suggest a molecular model whereby G-CSF infusion may drive, by the direct action on MSCs, HSPC egress from BM niches via synthesis and activation of MMPs. In this model, MMP-2 instead of MMP-9 is implicated, which constitutes a major difference with mouse mobilization models. PMID:22651889

  19. Dissociation of LPS-induced monocytic ex vivo production of granulocyte colony-stimulating factor (G-CSF) and TNF-alpha in patients with septic shock.

    PubMed

    Weiss, M; Fischer, G; Barth, E; Boneberg, E; Schneider, E M; Georgieff, M; Hartung, T

    2001-01-07

    Over a 6 month period, in 192 patients admitted to the intensive care unit (ICU), a longitudinal analysis of whole blood lipopolysaccharide (LPS)-induced ex vivo cytokine production was performed on a daily basis until discharge from the ICU or death. Twenty-one patients with proven infections were in septic shock for the first time and for at least 3 days' duration. Ex vivo LPS-inducible release of granulocyte colony-stimulating factor (G-CSF) was upregulated and that of TNF-alpha was downregulated in patients with septic shock, regardless whether they survived or died. In conclusion, LPS-induced ex vivo TNF-alpha and G-CSF cytokine release by monocytes is regulated differentially in patients with septic shock. Since upregulation of LPS-induced production of G-CSF occurred earlier in survivors than in non-survivors, rapidly elevated and sustained G-CSF responsiveness may contribute to survival in septic shock.

  20. [A case of bladder cancer producing granulocyte colony-stimulating factor and interleukin-6 causing respiratory failure treated with neoadjuvant systemic chemotherapy along with sivelestat].

    PubMed

    Matsuzaki, Kyosuke; Okumi, Masayoshi; Kishimoto, Nozomu; Yazawa, Koji; Miyagawa, Yasushi; Uchida, Kinya; Nonomura, Norio

    2013-07-01

    A 67-year-old man visited an urological clinic with a chief complaint of urination pain. Cystourethroscopy and magnetic resonance imaging (MRI) examination revealed a bladder tumor (cT3bN0M0). Marked leukocytosis and respiratory distress with pleural effusion appeared. Pulse steroid therapy improved the general condition partially. The patient was sent to our hospital for further examination. Serum granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) were high and the pathological findings of bladder tumor obtained by transurethral resection (TUR) revealed an urothelial carcinoma that produced G-CSF and IL-6. Neoadjuvant systemic chemotherapy was performed along with use of steroid and sivelestat, which ameliorated the respiratory distress. After three courses of systemic chemotherapy, serum G-CSF and IL-6 normalized and cystoprostatectomy was performed. The patient has been in good health at 20 months after the surgery with no evidence of recurrence.

  1. Granulocyte colony-stimulating factor (G-CSF): a mediator in endometrial receptivity for a patient with polycystic ovary (PCO) undergoing in vitro maturation (IVM).

    PubMed

    Lucena, Elkin; Moreno-Ortiz, Harold

    2013-04-18

    Proliferative and secretory changes at the endometrial lining are the result of a complex intrauterine environment where sex steroid hormones and different local factors play an important role for endometrial thickening. Optimal endometrial thickness reflects an adequate maturation which is a key factor for embryo implantation. Here, we present a case of a woman with polycystic ovary who was treated using in vitro maturation (IVM) techniques. In addition, this patient showed a dyssynchrony between the endometrial phase characterised by endometrial thinning and the embryo development which had a negative impact for embryo implantation. A protocol using uterine perfusion of granulocyte colony-stimulating factor (G-CSF) was performed as an alternative treatment for the unresponsive endometrium. We found that uterine infusion of G-CSF quickly increased endometrial thickness resulting in a successful pregnancy and healthy born baby. These results suggest that G-CSF is a factor that participates during endometrial remodelling enhancing the synchronisation between uterine environment and embryo development.

  2. Granulocyte colony stimulating factor (G-CSF) can allow treatment with clozapine in a patient with severe benign ethnic neutropaenia (BEN): a case report.

    PubMed

    Spencer, Benjamin W J; Williams, Hugh R J; Gee, Siobhan H; Whiskey, Eromona; Rodrigues, Joseph P; Mijovic, Aleksandar; MacCabe, James H

    2012-09-01

    Clozapine is the treatment of choice for treatment-resistant schizophrenia, but it is associated with a risk of neutropaenia and agranulocytosis. Clozapine use is regulated by mandatory blood monitoring in the UK, requiring cessation of treatment should the absolute neutrophil count (ANC) drop below specified values. Benign reductions in the ANC in non-white populations are common, and this can preclude a patient from receiving treatment with clozapine. A diagnosis of benign ethnic neutropaenia can reduce these treatment restrictions (UK specific), but the degree of neutropaenia can be significant enough to still prevent treatment. In this report, we show that response to granulocyte colony stimulating factor (G-CSF) may be quite variable and difficult to predict, but with careful monitoring it can be used to increase the ANC count and allow continued treatment with clozapine.

  3. Enhancement of Umbilical Cord Blood Cell Hematopoiesis by Maitake Beta-Glucan Is Mediated by Granulocyte Colony-Stimulating Factor Production▿

    PubMed Central

    Lin, Hong; Cheung, Sandy W. Y.; Nesin, Mirjana; Cassileth, Barrie R.; Cunningham-Rundles, Susanna

    2007-01-01

    Maitake beta-glucan (MBG) is an extract from the fruit body of the Grifola frondosa mushroom that is being widely used to treat cancer in Asia. We have previously reported that MBG enhances mouse bone marrow cell (BMC) hematopoiesis in vitro and protects BMC from doxorubicin (DOX) toxicity. In the current study, we investigated the ability of MBG to enhance hematopoiesis and to reduce the toxic effects of DOX on fresh human umbilical cord blood (CB) cells. MBG treatment significantly enhanced the colony formation unit (CFU) response of granulocytes-macrophages (CFU-GM response) over the whole dose range of 12.5 to 100 μg/ml (P < 0.05). The addition of MBG to DOX-treated CB cells significantly protected granulocyte-macrophage colony formation from the toxicity of DOX, which otherwise produced strong hematopoietic repression. MBG also partially replaced recombinant human granulocyte colony-stimulating factor (rhG-CSF), as shown by a significant augmentation of the CFU-GM response in the absence of rhG-CSF. We found that MBG induces granulocyte colony-stimulating factor (G-CSF) production in CB CD33+ monocytes, as detected by intracellular cytokine flow cytometric assessment. In contrast, we found that adult peripheral blood monocytes did not produce a significant G-CSF response to MBG, whereas both adult and CB monocytes produced G-CSF in response to lipopolysaccharide. These studies provide the first evidence that MBG induces hematopoietic stem cell proliferation and differentiation of CFU-GM in umbilical CB cells and acts directly to induce G-CSF. PMID:17093103

  4. Granulocyte colony-stimulating factor inhibits CXCR4/SDF-1α signaling and overcomes stromal-mediated drug resistance in the HL-60 cell line.

    PubMed

    Sheng, Xianfu; Zhong, Hua; Wan, Haixia; Zhong, Jihua; Chen, Fangyuan

    2016-07-01

    Combining cytarabine, aclarubicin and granulocyte colony-stimulating factor (G-CSF) has demonstrated marked efficacy in the treatment of elderly and relapsed/refractory patients with acute myeloid leukemia (AML); however, the role of G-CSF remains poorly understood. The present study aimed to investigate the ability of G-CSF to overcome stromal-mediated drug resistance and the underlying molecular mechanism. Two types of co-culture models were established in the HS-5 human bone marrow/stromal and HL-60 human promyelocytic leukemia cell lines, in order to imitate the interactions between stromal and leukemia cells in vitro, which is mediated by the stromal cell-derived factor (SDF)-1α signaling axis. In the present study, HL-60 cells were attracted and adhered to HS-5 cells using migration assay and flow cytometry, respectively; however, these interactions were inhibited by treatment with G-CSF and/or the C-X-C chemokine receptor type 4 (CXCR4) antagonist, AMD3100. Co-culture with HS-5 cells, including direct and indirect contact, protected HL-60 cells against spontaneous apoptosis or drug-induced apoptosis; however, these protective effects were disrupted by treatment with G-CSF and/or AMD3100. Notably, G-CSF and/or AMD3100 did not alter cell viability or apoptosis when HL-60 cells were cultured with medium alone. In addition, G-CSF significantly reduced the expression levels of surface CXCR4 protein, total CXCR4 protein and CXCR4 mRNA, and significantly upregulated the expression of microRNA (miR)-146a. Conversely, AMD3100 significantly reduced surface CXCR4 expression levels, but not the total CXCR4, CXCR4 mRNA or miR-146a expression levels. The results of the present study suggested that interfering with the CXCR4/SDF-1α signaling axis via G-CSF inhibited the migration and adhesion of HL-60 cells to HS-5 cells and eliminated HS5 cell-mediated protective effects. Furthermore, G-CSF administration reduced CXCR4 expression levels by upregulating the expression of

  5. Randomized Prospective Controlled Trial of Recombinant Granulocyte Colony-Stimulating Factor as Adjunctive Therapy for Limb-Threatening Diabetic Foot Infection

    PubMed Central

    de Lalla, Fausto; Pellizzer, Giampietro; Strazzabosco, Marco; Martini, Zeno; Du Jardin, Giovanni; Lora, Luciano; Fabris, Paolo; Benedetti, Paolo; Erle, Giuseppe

    2001-01-01

    Adult diabetic patients admitted to our Diabetes Center from September 1996 to January 1998 for severe, limb-threatening foot infection were consecutively enrolled in a prospective, randomized, controlled clinical study aimed at assessing the safety and efficacy of recombinant human granulocyte colony-stimulating factor (G-CSF) (lenograstim) as an adjunctive therapy for the standard treatment of diabetic foot infection. Forty patients, all of whom displayed evidence of osteomyelitis and long-standing ulcer infection, were randomized 1:1 to receive either conventional treatment (i.e., antimicrobial therapy plus local treatment) or conventional therapy plus 263 μg of G-CSF subcutaneously daily for 21 days. The empiric antibiotic treatment (a combination of ciprofloxacin plus clindamycin) was further adjusted, when necessary, according to the results of cultures and sensitivity testing. Microbiologic assessment of foot ulcers was performed by both deep-tissue biopsy and swab cultures, performed at enrollment and on days 7 and 21 thereafter. Patients were monitored for 6 months; the major endpoints (i.e., cure, improvement, failure, and amputation) were blindly assessed at weeks 3 and 9. At enrollment, both patient groups were comparable in terms of both demographic and clinical data. None of the G-CSF-treated patients experienced either local or systemic adverse effects. At the 3- and 9-week assessments, no significant differences between the two groups could be observed concerning the number of patients either cured or improved, the number of patients displaying therapeutic failure, or the species and number of microorganisms previously yielded from cultures at day 7 and day 21. Conversely, among this small series of patients the cumulative number of amputations observed after 9 weeks of treatment appeared to be lower in the G-CSF arm; in fact, only three patients (15%) in this group had required amputation, whereas nine patients (45%) in the other group had

  6. Effects of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor on glial scar formation after spinal cord injury in rats.

    PubMed

    Chung, Joonho; Kim, Moon Hang; Yoon, Yong Je; Kim, Kil Hwan; Park, So Ra; Choi, Byung Hyune

    2014-12-01

    This study investigated the effects of granulocyte colony-stimulating factor (G-CSF) on glial scar formation after spinal cord injury (SCI) in rats and compared the therapeutic effects between G-CSF and granulocytemacrophage colony-stimulating factor (GM-CSF) to evaluate G-CSF as a potential substitute for GM-CSF in clinical application. Rats were randomly assigned to 1 of 4 groups: a sham-operated group (Group 1), an SCI group without treatment (Group 2), an SCI group treated with G-CSF (Group 3), and an SCI group treated with GM-CSF (Group 4). G-CSF and GM-CSF were administered via intraperitoneal injection immediately after SCI. The effects of G-CSF and GM-CSF on functional recovery, glial scar formation, and axonal regeneration were evaluated and compared. The rats in Groups 3 and 4 showed better functional recovery and more decreased cavity sizes than those in Group 2 (p < 0.05). Both G-CSF and GM-CSF suppressed intensive expression of glial fibrillary acidic protein around the cavity at 4 weeks and reduced the expression of chondroitin sulfate proteoglycans (p < 0.05). Also, early administration of G-CSF and GM-CSF protected axon fibers from destructive injury and facilitated axonal regeneration. There were no significant differences in comparisons of functional recovery, glial scar formation, and axonal regeneration between G-CSF and GM-CSF. G-CSF suppressed glial scar formation after SCI in rats, possibly by restricting the expression of glial fibrillary acidic protein and chondroitin sulfate proteoglycans, which might facilitate functional recovery from SCI. GM-CSF and G-CSF had similar effects on glial scar formation and functional recovery after SCI, suggesting that G-CSF can potentially be substituted for GM-CSF in the treatment of SCI.

  7. Toxoplasma gondii Induces Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor Secretion by Human Fibroblasts: Implications for Neutrophil Apoptosis

    PubMed Central

    Channon, Jacqueline Y.; Miselis, Kristin A.; Minns, Laurie A.; Dutta, Chaitali; Kasper, Lloyd H.

    2002-01-01

    Human neutrophils are rescued from apoptosis following incubation with once-washed, fibroblast-derived Toxoplasma gondii tachyzoites. Both infected and uninfected neutrophils are rescued, implicating a soluble mediator. In this study we investigated the origin and identity of this soluble mediator. Neutrophils were incubated either with purified tachyzoites or with conditioned medium derived from T. gondii-infected human fibroblasts. Conditioned medium was found to be a potent stimulus that delayed neutrophil apoptosis up to 72 h, whereas purified and extensively washed tachyzoites had no effect. Delayed apoptosis correlated with up-regulation of the neutrophil antiapoptotic protein, Mcl-1, and the neutrophil interleukin 3 receptor α subunit (IL-3Rα), suggesting a role for granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF and granulocyte colony-stimulating factor (G-CSF) were measurable in conditioned medium by enzyme-linked immunosorbent assay. Neutralizing antibodies to GM-CSF and G-CSF were additive in abrogating delayed neutrophil apoptosis induced by conditioned medium. Inhibitors of Src family tyrosine kinases, Gi proteins, phosphatidylinositol 3-kinase, p44erk1 and p42erk2 mitogen-activated protein kinases, and Jak2 kinases partially attenuated the effect of conditioned medium, consistent with a role for G-CSF and/or GM-CSF. Hence, delayed neutrophil apoptosis is mediated by GM-CSF and G-CSF secreted by T. gondii-infected human fibroblasts. This enhanced neutrophil survival may contribute to the robust proinflammatory response elicited in the T. gondii-infected host. PMID:12379681

  8. Delayed granulocyte colony-stimulating factor treatment in rats attenuates mechanical allodynia induced by chronic constriction injury of the sciatic nerve.

    PubMed

    Koda, Masao; Furuya, Takeo; Kato, Kei; Mannoji, Chikato; Hashimoto, Masayuki; Inada, Taigo; Kamiya, Koshiro; Ota, Mitsutoshi; Maki, Satoshi; Okawa, Akihiko; Takahashi, Kazuhisa; Ishikawa, Tetsuhiro; Yamazaki, Masashi

    2014-02-01

    Animal experimental study with intervention. The aim of this study was to elucidate therapeutic effects of delayed granulocyte colony-stimulating factor treatment for mechanical allodynia induced by chronic constriction injury (CCI) of the sciatic nerve in rats. Granulocyte colony-stimulating factor (G-CSF) is used clinically for patients with hematological disorders. Previous reports showed that immediate G-CSF attenuates neuropathic pain in CCI of the sciatic nerve. However, the acute treatment for neuropathic pain prior to accurate diagnosis is not realistic in clinical settings. Adult, female Sprague-Dawley rats were subjected to the CCI model. This model induces mechanical allodynia on the ipsilateral hind paw within the first week after the injury. One week after CCI, rats received intraperitoneal G-CSF (15.0 μg/kg) for 5 consecutive days. Mechanical allodynia was assessed using the von Frey hair test. Immunohistochemistry for phosphorylated p38 mitogen-activated kinase (p-p38MAPK) and OX-42 (a marker for activated microglia) on tissue slides from a subset of rats 2 weeks after surgery. Western blot analyses were carried out to determine protein expression level of p-p38MAPK and interleukin-1 β on spinal cord homogenates 2 weeks after CCI. Results of the von Frey filament test showed that G-CSF significantly attenuates mechanical allodynia induced by the CCI model. Immunohistochemistry revealed that G-CSF reduced the number of p-p38MAPK-positive cells in the ipsilateral dorsal horn compared with that in the vehicle group rats. Immunofluorescent double staining revealed that p-p38MAPK-expressing cells in the spinal cord dorsal horn are mainly microglia. Western blot analysis indicated that G-CSF decreased the expression levels of both p-p38MAPK and interleukin-1 β in the ipsilateral dorsal horn compared with that in the vehicle group rats. The present results indicate a beneficial effect of delayed G-CSF treatment in an animal model of peripheral nerve

  9. An early granulocyte colony-stimulating factor treatment attenuates neuropathic pain through activation of mu opioid receptors on the injured nerve

    PubMed Central

    Liao, Ming-Feng; Yeh, Shin-Rung; Lo, Ai-Lun; Chao, Po-Kuan; Lee, Yun-Lin; Hung, Yu-Hui; Lu, Kwok-Tung; Ro, Long-Sun

    2016-01-01

    Several studies have shown that the mu opioid receptor (MOR) located in the peripheral nerves can be activated after nerve injury and that it attenuates peripheral nociceptive signals to the spinal dorsal horn. Various cytokines and phosphorylated-p38 (p-p38) activation in the dorsal horn also play an important role in neuropathic pain development. Granulocyte-colony stimulating factor (GCSF) is a growth factor that can stimulate granulocyte formation and has been shown to exert an analgesic effect on neuropathic pain through recruiting opioid-containing leukocytes to the injured nerve. However, the underlying mechanisms are not well understood. Herein, the results of behavior tests in addition to MOR levels in the injured sciatic nerve and the levels of p-p38 and various cytokines in the spinal dorsal horn were studied in vehicle-treated or GCSF-treated chronic constriction injured (CCI) rats at different time points (i.e., 1, 3, and 7 days, respectively) after nerve injury. The results showed that a single early systemic GCSF treatment after nerve injury can up-regulate MORs in the injured nerve, which can decrease peripheral nociceptive signals. Thereafter, those changes suppress the pro-inflammatory cytokine IL-6 but enhance the anti-inflammatory cytokine IL-4, followed by decreases in p-p38 in the dorsal horn, and thus further attenuate neuropathic pain. PMID:27180600

  10. Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) for sepsis: a meta-analysis

    PubMed Central

    2011-01-01

    Introduction To investigate the effects of G-CSF or GM-CSF therapy in non-neutropenic patients with sepsis. Methods A systematic literature search of Medline, Embase and Cochrane Central Register of Controlled Trials was conducted using specific search terms. A manual review of references was also performed. Eligible studies were randomized control trials (RCTs) that compared granulocyte-colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) therapy with placebo for the treatment of sepsis in adults. Main outcome measures were all-cause mortality at 14 days and 28 days after initiation of G-CSF or GM-CSF therapy, in-hospital mortality, reversal rate from infection, and adverse events. Results Twelve RCTs with 2,380 patients were identified. In regard to 14-day mortality, a total of 9 death events occurred among 71 patients (12.7%) in the treatment group compared with 13 events among 67 patients (19.4%) in the placebo groups. Meta-analysis showed there was no significant difference in 28-day mortality when G-CSF or GM-CSF were compared with placebo (relative risks (RR) = 0.93, 95% confidence interval (CI): 0.79 to 1.11, P = 0.44; P for heterogeneity = 0.31, I2 = 15%). Compared with placebo, G-CSF or GM-CSF therapy did not significantly reduce in-hospital mortality (RR = 0.97, 95% CI: 0.69 to 1.36, P = 0.86; P for heterogeneity = 0.80, I2 = 0%). However, G-CSF or GM-CSF therapy significantly increased the reversal rate from infection (RR = 1.34, 95% CI: 1.11 to 1.62, P = 0.002; P for heterogeneity = 0.47, I2 = 0%). No significant difference was observed in adverse events between groups (RR = 0.93, 95% CI: 0.70 to 1.23, P = 0.62; P for heterogeneity = 0.03, I2 = 58%). Sensitivity analysis by excluding one trial did not significantly change the results of adverse events (RR = 1.05, 95% CI: 0.84 to 1.32, P = 0.44; P for heterogeneity = 0.17, I2 = 36%). Conclusions There is no current evidence supporting the routine use of G-CSF or

  11. Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) for sepsis: a meta-analysis.

    PubMed

    Bo, Lulong; Wang, Fei; Zhu, Jiali; Li, Jinbao; Deng, Xiaoming

    2011-01-01

    To investigate the effects of G-CSF or GM-CSF therapy in non-neutropenic patients with sepsis. A systematic literature search of Medline, Embase and Cochrane Central Register of Controlled Trials was conducted using specific search terms. A manual review of references was also performed. Eligible studies were randomized control trials (RCTs) that compared granulocyte-colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) therapy with placebo for the treatment of sepsis in adults. Main outcome measures were all-cause mortality at 14 days and 28 days after initiation of G-CSF or GM-CSF therapy, in-hospital mortality, reversal rate from infection, and adverse events. Twelve RCTs with 2,380 patients were identified. In regard to 14-day mortality, a total of 9 death events occurred among 71 patients (12.7%) in the treatment group compared with 13 events among 67 patients (19.4%) in the placebo groups. Meta-analysis showed there was no significant difference in 28-day mortality when G-CSF or GM-CSF were compared with placebo (relative risks (RR) = 0.93, 95% confidence interval (CI): 0.79 to 1.11, P = 0.44; P for heterogeneity = 0.31, I2 = 15%). Compared with placebo, G-CSF or GM-CSF therapy did not significantly reduce in-hospital mortality (RR = 0.97, 95% CI: 0.69 to 1.36, P = 0.86; P for heterogeneity = 0.80, I2 = 0%). However, G-CSF or GM-CSF therapy significantly increased the reversal rate from infection (RR = 1.34, 95% CI: 1.11 to 1.62, P = 0.002; P for heterogeneity = 0.47, I2 = 0%). No significant difference was observed in adverse events between groups (RR = 0.93, 95% CI: 0.70 to 1.23, P = 0.62; P for heterogeneity = 0.03, I2 = 58%). Sensitivity analysis by excluding one trial did not significantly change the results of adverse events (RR = 1.05, 95% CI: 0.84 to 1.32, P = 0.44; P for heterogeneity = 0.17, I2 = 36%). There is no current evidence supporting the routine use of G-CSF or GM-CSF in patients with sepsis. Large

  12. A phase 1 study to address the safety and efficacy of granulocyte colony-stimulating factor for the mobilization of hematopoietic progenitor cells in active rheumatoid arthritis.

    PubMed

    McGonagle, D; Rawstron, A; Richards, S; Isaacs, J; Bird, H; Jack, A; Morgan, G; Emery, P

    1997-10-01

    To examine the safety and efficacy of granulocyte colony-stimulating factor (G-CSF) alone for the mobilization of peripheral blood progenitor cells in patients with resistant active rheumatoid arthritis (RA). Five patients with resistant active RA were studied. A dose of 5 microg/kg of G-CSF (Filgrastim) was given subcutaneously each day for 5 days, and the number of stem cells mobilized into the peripheral blood was assessed by daily CD34 counts. RA disease activity was assessed by standard clinical methods. The absolute numbers of peripheral blood CD34+ cells peaked on day 4, with a mean value of 0.025 x 10(9)/liter (range 0.013-0.048 x 10(9)/liter). There was no significant change in disease activity during the study or in the month following therapy. Using G-CSF alone, CD34+ progenitor peripheral blood cells were mobilized in numbers suitable for leukopheresis. G-CSF therapy was well-tolerated in patients with active RA, and was not associated with a flare during treatment or in the month following treatment.

  13. Pegfilgrastim and daily granulocyte colony-stimulating factor: patterns of use and neutropenia-related outcomes in cancer patients in Spain--results of the LEARN Study.

    PubMed

    Almenar, D; Mayans, J; Juan, O; Bueno, J M Garcia; Lopez, J I Jalon; Frau, A; Guinot, M; Cerezuela, P; Buscalla, E Garcia; Gasquet, J A; Sanchez, J

    2009-05-01

    Daily granulocyte colony-stimulating factors [(G-CSFs); e.g. filgrastim, lenograstim] are frequently used to reduce the duration of chemotherapy-induced neutropenia (CIN) and the incidence of febrile neutropenia (FN) in cancer patients. A pegylated formulation of filgrastim, pegfilgrastim, which is administered once per cycle, was introduced in Spain in 2003. LEARN was a multi-centre, retrospective, observational study in Spain comparing patterns of use of daily G-CSF and pegfilgrastim, and CIN-related outcomes in adults with non-myeloid malignancies receiving myelosuppressive chemotherapy. Outcome measures were the percentage of patients receiving G-CSF for primary prophylaxis versus secondary prophylaxis/treatment, duration of treatment with G-CSF and incidence of CIN-related complications. Medical records from consecutive patients with documented pegfilgrastim (n = 75) or daily G-CSF (n = 111) use during 2003 were included. The proportion of patients receiving primary or secondary prophylaxis was comparable between the pegfilgrastim (39 and 48% respectively) and daily G-CSF (40 and 48% respectively) groups. However, there was a trend towards less frequent use to treat a neutropenic event such as FN or neutropenia in the pegfilgrastim group (17 versus 30% with daily G-CSF). Chemotherapy-induced neutropenia-related complications were less frequent in patients receiving pegfilgrastim (e.g. FN 11 versus 24% with daily G-CSF). This is the first study to show the potential benefits of pegfilgrastim over daily G-CSF in Spanish clinical practice.

  14. Cost-effectiveness of on-demand plerixafor added to chemotherapy and granulocyte-colony stimulating factor for peripheral blood stem cell mobilization in multiple myeloma.

    PubMed

    Milone, Giuseppe; Martino, Massimo; Leotta, Salvatore; Spadaro, Andrea; Zammit, Valentina; Cupri, Alessandra; Avola, Giuseppe; Camuglia, Maria Grazia; Di Marco, Annalia; Scalzulli, Potito; Morelli, Mara; Olivieri, Attilio; Tripepi, Giovanni

    2018-01-01

    We here report final results of a phase II/III prospective study that evaluated in Multiple Myeloma the use of on-demand plerixafor (PLX) added to mobilizing chemotherapy for patients showing predictive signs of mobilization failure. A total of 111 patients with MM were registered, all received cyclophosphamide 4 g/m(2) and granulocyte colony-stimulating factor (G-CSF). Overall, a successful CD34+ cell mobilization was achieved in 97.2% (108/111) of patients. Minimum harvest (≥2.0 × 10(6) CD34+ cells/kg) was achieved in 97.2% (108/111) and optimal harvest success (≥4.0 × 10(6) CD34+ cells/kg) was achieved in 84.6% (94/111). Multivariate analysis showed that patients who received on-demand PLX treatment had significantly higher likelihoods of successfully achieving both the minimal (p = .006) and optimal harvest (p = .05) in respect to a historical control group mobilized without any PLX. The incremental cost-effectiveness ratio, for each 1% increase in probability of achieving a successful minimal harvest, was €40.6 per patient.

  15. Pegfilgrastim and daily granulocyte colony-stimulating factor: patterns of use and neutropenia-related outcomes in cancer patients in Spain – results of the LEARN Study

    PubMed Central

    ALMENAR, D; MAYANS, J; JUAN, O; BUENO, JM GARCIA; LOPEZ, JI JALON; FRAU, A; GUINOT, M; CEREZUELA, P; BUSCALLA, E GARCIA; GASQUET, JA; SANCHEZ, J

    2009-01-01

    Daily granulocyte colony-stimulating factors [(G-CSFs); e.g. filgrastim, lenograstim] are frequently used to reduce the duration of chemotherapy-induced neutropenia (CIN) and the incidence of febrile neutropenia (FN) in cancer patients. A pegylated formulation of filgrastim, pegfilgrastim, which is administered once per cycle, was introduced in Spain in 2003. LEARN was a multi-centre, retrospective, observational study in Spain comparing patterns of use of daily G-CSF and pegfilgrastim, and CIN-related outcomes in adults with non-myeloid malignancies receiving myelosuppressive chemotherapy. Outcome measures were the percentage of patients receiving G-CSF for primary prophylaxis versus secondary prophylaxis/treatment, duration of treatment with G-CSF and incidence of CIN-related complications. Medical records from consecutive patients with documented pegfilgrastim (n = 75) or daily G-CSF (n = 111) use during 2003 were included. The proportion of patients receiving primary or secondary prophylaxis was comparable between the pegfilgrastim (39 and 48% respectively) and daily G-CSF (40 and 48% respectively) groups. However, there was a trend towards less frequent use to treat a neutropenic event such as FN or neutropenia in the pegfilgrastim group (17 versus 30% with daily G-CSF). Chemotherapy-induced neutropenia-related complications were less frequent in patients receiving pegfilgrastim (e.g. FN 11 versus 24% with daily G-CSF). This is the first study to show the potential benefits of pegfilgrastim over daily G-CSF in Spanish clinical practice. PMID:19076208

  16. Effect of granulocyte colony-stimulating factor mobilization on the expression patterns, clonality and signal transduction of TRAV and TRBV repertoire.

    PubMed

    Xuan, Li; Wu, Xiuli; Wu, Meiqing; Zhang, Yu; Liu, Hui; Fan, Zhiping; Sun, Jing; Liu, Qifa

    2012-08-01

    The immune modulatory effect of granulocyte colony-stimulating factor (G-CSF) on T cells resulted in an unexpected low incidence of graft-versus-host disease (GVHD) in allogeneic peripheral blood stem cell transplantation (allo-PBSCT). Recently, αβ(+) T cells are identified as the primary effector cells for GVHD. However, whether G-CSF could influence the repertoire of αβ(+) T cells (TRAV and TRBV repertoire) and CD3 genes remains unclear. To further characterize this feature, we investigated the effect of G-CSF mobilization on the T cell receptors (TCR) of αβ(+) T cells (TRAV and TRBV repertoire) and CD3 genes, as well as the association between the changes of TCR repertoire and GVHD in patients undergoing G-CSF mobilized allo-PBSCT. We found that G-CSF mobilization had an effect on the expression patterns, clonality and signal transduction of TRAV and TRBV repertoire. This alteration might play a role in mediating GVHD in G-CSF mobilized allo-PBSCT. Copyright © 2012 Elsevier GmbH. All rights reserved.

  17. Severe Hypoxemia in a Healthy Donor for Allogeneic Hematopoietic Stem Cell Transplantation after Only the First Administration of Granulocyte-Colony Stimulating Factor

    PubMed Central

    Yamamoto, Keita; Doki, Noriko; Senoo, Yasushi; Najima, Yuho; Kobayashi, Takeshi; Kakihana, Kazuhiko; Haraguchi, Kyoko; Okuyama, Yoshiki; Sakamaki, Hisashi; Ohashi, Kazuteru

    2016-01-01

    Background Granulocyte-colony stimulating factor (G-CSF) is widely used to mobilize peripheral blood stem cells (PBSCs) in healthy donors. A few reports have shown that some healthy donors developed acute respiratory distress syndrome or capillary leak syndrome after more than several rounds of G-CSF administration or leukapheresis. Case Report We report the case of a healthy donor for allogeneic stem cell transplantation who developed severe hypoxemia 1 h after only the first administration of G-CSF. The donor was administered 10 μg/kg G-CSF (lenograstim) subcutaneously for PBSC mobilization. 1 h after the first administration of G-CSF, the donor suddenly presented with dry cough and dyspnea. The oxygen saturation by pulse oximetry (SpO2) in the room air was 88%. An electrocardiogram and chest radiography revealed no abnormalities. We excluded other causes of severe hypoxemia and diagnosed the donor with hypoxemia due to G-CSF administration, which was subsequently terminated. The donor was administered 2 l/min oxygen via a nasal cannula and 100 mg hydrocortisone intravenously. He subsequently recovered, and SpO2 in the room air returned to 98% 10 h after hypoxemia. Conclusion These respiratory symptoms might be related to anaphylactoid or hypersensitivity reaction. The donors should be observed for at least 1 h after the first administration of G-CSF. PMID:27994532

  18. Therapeutic outcomes of transplanting autologous granulocyte colony-stimulating factor-mobilised peripheral mononuclear cells in diabetic patients with critical limb ischaemia.

    PubMed

    Mohammadzadeh, L; Samedanifard, S H; Keshavarzi, A; Alimoghaddam, K; Larijani, B; Ghavamzadeh, A; Ahmadi, A S; Shojaeifard, A; Ostadali, M R; Sharifi, A M; Amini, M R; Mahmoudian, A; Fakhraei, H; Aalaa, M; Mohajeri-Tehrani, M R

    2013-01-01

    The efficacy and safety of transplanting autologous mesenchymal stem cells (MSCs), from granulocyte-colony-stimulating factor (G-CSF)-mobilised peripheral blood, was investigated in diabetic patients with critical limb ischaemia (CLI). After 3 months, the transplanted group of patients (n=7) showed a significant improvement in ischaemia manifestations, including pain and neurological signs, wound healing and the rate of lower-limb amputation, compared to the control group of patients (n=14). Pain was significantly reduced in the transplanted group compared to controls (P=0.014). The ankle-brachial index (ABI) and the pulse strength within ischaemic tissues of the transplanted group were significantly improved (P=0.035 and P=0.01, respectively). Importantly, 50% of the control group (7/14 patients) faced major amputation of a limb at the study's conclusion, compared to none of 7 patients in the transplanted group (P=0.047). The safety of transplantation was confirmed by observing no adverse reactions among the transplanted group, including infection and immunological rejection. Hence, this study provides further evidence that transplantation of autologous peripheral blood MSCs, mobilised by G-CSF, induces angiogenesis and improves the wound healing process in diabetic patients with CLI.

  19. Identification and in vitro characterization of novel nanobodies against human granulocyte colony-stimulating factor receptor to provide inhibition of G-CSF function.

    PubMed

    Bakherad, Hamid; Gargari, Seyed Latif Mousavi; Sepehrizadeh, Zargham; Aghamollaei, Hossein; Taheri, Ramezan Ali; Torshabi, Maryam; Yazdi, Mojtaba Tabatabaei; Ebrahimizadeh, Walead; Setayesh, Neda

    2017-09-01

    It has been shown that Granulocyte colony-stimulating factor (G-CSF) has a higher expression in malignant tumors, and anti-G-CSF therapy considerably decreases tumor growth, tumor vascularization and metastasis. Thus, blocking the signaling pathway of G-CSF could be beneficial in cancer therapy. This study is aimed at designing and producing a monoclonal nanobody that could act as an antagonist of G-CSF receptor. Nanobodies are the antigen binding fragments of camelid single-chain antibodies, also known as VHH. These fragments have exceptional properties which makes them ideal for tumor imaging and therapeutic applications. We have used our previously built nanobody phage libraries to isolate specific nanobodies to the G-CSF receptor. After a series of cross-reactivity and affinity experiments, two unique nanobodies were selected for functional analysis. Proliferation assay, real-time PCR and immunofluorescence assays were used to characterize these nanobodies. Finally, VHH26 nanobody that was able to specifically bind G-CSF receptor (G-CSF-R) on the surface of NFS60 cells and efficiently block G-CSF-R downstream signaling pathway in a dose-dependent manner was selected. This nanobody could be further developed into a valuable tool in tumor therapy and it forms a basis for additional studies in preclinical animal models. Copyright © 2017. Published by Elsevier Masson SAS.

  20. Granulocyte colony-stimulating factor (G-CSF): A saturated fatty acid-induced myokine with insulin-desensitizing properties in humans

    PubMed Central

    Ordelheide, Anna-Maria; Gommer, Nadja; Böhm, Anja; Hermann, Carina; Thielker, Inga; Machicao, Fausto; Fritsche, Andreas; Stefan, Norbert; Häring, Hans-Ulrich; Staiger, Harald

    2016-01-01

    Objective Circulating long-chain free fatty acids (FFAs) are important metabolic signals that acutely enhance fatty acid oxidation, thermogenesis, energy expenditure, and insulin secretion. However, if chronically elevated, they provoke inflammation, insulin resistance, and β-cell failure. Moreover, FFAs act via multiple signaling pathways as very potent regulators of gene expression. In human skeletal muscle cells differentiated in vitro (myotubes), we have shown in previous studies that the expression of CSF3, the gene encoding granulocyte colony-stimulating factor (G-CSF), is markedly induced upon FFA treatment and exercise. Methods and results We now report that CSF3 is induced in human myotubes by saturated, but not unsaturated, FFAs via Toll-like receptor 4-dependent and -independent pathways including activation of Rel-A, AP-1, C/EBPα, Src, and stress kinases. Furthermore, we show that human adipocytes and myotubes treated with G-CSF become insulin-resistant. In line with this, a functional polymorphism in the CSF3 gene affects adipose tissue- and whole-body insulin sensitivity and glucose tolerance in human subjects with elevated plasma FFA concentrations. Conclusion G-CSF emerges as a new player in FFA-induced insulin resistance and thus may be of interest as a target for prevention and treatment of type 2 diabetes. PMID:27069870

  1. Effect of Periodic Granulocyte Colony-Stimulating Factor Administration on Endothelial Progenitor Cells and Different Monocyte Subsets in Pediatric Patients with Muscular Dystrophies

    PubMed Central

    Sienkiewicz, Dorota; Grubczak, Kamil; Okurowska-Zawada, Bożena; Paszko-Patej, Grażyna; Miklasz, Paula; Singh, Paulina; Radzikowska, Urszula; Kulak, Wojciech

    2016-01-01

    Muscular dystrophies (MD) are heterogeneous group of diseases characterized by progressive muscle dysfunction. There is a large body of evidence indicating that angiogenesis is impaired in muscles of MD patients. Therefore, induction of dystrophic muscle revascularization should become a novel approach aimed at diminishing the extent of myocyte damage. Recently, we and others demonstrated that administration of granulocyte colony-stimulating factor (G-CSF) resulted in clinical improvement of patients with neuromuscular disorders. To date, however, the exact mechanisms underlying these beneficial effects of G-CSF have not been fully understood. Here we used flow cytometry to quantitate numbers of CD34+ cells, endothelial progenitor cells, and different monocyte subsets in peripheral blood of pediatric MD patients treated with repetitive courses of G-CSF administration. We showed that repetitive cycles of G-CSF administration induced efficient mobilization of above-mentioned cells including cells with proangiogenic potential. These findings contribute to better understanding the beneficial clinical effects of G-CSF in pediatric MD patients. PMID:26770204

  2. The effect of repeated administrations of granulocyte colony stimulating factor for blood stem cells mobilization in patients with progressive supranuclear palsy, corticobasal degeneration and multiple system atrophy.

    PubMed

    Pezzoli, Gianni; Tesei, Silvana; Canesi, Margherita; Sacilotto, Giorgio; Vittorio, Montefusco; Mizuno, Yoshi; Mochizuki, Hideki; Antonini, Angelo

    2010-01-01

    Granulocyte colony stimulating factor (GCSF) may boost physiological stem cell repair system in patients with cerebral lesions. Atypical parkinsonisms (PSP, CBD, MSA) are characterized by rapidly progressive course without significant benefit from current therapies. We treated 11 patients with atypical parkinsonism (MSA n=4, PSP n=5, CBD n=2) with GCSF (5mcg/kg s.c. daily for 6 days/month) for 3 months. We assessed CBC, CD34+ cells, routine biochemical and coagulation tests, UPDRS motor scores and safety. We did not observe significant adverse events during and following GCSF treatment. One patient withdrew informed consent. Three patients complained about bone pain that improved following steroid treatment. Four patients perceived a subjective benefit after treatment was completed. UPDRS motor score improved in three patients, remained stable in two and worsened in five. GCSF can be safely administered to patients with atypical parkinsonism and potentially meaningful clinical changes may be observed in some patients. These results are encouraging and warrant further studies. 2009 Elsevier B.V. All rights reserved.

  3. Granulocyte Colony-Stimulating Factor Induces Osteoblast Inhibition by B Lymphocytes and Osteoclast Activation by T Lymphocytes during Hematopoietic Stem/Progenitor Cell Mobilization.

    PubMed

    Li, Sidan; Li, Tianshou; Chen, Yongbing; Nie, Yinchao; Li, Changhong; Liu, Lanting; Li, Qiaochuan; Qiu, Lugui

    2015-08-01

    In the bone marrow (BM), hematopoietic stem and progenitor cells (HSPCs) reside in specialized niches near osteoblast cells at the endosteum. HSPCs that egress to peripheral blood are widely used for transplant, and mobilization is most commonly performed with recombinant human granulocyte colony-stimulating factor (G-CSF). However, the cellular targets of G-CSF that initiate the mobilization cascade and bone remodeling are not completely understood. Here, we examined whether T and B lymphocytes modulate the bone niche and influence HSPC mobilization. We used T and B defective mice to show that G-CSF-induced mobilization of HSPCs correlated with B lymphocytes but poorly with T lymphocytes. In addition, we found that defective B lymphocytes prevent G-CSF-mediated osteoblast disruption, and further study showed BM osteoblasts were reduced coincident with mobilization, induced by elevated expression of dickkopf1 of BM B lymphocytes. BM T cells were also involved in G-CSF-induced osteoclast activation by regulating the Receptor Activator of Nuclear Factor-κ B Ligand/Osteoprotegerin (RANKL/OPG) axis. These data provide evidence that BM B and T lymphocytes play a role in G-CSF-induced HSPC mobilization by regulating bone remodeling.

  4. Similar in vitro effects and pulp regeneration in ectopic tooth transplantation by basic fibroblast growth factor and granulocyte-colony stimulating factor.

    PubMed

    Takeuchi, N; Hayashi, Y; Murakami, M; Alvarez, F J; Horibe, H; Iohara, K; Nakata, K; Nakamura, H; Nakashima, M

    2015-01-01

    Granulocyte-colony stimulating factor (G-CSF) has been shown to have combinatorial trophic effects with dental pulp stem cells for pulp regeneration. The aim of this investigation is to examine the effects of basic fibroblast growth factor (bFGF) in vitro and in vivo compared with those of G-CSF and to assess the potential utility of bFGF as an alternative to G-CSF for pulp regeneration. Five different types of cells were examined in the in vitro effects of bFGF on cell migration, proliferation, anti-apoptosis, neurite outgrowth, angiogenesis, and odontogenesis compared with those of G-CSF. The in vivo regenerative potential of pulp tissue including vasculogenesis and odontoblastic differentiation was also compared using an ectopic tooth transplantation model. Basic fibroblast growth factor was similar to G-CSF in high migration, proliferation and anti-apoptotic effects and angiogenic and neurite outgrowth stimulatory activities in vitro. There was no significant difference between bFGF and G-CSF in the regenerative potential in vivo. The potential utility of bFGF for pulp regeneration is demonstrated as a homing/migration factor similar to the influence of G-CSF. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Granulocyte-Colony Stimulating Factor Increases Cerebral Blood Flow via a NO Surge Mediated by Akt/eNOS Pathway to Reduce Ischemic Injury

    PubMed Central

    Liew, Hock-Kean; Kuo, Jon-Son; Wang, Jia-Yi; Pang, Cheng-Yoong

    2015-01-01

    Granulocyte-colony stimulating factor (G-CSF) protects brain from ischemic/reperfusion (I/R) injury, and inhibition of nitric oxide (NO) synthases partially reduces G-CSF protection. We thus further investigated the effects of G-CSF on ischemia-induced NO production and its consequence on regional cerebral blood flow (rCBF) and neurological deficit. Endothelin-1 (ET-1) microinfused above middle cerebral artery caused a rapid reduction of rCBF (ischemia) which lasted for 30 minutes and was followed by a gradual recovery of blood flow (reperfusion) within the striatal region. Regional NO concentration increased rapidly (NO surge) during ischemia and recovered soon to the baseline. G-CSF increased rCBF resulting in shorter ischemic duration and an earlier onset of reperfusion. The enhancement of the ischemia-induced NO by G-CSF accompanied by elevation of phospho-Akt and phospho-eNOS was noted, suggesting an activation of Akt/eNOS. I/R-induced infarct volume and neurological deficits were also reduced by G-CSF treatment. Inhibition of NO synthesis by L-NG-Nitroarginine Methyl Ester (L-NAME) significantly reduced the effects of G-CSF on rCBF, NO surge, infarct volume, and neurological deficits. We conclude that G-CSF increases rCBF through a NO surge mediated by Akt/eNOS, which partially contributes to the beneficial effect of G-CSF on brain I/R injury. PMID:26146654

  6. Granulocyte-Colony Stimulating Factor Increases Cerebral Blood Flow via a NO Surge Mediated by Akt/eNOS Pathway to Reduce Ischemic Injury.

    PubMed

    Liew, Hock-Kean; Kuo, Jon-Son; Wang, Jia-Yi; Pang, Cheng-Yoong

    2015-01-01

    Granulocyte-colony stimulating factor (G-CSF) protects brain from ischemic/reperfusion (I/R) injury, and inhibition of nitric oxide (NO) synthases partially reduces G-CSF protection. We thus further investigated the effects of G-CSF on ischemia-induced NO production and its consequence on regional cerebral blood flow (rCBF) and neurological deficit. Endothelin-1 (ET-1) microinfused above middle cerebral artery caused a rapid reduction of rCBF (ischemia) which lasted for 30 minutes and was followed by a gradual recovery of blood flow (reperfusion) within the striatal region. Regional NO concentration increased rapidly (NO surge) during ischemia and recovered soon to the baseline. G-CSF increased rCBF resulting in shorter ischemic duration and an earlier onset of reperfusion. The enhancement of the ischemia-induced NO by G-CSF accompanied by elevation of phospho-Akt and phospho-eNOS was noted, suggesting an activation of Akt/eNOS. I/R-induced infarct volume and neurological deficits were also reduced by G-CSF treatment. Inhibition of NO synthesis by L-N(G)-Nitroarginine Methyl Ester (L-NAME) significantly reduced the effects of G-CSF on rCBF, NO surge, infarct volume, and neurological deficits. We conclude that G-CSF increases rCBF through a NO surge mediated by Akt/eNOS, which partially contributes to the beneficial effect of G-CSF on brain I/R injury.

  7. Granulocyte colony-stimulating factor mobilized CFU-F can be found in the peripheral blood but have limited expansion potential.

    PubMed

    Lund, Troy C; Tolar, Jakub; Orchard, Paul J

    2008-06-01

    Bone marrow mesenchymal stem cells are multipotent cells found lining the bone marrow cavity supporting the growth and differentiation of hematologic progenitors. There is growing evidence that these cells can, under the right circumstances, enter the peripheral circulation. We show that granulocyte colony-stimulating factor mobilized peripheral blood contains cells which form colonies and have a similar fibroblastic morphology (termed CFU-F) to bone marrow mesenchymal stem cells. These cells were found at a very low incidence (0.0002%). Mobilized peripheral blood CFU-F were successfully differentiated into osteogenic and adipogenic lineages. FACS analysis showed that the cells had a similar profile to bone marrow mesenchymal stem cells. Importantly, mobilized peripheral blood CFU-F had limited expansion potential and became senescent 20-25 days after isolation. Mobilized peripheral blood CFU-F also did not have any telomerase activity and displayed significant telomere shortening. The rarity of CFU-F in mobilized peripheral blood and the subsequent pressure to divide in cell culture probably contribute to early cellular senescence. Their potential for use in transplant or gene therapy is, therefore, limited.

  8. Oncostatin M is a member of a cytokine family that includes leukemia-inhibitory factor, granulocyte colony-stimulating factor, and interleukin 6.

    PubMed Central

    Rose, T M; Bruce, A G

    1991-01-01

    Oncostatin M (OSM), a glycoprotein of Mr approximately 28,000 produced by activated monocyte and T-lymphocyte cell lines, was previously identified by its ability to inhibit the growth of cells from melanoma and other solid tumors. We have detected significant similarities in the primary amino acid sequences and predicted secondary structures of OSM, leukemia-inhibitory factor (LIF), granulocyte colony-stimulating factor (G-CSF), and interleukin 6 (IL-6). Analysis of the genes encoding these proteins revealed a shared exon organization, suggesting evolutionary descent from a common ancestral gene. Using a panel of DNAs from somatic cell hybrids, we have shown that OSM, like LIF, is located on human chromosome 22. We have also demonstrated that OSM has the ability to inhibit the proliferation of murine M1 myeloid leukemic cells and can induce their differentiation into macrophage-like cells, a function shared by LIF, G-CSF, and IL-6. We propose that OSM, LIF, G-CSF, and IL-6 are structurally related members of a cytokine family that have in common the ability to modulate differentiation of a variety of cell types. Images PMID:1717982

  9. Therapeutic administration of recombinant human granulocyte colony-stimulating factor accelerates hemopoietic regeneration and enhances survival in a murine model of radiation-induced myelosuppression

    SciTech Connect

    Patchen, M.L.; MacVittie, T.J.; Solberg, B.D.; Souza, L.M.

    1990-01-01

    The primary cause of death after radiation exposure is infection resulting from myelosuppression. Because granulocytes play a critical role in host defense against infection and because granulocyte proliferation and differentiation are enhanced by granulocyte colony-stimulating factor (G-CSF), this agent was evaluated for the ability to accelerate hemopoietic regeneration and to enhance survival in irradiated mice. C3H/HeN mice were irradiated and G-CSF or saline was administered on days 3-12, 1-12 or 0-12 post-irradiation. Bone marrow, splenic and peripheral blood cellularity and bone marrow and splenic granulocyte-macrophage progenitor cell recoveries were evaluated in mice exposed to 6.5 Gy. Mice exposed to 8 Gy were evaluated for multipotent hemopoietic stem cell recovery (using endogenous spleen colony-forming units) and enhanced survival. Results demonstrated that therapeutic G-CSF (1) accelerates hemopoietic regeneration after radiation-induced myelosuppression, (2) enhances survival after potentially lethal irradiation and (3) is most effective when initiated 1 h following exposure.

  10. Therapeutic administration of recombinant human granulocyte colony-stimulating factor accelerates hemopoietic regeneration and enhances survival in a murine model of radiation-induced myelosuppression

    SciTech Connect

    Patchen, M.L.; MacVittie, T.J.; Solberg, B.D.; Souza, L.M. )

    1990-03-01

    The primary cause of death after radiation exposure is infection resulting from myelosuppression. Because granulocytes play a critical role in host defense against infection and because granulocyte proliferation and differentiation are enhanced by granulocyte colony-stimulating factor (G-CSF), this agent was evaluated for the ability to accelerate hemopoietic regeneration and to enhance survival in irradiated mice. C3H/HeN mice were irradiated and G-CSF (2.5 micrograms/day, s.c.) or saline was administered on days 3-12, 1-12 or 0-12 post-irradiation. Bone marrow, splenic and peripheral blood cellularity, and bone marrow and splenic granulocyte-macrophage progenitor cell recoveries were evaluated in mice exposed to 6.5 Gy. Mice exposed to 8 Gy were evaluated for multipotent hemopoietic stem cell recovery (using endogenous spleen colony-forming units) and enhanced survival. Results demonstrated that therapeutic G-CSF (1) accelerates hemopoietic regeneration after radiation-induced myelosuppression, (2) enhances survival after potentially lethal irradiation and (3) is most effective when initiated 1 h following exposure.

  11. Low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor priming regimen versus idarubicin plus cytarabine regimen as induction therapy for older patients with acute myeloid leukemia.

    PubMed

    Jin, Jie; Chen, Jian; Suo, Shanshan; Qian, Wenbin; Meng, Haitao; Mai, Wenyuan; Tong, Hongyan; Huang, Jian; Yu, Wenjuan; Wei, Juyin; Lou, Yinjun

    2015-06-01

    With limited data available on the low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor (CAG) regimen in newly diagnosed older patients with acute myeloid leukemia (AML), this study aimed at comparing the efficacy and toxicity of CAG with idarubicin plus cytarabine (IA) remission induction therapy in these patients. A total of 154 consecutive patients (52 with CAG and 102 with IA) were retrospectively analyzed. The patients in the CAG group had a higher median age (68 vs. 65 years, p = 0.002) and a higher proportion of previous myelodysplastic syndrome (25.0% vs. 2.9%, p < 0.0001) compared to those in the IA group. The complete remission rates with the CAG and IA regimens were 55.8% and 52.9% (p = 0.864). The median overall survival (12.1 vs. 11.7 months, p = 0.650) and 3-year disease-free survival rates (29.6% vs. 48.6%, p = 0.657) were not statistically different in the two groups. The CAG regimen might be an alternative to conventional chemotherapy in older patients with AML.

  12. The use of granulocyte-colony stimulating factor induced mobilization for isolation of dental pulp stem cells with high regenerative potential.

    PubMed

    Murakami, Masashi; Horibe, Hiroshi; Iohara, Koichiro; Hayashi, Yuki; Osako, Yohei; Takei, Yoshifumi; Nakata, Kazuhiko; Motoyama, Noboru; Kurita, Kenichi; Nakashima, Misako

    2013-12-01

    Human dental pulp stem cells (DPSCs) contain subsets of progenitor/stem cells with high angiogenic, neurogenic and regenerative potential useful for cell therapy. It is essential to develop a safe and efficacious method to isolate the clinical-grade DPSCs subsets from a small amount of pulp tissue without using conventional flow cytometry. Thus, a method for isolation of DPSCs subsets based on their migratory response to optimized concentration of 100 ng/ml of granulocyte-colony stimulating factor (G-CSF) was determined in this study. The DPSCs mobilized by G-CSF (MDPSCs) were enriched for CD105, C-X-C chemokine receptor type 4 (CXCR-4) and G-CSF receptor (G-CSFR) positive cells, demonstrating stem cell properties including high proliferation rate and stability. The absence of abnormalities/aberrations in karyotype and lack of tumor formation after transplantation in an immunodeficient mouse were demonstrated. The conditioned medium of MDPSCs exhibited anti-apoptotic activity, enhanced migration and immunomodulatory properties. Furthermore, transplantation of MDPSCs accelerated vasculogenesis in an ischemic hindlimb model and augmented regenerated pulp tissue in an ectopic tooth root model compared to that of colony-derived DPSCs, indicating higher regenerative potential of MDPSCs. In conclusion, this isolation method for DPSCs subsets is safe and efficacious, having utility for potential clinical applications to autologous cell transplantation. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. [Immunosuppressive therapy using antithymocyte globulin and cyclosporin A with or without human granulocyte colony-stimulating factor in children with acquired severe aplastic anemia].

    PubMed

    Liu, Xiaoming; Zou, Yao; Wang, Shuchun; Zhang, Li; Yang, Wenyu; Zhang, Jiayuan; Liu, Fang; Liu, Tianfeng; Chen, Xiaojuan; Ruan, Min; Zhou, Jianfeng; Cai, Xiaojin; Qi, Benquan; Chang, Lixian; An, Wenbin; Guo, Ye; Chen, Yumei; Zhu, Xiaofan

    2014-02-01

    To compare the efficacy and safety of four different regimens for pediatric severe aplastic anemia (SAA) with immuno-suppressive therapy (IST) with or without combined human granulocyte colony-stimulating factor (G-CSF). The authors retrospectively analyzed 105 children with SAA treated with IST with or without G-CSF in the hospital from February 2000 to September 2010. Regimen A, without G-CSF in the whole treatment, was used to treat Group A patients, n = 27; Regimen B, G-CSF, was initiated in Group B, n = 24, before the IST until hematologic recovery; Regimen C, G-CSF, was used together with the IST for Group C patients, n = 24, until hematologic recovery; Regimen D,G-CSF was used for Group D, n = 30, after the end of IST until hematologic recovery. The response rate, relapse rate, mortality, infection rate, infection-related death rate, risk of evolving into MDS/AML, survival rate, factors affecting the time of event-free survival and so on. (1) The response (CR+PR) rates 4, 6, 12 and 24 months after IST of the whole series of 105 SAA children were 50.5% (7.6%+42.9%) , 60.0% (21.9%+38.1%) , 67.6% (38.1%+29.5%) and 69.5% (40.0%+29.5%) respectively. The 2-year survival rate was 90.5%; the follow-up of the patients for 13 years showed that the whole survival rate was 87.6%. (2) The differences of the response rates 4, 6, 12 and 24 months after IST of the 4 groups were not significant (P > 0.05). (3) No significant differences were found in the mortalities 4, 6, 12 and 24 months among the 4 groups (P > 0.05). (4) Of the 105 patients, 4 children had relapsed disease in the period of time from 6 to 24 months after IST. All the four patients belonged to the groups with G-CSF. (5) The use of G-CSF could not decrease the infection period before IST (day) (P = 0.273), and it had no impact on the infection rate after IST (P = 0.066). It did not reduce the rates of septicemia and infectious shock. And to the infection-related death rate no significant conclusion can be

  14. Immunomodulation of Bu-Zhong-Yi-Qi-Tang on in vitro granulocyte colony-stimulating-factor and tumor necrosis factor-alpha production by peripheral blood mononuclear cells.

    PubMed

    Kao, S T; Yang, S L; Hsieh, C C; Yang, M D; Wang, T F; Lin, J G

    2000-11-01

    Bu-Zhong-Yi-Qi-Tang (BZYQT) is a Chinese medicine, and has been used for the treatment of hepatocellular carcinoma (HCC) patients. At present, we still do not fully understand the effects of BZYQT on the cellular physiology. Present in vitro study demonstrated that BZYQT is capable of increasing granulocyte colony-stimulating-factor (G-CSF) and tumor necrosis factor-alpha (TNF-alpha) production by peripheral blood mononuclear cells (PBMC) in healthy volunteers and patients with HCC. The productions of G-CSF and TNF-alpha by PBMC of volunteers were significantly stimulated by more than 125 microg/ml of BZYQT. G-CSF levels stimulated by PBMC of healthy volunteers were higher than in PBMC of the HCC patients when more than 625 microg/ml of BZYQT was administrated. The reason may be due to the impaired immunologic reactivity of mononuclear cells in HCC patients. However, the production levels of TNF-alpha in HCC patients can be stimulated to levels as high as those in healthy volunteers. When adding high concentration (3.125 mg/ml) of BZYQT to the cultured PBMC, the increments of G-CSF and TNF-alpha production decreased although there were no obvious changes in the number of metabolic active PBMC changed. TNF-alpha andG-CSF are known to play important roles in the biological defensive mechanism. These findings show that BZYQT is a unique formula for the stimulation of PBMC to produce G-CSF and TNF-alpha. Administration of BZYQT may be beneficial for patients with HCC to modulate these cytokines.

  15. Efficacy of LL-37 and granulocyte colony-stimulating factor in a neutropenic murine sepsis due to Pseudomonas aeruginosa.

    PubMed

    Cirioni, Oscar; Ghiselli, Roberto; Tomasinsig, Linda; Orlando, Fiorenza; Silvestri, Carmela; Skerlavaj, Barbara; Riva, Alessandra; Rocchi, Marco; Saba, Vittorio; Zanetti, Margherita; Scalise, Giorgio; Giacometti, Andrea

    2008-10-01

    A promising therapeutic strategy for the management of severe Pseudomonas infection in neutropenic patients may result from the coadministration of colony-stimulating factors (CSFs) that help maintain immune competence and antimicrobial peptides, a novel generation of adjunctive therapeutic agents with antimicrobial and anti-inflammatory properties. A promising peptide with these properties is LL-37, the only member of the cathelicidin family of antimicrobial peptides found in humans. BALB/c male mice were rendered neutropenic by intraperitoneal administration of cyclophosphamide on days -4 and -2 preinfection. Septic shock was induced at time 0 by intraperitoneal injection of 2x10 colony-forming units of P. aeruginosa American Type Culture Collection (ATCC) 27853. All animals were randomized to receive intravenously isotonic sodium chloride solution, 1 mg/kg of LL-37, 20 mg/kg of imipenem, 0.1 mg/kg of granulocyte CSF (G-CSF), 1 mg/kg of LL-37+0.1 mg/kg of G-CSF, or 20 mg/kg of imipenem+0.1 mg/kg of G-CSF. Lethality and bacterial growth in blood, peritoneum, spleen, liver, and kidney were evaluated. All regimens were significantly superior to controls at reducing the mouse lethality rate and bacterial burden in organs. Particularly, the combination between LL-37 and G-CSF was the most effective in protecting neutropenic mice from the onset of sepsis and in vitro significantly reduced the apoptosis of neutrophils. Combination therapy between LL-37 and G-CSF is a promising therapeutic strategy for the management of severe Pseudomonas infection complicated by neutropenia.

  16. miR-155 Is Associated with the Leukemogenic Potential of the Class IV Granulocyte Colony-Stimulating Factor Receptor in CD34+ Progenitor Cells

    PubMed Central

    Zhang, HaiJiao; Goudeva, Lilia; Immenschuh, Stephan; Schambach, Axel; Skokowa, Julia; Eiz-Vesper, Britta; Blasczyk, Rainer; Figueiredo, Constança

    2014-01-01

    Granulocyte colony-stimulating factor (G-CSF) is a major regulator of granulopoiesis on engagement with the G-CSF receptor (G-CSFR). The truncated, alternatively spliced, class IV G-CSFR (G-CSFRIV) has been associated with defective differentiation and relapse risk in pediatric acute myeloid leukemia (AML) patients. However, the detailed biological properties of G-CSFRIV in human CD34+ hematopoietic stem and progenitor cells (HSPCs) and the potential leukemogenic mechanism of this receptor remain poorly understood. In the present study, we observed that G-CSFRIV–overexpressing (G-CSFRIV+) HSPCs demonstrated an enhanced proliferative and survival capacity on G-CSF stimulation. Cell cycle analyses showed a higher frequency of G-CSFRIV+ cells in the S and G2/M phase. Also, apoptosis rates were significantly lower in G-CSFRIV+ HSPCs. These findings were shown to be associated with a sustained Stat5 activation and elevated miR-155 expression. In addition, G-CSF showed to further induce G-CSFRIV and miR-155 expression of peripheral blood mononuclear cells isolated from AML patients. A Stat5 pharmacological inhibitor or ribonucleic acid (RNA) interference–mediated silencing of the expression of miR-155 abrogated the aberrant proliferative capacity of the G-CSFRIV+ HSPCs. Hence, the dysregulation of Stat5/miR-155 pathway in the G-CSFRIV+ HSPCs supports their leukemogenic potential. Specific miRNA silencing or the inhibition of Stat5-associated pathways might contribute to preventing the risk of leukemogenesis in G-CSFRIV+ HSPCs. This study may promote the development of a personalized effective antileukemia therapy, in particular for the patients exhibiting higher expression levels of G-CSFRIV, and further highlights the necessity of pre-screening the patients for G-CSFR isoforms expression patterns before G-CSF administration. PMID:25730818

  17. The efficacy of intrauterine instillation of granulocyte colony-stimulating factor in infertile women with a thin endometrium: A pilot study

    PubMed Central

    Lee, Dayong; Jo, Jae Dong; Kim, Seul Ki; Kim, Seok Hyun

    2016-01-01

    Objective The study aimed to investigate the efficacy of intrauterine instillation of granulocyte colony-stimulating factor (G-CSF) on the day of ovulation triggering or oocyte retrieval in infertile women with a thin endometrium. Methods Fifty women whose endometrial thickness (EMT) was ≤8 mm at the time of triggering during at least one previous in vitro fertilization (IVF) cycle and an index IVF cycle were selected. On the day of triggering (n=12) or oocyte retrieval (n=38), 300 µg of G-CSF was instilled into the uterine cavity. Results In the 50 index IVF cycles, the mean EMT was 7.2±0.6 mm on the triggering day and increased to 8.5±1.5 mm on the embryo transfer day (p<0.001). The overall clinical pregnancy rate was 22.0%, the implantation rate was 15.9%, and the ongoing pregnancy rate was 20%. The clinical pregnancy rate (41.7% vs. 15.8%), the implantation rate (26.7% vs. 11.7%), and the ongoing pregnancy rate (41.7% vs. 13.2%) were higher when G-CSF was instilled on the triggering day than when it was instilled on the retrieval day, although this tendency was likewise not statistically significant. Aspects of the stimulation process and mean changes in EMT were similar in women who became pregnant and women who did not. Conclusion Intrauterine instillation of G-CSF enhanced endometrial development and resulted in an acceptable pregnancy rate. Instillation of G-CSF on the triggering day showed better outcomes. G-CSF instillation should be considered as a strategy for inducing endometrial growth and good pregnancy results in infertile women with a thin endometrium. PMID:28090464

  18. pH responsive granulocyte colony-stimulating factor variants with implications for treating Alzheimer's disease and other central nervous system disorders.

    PubMed

    Heinzelman, Pete; Schoborg, Jennifer A; Jewett, Michael C

    2015-10-01

    Systemic injection of granulocyte colony-stimulating factor (G-CSF) has yielded encouraging results in treating Alzheimer's Disease (AD) and other central nervous system (CNS) disorders. Making G-CSF a viable AD therapeutic will, however, require increasing G-CSF's ability to stimulate neurons within the brain. This objective could be realized by increasing transcytosis of G-CSF across the blood brain barrier (BBB). An established correlation between G-CSF receptor (G-CSFR) binding pH responsiveness and increased recycling of G-CSF to the cell exterior after endocytosis motivated development of G-CSF variants with highly pH responsive G-CSFR binding affinities. These variants will be used in future validation of our hypothesis that increased BBB transcytosis can enhance G-CSF therapeutic efficacy. Flow cytometric screening of a yeast-displayed library in which G-CSF/G-CSFR interface residues were mutated to histidine yielded a G-CSF triple His mutant (L109H/D110H/Q120H) with highly pH responsive binding affinity. This variant's KD, measured by surface plasmon resonance (SPR), increases ∼20-fold as pH decreases from 7.4 to below histidine's pKa of ∼6.0; an increase 2-fold greater than for previously reported G-CSF His mutants. Cell-free protein synthesis (CFPS) enabled expression and purification of soluble, bioactive G-CSF triple His variant protein, an outcome inaccessible via Escherichia coli inclusion body refolding. This purification and bioactivity validation will enable future identification of correlations between pH responsiveness and transcytosis in BBB cell culture model and animal experiments. Furthermore, the library screening and CFPS methods employed here could be applied to developing other pH responsive hematopoietic or neurotrophic factors for treating CNS disorders.

  19. The efficacy of intrauterine instillation of granulocyte colony-stimulating factor in infertile women with a thin endometrium: A pilot study.

    PubMed

    Lee, Dayong; Jo, Jae Dong; Kim, Seul Ki; Jee, Byung Chul; Kim, Seok Hyun

    2016-12-01

    The study aimed to investigate the efficacy of intrauterine instillation of granulocyte colony-stimulating factor (G-CSF) on the day of ovulation triggering or oocyte retrieval in infertile women with a thin endometrium. Fifty women whose endometrial thickness (EMT) was ≤8 mm at the time of triggering during at least one previous in vitro fertilization (IVF) cycle and an index IVF cycle were selected. On the day of triggering (n=12) or oocyte retrieval (n=38), 300 µg of G-CSF was instilled into the uterine cavity. In the 50 index IVF cycles, the mean EMT was 7.2±0.6 mm on the triggering day and increased to 8.5±1.5 mm on the embryo transfer day (p<0.001). The overall clinical pregnancy rate was 22.0%, the implantation rate was 15.9%, and the ongoing pregnancy rate was 20%. The clinical pregnancy rate (41.7% vs. 15.8%), the implantation rate (26.7% vs. 11.7%), and the ongoing pregnancy rate (41.7% vs. 13.2%) were higher when G-CSF was instilled on the triggering day than when it was instilled on the retrieval day, although this tendency was likewise not statistically significant. Aspects of the stimulation process and mean changes in EMT were similar in women who became pregnant and women who did not. Intrauterine instillation of G-CSF enhanced endometrial development and resulted in an acceptable pregnancy rate. Instillation of G-CSF on the triggering day showed better outcomes. G-CSF instillation should be considered as a strategy for inducing endometrial growth and good pregnancy results in infertile women with a thin endometrium.

  20. Expression cloning of a human granulocyte colony-stimulating factor receptor: a structural mosaic of hematopoietin receptor, immunoglobulin, and fibronectin domains

    PubMed Central

    1990-01-01

    We report the isolation from a placental library, of two cDNAs that can encode high affinity receptors for granulocyte colony-stimulating factor (G-CSF) when expressed in COS-7 cells. The cDNAs are predicted to encode integral membrane proteins of 759 and 812 amino acids in length. The predicted extracellular and membrane spanning sequences of the two clones are identical, as are the first 96 amino acids of their respective cytoplasmic regions. Different COOH termini of 34 or 87 residues are predicted for the two cDNAs, due apparently to alternate splicing. The receptor with the longer cytoplasmic domain is the closest human homologue of the murine G-CSF receptor recently described by Fukunaga et al. (Fukunaga, R., E. Ishizaka-Ikeda, Y. Seto, and S. Nagata. 1990. Cell. 61:341). A hybridization probe derived from the placental G-CSF receptor cDNA detects a approximately 3-kb transcript in RNAs isolated from placenta and a number of lymphoid and myeloid cells. The extracellular region of the G-CSF receptors is composed of four distinct types of structural domains, previously recognized in other cell surface proteins. In addition to the two domains of the HP receptor family-defining region (Patthy, L. 1990. Cell. 61:13) it incorporates one NH2-terminal Ig-like domain, and three additional repeats of fibronectin type III-like domains. The presence of both an NH2-terminal Ig-like domain and multiple membrane-proximal FN3-like domains suggests that the G-CSF receptor may be derived from an ancestral NCAM-like molecule and that the G-CSF receptor may function in some adhesion or recognition events at the cell surface in addition to the binding of G-CSF. PMID:2147944

  1. Effectiveness of daily versus non-daily granulocyte colony-stimulating factors in patients with solid tumours undergoing chemotherapy: a multivariate analysis of data from current practice

    PubMed Central

    Almenar Cubells, D; Bosch Roig, C; Jiménez Orozco, E; Álvarez, R; Cuervo, JM; Díaz Fernández, N; Sánchez Heras, AB; Galán Brotons, A; Giner Marco, V; Codes M De Villena, M

    2013-01-01

    We conducted a multicentre, retrospective, observational study including patients with solid tumours (excluding breast cancer) that received granulocyte colony-stimulating factors (G-CSF) and chemotherapy. We investigated the effectiveness of daily vs. non-daily G-CSFs (pegfilgrastim) adjusting by potential confounders. The study included 391 patients (211 daily G-CSF; 180 pegfilgrastim), from whom 47.3% received primary prophylaxis (PP) (57.8% pegfilgrastim), 26.3% secondary prophylaxis (SP: initiation after cycle 1 and no reactive treatment in any cycle) (51.5% pegfilgrastim) and 26.3% reactive treatment (19.4% pegfilgrastim). Only 42.2% of patients with daily G-CSF and 46.2% with pegfilgrastim initiated prophylaxis within 72 h after chemotherapy, and only 10.5% of patients with daily G-CSF received it for ≥7 days. In the multivariate models, daily G-CSF was associated with higher risk of grade 3-4 neutropenia (G3-4N) vs. pegfilgrastim [odds ratio (OR): 1.73, 95% confidence interval (CI): 1.004–2.97]. Relative to SP, PP protected against G3-4N (OR for SP vs. PP: 6.0, 95%CI: 3.2–11.4) and febrile neutropenia (OR: 3.1, 95%CI: 1.1–8.8), and was associated to less chemotherapy dose delays and reductions (OR for relative dose intensity <85% for SP vs. PP: 3.1, 95%CI: 1.7–5.4) and higher response rate (OR: 2.1, 95%CI: 1.2–3.7). Data suggest that pegfilgrastim, compared with a daily G-CSF, and PP, compared with SP, could be more effective in preventing neutropenia and its related events in the clinical practice. PMID:23331323

  2. Efficacy of granulocyte colony stimulating factor as a secondary prophylaxis along with full-dose chemotherapy following a prior cycle of febrile neutropenia.

    PubMed

    Gupta, Seema; Singh, Pankaj K; Bhatt, Madan L B; Pant, Mohan C; Gupta, Rajeev; Negi, Mahendra P S

    2010-10-01

    Secondary prophylaxis with recombinant human granulocyte colony stimulating factor (G-CSF) is recommended where patients have experienced febrile neutropenia in an earlier chemotherapy cycle and for whom the maintenance of chemotherapy dose intensity is important; or where febrile neutropenia has not occurred but prolonged neutropenia is causing excessive dose delay or reduction, where maintenance of dose intensity is important. The objective of this study was to determine the efficacy and feasibility of G-CSF as secondary prophylaxis when used along with full dose moderately myelotoxic chemotherapy following a prior cycle with febrile-neutropenia. Fifty-two patients aged 22-75 years with febrile neutropenia that required intravenous antibiotics following moderately myelotoxic chemotherapy were included. These patients received the next cycle of the same chemotherapy regime without dose modification but with support of filgrastim 24 h after completion of chemotherapy (300 μg/day/subcutaneously (s.c.) for weight < 60 kg, 480 μg/day/s.c. for weight > 60 kg, for at least 10 consecutive days), patients in whom neutropenia was associated with a life-threatening infection and those who developed prolonged myelosuppression were excluded. The use of the hematopoietic growth factor G-CSF was shown to shorten the neutrophil recovery time, resulting in significant reduction of incidence of febrile neutropenia, hospitalization and use of broad spectrum antibiotics. There was no drug related death or adverse events associated with either cycle. In conclusion, recombinant human G-CSF is effective and relatively safe as a secondary prophylaxis with full dose chemotherapy in patients who develop febrile neutropenia following prior cycles of moderately myelotoxic chemotherapy.

  3. Increased susceptibility to liver injury after hemorrhagic shock in rats chronically fed ethanol: role of nuclear factor-kappa B, interleukin-6, and granulocyte colony-stimulating factor.

    PubMed

    Ono, Masafumi; Yu, Bi; Hardison, Edith G; Mastrangelo, Mary-Ann A; Tweardy, David J

    2004-06-01

    Chronic ethanol use preceding severe trauma and hemorrhagic shock (HS) is associated with an increased incidence of multiorgan failure (MOF) and death; however, the molecular basis for this increased susceptibility is unknown. We previously demonstrated that production of interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF), mediated by nuclear factor-kappa B (NF-kappa B), each make essential contributions to organ injury and inflammation in a rodent model of controlled HS, and we proposed in this study to examine the hypothesis that the increased susceptibility to MOF after shock/trauma in the setting of chronic ethanol use is due to an exaggerated activation of NF-kappa B and production of these proinflammatory cytokines. We observed increased HS-induced liver injury 4 h after resuscitation in rats fed the ethanol-containing Lieber-DeCarli liquid diet for 8 weeks compared with rats fed the control liquid diet (3-fold increase in serum alanine aminotransferase [ALT], P = 0.008, and 2-fold increase in focal liver necrosis, P = 0.005). The increased liver injury in the ethanol-fed HS rats was accompanied by a 70% increase in liver NF-kappa B activation (P < 0.05), a 3- to 5-fold increase in hepatocyte and Kupffer cell production of IL-6 and G-CSF (P < 0.05 for each), and a 2-fold increase in neutrophil infiltration (P < 0.005) compared with the control diet-fed HS rats. Thus, increased susceptibility to HS-induced liver injury in the setting of chronic ethanol use may be mediated, at least in part, by increased NF-kappa B activation resulting in increased local production of IL-6 and G-CSF and increased infiltration of neutrophils, which can damage liver cells directly and contribute to impaired sinusoidal blood flow.

  4. Acute exposure to cadmium induces prolonged neutrophilia along with delayed induction of granulocyte colony-stimulating factor in the livers of mice.

    PubMed

    Horiguchi, Hyogo; Oguma, Etsuko

    2016-12-01

    Acute exposure to cadmium (Cd), a toxic heavy metal, causes systemic inflammation characterized by neutrophilia. To elucidate the mechanism of neutrophilia induced by Cd, we investigated the induction of granulocyte colony-stimulating factor (G-CSF), which regulates neutrophil production, in mice with acute Cd toxicity, and compared it with mice injected with lipopolysaccharide (LPS) as an inducer of general inflammatory responses. We injected BALB/c mice with Cd at 2.5 mg/kg i.p. or LPS at 0.5 mg/kg i.p. and sampled the peripheral blood and organs at time points up to 24 h. In Cd-treated mice, the peripheral neutrophil count increased steadily up to 24 h, whereas LPS-treated mice showed a more rapid increase with a peak at 12 h. The serum G-CSF level increased gradually to reach a plateau at 12-18 h in Cd-treated mice, but LPS-treated mice showed a marked increase, reaching a peak at 2-3 h. A gradual elevation of G-CSF mRNA expression up to 24 h was detected by real-time PCR in the livers of Cd-treated mice, but in LPS-treated mice its highest expression was observed in the liver with a rapid increase at 2 h. By in situ hybridization using G-CSF RNA probes, hepatic Kupffer cells were identified as G-CSF-producing cells in the liver. These results indicated that Cd has a characteristic effect of delayed induction of G-CSF in the liver, causing systemic inflammation accompanied by prolonged neutrophilia.

  5. Efficacy of polyethylene glycol-conjugated bovine granulocyte colony-stimulating factor for reducing the incidence of naturally occurring clinical mastitis in periparturient dairy cows and heifers.

    PubMed

    Hassfurther, Renee L; TerHune, Terry N; Canning, Peter C

    2015-03-01

    To evaluate effects of various doses of polyethylene glycol (PEG)-conjugated bovine granulocyte colony-stimulating factor (bG-CSF) on the incidence of naturally occurring clinical mastitis in periparturient dairy cattle. 211 periparturient Holstein cows and heifers. Approximately 7 days before the anticipated date of parturition (day of parturition = day 0), healthy cattle received SC injections of sterile saline (0.9% NaCl) solution (control treatment) or PEG-bG-CSF at 5, 10, or 20 μg/kg. Cattle were commingled and housed in a pen with dirt flooring, which was kept wet to maximize the incidence of naturally occurring clinical mastitis. Within 24 hours after parturition, each animal again received the assigned treatment. Mammary glands and milk were visually scored for abnormalities twice daily for 28 days after parturition. Milk samples were aseptically collected from mammary glands with an abnormal appearance or abnormal milk and submitted for microbial culture. Daily milk production was recorded, and milk composition was assessed on days 3, 5, 7, and 10. Cattle treated with PEG-bG-CSF at 10 and 20 μg/kg had significantly fewer cases of clinical mastitis (9/54 and 5/53, respectively), compared with control cattle (18/53). Administration of PEG -bG-CSF did not significantly affect daily milk production or milk composition. Results suggested that PEG-bG-CSF was effective for reducing the incidence of naturally occurring clinical mastitis in periparturient dairy cattle. Further investigations of the use of PEG-bG-CSF as a potential preventative intervention should be conducted.

  6. Rejuvenation of aged pig facial skin by transplanting allogeneic granulocyte colony-stimulating factor-induced peripheral blood stem cells from a young pig.

    PubMed

    Harn, Horng-Jyh; Huang, Mao-Hsuan; Huang, Chi-Ting; Lin, Po-Cheng; Yen, Ssu-Yin; Chou, Yi-Wen; Ho, Tsung-Jung; Chu, Hen-Yi; Chiou, Tzyy-Wen; Lin, Shinn-Zong

    2013-01-01

    Following a stroke, the administration of stem cells that have been treated with granulocyte colony-stimulating factor (GCSF) can ameliorate functional deficits in both rats and humans. It is not known, however, whether the application of GCSF-mobilized peripheral blood stem cells (PBSCs) to human skin can function as an antiaging treatment. We used a Lanyu pig (Sus scrofa) model, since compared with rodents, the structure of a pig's skin is very similar to human skin, to provide preliminary data on whether these cells can exert antiaging effects over a short time frame. GCSF-mobilized PBSCs from a young male Lanyu pig (5 months) were injected intradermally into the cheek skin of aged female Lanyu pigs, and tissues before and after the cell injections were compared to determine whether this treatment caused skin rejuvenation. Increased levels of collagen, elastin, hyaluronic acid, and the hyaluronic acid receptor CD44 were observed in both dermal and subcutaneous layers following the injection of PBSCs. In addition, the treated skin tissue was tighter and more elastic than adjacent control regions of aged skin tissue. In the epidermal layer, PBSC injection altered the levels of both involucrin and integrin, indicating an increased rate of epidermal cell renewal as evidenced by reductions in both cornified cells and cells of the spinous layers and increases in the number of dividing cells within the basal layer. We found that the exogenous PBSCs, visualized using fluorescence in situ hybridization, were located primarily in hair follicles and adjacent tissues. In summary, PBSC injection restored young skin properties in the skin of aged (90 months) pigs. On the basis of our preliminary data, we conclude that intradermal injection of GCSF-mobilized PBSCs from a young pig can rejuvenate the skin in aged pigs.

  7. Granulocyte-colony stimulating factor for mobilizing bone marrow stem cells in subacute stroke: the stem cell trial of recovery enhancement after stroke 2 randomized controlled trial.

    PubMed

    England, Timothy J; Abaei, Maryam; Auer, Dorothee P; Lowe, James; Jones, D Rhodri E; Sare, Gillian; Walker, Marion; Bath, Philip M W

    2012-02-01

    Granulocyte-colony stimulating factor (G-CSF) is neuroprotective in experimental stroke and mobilizes CD34(+) peripheral blood stem cells into the circulation. We assessed the safety of G-CSF in recent stroke in a phase IIb single-center randomized, controlled trial. G-CSF (10 μg/kg) or placebo (ratio 2:1) was given SC for 5 days to 60 patients 3 to 30 days after ischemic or hemorrhagic stroke. The primary outcome was the frequency of serious adverse events. Peripheral blood counts, CD34(+) count, and functional outcome were measured. MRI assessed lesion volume, atrophy, and the presence of iron-labeled CD34(+) cells reinjected on day 6. Sixty patients were recruited at mean of 8 days (SD ± 5) post ictus, with mean age 71 years (± 12 years) and 53% men. The groups were well matched for baseline minimization/prognostic factors. There were no significant differences between groups in the number of participants with serious adverse events: G-CSF 15 (37.5%) of 40 versus placebo 7 (35%) of 20, death or dependency (modified Rankin Score: G-CSF 3.3 ± 1.3, placebo 3.0 ± 1.3) at 90 days, or the number of injections received. G-CSF increased CD34(+) and total white cell counts of 9.5- and 4.2-fold, respectively. There was a trend toward reduction in MRI ischemic lesion volume with respect to change from baseline in G-CSF-treated patients (P=0.06). In 1 participant, there was suggestion that labeled CD34(+) cells had migrated to the ischemic lesion. This randomized, double-blind, placebo-controlled trial suggests that G-CSF is safe when administered subacutely. It is feasible to label and readminister iron-labeled CD34(+) cells in patients with ischemic stroke. URL: www.controlled-trials.com. Unique identifier: ISRCTN63336619.

  8. G(AnH)MTetra, a naturally occurring 1,6-anhydro muramyl dipeptide, induces granulocyte colony-stimulating factor expression in human monocytes: a molecular analysis.

    PubMed Central

    Dokter, W H; Dijkstra, A J; Koopmans, S B; Mulder, A B; Stulp, B K; Halie, M R; Keck, W; Vellenga, E

    1994-01-01

    N-Acetylglucosaminyl-1,6-anhydro-N-acetylmuramyl-L-alanyl-D-isoglutam yl-m- diaminopimelyl-D-alanine [G (Anh)MTetra], a naturally occurring breakdown product of peptidoglycan from bacterial cell walls, was studied for its ability to induce granulocyte colony-stimulating factor (G-CSF) mRNA and protein expression in human adherent monocytes. Resting monocytes did not express G-CSF mRNA or secrete G-CSF protein. In contrast, monocytes exposed to G(Anh)MTetra showed a dose-dependent increase in G-CSF mRNA accumulation, which correlates with the secretion of G-CSF protein. Maximal levels of G-CSF mRNA were reached within 2 h of activation. Expression of G-CSF was mediated by an increase in the stability of G-CSF transcripts rather than by an increase in the transcription rate of the G-CSF gene. Experiments with the protein synthesis inhibitor cycloheximide revealed that G(Anh)MTetra-induced G-CSF mRNA expression was independent of new protein synthesis. Furthermore, it was shown that the effect of G(Anh)MTetra was regulated by a protein kinase C-dependent pathway, whereas protein kinase A and tyrosine kinases were not involved. Finally, it was shown that G(Anh)MTetra also induced G-CSF mRNA expression in human endothelial cells. The data indicate that, besides lipopolysaccharide, other naturally occurring bacterial cell wall components are able to induce G-CSF expression in different hematopoietic cells. Images PMID:7516314

  9. Incidence of chemotherapy-induced neutropenia and current practice of prophylaxis with granulocyte colony-stimulating factors in cancer patients in Spain: a prospective, observational study.

    PubMed

    Jolis, L; Carabantes, F; Pernas, S; Cantos, B; López, A; Torres, P; Funes, C; Caballero, D; Benedit, P; Salar, A

    2013-07-01

    We aimed to describe the incidence of neutropenia in breast cancer and lymphoma patients and granulocyte colony-stimulating factors (G-CSF) use in clinical practice. We conducted a multicentre, prospective, observational study including breast cancer and lymphoma patients initiating chemotherapy (≥ 10% febrile neutropenia risk). We included 734 patients with breast cancer and 291 with lymphoma. Over the first four chemotherapy cycles, patients had an incidence of 11.0% grade 3-4 neutropenia (absolute neutrophil count <1.0 × 10(9) /L) and 4.3% febrile neutropenia (absolute neutrophil count <0.5 × 10(9) /L and fever ≥ 38 °C) in the breast cancer cohort, and 40.5% and 14.8% in the lymphoma cohort. Full dose on schedule (>85% of planned chemotherapy dose and ≤ 3 days delay) was achieved by 85.6% of breast cancer and 68.9% of lymphoma patients. Hospitalisation due to febrile neutropenia was required in 2.0% and 12.0% of breast cancer and lymphoma patients respectively. G-CSF was administered to 70.0% of breast cancer and 83.8% of lymphoma patients, and initiated from the first chemotherapy cycle (primary prophylaxis) in 60.6% and 64.2% of cases. Severe neutropenia affects approximately one in 10 breast cancer patients and one in two lymphoma patients receiving chemotherapy with moderate or greater risk of febrile neutropenia. Most patients received treatment with G-CSF in Spanish clinical practice. © 2013 John Wiley & Sons Ltd.

  10. Attitudes of physicians toward assessing risk and using granulocyte colony-stimulating factor as primary prophylaxis in patients receiving chemotherapy associated with an intermediate risk of febrile neutropenia.

    PubMed

    Freyer, Gilles; Kalinka-Warzocha, Ewa; Syrigos, Konstantinos; Marinca, Mihai; Tonini, Giuseppe; Ng, Say Liang; Wong, Zee Wan; Salar, Antonio; Steger, Guenther; Abdelsalam, Mahmoud; DeCosta, Lucy; Szabo, Zsolt

    2015-10-01

    Febrile neutropenia (FN) is a potentially fatal complication of chemotherapy. This prospective, observational study describes physicians' approaches toward assessing FN risk in patients receiving chemotherapy regimens with an intermediate (10-20 %) FN risk. In the baseline investigator assessment, physicians selected factors considered important when assessing overall FN risk and deciding on granulocyte colony-stimulating factor (G-CSF) primary prophylaxis (PP). Physicians then completed patient assessments using the same lists of factors. The final FN risk scores and whether G-CSF PP was planned were reported. The final analysis included 165 physicians and 944 patients. The most frequently considered factor in both assessments was chemotherapy agents in the backbone (88 % of investigator and 93 % of patient assessments). History of FN (83 %), baseline laboratory values (76 %) and age (73 %) were commonly selected at baseline, whereas tumor type (72 %), guidelines (62 %) and tumor stage (43 %) were selected most during patient assessments. Median investigator-reported FN risk threshold for G-CSF PP was 20 % (range 10-85 %). G-CSF PP was planned in 82 % of patients with an FN risk at or above this threshold; therefore, almost one-fifth of qualifying patients would not receive G-CSF PP. Physicians generally follow guidelines, but also consider individual patient characteristics when assessing FN risk and deciding on G-CSF PP. A standardized FN risk assessment may optimize the use of G-CSF PP, which may minimize the incidence of FN in patients undergoing chemotherapy with an intermediate FN risk. ClinicalTrials.gov Identifier: NCT01813721.

  11. Characterization of buffy coat-derived granulocytes for clinical use: a comparison with granulocyte colony-stimulating factor/dexamethasone-pretreated donor-derived products.

    PubMed

    van de Geer, A; Gazendam, R P; Tool, A T J; van Hamme, J L; de Korte, D; van den Berg, T K; Zeerleder, S S; Kuijpers, T W

    2017-02-01

    Buffy coat-derived granulocytes have been described as an alternative to the apheresis product from donors pretreated with dexamethasone and granulocyte colony-stimulating factor (G-CSF). The latter is - dependent on the local and national settings - obtained following a demanding and time-consuming procedure, which is undesirable in critically ill septic patients. In contrast, buffy coat-derived products have a large volume and are often heavily contaminated with red cells and platelets. We developed a new pooled buffy coat-derived product with high purity and small volume, and performed a comprehensive functional characterization of these granulocytes. We pooled ten buffy coats following the production of platelet concentrates. Saline 0·9% was added to decrease the viscosity and the product was split into plasma, red cells and a 'super' buffy coat. Functional data of the granulocytes were compared to those obtained with granulocytes from healthy controls and G-CSF/dexamethasone-pretreated donors. Buffy coat-derived granulocytes showed adhesion, chemotaxis, reactive oxygen species production, degranulation, NETosis and in vitro killing of Staphylococcus aureus, Escherichia coli and Aspergillus species comparable to control and G-CSF/dexamethasone-derived granulocytes. Candida killing was superior compared to G-CSF/dexamethasone-derived granulocytes. Immunophenotyping was normal; especially no signs of activation in the buffy coat-derived granulocytes were seen. Viability was reduced. Buffy coats are readily available in the regular blood production process and would take away the concerns around the apheresis product. The product described appears a promising alternative for transfusion purposes. © 2017 International Society of Blood Transfusion.

  12. Close Association between Clearance of Recombinant Human Granulocyte Colony-Stimulating Factor (G-CSF) and G-CSF Receptor on Neutrophils in Cancer Patients

    PubMed Central

    Terashi, Kenji; Oka, Mikio; Ohdo, Shigehiro; Furukubo, Taku; Ikeda, Chizuko; Fukuda, Minoru; Soda, Hiroshi; Higuchi, Shun; Kohno, Shigeru

    1999-01-01

    Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is used to counter chemotherapy-induced neutropenia. Our previous study showed an inverse correlation between serum rhG-CSF levels and the number of circulating neutrophils in cancer patients (H. Takatani, H. Soda, M. Fukuda, M. Watanabe, A. Kinoshita, T. Nakamura, and M. Oka, Antimicrob. Agents Chemother. 40:988–991, 1996). The aim of this study was to clarify the relationship between rhG-CSF clearance and G-CSF receptors on circulating neutrophils. In five cancer patients receiving chemotherapy, a bolus dose of rhG-CSF (5 μg/kg) was injected intravenously during defined phases of posttreatment neutropenia and neutrophilia. Serum rhG-CSF levels were measured by a chemiluminescence enzyme immunoassay and analyzed by moment analysis. G-CSF receptors on neutrophils were detected by flow cytometry with biotinylated rhG-CSF. rhG-CSF clearance was significantly higher at neutrophilia than at neutropenia (1,497 ± 132 versus 995 ± 266 ml/h; P < 0.01). The percentage of G-CSF receptor-positive neutrophils, reflecting the number of G-CSF receptors per cell, was low at neutropenia without rhG-CSF therapy (44.5% ± 22.1%) and high at neutrophilia with rhG-CSF therapy (73.0% ± 11.4%; P < 0.01). rhG-CSF clearance closely correlated with the percentage of G-CSF receptor-positive neutrophils (r2 = 0.91; P < 0.0001) and neutrophil count (r2 = 0.72; P < 0.005). Our results indicate that, in cancer patients receiving chemotherapy, rhG-CSF increases the number of G-CSF receptors per cell as well as circulating neutrophil counts, resulting in modulation of its own clearance. PMID:9869559

  13. Subcutaneous versus intravenous granulocyte colony stimulating factor for the treatment of neutropenia in hospitalized hemato-oncological patients: randomized controlled trial.

    PubMed

    Paul, Mical; Ram, Ron; Kugler, Eitan; Farbman, Laura; Peck, Anat; Leibovici, Leonard; Lahav, Meir; Yeshurun, Moshe; Shpilberg, Ofer; Herscovici, Corina; Wolach, Ofir; Itchaki, Gilad; Bar-Natan, Michal; Vidal, Liat; Gafter-Gvili, Anat; Raanani, Pia

    2014-03-01

    Intravenous (IV) granulocyte colony stimulating factor (G-CSF) might be safer and more convenient than subcutaneous (SC) administration to hospitalized hemato-oncological patients receiving chemotherapy. To compare IV vs. SC G-CSF administration, we conducted a randomized, open-label trial. We included inpatients receiving chemotherapy for acute myeloid leukemia, acute lymphoblastic leukemia, lymphoma or multiple myeloma, and allogeneic or autologous hematopoietic cell transplantation (HCT). Patients were randomized to 5 mcg/kg single daily dose of IV bolus versus SC filgrastim given for its clinical indications. Patients were crossed-over to the alternate study arm on the subsequent chemotherapy course. The primary outcomes were time from initiation of filgrastim to recovery of stable neutrophil count of >500 cells/µL and a composite clinical outcome of infection or death assessed for the first course post-randomization. The study was stopped on the second interim analysis. Of 120 patients randomized, 118 were evaluated in the first treatment course. The mean time to neutropenia resolution was longer with IV G-CSF [7.9 days, 95% confidence interval (CI) 6.6-9.1] compared with SC G-CSF (5.4 days, 95% CI 4.6-6.2), log-rank P = 0.001. Longer neutropenia duration was observed in all patient subgroups, except for patients undergoing autologous HCT. There was no significant difference between groups in the occurrence of infection or death, but more deaths were observed with IV (4/57, 7%) versus SC (1/61, 1.6%) G-CSF administration, P = 0.196. Similar results were observed when all 158 courses following cross-over were analyzed. Patients reported similar pain and satisfaction scores in both groups. Bolus IV administration of G-CSF results in longer neutropenia duration than SC administration, with no difference in clinical or quality-of-life measures.

  14. Granulocyte-colony stimulating factor therapy improves survival in patients with hepatitis B virus-associated acute-on-chronic liver failure

    PubMed Central

    Duan, Xue-Zhang; Liu, Fang-Fang; Tong, Jing-Jing; Yang, Hao-Zhen; Chen, Jing; Liu, Xiao-Yan; Mao, Yuan-Li; Xin, Shao-Jie; Hu, Jin-Hua

    2013-01-01

    AIM: To evaluate the safety and efficacy of granulocyte-colony stimulating factor (G-CSF) therapy in patients with hepatitis B virus (HBV)-associated acute-on-chronic liver failure (ACLF). METHODS: Fifty-five patients with HBV-associated ACLF were randomized into two groups: the treatment group and the control group. Twenty-seven patients in the treatment group received G-CSF (5 μg/kg per day, six doses) treatment plus standard therapy, and 28 patients in the control group received standard therapy only. The peripheral CD34+ cell count was measured consecutively by flow cytometry. Circulating white blood cell count, biochemical parameters, and other clinical data of these patients were recorded and analyzed. All patients were followed up for a period of 3 mo to evaluate the changes in liver function and survival rate. RESULTS: The peripheral neutrophil and CD34+ cell counts in the G-CSF group increased on day 3 from the onset of therapy, continued to rise on day 7, and remained elevated on day 15 compared to those of the control group. Child-Turcotte-Pugh score of patients in the treatment group was improved on day 30 from the onset of G-CSF therapy, compared to that in the controls (P = 0.041). Model for End-Stage of Liver Disease score of patients in the treatment group was improved on day 7 (P = 0.004) and remained high on day 30 from the onset of G-CSF therapy (P < 0.001) compared to that in controls. After 3 mo of follow-up observation, the survival rate in the treatment group (48.1%) was significantly higher than that in the control group (21.4%) (P = 0.0181). CONCLUSION: G-CSF therapy promoted CD34+ cell mobilization in patients with HBV-associated ACLF, and improved the liver function and the survival rate of these patients. PMID:23467275

  15. Granulocyte-colony stimulating factor therapy improves survival in patients with hepatitis B virus-associated acute-on-chronic liver failure.

    PubMed

    Duan, Xue-Zhang; Liu, Fang-Fang; Tong, Jing-Jing; Yang, Hao-Zhen; Chen, Jing; Liu, Xiao-Yan; Mao, Yuan-Li; Xin, Shao-Jie; Hu, Jin-Hua

    2013-02-21

    To evaluate the safety and efficacy of granulocyte-colony stimulating factor (G-CSF) therapy in patients with hepatitis B virus (HBV)-associated acute-on-chronic liver failure (ACLF). Fifty-five patients with HBV-associated ACLF were randomized into two groups: the treatment group and the control group. Twenty-seven patients in the treatment group received G-CSF (5 μg/kg per day, six doses) treatment plus standard therapy, and 28 patients in the control group received standard therapy only. The peripheral CD34(+) cell count was measured consecutively by flow cytometry. Circulating white blood cell count, biochemical parameters, and other clinical data of these patients were recorded and analyzed. All patients were followed up for a period of 3 mo to evaluate the changes in liver function and survival rate. The peripheral neutrophil and CD34(+) cell counts in the G-CSF group increased on day 3 from the onset of therapy, continued to rise on day 7, and remained elevated on day 15 compared to those of the control group. Child-Turcotte-Pugh score of patients in the treatment group was improved on day 30 from the onset of G-CSF therapy, compared to that in the controls (P = 0.041). Model for End-Stage of Liver Disease score of patients in the treatment group was improved on day 7 (P = 0.004) and remained high on day 30 from the onset of G-CSF therapy (P < 0.001) compared to that in controls. After 3 mo of follow-up observation, the survival rate in the treatment group (48.1%) was significantly higher than that in the control group (21.4%) (P = 0.0181). G-CSF therapy promoted CD34(+) cell mobilization in patients with HBV-associated ACLF, and improved the liver function and the survival rate of these patients.

  16. Identification of Granulocyte Colony-Stimulating Factor and Interleukin-6 as Candidate Biomarkers of CBLB502 Efficacy as a Medical Radiation Countermeasure

    PubMed Central

    Krivokrysenko, Vadim I.; Shakhov, Alexander N.; Singh, Vijay K.; Bone, Frederick; Kononov, Yevgeniy; Shyshynova, Inna; Cheney, Alec; Maitra, Ratan K.; Purmal, Andrei; Whitnall, Mark H.; Feinstein, Elena

    2012-01-01

    Given an ever-increasing risk of nuclear and radiological emergencies, there is a critical need for development of medical radiation countermeasures (MRCs) that are safe, easily administered, and effective in preventing and/or mitigating the potentially lethal tissue damage caused by acute high-dose radiation exposure. Because the efficacy of MRCs for this indication cannot be ethically tested in humans, development of such drugs is guided by the Food and Drug Administration's Animal Efficacy Rule. According to this rule, human efficacious doses can be projected from experimentally established animal efficacious doses based on the equivalence of the drug's effects on efficacy biomarkers in the respective species. Therefore, identification of efficacy biomarkers is critically important for drug development under the Animal Efficacy Rule. CBLB502 is a truncated derivative of the Salmonella flagellin protein that acts by triggering Toll-like receptor 5 (TLR5) signaling and is currently under development as a MRC. Here, we report identification of two cytokines, granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6), as candidate biomarkers of CBLB502's radioprotective/mitigative efficacy. Induction of both G-CSF and IL-6 by CBLB502 1) is strictly TLR5-dependent, 2) occurs in a CBLB502 dose-dependent manner within its efficacious dose range in both nonirradiated and irradiated mammals, including nonhuman primates, and 3) is critically important for the ability of CBLB502 to rescue irradiated animals from death. After evaluation of CBLB502 effects on G-CSF and IL-6 levels in humans, these biomarkers will be useful for accurate prediction of human efficacious CBLB502 doses, a key step in the development of this prospective radiation countermeasure. PMID:22837010

  17. Four-Week Repeated Intravenous Dose Toxicity and Toxicokinetic Study of TS-DP2, a Novel Human Granulocyte Colony Stimulating Factor in Rats

    PubMed Central

    Lee, JooBuom; Lee, Kyungsun; Choe, Keunbum; Jung, Hyunseob; Cho, Hyunseok; Choi, Kiseok; Kim, Taegon; Kim, Seojin; Lee, Hyeong-Seok; Cha, Mi-Jin; Song, Si-Whan; Lee, Chul Kyu; Chun, Gie-Taek

    2015-01-01

    TS-DP2 is a recombinant human granulocyte colony stimulating factor (rhG-CSF) manufactured by TS Corporation. We conducted a four-week study of TS-DP2 (test article) in repeated intravenous doses in male and female Sprague-Dawley (SD) rats. Lenograstim was used as a reference article and was administered intravenously at a dose of 1000 μg/kg/day. Rats received TS-DP2 intravenously at doses of 250, 500, and 1000 μg/kg/day once daily for 4 weeks, and evaluated following a 2-week recovery period. Edema in the hind limbs and loss of mean body weight and body weight gain were observed in both the highest dose group of TS-DP2 and the lenograstim group in male rats. Fibro-osseous lesions were observed in the lenograstim group in both sexes, and at all groups of TS-DP2 in males, and at doses of TS-DP2 500 μg/kg/day and higher in females. The lesion was considered a toxicological change. Therefore, bone is the primary toxicological target of TS-DP2. The lowest observed adverse effect level (LOAEL) in males was 250 μg/kg/day, and no observed adverse effect level (NOAEL) in females was 250 μg/kg/day in this study. In the toxicokinetic study, the serum concentrations of G-CSF were maintained until 8 hr after administration. The systemic exposures (AUC0-24h and C0) were not markedly different between male and female rats, between the administration periods, or between TS-DP2 and lenograstim. In conclusion, TS-DP2 shows toxicological similarity to lenograstim over 4-weeks of repeated doses in rats. PMID:26877840

  18. The effect of ammonia on the O-linked glycosylation of granulocyte colony-stimulating factor produced by chinese hamster ovary cells

    SciTech Connect

    Andersen, D.C.; Goochee, C.F.

    1995-07-05

    Ammonium ion concentrations ranging from 0 to 10 mM are shown to significantly reduce the sialylation of granulocyte colony-stimulating factor (G-CSF) produced by recombinant Chinese hamster ovary cells. Specifically, the degree of completion of the final reaction in the O-linked glycosylation pathway, the addition of sialic acid in an {alpha}(2,6) linkage to N-acetylgalactosamine, is reduced by NH{sub 4}{sup +} concentrations of as low as 2 mM. The effect of ammonia on sialylation is rapid, sustained, and does not affect the secretion rate of G-CSF. Additionally, the effect can be mimicked using the weak base chloroquine, suggesting that the effect is related to the weak base characteristics of ammonia. In support of this hypothesis, experiments using brefeldin A suggest that the addition of sialic acid in an {alpha}(2,6) linkage to N-acetylgalactosamine occurs in the trans-Golgi compartment prior to the trans-Golgi network, which would be expected under normal conditions to have a slightly acidic pH in the range from 6.5 to 6.75. Ammonium ion concentrations of 10mM would be expected to reduce significantly the differences in pH between acidic intracellular compartments and the cytoplasm. The pH-activity profile for the CHO O-linked {alpha}(2,6)sialytransferase using monosialylated G-CSF as a substrate reveals a twofold decrease in enzymatic activity across the pH range from 6.75 to 7.0. Mathematical modeling of this sialylation reaction supports the hypothesis that this twofold decrease in sialyltransferase activity resulting from an ammonia-induced increase in trans-Golgi pH could produce the observed decrease in G-CSF sialylation.

  19. Granulocyte Colony-Stimulating Factor Ameliorates Skeletal Muscle Dysfunction in Amyotrophic Lateral Sclerosis Mice and Improves Proliferation of SOD1-G93A Myoblasts in vitro.

    PubMed

    Rando, Amaya; Gasco, Samanta; de la Torre, Miriam; García-Redondo, Alberto; Zaragoza, Pilar; Toivonen, Janne M; Osta, Rosario

    2017-01-01

    Amyotrophic lateral sclerosis (ALS) causes loss of upper and lower motor neurons as well as skeletal muscle (SKM) dysfunction and atrophy. SKM is one of the tissues involved in the development of ALS pathology, and studies in a SOD1-G93A mouse model of ALS have demonstrated alterations in SKM degeneration/regeneration marker expression in vivo and defective mutant myoblast proliferation in vitro. Granulocyte colony-stimulating factor (G-CSF) has been shown to alleviate SOD1-G93A pathology. However, it is unknown whether G-CSF may have a direct effect on SKM or derived myoblasts. To investigate effects of G-CSF and its analog pegfilgrastim (PEGF) on SOD1-G93A- associated SKM markers in vivo and those of G-CSF on myoblast proliferation in vitro. The effect of PEGF treatment on hematopoietic stem cell mobilization, survival, and motor function was determined. RNA expression of SKM markers associated with mutant SOD1 expression was quantified in response to PEGF treatment in vivo, and the effect of G-CSF on the proliferation of myoblasts derived from mutant and control muscles was determined in vitro. Positive effects of PEGF on hematopoietic stem cell mobilization, survival, and functional assays in SOD1-G93A animals were confirmed. In vivo PEGF treatment augmented the expression of its receptor Csf3r and alleviated typical markers for mutant SOD1 muscle. Additionally, G-CSF was found to directly increase the proliferation of SOD1-G93A, but not wild-type primary myoblasts in vitro. Our results support the beneficial role of the G-CSF analog PEGF in a SOD1-G93A model of ALS. Thus, G-CSF and its analogs may be directly beneficial in diseases where the SKM function is compromised. © 2016 S. Karger AG, Basel.

  20. Granulocyte colony-stimulating factor (G-CSF) depresses angiogenesis in vivo and in vitro: implications for sourcing cells for vascular regeneration therapy.

    PubMed

    Tura, O; Crawford, J; Barclay, G R; Samuel, K; Hadoke, P W F; Roddie, H; Davies, J; Turner, M L

    2010-07-01

    The most common source of hematopoietic progenitor cells (HPCs) for hematopoietic reconstitution comprises granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSCs). It has been proposed that endothelial progenitor cells (EPCs) share precursors with HPCs, and that EPC release may accompany HPC mobilization to the circulation following G-CSF administration. To investigate EPC activity following HPC mobilization, and the direct effects of exogenous G-CSF administration on human umbilical vein endothelial cells (HUVECs) and endothelial outgrowth cells (EOCs), using in vitro and in vivo correlates of angiogenesis. Heparinized venous blood samples were collected from healthy volunteers and from cord blood at parturition. G-CSF-mobilized samples were collected before administration, at apheresis harvest, and at follow-up. PBSCs were phenotyped by flow cytometry, and cultured in standard colony-forming unit (CFU)-EPC and EOC assays. The effect of exogenous G-CSF was investigated by addition of it to HUVECs and EOCs in standard tubule formation and aortic ring assays, and in an in vivo sponge implantation model. Our data show that G-CSF mobilization of PBSCs produces a profound, reversible depression of circulating CFU-EPCs. Furthermore, G-CSF administration did not mobilize CD34+CD133- cells, which include precursors of EOCs. No EOCs were cultured from any mobilized PBSCs studied. Exogenous G-CSF inhibited CFU-EPC generation, HUVEC and EOC tubule formation, microvessel outgrowth, and implanted sponge vascularization in mice. G-CSF administration depresses both endothelial cell angiogenesis and monocyte proangiogenic activity, and we suggest that any angiogenic benefit observed following implantation of cells mobilized by G-CSF may come only from a paracrine effect from HPCs.

  1. Low-dose granulocyte colony-stimulating factor overcomes neutropenia in the treatment of non-Hodgkin's lymphoma with higher cost-effectiveness.

    PubMed

    Hara, Takeshi; Tsurumi, Hisashi; Kasahara, Senji; Kanemura, Nobuhiro; Yoshikawa, Takeshi; Goto, Naoe; Kojima, Yasushi; Yamada, Toshiki; Sawada, Michio; Takahashi, Takeshi; Oyama, Masami; Tomita, Eiichi; Moriwaki, Hisataka

    2005-12-01

    To facilitate more economical medical care, we carried out a prospective study of whether a THP-COP regimen (cyclophosphamide, pirarubicin, vincristine, and prednisolone) with low-dose granulocyte colony-stimulating factor (G-CSF) would effectively treat non-Hodgkin's lymphoma (NHL). From April 2003 through March 2004, we enrolled 19 consecutive patients with newly diagnosed NHL treated at our hospital. The patients were divided into young and elderly groups. Each patient underwent chemotherapy with 8 courses of a THP-COP regimen with a 50-microg dose of lenograstim. Age- and sex-matched historical control patients (n = 141) received NHL diagnoses between 1998 and 2003. Each patient in the control group underwent the same chemotherapy and received a 100-microg dose of lenograstim. The mean (+/-SD) total amounts of G-CSF per cycle of chemotherapy were 332 +/- 103 microg (young patients) and 345 +/- 128 microg (elderly patients) in the low-dose group and 594 +/- 439 microg (young) and 730 +/- 551 microg (elderly) in the control group. The duration of fever in 1 cycle of chemotherapy was 0.3 +/- 1.0 days (young) and 0.1 +/- 0.8 days (elderly) in the low-dose group and 0.5 +/- 1.3 days (young) and 0.8 +/- 2.0 days (elderly) in the control group. A THP-COP regimen with low-dose G-CSF could be administered to NHL patients with safety. Administration of a 50-microg dose of lenograstim is sufficient and recommended for the treatment of NHL.

  2. Transplanted Peripheral Blood Stem Cells Mobilized by Granulocyte Colony-Stimulating Factor Promoted Hindlimb Functional Recovery After Spinal Cord Injury in Mice.

    PubMed

    Takahashi, Hiroshi; Koda, Masao; Hashimoto, Masayuki; Furuya, Takeo; Sakuma, Tsuyoshi; Kato, Kei; Okawa, Akihiko; Inada, Taigo; Kamiya, Koshiro; Ota, Mitsutoshi; Maki, Satoshi; Takahashi, Kazuhisa; Yamazaki, Masashi; Mannoji, Chikato

    2016-01-01

    Granulocyte colony-stimulating factor (G-CSF) mobilizes peripheral blood stem cells (PBSCs) derived from bone marrow. We hypothesized that intraspinal transplantation of PBSCs mobilized by G-CSF could promote functional recovery after spinal cord injury. Spinal cords of adult nonobese diabetes/severe immunodeficiency mice were injured using an Infinite Horizon impactor (60 kdyn). One week after the injury, 3.0 µl of G-CSF-mobilized human mononuclear cells (MNCs; 0.5 × 10(5)/µl), G-CSF-mobilized human CD34-positive PBSCs (CD34; 0.5 × 10(5)/µl), or normal saline was injected to the lesion epicenter. We performed immunohistochemistry. Locomotor recovery was assessed by Basso Mouse Scale. The number of transplanted human cells decreased according to the time course. The CD31-positive area was significantly larger in the MNC and CD34 groups compared with the vehicle group. The number of serotonin-positive fibers was significantly larger in the MNC and CD34 groups than in the vehicle group. Immunohistochemistry revealed that the number of apoptotic oligodendrocytes was significantly smaller in cell-transplanted groups, and the areas of demyelination in the MNC- and CD34-transplanted mice were smaller than that in the vehicle group, indicating that cell transplantation suppressed oligodendrocyte apoptosis and demyelination. Both the MNC and CD34 groups showed significantly better hindlimb functional recovery compared with the vehicle group. There was no significant difference between the two types of transplanted cells. Intraspinal transplantation of G-CSF-mobilized MNCs or CD34-positive cells promoted angiogenesis, serotonergic fiber regeneration/sparing, and preservation of myelin, resulting in improved hindlimb function after spinal cord injury in comparison with vehicle-treated control mice. Transplantation of G-CSF-mobilized PBSCs has advantages for treatment of spinal cord injury in the ethical and immunological viewpoints, although further exploration

  3. Recombinant Human Granulocyte Colony-Stimulating Factor Promotes Preinvasive and Invasive Estrogen Receptor-Positive Tumor Development in MMTV-erbB2 Mice

    PubMed Central

    Zhao, Chun Ling; Zhang, Guang Ping; Xiao, Zheng Zheng; Ma, Zhi Kun; Lei, Cai Peng; Song, Shi Yuan; Feng, Ying Ying; Zhao, Ya Chao

    2015-01-01

    Purpose We investigated whether recombinant human granulocyte colony-stimulating factor (rhG-CSF) could promote the development of preinvasive and invasive breast cancer in mouse mammary tumor virus (MMTV-erbB2) mice with estrogen receptor-positive tumors. Methods MMTV-erbB2 mice were randomly divided into three experimental groups with 20 mice in each group. MMTV-erbB2 mice were treated with daily subcutaneous injections of vehicle or rhG-CSF (low-rhG-CSF group, rhG-CSF 0.125 µg; vehicle-rhG-CSF group, normal saline 0.25 µg; and high-rhG-CSF group, rhG-CSF 0.25 µg) at 3 months of age. Cellular and molecular mechanisms of G-CSF action in mammary glands were investigated via immunohistochemistry and reverse transcription polymerase chain reaction. Results Low, but not high, rhG-CSF doses significantly accelerated mammary tumorigenesis in MMTV-erbB2 mice. Short-term treatment with rhG-CSF could significantly promote the development of preinvasive mammary lesions. The cancer prevention effect was associated with reduced expression of proliferating cell nuclear antigen, cluster of differentiation 34, and signal transducers and activators of transcription 3 in mammary glands by >80%. Conclusion We found that G-CSF was regulated by rhG-CSF both in vitro and in vivo. Identification of G-CSF genes helped us further understand the mechanism by which G-CSF promotes cancer. Low doses of rhG-CSF could significantly increase tumor latency and increase tumor multiplicity and burden. Moreover, rhG-CSF effectively promotes development of both malignant and premalignant mammary lesions in MMTV-erbB2 mice. PMID:26155288

  4. Granulocyte colony-stimulating factor significantly decreases density of hippocampal caspase 3-positive nuclei, thus ameliorating apoptosis-mediated damage, in a model of ischaemic neonatal brain injury.

    PubMed

    Pastuszko, Peter; Schears, Gregory J; Kubin, Joanna; Wilson, David F; Pastuszko, Anna

    2017-10-01

    Ischaemic brain injury is a major complication in patients undergoing surgery for congenital heart disease, with the hippocampus being a particularly vulnerable region. We hypothesized that neuronal injury resulting from cardiopulmonary bypass and associated circulatory arrest is ameliorated by pretreatment with granulocyte colony-stimulating factor (G-CSF), a cytokine and an anti-apoptotic neurotrophic factor. In a model of ischaemic brain injury, 4 male newborn piglets were anaesthetized and subjected to deep hypothermic circulatory arrest (DHCA) (cooled to 18°C, DHCA maintained for 60 min, rewarmed and recovered for 8-9 h), while 4 animals received G-CSF (34 µg/kg, intravenously) 2 h prior to the DHCA procedure. At the end of each experiment, the animals were perfused with a fixative, the hippocampus was extracted, cryoprotected, cut and the brain sections were immunoprocessed for activated caspase 3, a pro-apoptotic factor. Immunopositive neuronal nuclei were counted in multiple counting boxes (440 × 330 µm) centred on the CA1 or CA3 hippocampal regions and their mean numbers compared between the different treatment groups and regions. G-CSF pretreatment resulted in significantly lower counts of caspase 3-positive nuclei per counting box in both the CA1 [52.2 ± 9.3 (SD) vs 61.6 ± 8.4, P < 0.001] and CA3 (41.2 ± 6.9 vs 60.4 ± 16.4, P < 0.00002) regions of the hippocampus as compared to DHCA groups. The effects of G-CSF were significant for pyramidal cells of both regions and for interneurons in the CA3 region. In an animal model of ischaemic brain injury, G-CSF reduces neuronal injury in the hippocampus, thus potentially having beneficial effect on neurologic outcomes.

  5. Relationship between native-state solubility and non-native aggregation of recombinant human granulocyte colony stimulating factor: practical implications for protein therapeutic development.

    PubMed

    Banks, Douglas D; Zhang, Jun; Siska, Christine C

    2014-10-06

    Prescreening methods are needed in the biotechnology industry for rapid selection of protein therapeutic candidates and formulations of low aggregation propensity. In recent reports solubility measurements have shown promise as one such method, although the connection between protein solubility and non-native aggregation is not well understood. In the present investigation, recombinant human granulocyte colony stimulating factor (rhGCSF) was used to explore this relationship since it was previously shown to rapidly undergo non-native aggregation/precipitation under physiological conditions in a reaction attenuated by the addition of sucrose [Krishnan, S.; et al. Biochemistry 2002, 41, 6422-6431]. Strong correlations were found between rhGCSF non-native aggregation and both solubility and thermal stability as a function of sucrose concentration. We believe these results make sense in the context of an rhGCSF aggregation mechanism where loss of monomer to insoluble aggregate is limited by association to an observable dimer from a less soluble (and aggregation competent) intermediate species that exists in a temperature sensitive pre-equilibrium with the native monomer. Both solubility and measures of conformational stability report on the position of this equilibrium and therefore the concentration of reactive intermediate. Interestingly, aggregation also correlated with rhGCSF solubility as a function of salting-in concentrations of phosphate since both are dependent on the colloidal stability of the reactive intermediate but not with conformational stability. In lieu of a complete understanding of the aggregation processes that limit protein therapeutic shelf life, these results highlight the potential of using simple solubility measurements as an additional tool in the biotechnology prescreening repertoire.

  6. Crystallization of a 2:2 complex of granulocyte-colony stimulating factor (GCSF) with the ligand-binding region of the GCSF receptor

    SciTech Connect

    Honjo, Eijiro; Tamada, Taro; Maeda, Yoshitake; Koshiba, Takumi; Matsukura, Yasuko; Okamoto, Tomoyuki; Ishibashi, Matsujiro; Tokunaga, Masao; Kuroki, Ryota

    2005-08-01

    A 2:2 complex of highly purified GCSF receptor (Ig-CRH) with GCSF was crystallized. The crystal diffracted to 2.8 Å resolution with sufficient quality for further structure determination. The granulocyte-colony stimulating factor (GCSF) receptor receives signals for regulating the maturation, proliferation and differentiation of the precursor cells of neutrophilic granulocytes. The signalling complex composed of two GCSFs (GCSF, 19 kDa) and two GCSF receptors (GCSFR, 34 kDa) consisting of an Ig-like domain and a cytokine-receptor homologous (CRH) domain was crystallized. A crystal of the complex was grown in 1.0 M sodium formate and 0.1 M sodium acetate pH 4.6 and belongs to space group P4{sub 1}2{sub 1}2 (or its enantiomorph P4{sub 3}2{sub 1}2), with unit-cell parameters a = b = 110.1, c = 331.8 Å. Unfortunately, this crystal form did not diffract beyond 5 Å resolution. Since the heterogeneity of GCSF receptor appeared to prevent the growth of good-quality crystals, the GCSF receptor was fractionated by anion-exchange chromatography. Crystals of the GCSF–fractionated GCSF receptor complex were grown as a new crystal form in 0.2 M ammonium phosphate. This new crystal form diffracted to beyond 3.0 Å resolution and belonged to space group P3{sub 1}21 (or its enantiomorph P3{sub 2}21), with unit-cell parameters a = b = 134.8, c = 105.7 Å.

  7. [The plasma levels and diagnostic utility of granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage - colony stimulating factor (GM-CSF) in patients with I and II stage of breast cancer].

    PubMed

    Ławicki, Sławomir; Czygier, Małgorzata; Wojtukiewicz, Marek; Szmitkowski, Maciej

    2009-01-01

    Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage - colony stimulating factor (GM-CSF) belong to hematopoetic growth factors (HGFs). Few clinical investigation have shown their autologous production both in vitro by human cell lines and in vivo by tumors, for example in breast cancer. We have investigated the plasma levels of G-CSF, GM-CSF and commonly accepted tumor marker (CA 15-3) before treatment of breast cancer patients in relation to the healthy controls. Additionally, the diagnostic criteria: sensitivity, specificity, the predictive value of positive and negative results were defined. Tested group--50 patients with breast cancer, control group--30 healthy women. G-CSF and GM-CSF were determined using ELISA method, CA 15-3--was measured by chemilumunescence immunoassay (CMIA) (ABBOTT). Median values of G-CSF, GM-CSF and CA 15-3 plasma levels were significantly higher in the II stage of breast cancer patients before surgery compared to the control group. The diagnostic sensitivity of G-CSF and GM-CSF was slightly lower than CA 15-3. The higher range of the diagnostic sensitivity of tested cytokines and CA 15-3 in more advanced breast stages was observed. The combined use of both cytokines and CA 15-3 analysis resulted also in the increased sensitivity range (69%). The diagnostic specificities of tested cytokines were high for both cytokines (equal 90%) and CA 15-3 (95%). The positive and negative predictive values were high for all tested parameters and were higher in more advanced tumor stage. This study suggests that tested cytokines, especially G-CSF, can be clinically useful in diagnostics of breast cancer patients, but further investigation and confirmation by a prospective study are necessary.

  8. Treatment of adjuvant arthritis with granulocyte-colony stimulating factor and peptide derived from heat shock protein 65.

    PubMed

    Brendolan, Andrea; Higuchi, Masanori; Sibley, Richard; Strober, Samuel

    2003-01-01

    Adjuvant arthritis in Lewis rats is induced by the subcutaneous injection of Mycobacterium tuberculosis in mineral oil, and the predominant T cell immune reactivity is against the heat shock protein 65 derived peptide 176-190. We treated Lewis rats with human recombinant G-CSF followed by (i.v) administration of peptide 176-190 after induction of adjuvant arthritis (AA), and observed decreased disease severity, joint destruction, new bone formation and joint ankylosis. Treatment with G-CSF alone was also effective, but to a lesser extent. In addition, we found that splenocytes from rats treated with G-CSF had reduced antigen presenting capacity compared with splenocytes from vehicle treated rats. Primed lymph node cells from G-CSF plus peptide treated rats showed a marked reduction in proliferation and secretion of IFN-gamma after stimulation with the heat shock protein peptide in vitro as compared to controls.

  9. Granulocyte colony-stimulating factor improves host defense to resuscitated shock and polymicrobial sepsis without provoking generalized neutrophil-mediated damage.

    PubMed

    Patton, J H; Lyden, S P; Ragsdale, D N; Croce, M A; Fabian, T C; Proctor, K G

    1998-05-01

    Granulocyte colony-stimulating factor (G-CSF) increases production and release of neutrophil precursors and activates multiple functions of circulating polymorphonuclear neutrophils (PMNs). G-CSF has therapeutic effects in many experimental models of sepsis; its actions with superimposed reperfusion insults are unknown. In traumatic conditions, G-CSF could exacerbate unregulated, PMN-dependent injury to otherwise normal host tissue or, it could partially reverse trauma-induced immune suppression, which may improve long-term outcome. This study tested whether stimulating PMN proliferation and function with G-CSF during recovery from trauma+sepsis potentiated reperfusion injury or whether it improved host defense. Anesthetized swine were subjected to cecal ligation and incision, 35% hemorrhage, and 1 hr of hypotension. Resuscitation consisted of intravenous G-CSF (5 microg/kg) or placebo followed by shed blood and 40 mL/kg of lactated Ringer's solution. The control group received laparotomy only. G-CSF or placebo was given daily. Animals were killed at 4 days. Observers, blind to the protocol, graded autopsy samples for localization of infection and quality of abscess wall formation. Data included complete blood count, granulocyte oxidative burst after phorbol myristate acetate stimulation in vitro (GO2B), bronchoalveolar lavage (BAL) cell count, BAL noncellular protein, lipopolysaccharide-stimulated tumor necrosis factor production in whole blood in vitro (lipopolysaccharide-tumor necrosis factor), and lung tissue myeloperoxidase (MPO). Neutrophilia and localization of infection, were significantly improved by G-CSF. Variables altered by G-CSF, though not significantly, showed GO2B potential increased by 50%, lipopolysaccharide-tumor necrosis factor decreased by 50%, and improved survival versus placebo (100% vs. 70%). G-CSF did not increase lung MPO, BAL cell count, or BAL protein. Both arterial and venous O2 saturations were unaltered. Our data show that G

  10. A randomised study comparing granulocyte-colony stimulating factor (G-CSF) with G-CSF plus thymostimulin in the treatment of haematological toxicity in patients with advanced breast cancer after high dose mitoxantrone therapy.

    PubMed

    Sanchiz, F; Milla, A

    1996-01-01

    54 patients with advanced breast cancer were randomised into a prospective, non-blinded, controlled trial to receive: mitoxantrone 28 mg/m2 intravenous day 1 and granulocyte-colony stimulating factor (G-CSF) 5 micrograms/kg/day subcutaneously days 2 to 16 (n = 27) or the same regimen plus thymostimulin (TS) 50 mg/day intramuscular at days 2 to 16 (n = 27). The median time to reach a neutrophil count greater than 0.5 x 10(9)/l was lower in the G-CSF+TS treated group (9.13 versus 3.24 days; P < 0.0005). More patients experienced neutropenic fever in the G-CSF group than in the G-CSF+TS group (59.3% versus 22.2%, P = 0.0119). The incidence, duration and severity of clinically or bacteriologically documented infection were lower in patients who received TS. 16 patients (59.3%) in the G-CSF group contracted infection, and 4 patients (14.8%) receiving G-CSF+TS (P = 0.0016). These data indicate that the combination of G-CSF and TS is well-tolerated and may enhance haematological recovery following myelosuppressive chemotherapy in patients with advanced breast cancer.

  11. Granulocyte-colony stimulating factor for hematopoietic stem cell donation from healthy female donors during pregnancy and lactation: what do we know?

    PubMed

    Pessach, Ilias; Shimoni, Avichai; Nagler, Arnon

    2013-01-01

    BACKGROUND Hematopoietic growth factors (HGFs) are mostly used as supportive measures to reduce infectious complications associated with neutropenia. Over the past decade, the use of HGFs became a common method for mobilizing human CD34+ stem cells, either for autologous or allogeneic transplantation. However, since their introduction the long-term safety of the procedure has become a major focus of discussion and research. Most information refers to healthy normal donors and data concerning pregnant and lactating women are scarce. The clinical question, which is the core of this review, is whether stem cell donation, preceded by administration of granulocyte-colony stimulating factor (G-CSF) for mobilization, is a safe procedure for pregnant donors. METHODS Literature searches were performed in Pubmed for English language articles published before the end of May 2012, focusing on G-CSF administration during pregnancy, lactation and hematopoietic stem cell donation. Searches included animal and human studies. RESULTS Data from animals (n = 15 studies) and women (n = 46 studies) indicate that G-CSF crosses the placenta, stimulates fetal granulopoiesis, improves neonatal survival mostly for very immature infants, promotes trophoblast growth and placental metabolism and has an anti-abortive role. Granulocyte macrophage-CSF is a key cytokine in the maternal immune tolerance towards the implanted embryo and exerts protective long-term programming effects to preimplantation embryos. The available data suggest that probably CSFs should not be administered during the time of most active organogenesis (first trimester), except perhaps for the first week during which implantation takes place. Provided CSF is administered during the second and third trimesters, it appears to be safe, and pregnant women receiving the CSF treatment can become hematopoietic stem cell donors. There are also risks related to the anesthesia, which is required for the bone marrow aspiration. During

  12. Increased presence of anti-HLA antibodies early after allogeneic granulocyte colony-stimulating factor-mobilized peripheral blood hematopoietic stem cell transplantation compared with bone marrow transplantation.

    PubMed

    Lapierre, Valérie; Aupérin, Anne; Tayebi, Hakim; Chabod, Jacqueline; Saas, Philippe; Michalet, Mauricette; François, Sylvie; Garban, Frédéric; Giraud, Christine; Tramalloni, Dominique; Oubouzar, Nadia; Blaise, Didier; Kuentz, Matthieu; Robinet, Eric; Tiberghien, Pierre

    2002-08-15

    We have recently shown that the use of allogeneic granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood hematopoietic stem cell transplantation (PBHSCT), as compared with bone marrow transplantation (BMT), is associated with increased titers of antibodies (Abs) directed against red blood cell ABO antigens. To further evaluate the influence of a G-CSF-mobilized PBHSCT graft on alloimmune Ab responses, we examined the frequency of anti-HLA Abs after transplantation in the setting of the same randomized study, comparing PBHSCT with BMT in adults. Anti-HLA Ab presence was determined by complement-dependent cytotoxicity assay (CDC) and flow cytometry in the recipient before and 30 days after transplantation as well as in the donor before graft donation. The use of PBHSCT was significantly associated with increased detection of anti-HLA immunoglobulin G (IgG) Abs early after transplantation as evidenced by flow cytometry (11 of 24 versus 4 of 27 transplant recipients, P =.03) and, less so, by CDC (5 of 24 versus 1 of 27 transplant recipients, P =.09). The difference between PBHSCT and BMT was further heightened when analysis was restricted to anti-HLA IgG Ab-negative donor/recipient pairs. In such a setting, early anti-HLA Ab was never detected after BMT but was repeatedly detected after PBHSCT (flow cytometry, 6 of 18 versus 0 of 17 transplant recipients, P =.02; CDC, 4 of 23 versus 0 of 26 transplant recipients, P =.04). Importantly, the PBHSCT-associated increase in anti-HLA Ab detection was observed despite a reduction in the median number of platelet-transfusion episodes per patient in PBHSC transplant versus BM transplant recipients (3 platelet-transfusion episodes [range, 1-21] in PBHSCT group vs 6 platelet-transfusion episodes [range, 3-33] in the BMT group; P =.02). In conclusion, this study strongly suggests that G-CSF-mobilized PBHSCT results in an increased incidence of circulating anti-HLA Abs and further confirms that the use of such a

  13. Granulocyte colony-stimulating factor therapy for stem cell mobilization following anterior wall myocardial infarction: the CAPITAL STEM MI randomized trial

    PubMed Central

    Hibbert, Benjamin; Hayley, Bradley; Beanlands, Robert S.; Le May, Michel; Davies, Richard; So, Derek; Marquis, Jean-François; Labinaz, Marino; Froeschl, Michael; O’Brien, Edward R.; Burwash, Ian G.; Wells, George A.; Pourdjabbar, Ali; Simard, Trevor; Atkins, Harold; Glover, Christopher

    2014-01-01

    Background: Small studies have yielded divergent results for administration of granulocyte colony-stimulating factor (G-CSF) after acute myocardial infarction. Adequately powered studies involving patients with at least moderate left ventricular dysfunction are lacking. Methods: Patients with left ventricular ejection fraction less than 45% after anterior-wall myocardial infarction were treated with G-CSF (10 μg/kg daily for 4 days) or placebo. After initial randomization of 86 patients, 41 in the placebo group and 39 in the G-CSF group completed 6-month follow-up and underwent measurement of left ventricular ejection fraction by radionuclide angiography. Results: Baseline and 6-week mean ejection fraction was similar for the G-CSF and placebo groups: 34.8% (95% confidence interval [CI] 32.6%–37.0%) v. 36.4% (95% CI 33.5%–39.2%) at baseline and 39.8% (95% CI 36.2%–43.4%) v. 43.1% (95% CI 39.2%–47.0%) at 6 weeks. However, G-CSF therapy was associated with a lower ejection fraction at 6 months relative to placebo (40.8% [95% CI 37.4%–44.2%] v. 46.0% [95% CI 42.7%–44.3%]). Both groups had improved left ventricular function, but change in left ventricular ejection fraction was lower in patients treated with G-CSF than in those who received placebo (5.7 [95% CI 3.4–8.1] percentage points v. 9.2 [95% CI 6.3–12.1] percentage points). One or more of a composite of several major adverse cardiac events occurred in 8 patients (19%) within each group, with similar rates of target-vessel revascularization. Interpretation: In patients with moderate left ventricular dysfunction following anterior-wall infarction, G-CSF therapy was associated with a lower 6-month left ventricular ejection fraction but no increased risk of major adverse cardiac events. Future studies of G-CSF in patients with left ventricular dysfunction should be monitored closely for safety. Trial registration: ClinicalTrials.gov, no. NCT00394498 PMID:24934893

  14. Granulocyte colony stimulating factor reduces brain injury in a cardiopulmonary bypass-circulatory arrest model of ischemia in a newborn piglet

    PubMed Central

    Pastuszko, Peter; Schears, Gregory J.; Greeley, William J.; Kubin, Joanna; Wilson, David F.; Pastuszko, Anna

    2014-01-01

    Background Ischemic brain injury continues to be of major concern in patients undergoing cardiopulmonary bypass (CPB) surgery for congenital heart disease. Striatum and hippocampus are particularly vulnerable to injury during these processes. Our hypothesis is that the neuronal injury resulting from CPB and the associated circulatory arrest can be at least partly ameliorated by pre-treatment with granulocyte colony stimulating factor (G-CSF). Material and Methods Fourteen male newborn piglets were assigned to three groups: deep hypothermic circulatory arrest (DHCA), DHCA with G-CSF, and sham-operated. The first two groups were placed on CPB, cooled to 18°C, subjected to 60 min of DHCA, re-warmed and recovered for 8-9 hrs. At the end of experiment, the brains were perfused, fixed and cut into 10 μm transverse sections. Apoptotic cells were visualized by in-situ DNA fragmentation assay (TUNEL), with the density of injured cells expressed as a mean number ± SD per mm2. Results The number of injured cells in the striatum and CA1 and CA3 regions of the hippocampus increased significantly following DHCA. In the striatum, the increase was from 0.46±0.37 to 3.67±1.57 (p=0.002); in the CA1, from 0.11±0.19 to 5.16±1.57 (p=0.001), and in the CA3, from 0.28±0.25 to 2.98±1.82 (p=0.040). Injection of G-CSF prior to bypass significantly reduced the number of injured cells in the striatum and CA1 region, by 51% and 37%, respectively. In the CA3 region, injured cell density did not differ between the G-CSF and control group. Conclusion In a model of hypoxic brain insult associated with CPB, G-CSF significantly reduces neuronal injury in brain regions important for cognitive functions, suggesting it can significantly improve neurological outcomes from procedures requiring DHCA. PMID:25082120

  15. Effects of recombinant human granulocyte colony-stimulating factor on central and peripheral T lymphocyte reconstitution after sublethal irradiation in mice

    PubMed Central

    Zhao, Hongxia; Guo, Mei; Sun, Xuedong; Sun, Wanjun; Hu, Hailan; Wei, Li; Ai, Huisheng

    2013-01-01

    Granulocyte colony-stimulating factor (G-CSF) is one of the most critical cytokines used for the treatment of acute radiation syndrome (ARS). In addition to the hematopoietic effects of G-CSF on the differentiation and proliferation of myeloid progenitor cells, G-CSF is also known to have immunomodulatory effects. The aim of the present study was to investigate whether G-CSF could accelerate central and peripheral T lymphocyte recovery after a sublethal dose of irradiation. Female BALB/c mice were subjected to 6 Gy of total body irradiation and then were treated with either 100 μg/kg G-CSF or an equal volume of PBS once daily for 14 days. Percentages of thymocyte subpopulations including CD4 − CD8 − , CD4 + CD8 + , CD4 + CD8− and CD4 − CD8+ T cells, peripheral CD3 + , CD4+ and CD8+ cells were analyzed by flow cytometry. Recent thymic emigrants (RTEs) were assessed by real-time polymerase chain reaction (PCR) using primers specific to the 257-bp T cell receptor rearrangement excision circles (sjTRECs). The proliferative capacity of splenic mononuclear cells upon exposure to ConA was measured by using the Cell Count Kit-8 (CCK-8). G-CSF treatment promoted thymocyte regeneration, accelerated the recovery of CD4 + CD8+ cells and increased the frequency of thymocyte sjTRECs. These effects were more prominent at early time points (Day 28) after irradiation. G-CSF also increased the rate of recovery of peripheral CD3 + , CD4+ and CD8+ cells and shortened the period of severe lymphopenia following irradiation. G-CSF also increased the splenic mononuclear cell mitotic responsiveness to ConA more than control-treated cells. Our results show that G-CSF accelerates T cell recovery through both thymic-dependent and thymic-independent pathways, which could be used to increase the rate of immune reconstitution after sublethal irradiation. PMID:23001765

  16. Soluble prokaryotic overexpression and purification of bioactive human granulocyte colony-stimulating factor by maltose binding protein and protein disulfide isomerase.

    PubMed

    Do, Bich Hang; Ryu, Han-Bong; Hoang, Phuong; Koo, Bon-Kyung; Choe, Han

    2014-01-01

    Human granulocyte colony-stimulating factor (hGCSF), a neutrophil-promoting cytokine, is an effective therapeutic agent for neutropenia patients who have undergone several cancer treatments. Efficient production of hGCSF using E. coli is challenging because the hormone tends to aggregate and forms inclusion bodies. This study examined the ability of seven different N-terminal fusion tags to increase expression of soluble hGCSF in E. coli. Four tag proteins, namely maltose-binding protein (MBP), N-utilization substance protein A, protein disulfide isomerase (PDI), and the b'a' domain of PDI (PDIb'a'), increased the solubility of hGCSF under normal conditions. Lowering the expression temperature from 30°C to 18°C also increased the solubility of thioredoxin-tagged and glutathione S-transferase-tagged hGCSF. By contrast, hexahistidine-tagged hGCSF was insoluble at both temperatures. Simple conventional chromatographic methods were used to purify hGCSF from the overexpressed PDIb'a'-hGCSF and MBP-hGCSF proteins. In total, 11.3 mg or 10.2 mg of pure hGCSF were obtained from 500 mL cultures of E. coli expressing PDIb'a'-hGCSF or MBP-hGCSF, respectively. SDS-PAGE analysis and silver staining confirmed high purity of the isolated hGCSF proteins, and the endotoxin levels were less than 0.05 EU/µg of protein. Subsequently, the bioactivity of the purified hGCSF proteins similar to that of the commercially available hGCSF was confirmed using the mouse M-NFS-60 myelogenous leukemia cell line. The EC50s of the cell proliferation dose-response curves for hGCSF proteins purified from MBP-hGCSF and PDIb'a'-hGCSF were 2.83±0.31 pM, and 3.38±0.41 pM, respectively. In summary, this study describes an efficient method for the soluble overexpression and purification of bioactive hGCSF in E. coli.

  17. The impact of donor characteristics on the immune cell composition of mixture allografts of granulocyte-colony-stimulating factor-mobilized marrow harvests and peripheral blood harvests.

    PubMed

    Wang, Yu-Tong; Zhao, Xiang-Yu; Zhao, Xiao-Su; Xu, Lan-Ping; Zhang, Xiao-Hui; Wang, Yu; Liu, Kai-Yan; Chang, Ying-Jun; Huang, Xiao-Jun

    2015-12-01

    The association of donor characteristics with immune cell composition in allografts remains poorly understood. In this retrospective study, the effects of donor characteristics on immune cell composition in allografts were investigated. The correlations of donor characteristics with the immune cell composition in mixture allografts of granulocyte-colony-stimulating factor-mobilized marrow harvests and peripheral blood harvests of 390 healthy donors (male, 240; female, 150; median age, 40 years old) were analyzed. The median doses of CD3+ T cells, CD4+ T cells, CD8+ T cells, CD3+CD4-CD8- T cells, and monocytes in mixture allografts were 160.57 × 10(6), 89.29 × 10(6), 56.16 × 10(6), 10.87 × 10(6), and 137.94 × 10(6)/kg, respectively. Multivariate analysis showed that younger donor age was associated with a higher dose of CD3+ T cells (p = 0.006), CD3+CD8+ T cells (p < 0.001), CD3+CD4-CD8- T cells (p = 0.004), and monocytes (p = 0.014), as well as a higher ratio of CD3+CD4-CD8- T cells/CD3+ T cells (p < 0.001) in the mixture allografts. A negative association of donor weight with CD3+ T cells (p < 0.001), CD4+ T cells (p = 0.002), CD8+ T cells (p < 0.001), and CD3+CD4-CD8- T cells (p = 0.044) was observed. The count of peripheral blood lymphocyte pre-peripheral blood apheresis was correlated with the yield of CD3+ T cells (p < 0.001) and CD4+ T cells (p = 0.001). The peripheral blood monocyte count before marrow harvest predicted the monocyte dose (p = 0.002). The results suggested that older and overweight donors should not be chosen. The monocyte and lymphocyte counts before harvest could predict the yield of immune cells in allografts. © 2015 AABB.

  18. Donor body mass index is an important factor that affects peripheral blood progenitor cell yield in healthy donors after mobilization with granulocyte-colony-stimulating factor.

    PubMed

    Chen, Jian; Burns, Kevin M; Babic, Aleksandar; Carrum, George; Kennedy, Martha; Segura, Francisco J; Garcia, Salvador; Potts, Sandra; Leveque, Christopher

    2014-01-01

    The use of hematopoietic progenitor cell (HPC) transplantation has rapidly expanded in recent years. Currently, several sources of HPCs are available for transplantation including peripheral blood HPCs (PBPCs), cord blood cells, and marrow cells. Of these, PBPC collection has become the major source of HPCs. An important variable in PBPC collection is the response to PBPC mobilization, which varies significantly and sometime causes mobilization failure. A retrospective study of 69 healthy donors who underwent PBPC donation by leukapheresis was performed. All of these donors received 10 μg/kg/day or more granulocyte-colony-stimulating factor (G-CSF) for 5 days before PBPC harvest. Donor factors were evaluated and correlated with mobilization responses, as indicated by the precollection CD34 count (pre-CD34). Donors with a pre-CD34 of more than 100 × 10(6) /L had higher body mass index (BMI) compared with donors whose pre-CD34 was 38 × 10(6) to 99 × 10(6) /L or less than 38 × 10(6) /L (32.0 ± 1.04 kg/m(2) vs. 28.7 ± 0.93 kg/m(2) vs. 25.9 ± 1.27 kg/m(2) , respectively; p < 0.05). In addition, donors with high BMIs had higher pre-CD34 on a per-kilogram-of-body-weight basis compared with donors with low BMIs. BMI is an important factor that affects donor's response to mobilization and consequently the HPC yield. This effect may be due to a relatively high dose of G-CSF administered to donors with higher BMI or due to the presence of unknown intrinsic factors affecting mobilization that correlate with the amount of adipose tissue in each donor. © 2013 American Association of Blood Banks.

  19. Transfusion-related acute lung injury (TRALI) induced by donor-derived anti-HLA antibodies in aplastic anemia: possible priming effect of granulocyte-colony stimulating factor (G-CSF) on the recipient neutrophils.

    PubMed

    Hishizawa, Masakatsu; Mitsuhashi, Ryuichi; Ohno, Tatsuharu

    2009-01-01

    Transfusion-related acute lung injury (TRALI) is currently the leading cause of transfusion-related death. A 67-year-old man with severe aplastic anemia developed TRALI, consisting of acute respiratory insufficiency with severe hypoxia and diffuse pulmonary infiltration 2 hours after the transfusion of platelet concentrates. Although he required intensive respiratory support, he promptly recovered within 4 days. The presence of anti-HLA antibody (anti-HLA B52) in the donated blood product was demonstrated, and a lymphocytotoxicity test disclosed antibody-mediated cytotoxicity against the patient's cells. Furthermore, administration of granulocyte-colony stimulating factor was suggested to predispose the patient to TRALI by priming the neutrophils.

  20. The pros and cons of split-dose granulocyte colony-stimulating factor alone rather than a single high dose for hematopoietic progenitor cell mobilization in small children (< 15 kg) with solid tumors.

    PubMed

    Merlin, Etienne; Piguet, Christophe; Auvrignon, Anne; Rubie, Hervé; Deméocq, François; Kanold, Justyna

    2006-07-01

    Hematopoietic progenitor cells were mobilized in 34 children with solid tumors weighing < or = 15 kg using granulocyte colony-stimulating factor alone at the doses of 10, 20 or 2 x 12 microg/kg/day. The mobilization with 2 x 12 microg/kg/day was more efficient than that with 10 mg/kg/day. Although the superiority of the split-dose compared to the single, high daily dose (20 microg/kg/day) was not statistically significant, our results suggest that the 2 x 12 microg/kg/day regimen is interesting.

  1. Synergy of interleukin 1 and granulocyte colony-stimulating factor: in vivo stimulation of stem-cell recovery and hematopoietic regeneration following 5-fluorouracil treatment of mice

    SciTech Connect

    Moore, M.A.S.; Warren, D.J.

    1987-10-01

    The human bladder carcinoma cell line 5637 produces hematopoietic growth factors (granulocyte and granulocyte/macrophage colony-stimulating factors (G-CSF and GM-CSF)) and hemopoietin 1, which synergizes with CSFs to stimulate colony formation by primitive hematopoietic stem cells in 5-fluorouracil-treated mouse bone marrow. Molecular and functional properties of hemopoietin 1 identified it as identical to interleukin 1..cap alpha.. (IL-1..cap alpha..). When bone marrow cells from 5-fluorouracil-treated mice were cultured in suspension for 7 days with recombinant human IL-1..cap alpha.. and/or G-CSF, it was found that the two factors synergized to enhance recovery of myelopoietic cells and colony-forming cells of both high and low proliferative potential. G-CSF alone did not sustain these populations, but the combination had greater-than-additive stimulating capacity. In vivo, 5-fluorouracil (150 mg/kg) produced profound myelosuppression and delayed neutrophil regeneration for up to 2 weeks in C3H/HeJ mice. Daily administration of recombinant human G-CSF or human IL-1..cap alpha.. accelerated recovery of stem cells, progenitor cells, and blood neutrophils by up to 4 days in 5-fluorouracil-treated C3H/HeJ and B6D2F/sub 1/ mice. The combination of IL-1..cap alpha.. and G-CSF acted synergistically, reducing neutropenia and accelerating recovery of normal neutrophil numbers by up to 7 days. These results indicate the possible therapeutic potential of combination therapy with IL-1 and hematopoietic growth factors such as G-CSF in the treatment of chemotherapy- or radiation-induced myelosuppression.

  2. Study of Cytokine Profile of Cultured "Early" and "Late" Endothelial Progenitor Cells in Peripheral Blood of Chronic Heart Failure Patients after Mobilization Course with Granulocyte Colony-Stimulating Factor.

    PubMed

    Bondarenko, N A; Poveshchenko, O V; Lykov, A P; Kim, I I; Surovtseva, M A; Poveshchenko, A F; Pokushalov, E A; Romanov, A B; Karas'kov, A M; Konenkov, V I

    2015-12-01

    The effect of cell culturing protocol with various adhesion proteins and different culture time on the profile of cytokine and growth factors produced by endothelial progenitor cells harvested after mobilization with granulocyte colony-stimulating factor was examined in patients with chronic heart failure. The endothelial progenitor cells cultured on fibronectin or gelatin produced a broad and overall similar spectrum of cytokines and growth factors, the levels of which depended on the culture time. On culture day 16, the cells grown on fibronectin diminished the production of cytokines and growth factors (IL-10, IL-18, IL-8, erythropoietin, and VEGF), while the cells grown on gelatin down-regulated the synthesis of TNF-α, IL-8, and erythropoietin, although they up-regulated the production of IL-10, IL-18, and VEGF.

  3. Tumor Progression of Skin Carcinoma Cells in Vivo Promoted by Clonal Selection, Mutagenesis, and Autocrine Growth Regulation by Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor

    PubMed Central

    Mueller, Margareta M.; Peter, Wolfgang; Mappes, Marion; Huelsen, Andrea; Steinbauer, Heinrich; Boukamp, Petra; Vaccariello, Michael; Garlick, Jonathan; Fusenig, Norbert E.

    2001-01-01

    Tumor microenvironment is crucial for cancer growth and progression as evidenced by reports on the significance of tumor angiogenesis and stromal cells. Using the HaCaT/HaCaT-ras human skin carcinogenesis model, we studied tumor progression from benign tumors to highly malignant squamous cell carcinomas. Progression of tumorigenic HaCaT-ras clones to more aggressive and eventually metastatic phenotypes was reproducibly achieved by their in vivo growth as subcutaneous tumors in nude mice. Their enhanced malignant phenotype was stably maintained in recultured tumor cells that represented, identified by chromosomal analysis, a distinct subpopulation of the parental line. Additional mutagenic effects were apparent in genetic alterations involving chromosomes 11 and 2, and in amplification and overexpression of the H-ras oncogene. Importantly, in vitro clonal selection of benign and malignant cell lines never resulted in late-stage malignant clones, indicating the importance of the in vivo environment in promoting an enhanced malignant phenotype. Independently of their H-ras status, all in vivo-progressed tumor cell lines (five of five) exhibited a constitutive and stable expression of the hematopoietic growth factors granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, which may function as autocrine/paracrine mediators of tumor progression in vivo. Thus, malignant progression favored by the in vivo microenvironment requires both clonal selection of subpopulations adapted to in vivo growth and mutational events leading to stable functional alterations. PMID:11583982

  4. Effect of low-dose cytarabine, homoharringtonine and granulocyte colony-stimulating factor priming regimen on patients with advanced myelodysplastic syndrome or acute myeloid leukemia transformed from myelodysplastic syndrome.

    PubMed

    Wu, Lingyun; Li, Xiao; Su, Jiying; Chang, Chunkang; He, Qi; Zhang, Xi; Xu, Li; Song, Luxi; Pu, Quan

    2009-09-01

    A total of 32 patients (25 with advanced MDS and 7 with t-AML) were enrolled in this study to evaluate the efficacy and toxicity of the low-dose cytarabine and homoharringtonine in combination with granulocyte colony-stimulating factor (G-CSF) (CHG protocol) in patients with advanced myelodysplastic syndromes (MDS) or MDS-transformed acute myeloid leukemia (t-AML). All the patients were administered the CHG regimen comprising low-dose cytarabine (25 mg/day, intravenous continuous infusion, days 1-14), homoharringtonine (1 mg/day, intravenous continuous infusion, days 1-14), and G-CSF (300 microg/day, subcutaneous injection, days 0-14, interrupted when the peripheral white blood cell count reached >20 x 10(9)/L). The overall response rate was 71.9% after the administration of one course of the CHG regimen. Of the 32 patients, 15 (46.9%) achieved complete remission (CR) and 8 (25%) achieved partial remission (PR). This regimen was followed by a post-remission therapy that included conventional chemotherapy, when CR was achieved. Of the patients with CR who just received post-remission regimens as homoharringtonine and cytarabine (HA) and daunorubicin and cytarabine (DA) 6 relapsed rapidly and just had a mean 6.1 months of CR. Otherwise, the other 8 out of 14 patients with CR alternatively received subsequent chemotherapy, which combined mitoxantrone, idarubicin, pirarubicin, or aclarubicin with cytarabine. The mean CR duration of the 8 patients had reached 10.6 months, and 5 of the 8 still kept a continuous CR. The median overall survival (OS) was 18.2 months. There were no statistically significant differences for CR, PR, and OS when the patients were grouped by age, blasts in bone marrow, and karyotypes, respectively. No treatment-related deaths were observed. Myelosuppression was mild to moderate, and no severe non-hematological toxicity was observed. Thus, a CHG priming regimen as an induction therapy was well tolerated and effective in patients with advanced MDS

  5. Granulocyte Colony Stimulating Factor and Physiotherapy after Stroke: Results of a Feasibility Randomised Controlled Trial: Stem Cell Trial of Recovery EnhanceMent after Stroke-3 (STEMS-3 ISRCTN16714730).

    PubMed

    Sprigg, Nikola; O'Connor, Rebecca; Woodhouse, Lisa; Krishnan, Kailash; England, Timothy J; Connell, Louise A; Walker, Marion F; Bath, Philip M

    2016-01-01

    Granulocyte-colony stimulating factor (G-CSF) mobilises endogenous haematopoietic stem cells and enhances recovery in experimental stroke. Recovery may also be dependent on an enriched environment and physical activity. G-CSF may have the potential to enhance recovery when used in combination with physiotherapy, in patients with disability late after stroke. A pilot 2 x 2 factorial randomised (1:1) placebo-controlled trial of G-CSF (double-blind), and/or a 6 week course of physiotherapy, in 60 participants with disability (mRS >1), at least 3 months after stroke. Primary outcome was feasibility, acceptability and tolerability. Secondary outcomes included death, dependency, motor function and quality of life measured 90 and 365 days after enrolment. Recruitment to the trial was feasible and acceptable; of 118 screened patients, 92 were eligible and 32 declined to participate. 60 patients were recruited between November 2011 and July 2013. All participants received some allocated treatment. Although 29 out of 30 participants received all 5 G-CSF/placebo injections, only 7 of 30 participants received all 18 therapy sessions. G-CSF was well tolerated but associated with a tendency to more adverse events than placebo (16 vs 10 patients, p = 0.12) and serious adverse events (SAE) (9 vs 3, p = 0.10). On average, patients received 14 (out of 18 planned) therapy sessions, interquartile range [12, 17]. Only a minority (23%) of participants completed all physiotherapy sessions, a large proportion of sessions (114 of 540, 21%) were cancelled due to patient (94, 17%) and therapist factors (20, 4%). No significant differences in functional outcomes were detected in either the G-CSF or physiotherapy group at day 90 or 365. Delivery of G-CSF is feasible in chronic stroke. However, the study failed to demonstrate feasibility for delivering additional physiotherapy sessions late after stroke therefore a definitive study using this trial design is not supported. Future work should

  6. Granulocyte Colony Stimulating Factor and Physiotherapy after Stroke: Results of a Feasibility Randomised Controlled Trial: Stem Cell Trial of Recovery EnhanceMent after Stroke-3 (STEMS-3 ISRCTN16714730)

    PubMed Central

    Sprigg, Nikola; O’Connor, Rebecca; Woodhouse, Lisa; Krishnan, Kailash; England, Timothy J.; Connell, Louise A.; Walker, Marion F.; Bath, Philip M.

    2016-01-01

    Background Granulocyte-colony stimulating factor (G-CSF) mobilises endogenous haematopoietic stem cells and enhances recovery in experimental stroke. Recovery may also be dependent on an enriched environment and physical activity. G-CSF may have the potential to enhance recovery when used in combination with physiotherapy, in patients with disability late after stroke. Methods A pilot 2 x 2 factorial randomised (1:1) placebo-controlled trial of G-CSF (double-blind), and/or a 6 week course of physiotherapy, in 60 participants with disability (mRS >1), at least 3 months after stroke. Primary outcome was feasibility, acceptability and tolerability. Secondary outcomes included death, dependency, motor function and quality of life measured 90 and 365 days after enrolment. Results Recruitment to the trial was feasible and acceptable; of 118 screened patients, 92 were eligible and 32 declined to participate. 60 patients were recruited between November 2011 and July 2013. All participants received some allocated treatment. Although 29 out of 30 participants received all 5 G-CSF/placebo injections, only 7 of 30 participants received all 18 therapy sessions. G-CSF was well tolerated but associated with a tendency to more adverse events than placebo (16 vs 10 patients, p = 0.12) and serious adverse events (SAE) (9 vs 3, p = 0.10). On average, patients received 14 (out of 18 planned) therapy sessions, interquartile range [12, 17]. Only a minority (23%) of participants completed all physiotherapy sessions, a large proportion of sessions (114 of 540, 21%) were cancelled due to patient (94, 17%) and therapist factors (20, 4%). No significant differences in functional outcomes were detected in either the G-CSF or physiotherapy group at day 90 or 365. Conclusions Delivery of G-CSF is feasible in chronic stroke. However, the study failed to demonstrate feasibility for delivering additional physiotherapy sessions late after stroke therefore a definitive study using this trial design

  7. Plasma granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor levels in critical illness including sepsis and septic shock: relation to disease severity, multiple organ dysfunction, and mortality.

    PubMed

    Presneill, J J; Waring, P M; Layton, J E; Maher, D W; Cebon, J; Harley, N S; Wilson, J W; Cade, J F

    2000-07-01

    To define the circulating levels of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) during critical illness and to determine their relationship to the severity of illness as measured by the Acute Physiology and Chronic Health Evaluation (APACHE) II score, the development of multiple organ dysfunction, or mortality. Prospective cohort study. University hospital intensive care unit. A total of 82 critically ill adult patients in four clinically defined groups, namely septic shock (n = 29), sepsis without shock (n = 17), shock without sepsis (n = 22), and nonseptic, nonshock controls (n = 14). None. During day 1 of septic shock, peak plasma levels of G-CSF, interleukin (IL)-6, and leukemia inhibitory factor (LIF), but not GM-CSF, were greater than in sepsis or shock alone (p < .001), and were correlated among themselves (rs = 0.44-0.77; p < .02) and with the APACHE II score (rs = 0.25-0.40; p = .03 to .18). G-CSF, IL-6, and UF, and sepsis, shock, septic shock, and APACHE II scores were strongly associated with organ dysfunction or 5-day mortality by univariate analysis. However, multiple logistic regression analysis showed that only septic shock remained significantly associated with organ dysfunction and only APACHE II scores and shock with 5-day mortality. Similarly, peak G-CSF, IL-6, and LIF were poorly predictive of 30-day mortality. Plasma levels of G-CSF, IL-6, and LIF are greatly elevated in critical illness, including septic shock, and are correlated with one another and with the severity of illness. However, they are not independently predictive of mortality, or the development of multiple organ dysfunction. GM-CSF was rarely elevated, suggesting different roles for G-CSF and GM-CSF in human septic shock.

  8. Progressive transfusion and growth factor independence with adjuvant sertraline in low risk myelodysplastic syndrome treated with an erythropoiesis stimulating agent and granulocyte-colony stimulating factor

    PubMed Central

    Nautiyal, Kirtan; Li, Rui; Yellapragada, Sarvari; Thiagarajan, Perumal; Mims, Martha; Rivero, Gustavo

    2014-01-01

    Refractoriness to growth factor therapy is commonly associated with inferior outcome in patients with low-risk myelodysplastic syndrome (LR-MDS) who require treatment for cytopenias. However, the mechanisms leading to refractoriness are unknown. Here we describe a clinically depressed 74-year-old male with refractory cytopenia with multilineage dysplasia (RCMD) and documented growth factor refractory anemia after erythropoeisis stimulating agent (ESA) therapy, who attained transfusion and growth factor independence after the addition of sertraline to his medication regimen. Our case demonstrates hematological improvement-erythroid (HI-E) in growth factor refractory, low risk MDS and highlights a potential mechanistic link between common inflammatory diseases and LR-MDS. PMID:25709889

  9. Early measurement of CD34+ cells in peripheral blood after cyclophosphamide and granulocyte colony-stimulating factor treatment predicts later CD34+ mobilisation failure and is a possible criterion for guiding “on demand” use of plerixafor

    PubMed Central

    Milone, Giuseppe; Tripepi, Giovanni; Martino, Massimo; Ancora, Flavia; Bartolozzi, Benedetta; Spadaro, Andrea; Nozzoli, Chiara; La Fauci, Alessia; Amico, Irene; Leotta, Salvatore; Poidomani, Massimo; Irrera, Giuseppe; Iacopino, Pasquale; Saccardi, Riccardo; Guidi, Stefano; Bosi, Alberto

    2013-01-01

    Background Early identification of predictive factors of failure to mobilise CD34+ cells could enable rational use of plerixafor during first mobilisation, avoiding the need for a second mobilisation course. However, “on demand” administration of plerixafor needs to be driven by established parameters to avoid inappropriate use. Materials and methods To address this issue, we studied the value of the peripheral blood CD34+ count, measured early (on days +10, +11, +12 and +13), in predicting the mobilisation outcome in the ensuing days. We retrospectively collected data from three Italian centres on 233 patients affected by multiple myeloma or lymphoma who underwent a first or second attempt at mobilisation with cyclophosphamide 4 g/m2 and granulocyte colony-stimulating factor. To assess the diagnostic value of peripheral blood white blood cell and CD34+ cell counts with respect to “mobilisation failure”, we considered failed mobilisation as “disease” and the CD34+ cell count in peripheral blood, on a specific day, as a “diagnostic test”. For various thresholds, we measured sensitivity, false positive rate, specificity and positive predictive value (PPV) as well as the area under the receiver-operating characteristic curves (AUC). Results A CD34+ cell count <10×106/L on day 13 had high sensitivity (1.00) and high specificity (1.00) for predicting subsequent mobilisation failure, with an AUC of 1.0. However, good prediction was also obtained using a lower threshold (CD34+ cell count: <6×106/L) at an earlier time (day 12). The PPV of the day 13 threshold was 1.00 while that of the day 12 one was 0.87. Discussion We propose that patients with <6×106/L CD34+ cells in peripheral blood on day 12 and <10×106/L on day 13 following mobilisation with cyclophosphamide 4 g/m2 and granulocyte colony-stimulating factor are candidates for “on demand” use of plerixafor, making the administration of this expensive agent more efficient and avoiding its

  10. Nerve growth factor and brain-derived neurotrophic factor but not granulocyte colony-stimulating factor, nimodipine and dizocilpine, require ATP for neuroprotective activity after oxygen-glucose deprivation of primary neurons.

    PubMed

    Ferenz, Katja B; Gast, Ronald E; Rose, Karsten; Finger, Indra E; Hasche, Anja; Krieglstein, Josef

    2012-04-11

    In previous work, we have demonstrated by radiolabeling, mass spectrometry and site-directed mutagenesis that nerve growth factor (NGF) as well as brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 2 (FGF2) are capable of ATP-binding and that this binding appears to be essential for their neuroprotective activity. In this study, we attempted to shed some light on the question whether ATP is a general prerequisite for neuroprotection. Therefore, we used the non-ATP-binding granulocyte colony-stimulating factor (GCSF), the calcium antagonist nimodipine and the NMDA antagonist dizocilpine to find out whether they need ATP for neuroprotection comparable to NGF and BDNF. However, ATP was not necessary for the neuroprotective effects of GCSF, nimodipine and dizocilpine on primary cultures of rat cortical neurons damaged by oxygen-glucose deprivation whereas neuroprotection was demonstrable for NGF and BDNF only when ATP was present in the culture medium at a concentration higher than ca. 0.4nmol/l. In circular dichroism studies ATP caused changes of the secondary structure of NGF but not of GCSF. Taken together, we suggest that ATP is not a general prerequisite for neuroprotectivity but some growth factors like NGF and BDNF can stimulate their receptors only if they have bound ATP.

  11. Impaired bone metabolism in glycogen storage disease type 1 is associated with poor metabolic control in type 1a and with granulocyte colony-stimulating factor therapy in type 1b.

    PubMed

    Melis, D; Pivonello, R; Cozzolino, M; Della Casa, R; Balivo, F; Del Puente, A; Dionisi-Vici, C; Cotugno, G; Zuppaldi, C; Rigoldi, M; Parini, R; Colao, A; Andria, G; Parenti, G

    2014-01-01

    Glycogen storage disease type 1 (GSD1) is a rare and genetically heterogeneous metabolic defect of gluconeogenesis due to mutations of either the G6PC gene (GSD1a) or the SLC37A4 gene (GSD1b). Osteopenia is a known complication of GSD1. The aim of this study was to investigate the effects of poor metabolic control and/or use of GSD1-specific treatments on bone mineral density (BMD) and metabolism in GSD1 patients. In a multicenter, cross-sectional case-control study, we studied 38 GSD1 (29 GSD1a and 9 GSD1b) patients. Clinical, biochemical and instrumental parameters indicative of bone metabolism were analyzed; BMD was evaluated by dual-emission X-ray absorptiometry and quantitative ultrasound. Both GSD1a and GSD1b patients showed reduced BMD compared with age-matched controls. In GSD1a patients, these abnormalities correlated with compliance to diet and biochemical indicators of metabolic control. In GSD1b patients, BMD correlated with the age at first administration and the duration of granulocyte colony-stimulating factor (G-CSF) therapy. Our data indicate that good metabolic control and compliance with diet are highly recommended to improve bone metabolism in GSD1a patients. GSD1b patients on G-CSF treatment should be carefully monitored for the risk of osteopenia/osteoporosis.

  12. Randomized study of granulocyte colony stimulating factor for childhood B-cell non-Hodgkin lymphoma: a report from the Japanese pediatric leukemia/lymphoma study group B-NHL03 study.

    PubMed

    Tsurusawa, Masahito; Watanabe, Tomoyuki; Gosho, Masahiko; Mori, Tetsuya; Mitsui, Tetsuo; Sunami, Shosuke; Kobayashi, Ryoji; Fukano, Reiji; Tanaka, Fumiko; Fujita, Naoto; Inada, Hiroko; Sekimizu, Masahiro; Koh, Katsuyoshi; Kosaka, Yoshiyuki; Komada, Yoshihiro; Saito, Akiko M; Nakazawa, Atsuko; Horibe, Keizo

    2016-07-01

    The objective of this study was to assess the impact of the primary prophylaxis of granulocyte colony-stimulating factor (G-CSF) in the management of childhood B-cell non-Hodgkin lymphoma (B-NHL). Patients with advanced-stage mature B-NHL were randomized to receive prophylactic G-CSF (G-CSF+) or not receive G-CSF (G-CSF-) based on protocols of the B-NHL03 study. The G-CSF group received 5 μg/kg/d Lenograstim from day 2 after each course of six chemotherapy courses. Fifty-eight patients were assessable, 29 G-CSF + and 29 G-CSF-. G-CSF + patients showed a positive impact on the meantime to neutrophil recovery and hospital stay. On the other hand, they had no impact in the incidences of febrile neutropenia, serious infections, stomatitis and total cost. Our study showed that administration of prophylactic G-CSF through all six chemotherapy courses for childhood B-NHL showed no clinical and economic benefits for the management of childhood B-NHL treatment.

  13. Succinate ester derivative of δ-tocopherol enhances the protective effects against 60Co γ-ray-induced hematopoietic injury through granulocyte colony-stimulating factor induction in mice

    PubMed Central

    Li, Zhong-Tang; Wang, Li-Mei; Yi, Li-Rong; Jia, Chao; Bai, Fan; Peng, Ren-Jun; Yu, Zu-Yin; Xiong, Guo-Lin; Xing, Shuang; Shan, Ya-Jun; Yang, Ri-Fang; Dong, Jun-Xing; Cong, Yu-Wen

    2017-01-01

    α-tocopherol succinate (α-TOS), γ-tocotrienol (GT3) and δ-tocotrienol (DT3) have drawn large attention due to their efficacy as radioprotective agents. α-TOS has been shown to act superior to α-tocopherol (α-TOH) in mice by reducing lethality following total body irradiation (TBI). Because α-TOS has been shown to act superior to α-tocopherol (α-TOH) in mice by reducing lethality following total body irradiation (TBI), we hypothesized succinate may be contribute to the radioprotection of α-TOS. To study the contributions of succinate and to identify stronger radioprotective agents, we synthesized α-, γ- and δ-TOS. Then, we evaluated their radioprotective effects and researched further mechanism of δ-TOS on hematological recovery post-irradiation. Our results demonstrated that the chemical group of succinate enhanced the effects of α-, γ- and δ-TOS upon radioprotection and granulocyte colony-stimulating factor (G-CSF) induction, and found δ-TOS a higher radioprotective efficacy at a lower dosage. We further found that treatment with δ-TOS ameliorated radiation-induced pancytopenia, augmenting cellular recovery in bone marrow and the colony forming ability of bone marrow cells in sublethal irradiated mice, thus promoting hematopoietic stem and progenitor cell recovery following irradiation exposure. δ-TOS appears to be an attractive radiation countermeasure without known toxicity, but further exploratory efficacy studies are still required. PMID:28145432

  14. Granulocyte colony-stimulating factor-producing undifferentiated carcinoma of the colon mimicking a pulmonary giant cell carcinoma: a case showing overexpression of CD44 along with highly proliferating nestin-positive tumor vessels.

    PubMed

    Tajima, Shogo; Waki, Michihiko; Tsuchiya, Tomonori; Hoshi, Shoji

    2014-01-01

    Granulocyte colony-stimulating factor (G-CSF)-producing tumors are known for their aggressive behavior. Only four cases of G-CSF-producing colorectal carcinoma have been previously reported. Herein, we present a case of an undifferentiated carcinoma of the descending colon showing G-CSF production and giant cell carcinoma morphology in a 93-year-old woman. A tumor with a diameter of 80 mm was identified in the descending colon via computed tomography. Descending colectomy was performed involving the abdominal wall where tumor invasion was observed. The white blood cell count, which was elevated before resection, decreased to normal levels after intervention. However, local recurrence at the resected site was detected 39 days after surgery. Upon recurrence, increased white blood cell counts and serum G-CSF were seen. The patient died because of respiratory failure 98 days after colectomy. By using immunohistochemistry, G-CSF expression was detected in tumor cells in the resected specimen, along with overexpression of CD44 and highly proliferating nestin-positive tumor vessels. The poor clinical outcome of this patient is consistent with previous reports that the expression of these three molecules predict poor prognosis. While G-CSF can be a therapeutic target considering its auto/paracrine function to induce tumor growth via the G-CSF receptor, CD44 and nestin may also be possible candidate therapeutic targets. Further studies are required to assess the efficacy of treatments targeting these three molecules.

  15. A low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor priming regimen versus a daunorubicin plus cytarabine regimen as induction therapy for older patients with acute myeloid leukemia: A propensity score analysis.

    PubMed

    Minakata, Daisuke; Fujiwara, Shin-ichiro; Ito, Shoko; Mashima, Kiyomi; Umino, Kento; Nakano, Hirofumi; Kawasaki, Yasufumi; Sugimoto, Miyuki; Yamasaki, Ryoko; Yamamoto, Chihiro; Ashizawa, Masahiro; Hatano, Kaoru; Okazuka, Kiyoshi; Sato, Kazuya; Oh, Iekuni; Ohmine, Ken; Suzuki, Takahiro; Muroi, Kazuo; Kanda, Yoshinobu

    2016-03-01

    This retrospective analysis compared the efficacy of intensive induction therapy consisting of daunorubicin and cytarabine (DNR-AraC) to that of less-intensive therapy including low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor priming (CAG). Patients aged 60 years or older who were newly diagnosed as acute myeloid leukemia (AML) were analyzed. Sixty-four and 48 patients were treated with DNR-AraC and CAG, respectively. The complete remission rates, 3-year overall survival and event-free survival in the DNR-AraC group were significantly superior to those in the CAG group (65.6% vs. 29.2%, p<0.001, 38.4% vs. 12.3%, p=0.0033, and 20.3% vs. 7.8%, p=0.0030, respectively), although these differences were not statistically significant in multivariate analyses. Next, we calculated a propensity score for selecting the CAG regimen from six factors. The DNR-AraC regimen was associated with better survival than the CAG regimen in a low propensity score group, but there was no difference in survival between regimens in a high propensity score group. Intensive therapy should be performed for patients with sufficient general and comorbid conditions, but less-intensive therapy may be sufficient for patients with higher age, myelodysplasia-related changes, and lower white blood cell counts, which were relevant factors in the propensity score calculation.

  16. Fluorescence in situ hybridization (FISH) study of response to granulocyte colony stimulating factor (G-CSF) in myelodysplasia associated with monosomy 7: Evidence for differentiation of the dysplastic clone

    SciTech Connect

    Cicilline, M.; Mark, H.F.L.; Rintels, P.

    1994-09-01

    Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic differentiation which may respond to the administration of cytokines with increases in the number of circulating mature neutrophils. We used fluorescence in situ hybridization (FISH) to investigate a young patient with myelodyplasia associated with monosomy 7 to determine whether mature appearing polymorphonuclear cells present in response to treatment with granulocyte colony stimulating factor (G-CSF) were progeny of the dysplastic clone or represented stimulation of residual normal hematopoiesis. The patient is a 26 year old male with a long history of a complex stem cell disorder dating to age 5. A chromosome fragility test was negative. In October 1993 treatment was begun with G-CSF when the absolute neutrophil count (ANC) fell to 300/mm{sup 3} despite GM-CSF therapy. Cytogenetic study of bone marrow just prior to starting G-CSF revealed monosomy 7 in all metaphases. A study in July, 1992 was normal. On his most recent marrow examination (1/94), blasts had numerous dysplastic forms. FISH was performed on buffy coat smears of patient and control specimens using a biotin labelled alpha satellite probe to chromosome 7. At the time of study, the peripheral blood count was 12,500 mm{sup 3}, with 56% neutrophils, 6% bands and no circulating blasts. Cells were scored as either polymorphonuclear or mononuclear cells. In a healthy control, 22 of 190 scored as either polymorphonuclear cells (12%) contained one chromosome 7 signal, versus 193 of 200 (96.5%) in the patient. For mononuclear cells, the control demonstrated 23 of 137 nuclei (17%) with one signal, versus 300 of 511 nuclei (59%) in the patient. We conclude that G-CSF induced differentiation in the dysplastic clone in this case and did not stimulate normal hermatopoiesis.

  17. Reduction of Inappropriate Prophylactic Pegylated Granulocyte Colony-Stimulating Factor Use for Patients With Non-Small-Cell Lung Cancer Who Receive Chemotherapy: An ASCO Quality Training Program Project of the Cleveland Clinic Taussig Cancer Institute.

    PubMed

    Goodman, Lindsey Martin; Moeller, Machelle B; Azzouqa, Abdel-Ghani; Guthrie, Amy E; Dalby, Carole K; Earl, Marc A; Cheng, Connie; Pennell, Nathan A; Shapiro, Marc; Velcheti, Vamsidhar; Stevenson, James P

    2016-01-01

    Routine prophylactic pegylated granulocyte colony-stimulating factor (pGCSF) administration for patients receiving chemotherapy regimens associated with low risk (< 10%) for neutropenic fever (LRNF) is not recommended. Inappropriate use of pGCSF increases patient morbidity and health care costs. A multidisciplinary team reviewed the charts of patients with non-small-cell lung cancer (NSCLC) at the Taussig Cancer Institute in whom a new chemotherapy regimen was initiated from April through November 2013. pGCSF use was identified and deemed appropriate if prescribed for chemotherapy associated with high risk of neutropenic fever (> 20%) or intermediate risk (10% to 20%) if other risk factors for neutropenic fever were present. Use with LRNF chemotherapy was recorded as inappropriate. One hundred eighty patients with NSCLC received a new chemotherapy regimen during the specified time period. Thirty-four of 119 patients (28%) treated with LRNF chemotherapy received pGCSF. Each patient received an average of 2.6 doses of pGCSF (total, 89 doses). We implemented three plan-do-study-act cycles: education of providers, development of Taussig Cancer Institute consensus guidelines for pGCSF in NSCLC, and removal of standing pGCSF orders from LRNF chemotherapy in the electronic medical record. Analysis during the change period revealed 4% of patients with NSCLC treated with LRNF chemotherapy received pGCSF. Cost analysis showed an 84% decrease in billed charges per month. No increase in neutropenic fever admissions was found. pGCSF was excessively prescribed for patients with NSCLC. Factors contributing to inappropriate use included provider lack of familiarity with guidelines and knowledge with regard to the risk of neutropenic fever for individual chemotherapy regimens, and electronic medical record chemotherapy templates that contain standing GCSF orders. Interventions to address these gaps quickly produced improved compliance with guidelines and led to significant cost

  18. Proteolytic enzyme levels are increased during granulocyte colony-stimulating factor-induced hematopoietic stem cell mobilization in human donors but do not predict the number of mobilized stem cells.

    PubMed

    van Os, R; van Schie, M L J; Willemze, R; Fibbe, W E

    2002-06-01

    Previous studies from our laboratory indicate that functional, mature neutrophils are essential for interleukin-8 (IL-8)-induced stem cell mobilization. To study a possible role of neutrophils in granulocyte colony-stimulating factor (G-CSF) induced hematopoietic mobilization, we assessed the number of circulating CD34+ cells in healthy allogeneic stem cell donors on days 3, 4, and 5 of mobilization for comparison with the number of peripheral blood neutrophils and the plasma levels of IL-8, Flt3 ligand (FL), matrix metalloproteinase-9 (MMP-9), and human neutrophil elastase (HNE). Thirty-seven of 45 donors required 1 day of apheresis to obtain 5 x 10(6) CD34+/kg recipient body weight (high responders), the remaining 8 donors required 1 extra day of apheresis on day 6 (low responders). On day 5, CD34+ numbers in the blood were significantly highe in high responders (116 x 10(3) +/- 10.4/ml) than in low responders (54.1 x 10(3) +/- 10.3, p < 0.001). In all donors, MMP-9 and HNE levels were increased compared to nonmobilized individuals, but in high responders, plasma MMP-9 levels on days 3-5 of mobilization were substantially higher than in low responders (p < or = 0.02 for MMP-9 and p = 0.89, p = 0.05 and p = 0.52 for HNE on days 3, 4, and 5, respectively). These results are in accordance with the hypothesis that neutrophils play a role in G-CSF-induced mobilization through the release of proteases such as MMP-9 and elastase. No change in plasma levels of IL-8 or Flt3 ligand was observed, suggesting that these cytokines do not play a role in stem cell mobilization. However, because stem cell numbers could not be predicted by proteolytic enzyme levels and/or neutrophil numbers, other undefined factors may be more important.

  19. Routine Primary Prophylaxis for Febrile Neutropenia with Biosimilar Granulocyte Colony-Stimulating Factor (Nivestim) or Pegfilgrastim Is Cost Effective in Non-Hodgkin Lymphoma Patients undergoing Curative-Intent R-CHOP Chemotherapy.

    PubMed

    Wang, Xiao Jun; Tang, Tiffany; Farid, Mohamad; Quek, Richard; Tao, Miriam; Lim, Soon Thye; Wee, Hwee Lin; Chan, Alexandre

    2016-01-01

    This study aims to compare the cost-effectiveness of various strategies of myeloid growth factor prophylaxis for reducing the risk of febrile neutropenia (FN) in patients with non-Hodgkin lymphoma in Singapore who are undergoing R-CHOP chemotherapy with curative intent. A Markov model was created to compare seven prophylaxis strategies: 1) primary prophylaxis (PP) with nivestim (biosimilar filgrastim) throughout all cycles of chemotherapy; 2) PP with nivestim during the first two cycles of chemotherapy; 3) secondary prophylaxis (SP) with nivestim; 4) PP with pegfilgrastim throughout all cycles of chemotherapy; 5) PP with pegfilgrastim during the first two cycles of chemotherapy; 6) SP with pegfilgrastim; and 7) no prophylaxis (NP). The perspective of a hospital was taken and cost-effectiveness was expressed as the cost per episode of FN avoided over six cycles of chemotherapy. A probabilistic sensitivity analysis was conducted. Strategies 3, 6, and 7 were dominated in the base case analysis by strategy 5. The costs associated with strategies 2, 5, 1, and 4 were US$3,813, US$4,056, US$4,545, and US$5,331, respectively. The incremental cost-effectiveness ratios for strategy 5 vs. strategy 2, strategy 1 vs. strategy 5, and strategy 4 vs. strategy 1 were US$13,532, US$22,565, and US$30,452, respectively, per episode of FN avoided. Strategy 2 has the highest probability to be cost-effective (ranged from 48% to 60%) when the willingness to pay (WTP) threshold is lower than US$10,000 per FN episode prevented. In Singapore, routine PP with granulocyte colony-stimulating factor (nivestim or pegfilgrastim) is cost-effective for reducing the risk of FN in patients receiving R-CHOP.

  20. Routine Primary Prophylaxis for Febrile Neutropenia with Biosimilar Granulocyte Colony-Stimulating Factor (Nivestim) or Pegfilgrastim Is Cost Effective in Non-Hodgkin Lymphoma Patients undergoing Curative-Intent R-CHOP Chemotherapy

    PubMed Central

    Wang, Xiao Jun; Tang, Tiffany; Farid, Mohamad; Quek, Richard; Tao, Miriam; Lim, Soon Thye; Wee, Hwee Lin; Chan, Alexandre

    2016-01-01

    Objective This study aims to compare the cost-effectiveness of various strategies of myeloid growth factor prophylaxis for reducing the risk of febrile neutropenia (FN) in patients with non-Hodgkin lymphoma in Singapore who are undergoing R-CHOP chemotherapy with curative intent. Methods A Markov model was created to compare seven prophylaxis strategies: 1) primary prophylaxis (PP) with nivestim (biosimilar filgrastim) throughout all cycles of chemotherapy; 2) PP with nivestim during the first two cycles of chemotherapy; 3) secondary prophylaxis (SP) with nivestim; 4) PP with pegfilgrastim throughout all cycles of chemotherapy; 5) PP with pegfilgrastim during the first two cycles of chemotherapy; 6) SP with pegfilgrastim; and 7) no prophylaxis (NP). The perspective of a hospital was taken and cost-effectiveness was expressed as the cost per episode of FN avoided over six cycles of chemotherapy. A probabilistic sensitivity analysis was conducted. Results Strategies 3, 6, and 7 were dominated in the base case analysis by strategy 5. The costs associated with strategies 2, 5, 1, and 4 were US$3,813, US$4,056, US$4,545, and US$5,331, respectively. The incremental cost-effectiveness ratios for strategy 5 vs. strategy 2, strategy 1 vs. strategy 5, and strategy 4 vs. strategy 1 were US$13,532, US$22,565, and US$30,452, respectively, per episode of FN avoided. Strategy 2 has the highest probability to be cost-effective (ranged from 48% to 60%) when the willingness to pay (WTP) threshold is lower than US$10,000 per FN episode prevented. Conclusion In Singapore, routine PP with granulocyte colony-stimulating factor (nivestim or pegfilgrastim) is cost-effective for reducing the risk of FN in patients receiving R-CHOP. PMID:26871584

  1. A glycosylated recombinant human granulocyte colony stimulating factor produced in a novel protein production system (AVI-014) in healthy subjects: a first-in human, single dose, controlled study.

    PubMed

    Varki, Roslyn; Pequignot, Ed; Leavitt, Mark C; Ferber, Andres; Kraft, Walter K

    2009-01-28

    AVI-014 is an egg white-derived, recombinant, human granulocyte colony-stimulating factor (G-CSF). This healthy volunteer study is the first human investigation of AVI-014. 24 male and female subjects received a single subcutaneous injection of AVI-014 at 4 or 8 mcg/kg. 16 control subjects received 4 or 8 mcg/kg of filgrastim (Neupogen, Amgen) in a partially blinded, parallel fashion. The Geometric Mean Ratio (GMR) (90% CI) of 4 mcg/kg AVI-014/filgrastim AUC(0-72 hr) was 1.00 (0.76, 1.31) and Cmax was 0.86 (0.66, 1.13). At the 8 mcg/kg dose, the AUC(0-72) GMR was 0.89 (0.69, 1.14) and Cmax was 0.76 (0.58, 0.98). A priori pharmacokinetic bioequivalence was defined as the 90% CI of the GMR bounded by 0.8-1.25. Both the white blood cell and absolute neutrophil count area under the % increase curve AUC(0-9 days) and Cmax (maximal % increase from baseline)GMR at 4 and 8 mcg/kg fell within the 0.5-2.0 a priori bound set for pharmacodynamic bioequivalence. The CD 34+ % increase curve AUC(0-9 days) and Cmax GMR for both doses was approximately 1, but 90% confidence intervals were large due to inherent variance, and this measure did not meet pharmacodynamic bioequivalence. AVI-014 demonstrated a side effect profile similar to that of filgrastim. AVI-014 has safety, pharmacokinetic, and pharmacodynamic properties comparable to filgrastim at an equal dose in healthy volunteers. These findings support further investigation in AVI-014.

  2. A glycosylated recombinant human granulocyte colony stimulating factor produced in a novel protein production system (AVI-014) in healthy subjects: a first-in human, single dose, controlled study

    PubMed Central

    Varki, Roslyn; Pequignot, Ed; Leavitt, Mark C; Ferber, Andres; Kraft, Walter K

    2009-01-01

    Background AVI-014 is an egg white-derived, recombinant, human granulocyte colony-stimulating factor (G-CSF). This healthy volunteer study is the first human investigation of AVI-014. Methods 24 male and female subjects received a single subcutaneous injection of AVI-014 at 4 or 8 mcg/kg. 16 control subjects received 4 or 8 mcg/kg of filgrastim (Neupogen, Amgen) in a partially blinded, parallel fashion. Results The Geometric Mean Ratio (GMR) (90% CI) of 4 mcg/kg AVI-014/filgrastim AUC(0–72 hr) was 1.00 (0.76, 1.31) and Cmax was 0.86 (0.66, 1.13). At the 8 mcg/kg dose, the AUC(0–72) GMR was 0.89 (0.69, 1.14) and Cmax was 0.76 (0.58, 0.98). A priori pharmacokinetic bioequivalence was defined as the 90% CI of the GMR bounded by 0.8–1.25. Both the white blood cell and absolute neutrophil count area under the % increase curve AUC(0–9 days) and Cmax (maximal % increase from baseline)GMR at 4 and 8 mcg/kg fell within the 0.5–2.0 a priori bound set for pharmacodynamic bioequivalence. The CD 34+ % increase curve AUC(0–9 days) and Cmax GMR for both doses was ~1, but 90% confidence intervals were large due to inherent variance, and this measure did not meet pharmacodynamic bioequivalence. AVI-014 demonstrated a side effect profile similar to that of filgrastim. Conclusion AVI-014 has safety, pharmacokinetic, and pharmacodynamic properties comparable to filgrastim at an equal dose in healthy volunteers. These findings support further investigation in AVI-014. PMID:19175929

  3. Efficacy of a new formulation of lenograstim (recombinant glycosylated human granulocyte colony-stimulating factor) containing gelatin for the treatment of neutropenia after consolidation chemotherapy in patients with acute myeloid leukemia.

    PubMed

    Takeshita, A; Saito, H; Toyama, K; Horiuchi, A; Kuriya, S; Furusawa, S; Tsuruoka, N; Takiguchi, T; Matsuda, T; Utsumi, M; Shiku, H; Matsui, T; Egami, K; Tamura, K; Ohno, R

    2000-02-01

    The efficacy and safety of a new formulation of lenograstim (recombinant glycosylated granulocyte colony-stimulating factor) prepared by switching the stabilizer from human serum albumin (HSA) to gelatin was investigated for the treatment of neutropenia after consolidation chemotherapy in patients with acute myeloid leukemia (AML). The results obtained in the study using the gelatin-containing formulation (gelatin-lenograstim) were retrospectively compared to those obtained from a placebo-controlled double-blind randomized study (AML-DBT) using the HSA-containing formulation (HSA-lenograstim). The median time of neutrophil recovery to > or = 1000/mm3 was significantly shorter in the gelatin-lenograstim group (14 days) than in the placebo group (21 days, P = .0001), and there was no significant difference between the gelatin-lenograstim group and the HSA-lenograstim group (14.5 days of AML-DBT, P = .5462). The incidences of febrile neutropenia were significantly reduced in the gelatin-lenograstim group (24/43, 55.8%) compared to the placebo group (58/64, 90.6%, P < .0001). The incidence of fever and antibiotic use was also significantly lower in the gelatin-lenograstim group (69.8% and 83.7%, respectively) than in the placebo group (92.2%, P = .0034, and 96.9%, P = .0285, respectively). However, between the 2 groups there were no differences in the number of patients who had infectious episodes. No serious adverse drug reactions ascribed to gelatin-lenograstim were encountered. These results demonstrate that gelatin-lenograstim exerted beneficial effects in the acceleration of neutrophil recovery and in the reduction of fever, febrile neutropenia, and antibiotic use, and its efficacy was equivalent to HSA-lenograstim. Therefore, we concluded that the gelatin-lenograstim formulation, which offers no risk of virus contamination and can be stored at room temperature, is more beneficial than the HSA-lenograstim formulation.

  4. G-CSF use in patients receiving first-line chemotherapy for non-Hodgkin's lymphoma (NHL) and granulocyte-colony stimulating factors (G-CSF) as observed in clinical practice in Italy.

    PubMed

    Vitolo, Umberto; Angrili, Francesco; DeCosta, Lucy; Wetten, Sally; Federico, Massimo

    2016-12-01

    Treatment of non-Hodgkin lymphoma (NHL) requires chemotherapy regimens with significant risk of febrile neutropenia (FN). For patients at ≥20% FN risk, guidelines recommend primary prophylaxis (PP) with granulocyte-colony stimulating factor (G-CSF). This study assessed whether G-CSF use in NHL was in line with recommendations in routine practice. This was a retrospective, observational study of adult NHL patients receiving first-line (R)CHOP-like chemotherapy and G-CSF support between June 2010 and 2012, in Italy. The primary outcome was whether G-CSF was provided as PP, which was defined as G-CSF initiation on days 1-3 after chemotherapy, ≥3 days' use for daily G-CSFs and continued prophylaxis from cycle 1 across all cycles. Secondary prophylaxis was defined as continued prophylaxis from cycle 2 or later, and all other use was defined as Suboptimal. The analysis included 199 patients, 61% of whom had diffuse large B cell lymphoma and 21% follicular lymphoma. (R)CHOP-21 was given to 52% of patients and (R)CHOP-14 to 32%. Overall, 29% of patients received PP, while two-thirds received Suboptimal G-CSF. Of patients receiving daily G-CSF, 3% received PP and 94% received Suboptimal use; with pegfilgrastim, 65% received PP and 26% Suboptimal use. FN occurred in 13 patients (7%) and grade 3/4 neutropenia in 43%. Chemotherapy dose delays occurred in 22% and dose reductions in 18% of patients. Delivery of G-CSF, particularly daily G-CSFs, was not in accordance with guideline or product label recommendations in a large proportion of NHL patients receiving chemotherapy in Italy.

  5. The effectiveness and safety of same-day versus next-day administration of long-acting granulocyte colony-stimulating factors for the prophylaxis of chemotherapy-induced neutropenia: a systematic review.

    PubMed

    Lyman, Gary H; Allcott, Kim; Garcia, Jacob; Stryker, Scott; Li, Yanli; Reiner, Maureen T; Weycker, Derek

    2017-08-01

    Granulocyte colony-stimulating factors (G-CSF) are commonly used in clinical practice to prevent febrile neutropenia (FN). US and EU prescribing information and treatment guidelines from the NCCN, ASCO, and EORTC specify that pegfilgrastim, a long-acting (LA) G-CSF, should be administered at least 24 h after myelosuppressive chemotherapy. Nevertheless, many patients receive LA G-CSFs on the same day as chemotherapy. This systematic literature review evaluated the relative merits of same-day versus next-day dosing of LA G-CSFs. A broad Ovid MEDLINE® and Embase® literature search was conducted that examined all publications indexed before May 9, 2016 that compared same-day versus next-day LA G-CSF administration. A congress abstract literature search included congresses from January 1, 2011 to April 6, 2016. The parameters for this review were prospectively delineated in a research protocol and adhered to the PRISMA Guidelines. The first part of the systematic literature search identified 1736 publications. After elimination of duplicates, title/abstract screening was conducted on 1440 records, and full text review was conducted on 449 publications. Eleven publications met all criteria and are included in this systematic review; of these, four included data from randomized or single arm prospective studies, and seven were retrospective studies. In most studies included in this review and across a variety of tumor types, administration of pegfilgrastim at least 24 h after myelosuppressive chemotherapy resulted in improved patient outcomes. Data from multiple publications support administration of pegfilgrastim at least 1 day after chemotherapy.

  6. Late reperfusion of a totally occluded infarct-related artery increases granulocyte-colony stimulation factor and reduces stroma-derived factor-1alpha blood levels in patients with ongoing ischemia after acute myocardial infarction.

    PubMed

    Kuo, Li-Tang; Chen, Shih-Jen; Cherng, Wen-Jin; Yang, Ning-I; Lee, Chen-Chin; Cheng, Chi-Wen; Verma, Subodh; Wang, Chao-Hung

    2009-07-01

    After acute myocardial infarction (AMI), reopening of a totally occluded infarct-related artery (IRA) at a subacute stage is still controversial in symptom-free patients. However, in patients with persistent ischemic symptoms and inadequate collaterals to the infarct area, recanalization is thought to provide beneficial effects. In addition to augmenting myocardial perfusion, we hypothesized that the benefit of recanalization involves the manipulation of circulating stem cell-mobilizing cytokines. This study included 30 patients with a totally occluded IRA and ongoing ischemic symptoms (the study group) and 30 patients with a partially occluded IRA (the control group). All patients underwent successful angioplasty and/or stenting. Before and immediately after the coronary intervention, blood granulocyte-colony-stimulating factor (G-CSF), stem-cell factor (SCF), vascular endothelial growth factor (VEGF), and stroma-derived factor-1 (SDF-1alpha) were measured. After recanalization, G-CSF levels significantly increased in the study group compared to the control group (P=0.03). SDF-1alpha levels in the study group decreased relative to the controls (P=0.02). However, no significant changes in VEGF or SCF levels between the two groups were found. In the multivariate analysis, reopening of a totally occluded IRA was independently and significantly associated with changes in G-CSF and SDF-1alpha levels after recanalization. In conclusion, our data suggest that the benefits of late reperfusion of a totally occluded IRA in patients with ongoing myocardial ischemia may involve mechanisms associated with stem cell-mobilizing and plaque-stabilizing cytokines. This study provides the rationale to investigate serial changes in cytokines and the numbers of circulating progenitors after reperfusion in the future.

  7. Mobilization with granulocyte colony-stimulating factor blocks medullar erythropoiesis by depleting F4/80(+)VCAM1(+)CD169(+)ER-HR3(+)Ly6G(+) erythroid island macrophages in the mouse.

    PubMed

    Jacobsen, Rebecca N; Forristal, Catherine E; Raggatt, Liza J; Nowlan, Bianca; Barbier, Valerie; Kaur, Simranpreet; van Rooijen, Nico; Winkler, Ingrid G; Pettit, Allison R; Levesque, Jean-Pierre

    2014-07-01

    Similarly to other tissues, the bone marrow contains subsets of resident tissue macrophages, which are essential to maintain bone formation, functional hematopoietic stem cell (HSC) niches, and erythropoiesis. Pharmacologic doses of granulocyte colony-stimulating factor (G-CSF) mobilize HSC in part by interfering with the HSC niche-supportive function of BM resident macrophages. Because bone marrow macrophages are key to both maintenance of HSC within their niche and erythropoiesis, we investigated the effect of mobilizing doses of G-CSF on erythropoiesis in mice. We now report that G-CSF blocks medullar erythropoiesis by depleting the erythroid island macrophages we identified as co-expressing F4/80, vascular cell adhesion molecule-1, CD169, Ly-6G, and the ER-HR3 erythroid island macrophage antigen. Both broad macrophage depletion, achieved by injecting clodronate-loaded liposomes, and selective depletion of CD169(+) macrophages, also concomitantly depleted F4/80(+)VCAM-1(+)CD169(+)ER-HR3(+)Ly-6G(+) erythroid island macrophages and blocked erythropoiesis. This more precise phenotypic definition of erythroid island macrophages will enable studies on their biology and function in normal settings and on diseases associated with anemia. Finally, this study further illustrates that macrophages are a potent relay of innate immunity and inflammation on bone, hematopoietic, and erythropoietic maintenance. Agents that affect these macrophages, such as G-CSF, are likely to affect these three processes concomitantly. Copyright © 2014 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  8. Graft monocytic myeloid-derived suppressor cell content predicts the risk of acute graft-versus-host disease after allogeneic transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood stem cells.

    PubMed

    Vendramin, Antonio; Gimondi, Silvia; Bermema, Anisa; Longoni, Paolo; Rizzitano, Sara; Corradini, Paolo; Carniti, Cristiana

    2014-12-01

    Myeloid-derived suppressor cells (MDSCs) are powerful immunomodulatory cells that in mice play a role in infectious and inflammatory disorders, including acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. Their relevance in clinical acute GVHD is poorly known. We analyzed whether granulocyte colony-stimulating factor (G-CSF) administration, used to mobilize hematopoietic stem cells, affected the frequency of MDSCs in the peripheral blood stem cell grafts of 60 unrelated donors. In addition, we evaluated whether the MDSC content in the peripheral blood stem cell grafts affected the occurrence of acute GVHD in patients undergoing unrelated donor allogeneic stem cell transplantation. Systemic treatment with G-CSF induces an expansion of myeloid cells displaying the phenotype of monocytic MDSCs (Lin(low/neg)HLA-DR(-)CD11b(+)CD33(+)CD14(+)) with the ability to suppress alloreactive T cells in vitro, therefore meeting the definition of MDSCs. Monocytic MDSC dose was the only graft parameter to predict acute GVHD. The cumulative incidence of acute GVHD at 180 days after transplantation for recipients receiving monocytic MDSC doses below and above the median was 63% and 22%, respectively (P = .02). The number of monocytic MDSCs infused did not impact the relapse rate or the transplant-related mortality rate (P > .05). Although further prospective studies involving larger sample size are needed to validate the exact monocytic MDSC graft dose that protects from acute GVHD, our results strongly suggest the modulation of G-CSF might be used to affect monocytic MDSCs graft cell doses for prevention of acute GVHD. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  9. The granulocyte colony-stimulating factor (G-CSF) upregulates metalloproteinase-2 and VEGF through PI3K/Akt and Erk1/2 activation in human trophoblast Swan 71 cells.

    PubMed

    Furmento, V A; Marino, J; Blank, V C; Roguin, L P

    2014-11-01

    Although the expression of the granulocyte colony-stimulating factor (G-CSF) and its receptor (G-CSFR) in placental tissues suggests that the cytokine could play a role in placental development, the relevance of G-CSF:G-CSFR interaction in trophoblast cells remains to be studied. Thus, the possible functional role of G-CSF was examined in a human trophoblast cell line (Swan 71 cells). The expression of G-CSFR was detected by immunocytochemistry and Western blot assays. G-CSF treatment exerted neither a proliferative nor a protective effect on H2O2-mediated cell death in trophoblast cells. Gelatin zymography of supernatants collected from G-CSF-treated cells showed an increment of metalloproteinase-2 (MMP-2) activity. We also found higher MMP-2 and VEGF expression levels in conditioned medium from cells exposed to G-CSF. In addition, it was demonstrated that G-CSF induced the activation of PI3K/Akt and Erk1/2 pathways, which in turn activated NF-kB. By using selective pharmacological inhibitors, it was showed that these pathways are mediating the biological effects produced by G-CSF in Swan 71 cells. We have demonstrated for the first time that G-CSF increases MMP-2 activity and VEGF secretion in Swan 71 cells through activation of PI3K/Akt and Erk signaling pathways, both contributing to the translocation of NF-kB to the nucleus. These data suggest that G-CSF is involved in the regulation of trophoblast function, and should be considered as a locally produced cytokine probably contributing to embryo implantation and the development of a functional placenta. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. GRANULOCYTE COLONY-STIMULATING FACTOR (G-CSF) UPREGULATES β1 INTEGRIN AND INCREASES MIGRATION OF HUMAN TROPHOBLAST SWAN 71 CELLS VIA PI3K AND MAPK ACTIVATION

    PubMed Central

    Furmento, Verónica A.; Marino, Julieta; Blank, Viviana C.; Cayrol, María Florencia; Cremaschi, Graciela A.; Aguilar, Rubén C.; Roguin, Leonor P.

    2017-01-01

    Multiple cytokines and growth factors expressed at the fetal-maternal interface are involved in the regulation of trophoblast functions and placental growth, but the role of G-CSF has not been completely established. Based on our previous study showing that G-CSF increases the activity of matrix metalloproteinase-2 and the release of vascular endothelial growth factor in Swan 71 human trophoblast cells, in this work we explore the possible contribution of G-CSF to cell migration and the G-CSF-triggered signaling pathway. We found that G-CSF induced morphological changes on actin cytoskeleton consistent with a migratory cell phenotype. G-CSF also up-regulated the expression levels of β1 integrin and promoted Swan 71 cell migration. By using selective pharmacological inhibitors and dominant negative mutants we showed that PI3K, Erk 1/2 and p38 pathways are required for promoting Swan 71 cell motility. It was also demonstrated that PI3K behaved as an upstream regulator of Erk 1/2 and p38 MAPK. In addition, the increase of β1 integrin expression was dependent on PI3K activation. In conclusion, our results indicate that G-CSF stimulates β1 integrin expression and Swan 71 cell migration by activating PI3K and MAPK signaling pathways, suggesting that G-CSF should be considered as an additional regulatory factor that contributes to a successful embryo implantation and to the placenta development. PMID:26992288

  11. Granulocyte colony-stimulating factor (G-CSF) upregulates β1 integrin and increases migration of human trophoblast Swan 71 cells via PI3K and MAPK activation.

    PubMed

    Furmento, Verónica A; Marino, Julieta; Blank, Viviana C; Cayrol, María Florencia; Cremaschi, Graciela A; Aguilar, Rubén C; Roguin, Leonor P

    2016-03-15

    Multiple cytokines and growth factors expressed at the fetal-maternal interface are involved in the regulation of trophoblast functions and placental growth, but the role of G-CSF has not been completely established. Based on our previous study showing that G-CSF increases the activity of matrix metalloproteinase-2 and the release of vascular endothelial growth factor in Swan 71 human trophoblast cells, in this work we explore the possible contribution of G-CSF to cell migration and the G-CSF-triggered signaling pathway. We found that G-CSF induced morphological changes on actin cytoskeleton consistent with a migratory cell phenotype. G-CSF also up-regulated the expression levels of β1 integrin and promoted Swan 71 cell migration. By using selective pharmacological inhibitors and dominant negative mutants we showed that PI3K, Erk 1/2 and p38 pathways are required for promoting Swan 71 cell motility. It was also demonstrated that PI3K behaved as an upstream regulator of Erk 1/2 and p38 MAPK. In addition, the increase of β1 integrin expression was dependent on PI3K activation. In conclusion, our results indicate that G-CSF stimulates β1 integrin expression and Swan 71 cell migration by activating PI3K and MAPK signaling pathways, suggesting that G-CSF should be considered as an additional regulatory factor that contributes to a successful embryo implantation and to the placenta development.

  12. Optimization of gene transfer into primitive human hematopoietic cells of granulocyte-colony stimulating factor-mobilized peripheral blood using low-dose cytokines and comparison of a gibbon ape leukemia virus versus an RD114-pseudotyped retroviral vector.

    PubMed

    van der Loo, Johannes C M; Liu, B L; Goldman, A I; Buckley, S M; Chrudimsky, K S

    2002-07-20

    Primitive human hematopoietic cells in granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood (MPB) are more difficult to transduce compared to cells from umbilical cord blood. Based on the hypothesis that MPB cells may require different stimulation for efficient retroviral infection, we compared several culture conditions known to induce cycling of primitive hematopoietic cells. MPB-derived CD34(+) cells were stimulated in the presence or absence of the murine fetal liver cell line AFT024 in trans-wells with G-CSF, stem cell factor (SCF), and thrombopoietin (TPO) (G/S/T; 100 ng/ml) or Flt3-L, SCF, interleukin (IL)-7, and TPO (F/S/7/T; 10-20 ng/ml), and transduced using a GaLV-pseudotyped retroviral vector expressing the enhanced green fluorescence protein (eGFP). Compared to cultures without stroma, the presence of AFT024 increased the number of transduced colony-forming cells (CFC) by 3.5-fold (with G/S/T), long-term culture-initiating cells (LTC-IC) by 4.6-fold (with F/S/7/T), and nonobese diabetic/severe immunodeficiency disease (NOD/SCID)-repopulating cells (SRC) by 6.8-fold (with F/S/7/T). Similar numbers of long-term culture-initiating cells (LTC-IC) and SRC could be transduced using AFT024-conditioned medium (AFT-CM) or a defined medium that had been supplemented with factors identified in AFT-CM. Finally, using our best condition based on transduction with the gibbon ape leukemia virus (GaLV)-pseudotyped vector, we demonstrate a 33-fold higher level of gene transfer (p < 0.001) in SRC using an RD114-pseudotyped vector. In summary, using an optimized protocol with low doses of cytokines, and transduction with an RD114 compared to a GaLV-pseudotyped retroviral vector, the overall number of transduced cells in NOD/SCID mice could be improved 144-fold, with a gene-transfer efficiency in SRC of 16.3% (13.3-19.9; n = 6).

  13. The anti-inflammatory role of granulocyte colony-stimulating factor in macrophage-dendritic cell crosstalk after Lactobacillus rhamnosus GR-1 exposure.

    PubMed

    Martins, Andrew J; Spanton, Sarah; Sheikh, Haroon I; Kim, Sung Ouk

    2011-06-01

    MΦs are important sensory cells of the innate immune system and regulate immune responses through releasing different combinations of cytokines. In this study, we examined whether cytokines released by MΦs in response to the probiotic bacterial strain GR-1 modulate the responses of DCs. The cytokine profile released by GR-1-treated MΦs was characterized by low levels of TNF-α, GM-CSF, IL-6, and IL-12 but very high levels of G-CSF. GR-1 CM did not induce expression of the shared p40 subunit of IL-12 and IL-23 and costimulatory molecules CD80 or CD86 or increase T cell stimulatory capacity in DCs. However, in G-CSFR-deficient DCs or after antibody-mediated neutralization of G-CSF, GR-1 CM induced IL-12/23 p40 production significantly, indicating that G-CSF within the GR-1 CM inhibits IL-12/23 p40 production induced by other CM components. GR-1 CM and rG-CSF also inhibited LPS-induced IL-12 production at the mRNA and protein levels. The inhibition of IL-12 production by G-CSF was at least in part mediated through inhibition of JNK activation. Finally, splenic DCs of GR-1-injected mice produced less IL-12/23 p40 than those of PBS-injected mice in response to LPS ex vivo, and this was at least partially dependent on exposure to GR-1-induced G-CSF in vivo. Altogether, these results suggest that G-CSF modulates the IL-12/23 p40 response of DCs in the context of the probiotic GR-1 through MΦ-DC crosstalk.

  14. Early applications of granulocyte colony-stimulating factor (G-CSF) can stabilize the blood-optic-nerve barrier and ameliorate inflammation in a rat model of anterior ischemic optic neuropathy (rAION).

    PubMed

    Wen, Yao-Tseng; Huang, Tzu-Lun; Huang, Sung-Ping; Chang, Chung-Hsing; Tsai, Rong-Kung

    2016-10-01

    Granulocyte colony-stimulating factor (G-CSF) was reported to have a neuroprotective effect in a rat model of anterior ischemic optic neuropathy (rAION model). However, the therapeutic window and anti-inflammatory effects of G-CSF in a rAION model have yet to be elucidated. Thus, this study aimed to determine the therapeutic window of G-CSF and investigate the mechanisms of G-CSF via regulation of optic nerve (ON) inflammation in a rAION model. Rats were treated with G-CSF on day 0, 1, 2 or 7 post-rAION induction for 5 consecutive days, and a control group were treated with phosphate-buffered saline (PBS). Visual function was assessed by flash visual evoked potentials at 4 weeks post-rAION induction. The survival rate and apoptosis of retinal ganglion cells were determined by FluoroGold labeling and TUNEL assay, respectively. ON inflammation was evaluated by staining of ED1 and Iba1, and ON vascular permeability was determined by Evans Blue extravasation. The type of macrophage polarization was evaluated using quantitative real-time PCR (qRT-PCR). The protein levels of TNF-α and IL-1β were analyzed by western blotting. A therapeutic window during which G-CSF could rescue visual function and retinal ganglion cell survival was demonstrated at day 0 and day 1 post-infarct. Macrophage infiltration was reduced by 3.1- and 1.6-fold by G-CSF treatment starting on day 0 and 1 post-rAION induction, respectively, compared with the PBS-treated group (P<0.05). This was compatible with 3.3- and 1.7-fold reductions in ON vascular permeability after G-CSF treatment compared with PBS treatment (P<0.05). Microglial activation was increased by 3.8- and 3.2-fold in the early (beginning treatment at day 0 or 1) G-CSF-treated group compared with the PBS-treated group (P<0.05). Immediate (within 30 mins of infarct) treatment with G-CSF also induced M2 microglia/macrophage activation. The cytokine levels were lower in the group that received immediate G-CSF treatment compared to

  15. Effects of priming with recombinant human granulocyte colony-stimulating factor on conditioning regimen for high-risk acute myeloid leukemia patients undergoing human leukocyte antigen-haploidentical hematopoietic stem cell transplantation: a multicenter randomized controlled study in southwest China.

    PubMed

    Gao, Lei; Wen, Qin; Chen, Xinghua; Liu, Yao; Zhang, Cheng; Gao, Li; Kong, Peiyan; Zhang, Yanqi; Li, Yunlong; Liu, Jia; Wang, Qingyu; Su, Yi; Wang, Chunsen; Wang, Sanbin; Zeng, Yun; Sun, Aihua; Du, Xin; Zeng, Dongfeng; Liu, Hong; Peng, Xiangui; Zhang, Xi

    2014-12-01

    HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an effective and immediate treatment for high-risk acute myeloid leukemia (HR-AML) patients lacking matched donors. Relapse remains the leading cause of death for HR-AML patients after haplo-HSCT. Accordingly, the prevention of relapse remains a challenge in the treatment of HR-AML. In a multicenter randomized controlled trial in southwestern China, 178 HR-AML patients received haplo-HSCT with conditioning regimens involving recombinant human granulocyte colony-stimulating factor (rhG-CSF) or non-rhG-CSF. The cumulative incidences of relapse and graft-versus-host disease (GVHD), 2-year leukemia-free survival (LFS), and overall survival (OS) were evaluated. HR-AML patients who underwent the priming conditioning regimen with rhG-CSF had a lower relapse rate than those who were treated with non-rhG-CSF (38.2%; 95% confidence interval [CI], 28.1% to 48.3% versus 60.7%, 95% CI, 50.5% to 70.8%; P < .01). The cumulative incidences of acute GVHD, chronic GVHD, transplantation-related toxicity, and infectious complications appeared to be equivalent. In total, 53 patients in the rhG-CSF-priming group and 31 patients in the non-rhG-CSF-priming group were still alive at the median follow-up time of 42 months (range, 24 to 80 months). The 2-year probabilities of LFS and OS in the rhG-CSF-priming and non-rhG-CSF-priming groups were 55.1% (95% CI, 44.7% to 65.4%) versus 32.6% (95% CI, 22.8% to 42.3%) (P < .01) and 59.6% (95% CI, 49.4% to 69.7%) versus 34.8% (95% CI, 24.9% to 44.7%) (P < .01), respectively. Multivariate analyses indicated that the 2-year probability of LFS of patients who achieved complete remission (CR) before transplantation was better than that of patients who did not achieve CR. The 2-year probability of LFS of patients with no M4/M5/M6 subtype was better than that of patients with the M4/M5/M6 subtype in the G-CSF-priming group (67.4%; 95% CI, 53.8% to 80.9% versus 41.9%; 95% CI, 27

  16. Predicting poor peripheral blood stem cell collection in patients with multiple myeloma receiving pre-transplant induction therapy with novel agents and mobilized with cyclophosphamide plus granulocyte-colony stimulating factor: results from a Gruppo Italiano Malattie EMatologiche dell'Adulto Multiple Myeloma Working Party study.

    PubMed

    Musto, Pellegrino; Simeon, Vittorio; Grossi, Alberto; Gay, Francesca; Bringhen, Sara; Larocca, Alessandra; Guariglia, Roberto; Pietrantuono, Giuseppe; Villani, Oreste; D'Arena, Giovanni; Cuomo, Carmela; Musto, Clelia; Morabito, Fortunato; Petrucci, Maria Teresa; Offidani, Massimo; Zamagni, Elena; Tacchetti, Paola; Conticello, Concetta; Milone, Giuseppe; Palumbo, Antonio; Cavo, Michele; Boccadoro, Mario

    2015-04-17

    A still not well defined proportion of patients with multiple myeloma (MM) and eligible for autologous stem cell transplantation (AuSCT) fails to mobilize CD34+ peripheral blood stem cells (PBSC) at all or to collect an adequate number for a safe procedure or sufficient for multiple transplants. These so-called "poor-mobilizers" are difficult to be predicted, due to marked difference across previous heterogeneous studies. We aimed to develop a method based on simple clinical parameters for predicting unsuccessful (<2×10(6)/kg) or sub-optimal (<5×10(6)/kg) collections of CD34+ PBSC in newly diagnosed MM patients eligible for AuSCT, treated with novel agents and receiving an homogeneous mobilizing therapy with cyclophosphamide and granulocyte-colony stimulating factor (G-CSF). To this purpose, 1,348 patients enrolled in five consecutive Italian clinical trials were retrospectively analysed. Age, baseline low peripheral blood cell counts, use of lenalidomide, and haematological toxicity developed during induction were taken into account as possible factors associated with poor mobilization. Overall, 280 patients (20.8%) showed either sub-optimal (167 patients, 12.4%) or unsuccessful (113 patients, 8.4%) collections. All analysed parameters negatively influenced the procedure, but only age and haematological toxicity during induction maintained their significance at multivariate analysis. Based on ordinal logistic regression model, we constructed a risk heat-map where the four parameters were pooled and weighted according to their relevance as single or combined variables. This model was predictive for different probabilities of failure, suboptimal or optimal outcomes. We found that about one fifth of newly diagnosed MM fails to collect an adequate number of PBSC. Our model, based on a large group of patients treated frontline with novel agents and receiving the most popular mobilizing approach currently employed in Europe, is applicable in individual subjects and

  17. Rat granulocyte colony-forming unit (CFU-G) assay for the assessment of drug-induced hematotoxicity.

    PubMed

    Matsumura-Takeda, K; Kotosai, K; Ozaki, A; Hara, H; Yamashita, S

    2002-06-01

    To assess the drug-induced hematotoxicity to granulocyte progenitors, we established a modified colony-forming assay using rat bone marrow cells (BMCs). In the presence of various colony-stimulating factors (CSFs), rat BMCs were disseminated on methylcellulose at a concentration of 1.3 x 10(4) cells/cm(2) (5 x 10(4) cells/0.5 ml/well in a 12-well plate). Mouse granulocyte-macrophage colony-stimulating factor (mGM-CSF) stimulated the formation of almost all macrophage colonies. Human granulocyte colony-stimulating factor (hG-CSF) alone or in combination with mouse interleukin-3 (mIL-3) did not significantly effect on the number of rat colony-forming units in culture (CFU-C). When BMCs were seeded at 5.2 x 10(4) cells/cm(2) (5 x 10(5) cells/1 ml/dish in a 35-mm dish), hG-CSF increased the number of the colonies in a dose-dependent manner, and resulted in about 50 colonies at 50 ng/ml. The constituent cells of the colonies were identified as neutrophils. Under these conditions, the effects of 5-fluorouracil (5-FU) on granulocyte colony-forming units (CFU-G) were examined in rats and mice. The inhibitory effect of 5-FU on rat CFU-G was similar to the effect on mouse CFU-G. These results indicate that the rat CFU-G induced by hG-CSF is capable of being used for the evaluation of drug-induced hematotoxicity.

  18. Prognostic factors for re-mobilization using plerixafor and granulocyte colony-stimulating factor (G-CSF) in patients with malignant lymphoma or multiple myeloma previously failing mobilization with G-CSF with or without chemotherapy: the Korean multicenter retrospective study.

    PubMed

    Kim, Jin Seok; Yoon, Dok Hyun; Park, Seonyang; Yoon, Sung-Soo; Cho, Seok-Goo; Min, Chang-Ki; Lee, Je-Jung; Yang, Deok-Hwan; Kwak, Jae-Yong; Eom, Hyeon-Seok; Kim, Won Seog; Kim, Hawk; Do, Young Rok; Moon, Joon Ho; Lee, Jihye; Suh, Cheolwon

    2016-03-01

    Plerixafor in combination with granulocyte colony-stimulating factor (G-CSF) has been shown to improve the rates of successful peripheral blood stem cell (PBSC) mobilization in patients with malignant lymphoma or multiple myeloma (MM) who experienced prior failure of PBSC mobilization. We evaluated the mobilization results of re-mobilization using plerixafor and G-CSF in insufficiently mobilizing patients. Forty-four patients with lymphoma (n = 29) or MM (n = 15) were included in the study. The median age was 50 (range, 24-64) years. Previous mobilization regimens were chemotherapy with G-CSF (n = 28), including cyclophosphamide with G-CSF (n = 15), and G-CSF only (n = 16). All patients with lymphoma achieved at least partial response (PR) before the mobilization, including 13 complete responses (CRs). Eleven patients with MM achieved at least PR and four patients with MM were in stable disease before mobilization. The median number of apheresis was 3 (range, 1-6). The median yield of PBSC collections was 3.41 (0.13-38.11) × 10(6) CD34(+) cells/kg. Thirty-four (77.3 %) patients had successful collections defined as at least 2 × 10(6) CD34(+) cells/kg. The rate of successful collections was not different between the two underlying diseases (79.3 % in lymphoma and 73.3 % in MM). Of the entire cohort, 38 (86.4 %) of patients went on to receive an autologous transplant. Previous long-term use of high-risk drugs (>4 cycles use of alkylating agents, platinum-containing agents, or thalidomide) (HR 10.8, 95 % CI 1.1-110.0, P = 0.043) and low platelet count (<100 × 10(9)/L) 1 day before the first apheresis (HR 27.9, 95 % CI 2.9-273.7, P = 0.004) were independent prognostic factors for predicting failure of PBSC re-mobilization using plerixafor and G-CSF. In conclusion, re-mobilization using plerixafor and G-CSF showed a success rate of 77.3 % in patients with lymphoma or MM who experienced prior failure of PBSC

  19. A granulocyte-colony-stimulating factor gene promoter element responsive to inflammatory mediators is functionally distinct from an identical sequence in the granulocyte-macrophage colony-stimulating factor gene.

    PubMed

    Kuczek, E S; Shannon, M F; Pell, L M; Vadas, M A

    1991-04-01

    A number of mesenchymal cells produce hemopoietic growth factors in response to inflammatory mediators in vitro and in vivo. Induced transcription from the hemopoietic growth factor genes is at least partially responsible for their increased expression. We have previously identified a sequence, cytokine (CK)-1, in the granulocyte (G)-CSF gene promoter that responds to TNF-alpha and binds a transcription factor, NF-GMa. We report here that the CK-1 sequence responds in a time- and dose-dependent manner to IL-1 beta and that the mutations which affect NF-GMa binding correlate with decreased transcriptional activity after stimulation with either TNF-alpha or IL-1 beta. The CK-1 sequence also responds to the human T lymphotrophic virus-1 transactivator, tax, so that this promoter element may contribute to the overall response of the G-CSF gene to these various agents. Although NF-GMa binding is seen in a number of cell types, the ability of the G-CSF CK-1 sequence to act as a transcriptional enhancer is specific for fibroblasts and not T cells. Furthermore, we show that an identical sequence in the granulocyte macrophage CSF gene, although apparently binding the same protein in vitro, cannot respond to any of these stimuli in either fibroblasts or T cells. Modification interference experiments, using the CK-1 region in the context of the granulocyte macrophage-CSF and G-CSF genes, indicated that the contact points for NF-GMa differ in each case and suggest that differences in sequences flanking the 10-bp CK-1 region probably leads to an altered DNA:protein conformation, which may explain the differential response of this conserved promoter element.

  20. The addition of granulocyte-colony stimulating factor shifts the dose limiting toxicity and markedly increases the maximum tolerated dose and activity of the kinesin spindle protein inhibitor SB-743921 in patients with relapsed or refractory lymphoma: results of an international, multicenter phase I/II study.

    PubMed

    O'Connor, Owen A; Gerecitano, John; Van Deventer, Henrik; Hainsworth, John; Zullo, Kelly M; Saikali, Khalil; Seroogy, Joseph; Wolff, Andrew; Escandón, Rafael

    2015-01-01

    This was a phase I study of SB-743921 (SB-921) in patients with relapsed/refractory lymphoma. Previous studies established that neutropenia was the only dose limiting toxicity (DLT). The primary objective was to determine the DLT, maximum tolerated dose (MTD) and efficacy of SB-921 with and without granulocyte-colony stimulating factor (G-CSF). Sixty-eight patients were enrolled, 42 without G-CSF, 26 with G-CSF. In the cohort without G-CSF, SB-921 doses ranged from 2 to 7 mg/m(2), with 6 mg/m(2) being the MTD. In the cohort with G-CSF support, doses of 6-10 mg/m(2) were administered, with 9 mg/m(2) being the MTD, representing a 50% increase in dose density. Fifty-six patients were evaluable for efficacy. Four of 55 patients experienced a partial response (three in Hodgkin lymphoma and one in non-Hodgkin lymphoma, all at doses ≥ 6 mg/m(2)); 19 patients experienced stable disease, 33 patients developed progression of disease. G-CSF shifted the DLT from neutropenia to thrombocytopenia, allowing for a 50% increase in dose density. Responses were seen at higher doses with G-CSF support.

  1. Primary prophylaxis with granulocyte colony-stimulating factor (GCSF) reduces the incidence of febrile neutropenia in patients with non-Hodgkin lymphoma (NHL) receiving CHOP chemotherapy treatment without adversely affecting their quality of life: cost-benefit and quality of life analysis.

    PubMed

    Lee, Sophie; Knox, Angela; Zeng, Irene S L; Coomarasamy, Christin; Blacklock, Hilary; Issa, Samar

    2013-03-01

    Treatment of non-Hodgkin lymphoma (NHL) with cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP) is known to be associated with a significant risk of febrile neutropenia (FN) of up to 50% [Osby et al. 2003 Blood 101(10): 3840-3848; Lyman and Delgado 2003 Cancer 98(11): 2402-2409]. This study sought to examine the impact of primary granulocyte colony-stimulating factor (GCSF) prophylaxis on the incidence of FN, quality of life and overall cost. In this retrospective cohort study, a group of 65 consecutive patients who received CHOP chemotherapy for NHL between December 2006 and October 2009 was studied. Patients either received filgrastim (300 mcg, average of seven doses), pegylated filgrastim (6 mg, single dose), or no GCSF prophylaxis. In addition, 19 patients were asked to complete Functional Assessment of Cancer Therapy: General quality-of-life questionnaires. Overall, patients who received primary GCSF prophylaxis had significantly fewer FN compared to those who did not (5 vs. 60%, p < 0.0001; numbers needed to treat of 1.8; 95% confidence interval, 1.6-2.9). Cost-benefit analysis showed that the GCSF prophylaxis was associated with only a small increase in direct financial cost ($238 NZD [US$189] more to give primary GCSF prophylaxis per patient vs. no prophylaxis). The quality of life assessment showed that the patients' quality of life scores were similar to the published data from the validation study population (466 patients with mixed cancers) for Functional Assessment of Cancer Therapy. Our study shows that primary GCSF prophylaxis is effective in preventing FN in patients receiving CHOP chemotherapy for NHL without adversely affecting their quality of life, and is cost effective.

  2. A 3,387 bp 5'-flanking sequence of the goat alpha-S1-casein gene provides correct tissue-specific expression of human granulocyte colony-stimulating factor (hG-CSF) in the mammary gland of transgenic mice.

    PubMed

    Serova, Irina A; Dvoryanchikov, Gennady A; Andreeva, Ludmila E; Burkov, Ivan A; Dias, Luciene P B; Battulin, Nariman R; Smirnov, Alexander V; Serov, Oleg L

    2012-06-01

    A new expression vector containing the 1,944 bp 5'-flanking regulatory region together with exon 1 and intron 1 of the goat alpha-S1-casein gene (CSN1S1), the full-sized human granulocyte colony-stimulating factor gene (hGCSF) and the 3'-flanking sequence of the bovine CSN1S1, was created. The vector DNA was used for generation of four mouse transgenic lines. The transgene was integrated into chromosomes 8 and 12 of two founders as 2 and 5 copies, respectively. Tissue-specific secretion of hG-CSF into the milk of transgenic mice was in the range of 19-40 μg/ml. RT-PCR analysis of various tissues of the transgenic mice demonstrated that expression of hGCSF was detected in only the mammary gland in the progeny of all founders. Moreover, cells were shown to be positive for hG-CSF by immunofluorescent analysis in the mammary glands but not in any other tissues. There were no signs of mosaic expression in the mammary gland. Trace amounts of hG-CSF were detected in the serum of females of two transgenic lines during lactation only. However, no transgenic mice showed any changes in hematopoiesis based on the number of granulocytes in blood. Immunoblotting of hG-CSF in the milk of transgenic mice revealed two forms, presumably the glycosylated and non-glycosylated forms. The hematopoietic activity of hG-CSF in the milk of transgenic females is comparable to that of recombinant G-CSF. In general, the data obtained in this study show that the new expression vector is able to provide correct tissue-specific expression of hG-CSF with high biological activity in transgenic mice.

  3. Sitagliptin plus granulocyte colony-stimulating factor in patients suffering from acute myocardial infarction: A double-blind, randomized placebo-controlled trial of efficacy and safety (SITAGRAMI trial).

    PubMed

    Brenner, Christoph; Adrion, Christine; Grabmaier, Ulrich; Theisen, Daniel; von Ziegler, Franz; Leber, Alexander; Becker, Alexander; Sohn, Hae-Young; Hoffmann, Ellen; Mansmann, Ulrich; Steinbeck, Gerhard; Franz, Wolfgang-Michael; Theiss, Hans Diogenes

    2016-02-15

    In animal models, G-CSF based progenitor cell mobilization combined with a DPP4 inhibitor leads to increased homing of bone marrow derived progenitor cells to the injured myocardium via the SDF1/CXCR4 axis resulting in improved ejection fraction and survival after acute myocardial infarction (AMI). After successful revascularization in AMI, 174 patients were randomized 1:1 in a multi-centre, prospective, placebo-controlled, parallel group, double blind, phase III efficacy and safety trial to treatment with G-CSF and Sitagliptin (GS) or placebo. Diabetic and non-diabetic patients were included in our trial. The primary efficacy endpoint hierarchically combined global left and right ventricular ejection fraction changes from baseline to 6 months of follow-up (ΔLVEF, ΔRVEF), as determined by cardiac MRI. At follow-up ΔLVEF as well as ΔRVEF did not differ between the GS and placebo group. Patients in the placebo group had a similar risk for a major adverse cardiac event within 12 months of follow-up as compared to patients under GS. Progenitor cell therapy comprising the use of G-CSF and Sitagliptin after successfully revascularized acute myocardial infarction fails to show a beneficial effect on cardiac function and clinical events after 12 months. (EudraCT: 2007-003,941-34; ClinicalTrials.gov: NCT00650143, funding: Heinz-Nixdorf foundation). Copyright © 2015. Published by Elsevier Ireland Ltd.

  4. REpeated AutoLogous Infusions of STem cells In Cirrhosis (REALISTIC): a multicentre, phase II, open-label, randomised controlled trial of repeated autologous infusions of granulocyte colony-stimulating factor (GCSF) mobilised CD133+ bone marrow stem cells in patients with cirrhosis. A study protocol for a randomised controlled trial.

    PubMed

    King, A; Barton, D; Beard, H A; Than, N; Moore, J; Corbett, C; Thomas, J; Guo, K; Guha, I; Hollyman, D; Stocken, D; Yap, C; Fox, R; Forbes, S J; Newsome, P N

    2015-03-20

    Liver disease mortality and morbidity are rapidly rising and liver transplantation is limited by organ availability. Small scale human studies have shown that stem cell therapy is safe and feasible and has suggested clinical benefit. No published studies have yet examined the effect of stem cell therapy in a randomised controlled trial and evaluated the effect of repeated therapy. Patients with liver cirrhosis will be randomised to one of three trial groups: group 1: Control group, Standard conservative management; group 2 treatment: granulocyte colony-stimulating factor (G-CSF; lenograstim) 15 µg/kg body weight daily on days 1-5; group 3 treatment: G-CSF 15 µg/kg body weight daily on days 1-5 followed by leukapheresis, isolation and aliquoting of CD133+ cells. Patients will receive an infusion of freshly isolated CD133+ cells immediately and frozen doses at days 30 and 60 via peripheral vein (0.2×10(6) cells/kg for each of the three doses). Primary objective is to demonstrate an improvement in the severity of liver disease over 3 months using either G-CSF alone or G-CSF followed by repeated infusions of haematopoietic stem cells compared with standard conservative management. The trial is powered to answer two hypotheses of each treatment compared to control but not powered to detect smaller expected differences between the two treatment groups. As such, the overall α=0.05 for the trial is split equally between the two hypotheses. Conventionally, to detect a relevant standardised effect size of 0.8 point reduction in Model for End-stage Liver Disease score using two-sided α=0.05(overall α=0.1 split equally between the two hypotheses) and 80% power requires 27 participants to be randomised per group (81 participants in total). The trial is registered at Current Controlled Trials on 18 November 2009 (ISRCTN number 91288089, EuDRACT number 2009-010335-41). The findings of this trial will be disseminated to patients and through peer-reviewed publications

  5. Combination Therapy for Radiation-Induced Bone Marrow Aplasia in Nonhuman Primates Using Synthokine SC-55494 and Recombinant Human Granulocyte Colony-Stimulating Factor

    DTIC Science & Technology

    1996-05-15

    treated animals ( P < .05). t Significantly different from rhG-CSF ( P < .05). Stain; Ames Automated Slide Stainer , Elkhart, IN). Baseline levels...Grant FJ, Heipel MD, Burkhead SK, Kramer JM, Bell LA, Sprecher CA, Blumber H, Johnson R, h n k a r d D, Ching AFT, Mathewes SL, Balley MC, Forstrom...Swift S, Johnson MJ, Hsu RY, Parker VP, Suggs S, Skrine ID, Merewether LA, Clogston C, Hsu E, Hokom MM, Homkohl A, Choi E, Pangeliana M, Sun Y, Mar

  6. Combined intervention for the tertiary prevention of type 1 diabetes.

    PubMed

    Kawasaki, Eiji

    2016-05-01

    Recently published paper by Haller and coworkers in Journal of Clinical Investigation reported that a combination of low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte-colony stimulating factor (G-CSF) may preserve β-cell function in patients with established type 1 diabetes.

  7. Combined Administration of Recombinant Human Megakaryocyte Growth and Development Factor and Granulocyte Colony-Stimulating Factor Enhances Multilineage Hematopoietic Reconstitution in Nonhuman Primates after Radiation-Induced Marrow Aplasia

    DTIC Science & Technology

    1996-05-01

    9000; Serono-Baker, Allentown, PA) and differential counts (Wright-Giemsa stain; auto- mated slide stainer , Elkhart, IN). Assessment of hematologic...Begley, G.R. Johnson , N.A. Nicola, A.F. Lopez, and D.J. Williamsen. 1986. Effects of purified bacterially synthesized murine multi- CSF (IL-3) on

  8. Functional NF-IL6/CCAAT enhancer-binding protein is required for tumor necrosis factor alpha-inducible expression of the granulocyte colony- stimulating factor (CSF), but not the granulocyte/macrophage CSF or interleukin 6 gene in human fibroblasts [retracted by Adler G. In: J Exp Med 1997 Jul 7;186(1):171

    PubMed Central

    1995-01-01

    Tumor necrosis factor (TNF) alpha participates in the regulation of the acute-phase, immune, and inflammatory responses. Target genes known to be transcriptionally activated by TNF-alpha include the granulocyte (G)- colony-stimulating factor (CSF) gene, the granulocyte/macrophage (GM)- CSF gene, as well as the interleukin (IL) 6 gene. Functional nuclear factor (NF)-IL6 recognition sites have been identified in regulatory regions of these genes by transient transfection studies using deleted promoter constructs. In addition, NF-IL6 is known to form heterodimeric complexes with the NF-kappa B transcription factor, which is also engaged in the transcriptional regulation of these genes. The indispensable importance of NF-IL6 for regulating gene expression of proinflammatory cytokine genes in response to inflammatory stimuli in vivo remains, however, unclear. We here report, by using both antisense (AS) oligodesoxyribonucleotide (ODN) and ribozyme (RZ)-mediated specific elimination of NF-IL6 transcripts in human fibroblasts, that TNF-alpha-induced synthesis of G-CSF, but not of GM-CSF or IL-6, is abolished in the absence of functional NF-IL6 in vivo. Both AS ODN and RZ targeting of the NF-IL6 transcript eliminate NF-IL6 protein, as shown in Western blot analysis and electrophoretic mobility shift assays. Similarly, fibroblasts exposed to either the AS NF-IL6 ODN or the NF-IL6 RZ, but not to the sense or nonsense ODN or a mutated ribozyme, also failed to respond with functional activation of NF-IL6 as assayed in transient transfection studies using heterologous promoter constructs harboring the NF-IL6 recognition site. In contrast, protein synthesis, DNA-binding activity, and transcriptional activation capacity of the NF-kappa B transcription factor is not impaired upon exposure to either ODN or RZ. Fibroblasts that had been cultured in the presence of the AS NF-IL6 ODN or the NF-IL6RZ failed to synthesize G- CSF protein in response to TNF-alpha, while TNF

  9. Sulfur Mustard-induced Neutropenia: Treatment with Granulocyte Colony-stimulating Factor

    DTIC Science & Technology

    2006-01-01

    pegylated G-CSF ( peg -G-CSF) Hematological data from rats exposed to HD by inhalation have been approved by the U.S. Food and Drug Administration as...study was to determine the phocytes, at 24 hours after exposure. 4 Gold and Scharfd re- effectiveness of G-CSF and peg -G-CSF in ameliorating HD-in- ported...includ- exposure, G-CSF therapy (10 Ag/kg per day for 21 days) was ing nitrogen mustard, also induce severe neutropenia," an ex- initiated. Peg -G-CSF

  10. The discovery, development and clinical applications of granulocyte colony-stimulating factor.

    PubMed Central

    Dale, D. C.

    1998-01-01

    The story of the discovery, development and applications of G-CSF illustrates many of the best features of modern laboratory and clinical investigation. The initial discovery of the CSFs was somewhat serendipitous. The pathway to understanding the cellular and molecular base for the action of these substances was long, but fruitful and exciting for those who pursued it tirelessly. The power of modern molecular biology is illustrated by the rapid advances which followed the cloning of the G-CSF gene. Major advances in our understanding of the regulation of neutrophil production and deployment have followed, together with many important clinical observations. To date hundreds of thousands of patients have been treated with G-CSF and some individuals with severe chronic neutropenia have received daily therapy for more than ten years. Results of recent studies suggest that there will be many more interesting and important clinical applications for G-CSF. PMID:9601125

  11. Reduced salmonella fecal shedding in swine administered porcine granulocyte-colony stimulating factor (G-CSF)

    USDA-ARS?s Scientific Manuscript database

    Salmonella colonization of food animals is a concern for animal health, food safety and public health. Key objectives of pre-harvest food safety programs are to detect asymptomatic Salmonella carriage in food animals, reduce colonization, and prevent transmission of Salmonella to other animals and ...

  12. [Recombinant granulocyte-colony stimulating factor (filgrastim): optimization of conditions of isolation and purification from inclusion body].

    PubMed

    Kononova, N V; Iakovlev, A V; Zhuravko, A M; Pankeev, N N; Minaev, S V; Bobruskin, A I; Mart'ianov, V A

    2014-01-01

    We developed a unified process platform for two recombinant human GCSF medicines--one with the non-prolonged and the other with prolonged action. This unified technology led to a simpler and cheaper production while introduction of the additional pegylation stage to the technological line eased obtaining of the medicines with different action and allowed to standardize technological process documenting according to GMP requirements.

  13. Glycosylated and non-glycosylated recombinant human granulocyte colony-stimulating factor (rhG-CSF)--what is the difference?

    PubMed

    Höglund, M

    1998-12-01

    Two forms of recombinant human G-CSF (rhG-CSF) are available for clinical use: filgrastim is expressed in E coli and non-glycosylated, whereas lenograstim is derived from Chinese hamster ovary (CHO) cells and glycosylated. The function of the sugar chain, accounting for approximately 4% of the molecular weight of lenograstim (and native G-CSF), is not known. Glycosylation of the G-CSF molecule does not prolong its circulation half life. Lenograstim is more active than filgrastim (and research-use deglycosylated G-CSF) on a weight-by-weight basis in in vitro colony-forming and cell line assays. An international potency standard assigns a specific activity of 100,000 IU/microgram to filgrastim and 127,760 IU/microgram to lenograstim. Correspondingly, two randomised crossover studies in normal subjects, comparing mass equivalent doses of the two rhG-CSFs, have demonstrated a 25-30% higher concentration of blood stem cells (CD34+, CFU-GM) during lenograstim administration. No difference in side effects was observed. Results from a prospective, randomised, non-crossover trial in breast cancer patients suggest that bioequivalent doses of filgrastim and lenograstim have a similar effect on mobilisation of CD34+ cells and immature CD34+ cell subsets, respectively. Although comparisons outside the setting of stem cell mobilisation are lacking, the clinical relevance of the greater specific activity of lenograstim may thus be limited. The difference in potency between microgram identical doses of the two rhG-CSFs makes dosing in biological units (IU) rather than mass units (microgram) more appropriate.

  14. Assessing blood granulocyte colony-stimulating factor as a potential biomarker of acute traumatic brain injury in mice and humans.

    PubMed

    Banks, William A; Dohi, Kenji; Hansen, Kim; Thompson, Hilaire J

    2016-02-01

    Previous work has found that serum G-CSF was acutely elevated in mice 24h but not one week after controlled cortical impact (CCI). The purpose of this study was to investigate whether blood G-CSF correlates with the elevated brain cytokines in mice after CCI and also if it correlates with traumatic brain injury (TBI) in humans. Here, we found in mice undergoing CCI, a procedure that induces direct injury to the brain, that serum G-CSF correlated directly or indirectly with several brain cytokines, indicating it is a useful marker for the neuroinflammation of TBI. A pilot study in humans (phase I, n=19) confirmed that plasma G-CSF is acutely elevated on day 1 (p<0.001) of TBI and has returned to baseline by one week. In a second human sample (phase II) (n=80), we found plasma G-CSF peaks about 12h after arriving in the emergency department (41.6+/-5.4 pg/ml). Aging was weakly associated (p<0.05) with a less robust elevation in serum G-CSF, but there was no difference with gender. ISS, a measure of total severity of injury, correlated with the degree of elevation in serum G-CSF (r=.419; p<0.05), but severity of head injury (via AIS) did not. The latter may have been because of the statistically narrow range of head injuries among our cases and the high number of cases diagnosed with closed head injury (a non-codable diagnosis). In conclusion, plasma G-CSF may be a useful biomarker of TBI, correlating with neuroinflammation in the animal model and in the human studies with time since injury and total severity of injury. As such, it may be useful in determining whether TBI has occurred within the last 24h.

  15. Granulocyte-Colony Stimulating Factor (G-CSF) in Stroke Patients with Concomitant Vascular Disease—A Randomized Controlled Trial

    PubMed Central

    Duning, Thomas; Lating, Yvonne; Uhlenbrock, Jan; Schneider, Armin; Vogt, Gerhard; Laage, Rico; Koch, Winfried; Knecht, Stefan; Schäbitz, Wolf-Rüdiger

    2011-01-01

    Background G-CSF has been shown in animal models of stroke to promote functional and structural regeneration of the central nervous system. It thus might present a therapy to promote recovery in the chronic stage after stroke. Methods Here, we assessed the safety and tolerability of G-CSF in chronic stroke patients with concomitant vascular disease, and explored efficacy data. 41 patients were studied in a double-blind, randomized approach to either receive 10 days of G-CSF (10 µg/kg body weight/day), or placebo. Main inclusion criteria were an ischemic infarct >4 months prior to inclusion, and white matter hyperintensities on MRI. Primary endpoint was number of adverse events. We also explored changes in hand motor function for activities of daily living, motor and verbal learning, and finger tapping speed, over the course of the study. Results Adverse events (AEs) were more frequent in the G-CSF group, but were generally graded mild or moderate and from the known side-effect spectrum of G-CSF. Leukocyte count rose after day 2 of G-CSF dosing, reached a maximum on day 8 (mean 42/nl), and returned to baseline 1 week after treatment cessation. No significant effect of treatment was detected for the primary efficacy endpoint, the test of hand motor function. Conclusions These results demonstrate the feasibility, safety and reasonable tolerability of subcutaneous G-CSF in chronic stroke patients. This study thus provides the basis to explore the efficacy of G-CSF in improving chronic stroke-related deficits. Trial Registration ClinicalTrials.gov NCT00298597 PMID:21625426

  16. Combined administration of G-CSF and GM-CSF stimulates monocyte-derived pro-angiogenic cells in patients with acute myocardial infarction.

    PubMed

    Bruno, Stefania; Bussolati, Benedetta; Scacciatella, Paolo; Marra, Sebastiano; Sanavio, Fiorella; Tarella, Corrado; Camussi, Giovanni

    2006-04-01

    Mobilization of endothelial progenitor cells has been suggested to contribute to neo-vascularization of ischemic organs. Aim of this study was to investigate whether the combination of granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage (GM)-CSF may influence the expansion of circulating KDR+ cells in patients with acute myocardial infarction (AMI). KDR+ cells significantly increased in peripheral blood of AMI patients treated with G-CSF and GM-CSF compared to untreated patients. This KDR+ cells population was CD14+ but not CD34+ or CD133+. CD14+/KDR+ cells were also obtained in vitro by culturing mononuclear cells from healthy donors in a Rotary Cell Culture System in the presence of G-CSF + GM-CSF, but not of the individual growth factors. CD14+/KDR+ cells, obtained from patients or from in vitro culture, co-expressed hematopoietic (CD45, CD14) and endothelial markers (CD31, CD105, and VE-cadherin). CD14+/KDR+, but not CD14+/KDR- cells, stimulated the organization of human microvascular endothelial cells into capillary-like structures on Matrigel both in vitro and in vivo. The combination of G-CSF and GM-CSF induced a CD14+/KDR+ cell population with potential pro-angiogenic properties.

  17. Case Report. Prevention of Clozapine-Induced Granulocytopenia/Agranulocytosis with Granulocyte-Colony Stimulating Factor (G-CSF) in an Intellectually Disabled Patient with Schizophrenia

    ERIC Educational Resources Information Center

    Rajagopal, G.; Graham, J. G.; Haut, F. F. A.

    2007-01-01

    Background: While clozapine is an effective treatment for refractory schizophrenia, its use is limited by haematological side effects. Treatment options that allow continued prescription of clozapine by tackling these side effects will greatly aid patients for whom this medication is all too often their only hope of recovery. Method: In this case…

  18. Response to recombinant erythropoietin alpha, without the adjunct of granulocyte-colony stimulating factor, is associated with a longer survival in patients with transfusion-dependent myelodysplastic syndromes.

    PubMed

    Musto, Pellegrino; Villani, Oreste; Martorelli, Maria Carmen; Pietrantuono, Giuseppe; Guariglia, Roberto; Mansueto, Giovanna; D'Auria, Fiorella; Grieco, Vitina; Bianchino, Gabriella; Sparano, Anna; Zonno, Antonia; Lerose, Rosa; Sanpaolo, Grazia; Falcone, Antonietta

    2010-08-01

    This was a retrospective, comparative study focused on the extended follow-up of 192 transfusion-dependent patients with myelodysplastic syndromes treated (n. 83) or not treated (n. 109) with recombinant erythropoietin alpha (r-EPO) as single agent during the course of their disease. The results supported the safety of this treatment in the long term and also showed a significant survival advantage (median 52 months vs. 31 months, p<0.0095) in responding patients as compared to non-responding ones or to subjects never treated with r-EPO. At multivariate analysis, response to r-EPO maintained an independent prognostic value on OS.

  19. Establishment of the first international standard for PEGylated granulocyte colony stimulating factor (PEG-G-CSF): Report of an international collaborative study

    PubMed Central

    Wadhwa, Meenu; Bird, Chris; Dougall, Thomas; Rigsby, Peter; Bristow, Adrian; Thorpe, Robin

    2015-01-01

    We assessed the feasibility of developing a suitable international reference standard for determination of in vitro biological activity of human sequence recombinant PEG-G-CSF products with a 20 kD linear PEG linked to the N-terminal methionyl residue of G-CSF (INN Filgrastim), produced using a conjugation process and coupling chemistry similar to that employed for the lead PEGfilgrastim product. Based on initial data which showed that the current WHO 2nd international standard, IS for G-CSF (09/136) or alternatively, a PEG-G-CSF standard with a unitage traceable to the G-CSF IS may potentially serve as the IS for PEG-G-CSF products, two candidate preparations of PEG-G-CSF were formulated and lyophilized at NIBSC. These preparations were tested by 23 laboratories using in vitro bioassays in a multi-centre collaborative study. Results indicated that on the basis of parallelism, the current WHO 2nd IS for G-CSF or any of the PEG-G-CSF samples could be used as the international standard for PEG-G-CSF preparations. However, because of the variability in potency estimates seen when PEG-G-CSF preparations were compared with the current WHO 2nd IS for G-CSF, a candidate PEG-G-CSF was suitable as the WHO IS. The preparation 12/188 was judged suitable to serve as the WHO IS based on in vitro biological activity data. Therefore, the preparation coded 12/188 was established by the WHO Expert Committee on Biological Standardization (ECBS) in 2013 as the WHO 1st IS for human PEGylated G-CSF with an assigned in vitro bioactivity of 10,000 IU per ampoule. PMID:25450254

  20. Granulocyte colony-stimulating factor (G-CSF) positive effects on muscle fiber degeneration and gait recovery after nerve lesion in MDX mice

    PubMed Central

    Simões, Gustavo F; Benitez, Suzana U; Oliveira, Alexandre L R

    2014-01-01

    Background G-CSF has been shown to decrease inflammatory processes and to act positively on the process of peripheral nerve regeneration during the course of muscular dystrophy. Aims The aims of this study were to investigate the effects of treatment of G-CSF during sciatic nerve regeneration and histological analysis in the soleus muscle in MDX mice. Methods Six-week-old male MDX mice underwent left sciatic nerve crush and were G-CSF treated at 7 days prior to and 21 days after crush. Ten and twenty-one days after surgery, the mice were euthanized, and the sciatic nerves were processed for immunohistochemistry (anti-p75NTR and anti-neurofilament) and transmission electron microscopy. The soleus muscles were dissected out and processed for H&E staining and subsequent morphologic analysis. Motor function analyses were performed at 7 days prior to and 21 days after sciatic crush using the CatWalk system and the sciatic nerve index. Results Both groups treated with G-CSF showed increased p75NTR and neurofilament expression after sciatic crush. G-CSF treatment decreased the number of degenerated and regenerated muscle fibers, thereby increasing the number of normal muscle fibers. Conclusions The reduction in p75NTR and neurofilament indicates a decreased regenerative capacity in MDX mice following a lesion to a peripheral nerve. The reduction in motor function in the crushed group compared with the control groups may reflect the cycles of muscle degeneration/regeneration that occur postnatally. Thus, G-CSF treatment increases motor function in MDX mice. Nevertheless, the decrease in baseline motor function in these mice is not reversed completely by G-CSF. PMID:25328849

  1. Enhancement of innate immunity with granulocyte colony-stimulating factor did not prevent disease in pigs infected with a highly pathogenic Chinese PRRSV strain

    USDA-ARS?s Scientific Manuscript database

    Chinese highly pathogenic PRRSV (HP-PRRSV) strain JXwn06 has been shown to produce high fevers, loss of body condition, respiratory distress and death in pigs. Necropsy reveals extensive interstitial pneumonia, multi-systemic pathology and a high occurrence of secondary bacterial infections. The ful...

  2. Enhancement of innate immunity with granulocyte colony-stimulating factor did not mitigate disease in pigs infected with a highly pathogenic Chinese PRRSV strain

    USDA-ARS?s Scientific Manuscript database

    Porcine reproductive and respiratory syndrome virus (PRRSV) is responsible for one of the most economically important diseases in swine worldwide. It causes reproductive failure in sows and pneumonia in pigs that predisposes them to secondary bacterial infections. Methods to control PRRSV and/or lim...

  3. Recovery of pulmonary structure and exercise capacity by treatment with granulocyte-colony stimulating factor (G-CSF) in a mouse model of emphysema.

    PubMed

    Fortunato, Gustavo; Vidal, Daniel T A; Klein, Wilfried; Neto, Alberto; Angrizani, André; Vasconcelos, Juliana F; Kaneto, Carla; Souza, Bruno Solano de Freitas; Ribeiro-dos-Santos, Ricardo; Soares, Milena B P; Macambira, Simone G

    2014-04-01

    Emphysema is a chronic obstructive pulmonary disease characterized abnormal dilatation of alveolar spaces, which impairs alveolar gas exchange, compromising the physical capacity of a patient due to airflow limitations. Here we tested the effects of G-CSF administration in pulmonary tissue and exercise capacity in emphysematous mice. C57Bl/6 female mice were treated with elastase intratracheally to induce emphysema. Their exercise capacities were evaluated in a treadmill. Lung histological sections were prepared to evaluate mean linear intercept measurement. Emphysematous mice were treated with G-CSF (3 cycles of 200 μg/kg/day for 5 consecutive days, with 7-day intervals) or saline and submitted to a third evaluation 8 weeks after treatment. Values of run distance and linear intercept measurement were expressed as mean ± SD and compared applying a paired t-test. Effects of treatment on these parameters were analyzed applying a Repeated Measures ANOVA, followed by Tukey's post hoc analysis. p < 0.05 was considered statistically significant. Twenty eight days later, animals ran significantly less in a treadmill compared to normal mice (549.7 ± 181.2 m and 821.7 ± 131.3 m, respectively; p < 0.01). Treatment with G-CSF significantly increased the exercise capacity of emphysematous mice (719.6 ± 200.5 m), whereas saline treatment had no effect on distance run (595.8 ± 178.5 m). The PCR cytokines genes analysis did not detect difference between experimental groups. Morphometric analyses in the lung showed that saline-treated mice had a mean linear intercept significantly higher (p < 0.01) when compared to mice treated with G-CSF, which did not significantly differ from that of normal mice. Treatment with G-CSF promoted the recovery of exercise capacity and regeneration of alveolar structural alterations in emphysematous mice. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. Safety and Efficacy of a Mouth-Rinse with Granulocyte Colony Stimulating Factor in Patients with Chemotherapy-Induced Oral Mucositis.

    PubMed

    Wang, Lin; Huang, Xin-En; Ji, Zhu-Qing; Liu, Meng-Yan; Qian, Ting; Li, Li

    2016-01-01

    To assess the safety and effectiveness of a mouth-rinse with G-CSF (JiSaiXin, produced by NCPC Biotechnology Co., Ltd) in treating patients with chemotherapy-induced oral mucositis (CIM). A consecutive cohort of patients with advanced cancers and CIM were treated with mouth-rinse G-CSF. All chemotherapy for patients with advanced cancers was adopted from regimens suggested by NCCN guidelines. The mouth-rinse with G-CSF at a dose of 150-300ug plus 100ml-500ml normal saline was started from the time of oral mucositis was confirmed and continuously used for at least 7 days as one course. After at least two courses of treatment, safety and efficacy were evaluated. There were 7 female and 7 male patients with advanced cancer and CIM recruited into this study, including 5 with colorectal, 2 with lung, 1 patient with gastric, 1 with cervical and 1 with pancreatic cancer, as well as 2 patients with diffuse large B cell lymphomas, 1 with nasopharyngeal and 1 with gastric cancer. The median age was 57 (41-79) years. Grade 1 to 2 myelosuppression was observed in 3/14 patients, and Grade 4 myelosuppression in 1/14. Adverse effects on the gastrointestinal tract were documented in 5/14 patients, and were Grade 1 to Grade 3. No treatment related death was documented. Regarding CIM, the median response time to mouth rinse of G-CSF was 2 (1-5) days, and all patients with CIM demonstrated a positive response. Mouth-rinse with G-CSF proved to be safe and effective in treating patients with advanced cancers and CIM. However, further randomized controlled studies should be conducted to clarify the effectiveness of this treatment with other lesions.

  5. Analytical techniques and bioactivity assays to compare the structure and function of filgrastim (granulocyte-colony stimulating factor) therapeutics from different manufacturers.

    PubMed

    Levy, Michaella J; Gucinski, Ashley C; Sommers, Cynthia D; Ghasriani, Houman; Wang, Bo; Keire, David A; Boyne, Michael T

    2014-10-01

    The FDA has approved more than 100 protein and peptide drugs with hundreds more in the pipeline (Lanthier et al. in Nat Rev Drug Discov 7(9):733-737, 2008). Many of these originator biologic products are now coming off patent and are being manufactured by alternate methods than the innovator as follow-on drugs. Because changes to the production method often lead to subtle differences (e.g., degradation products, different posttranslational modifications or impurities) in the therapeutic (Schiestl et al. in Nat Biotechnol 29(4):310-312, 2011), there is a critical need to define techniques to test and insure the quality of these drugs. In addition, the emergence of protein therapeutics manufactured by unapproved methodologies presents an ongoing and growing regulatory challenge. In this work, high-resolution mass spectrometry was used to determine the presence or absence of posttranslational modifications for one FDA-approved and three foreign-sourced, unapproved filgrastim products. Circular dichroism (CD) was used to compare the secondary structure and probe the temperature stability of these products. Native 2D (1)H,(15)N-heteronuclear singular quantum coherence (HSQC) NMR test was applied to these samples to compare the higher-order structure of the four products. Finally, a cell proliferation assay was performed on the filgrastims to compare their bioactivity, and stressed filgrastim was tested in the bioassay to better understand the effects of changes in protein structure on activity. The results showed that orthogonal approaches are capable of characterizing the physiochemical properties of this protein drug and assessing the impact of structural changes on filgrastim purity and potency.

  6. Favorable effect of priming with granulocyte colony-stimulating factor in remission induction of acute myeloid leukemia restricted to dose escalation of cytarabine.

    PubMed

    Pabst, Thomas; Vellenga, Edo; van Putten, Wim; Schouten, Harry C; Graux, Carlos; Vekemans, Marie-Christiane; Biemond, Bart; Sonneveld, Peter; Passweg, Jakob; Verdonck, Leo; Legdeur, Marie-Cecile; Theobald, Matthias; Jacky, Emanuel; Bargetzi, Mario; Maertens, Johan; Ossenkoppele, Gert Jan; Löwenberg, Bob

    2012-06-07

    The clinical value of chemotherapy sensitization of acute myeloid leukemia (AML) with G-CSF priming has remained controversial. Cytarabine is a key constituent of remission induction chemotherapy. The effect of G-CSF priming has not been investigated in relationship with variable dose levels of cytarabine. We randomized 917 AML patients to receive G-CSF (456 patients) or no G-CSF (461 patients) at the days of chemotherapy. In the initial part of the study, 406 patients were also randomized between 2 cytarabine regimens comparing conventional-dose (199 patients) versus escalated-dose (207 patients) cytarabine in cycles 1 and 2. We found that patients after induction chemotherapy plus G-CSF had similar overall survival (43% vs 40%, P = .88), event-free survival (37% vs 31%, P = .29), and relapse rates (34% vs 36%, P = .77) at 5 years as those not receiving G-CSF. However, patients treated with the escalated-dose cytarabine regimen benefited from G-CSF priming, with improved event-free survival (P = .01) and overall survival (P = .003), compared with patients without G-CSF undergoing escalated-dose cytarabine treatment. A significant survival advantage of sensitizing AML for chemotherapy with G-CSF was not apparent in the entire study group, but it was seen in patients treated with escalated-dose cytarabine during remission induction. The HOVON-42 study is registered under The Netherlands Trial Registry (www.trialregister.nl) as #NTR230.

  7. [Granulocyte- colony stimulating factor (G-CSF) use in clinical practice in patients receiving chemotherapy for breast cancer: The Opaline Study].

    PubMed

    Jacot, William; Antoine, Eric-Charles; Hacini, Maya; Giron, Cathy; Rivière, Alain; Moureau-Zabotto, Laurence; Cassin, Daniel; Yazbek, Gabriel; Orfeuvre, Hubert; Sakek, Nacera; Diab, Rafik; Bastit, Laurent; Mille, Dominique; Azria, David

    2015-12-01

    To describe the French routine use of G-CSF in patients treated for breast cancer as per the EORTC recommendations. A prospective multicenter observational study conducted between February 2008 and September 2009 in 869 breast cancer patients treated by chemotherapy (CT) and for whom G-CSF treatment will be delivered in primary (PP) or secondary prophylaxis. The mean age was 55 years. A total of 80.3% of CT was in neoadjuvant/adjuvant setting (NAS). PP was delivered in 78.9% of the NAS patients and 67.5% in metastatic situation. Of the 702 evaluable patients, incidences of severe (SN) and febrile neutropenias (FN) in patients who received PP were 9.3% and 4.2%, respectively. In patients who did not received G-CSF at first cycle, SN and FN were 12.4% and 7.3%, respectively. The use of PP was mainly driven by the type of CT for patients treated in the NAS and by patient or disease related risk factors in the locally advanced/metastatic setting. This study has shown that the use of G-CSF was in accordance with the 2010 updates of the EORTC recommendations. However, G-CSF appears more widely used in the routine practice. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  8. Acute iritis induced by granulocyte colony-stimulating factor used for mobilization in a volunteer unrelated peripheral blood progenitor cell donor.

    PubMed

    Parkkali, T; Volin, L; Sirén, M K; Ruutu, T

    1996-03-01

    We describe a volunteer unrelated peripheral blood progenitor cell donor with previously diagnosed dermatitis herpetiformis in whom the administration of G-CSF for the mobilization of precursor cells induced acute iritis. G-CSF has been administered to healthy people with minimal side-effects but when used in patients with autoimmune disorders worsening of symptoms or new manifestations may be a potential concern.

  9. [Use of filgrastim, granulocyte colony stimulating factor (G-CSF), in radiotherapy to reduce drop-outs because of radiogenic leukopenia].

    PubMed

    Gava, A; Bertossi, L; Ferrarese, F; Coghetto, F; Marazzato, G; Andrulli, A D; Zorat, P L

    1998-03-01

    Radiotherapy patients are at risk of developing leukopenia, which risk depends on the irradiated volume, the rate of irradiated bone marrow and the radiation dose. Radiogenic leukopenia may cause radiotherapy drop-out, with consequent effects, on local tumor control and clinical outcome. The introduction of granulocyte growth factors, such as filgrastim, has permitted to accelerate normal neutrophil count recovery in irradiation-related neutropenia both in vitro and animal models; clinical experience in humans is still lacking, relative to both indications and scheduling. In the Oncologic Radiotherapy Department of Treviso Hospital, 31 patients irradiated for Hodgkin disease, rectal cancer and other malignancies, who presented leukopenia requiring treatment discontinuation, were given filgrastim to assess its actual effect in avoiding further drop-outs and to compare two administration schedules (2 or 3 vials, 30 MIU, weekly). Filgrastim treatment was continued throughout the radiotherapy cycles, for 1 to 5 weeks. Eighteen patients had received previous chemotherapy and 11 were undergoing concurrent 5-fluorouracil chemotherapy-irradiation. A mean 203% increase in leukocyte count was observed (136% in the patients treated with 2 vials/week and 274% in those receiving 3 vials/week); this increase was more apparent in women that in men (256% versus 91%) and slightly higher in patients 50 years old and with target volumes < 5000 ml. Filgrastin treatment was well tolerated by all patients, with no discontinuations due to adverse effects; 9 patients (29%) reported skeletal pain, which was marked in 2 of them only. Eighty percent of patients completed all the radiotherapy cycles with no discontinuation, while 6 patients dropped out because leukopenia persisted. Biweekly filgrastim administration was effective to prevent unscheduled radiotherapy discontinuation in 75% of patients and triweekly administration was effective in 86% of patients. In our experience, filgrastim administration was well tolerated and effective in decreasing the irradiation drop-outs caused by treatment-related leukopenia. Since this drug is rather expensive, we decided to use routinely the lower dosage of biweekly administration (with one vial given on Friday and Saturday, to permit neutrophil recovery during the day off) and to reserve the higher dosage (3 vials a week) to the patients with large body areas, big target volumes and persistent leukopenia during previous chemotherapy.

  10. Severe Agranulocytosis following Simultaneous Administration of Chlorpromazine and Trimethoprim-Sulfamethoxazole in a Patient with Sepsis: A Possible Toxic Combination

    PubMed Central

    Jha, Anil; Ghoz, Hassan

    2016-01-01

    Background. Chlorpromazine and trimethoprim-sulfamethoxazole (TMP/SMX) are two commonly prescribed medications by physicians. Either of those medications could cause fatal drug-induced agranulocytosis, with an unclear underlying mechanism. The likelihood of simultaneous prescription of both medications is high and could hypothetically result in severe agranulocytosis that is resistant to treatment. Case Presentation. We are presenting a case of a patient with psychosis on chlorpromazine who was prescribed TMP/SMX for a urinary tract infection. Consequently, the patient developed severe agranulocytosis and septicemia. Patient was managed by granulocyte colony-stimulating factor; however, the time to neutrophil recovery was delayed when compared to the average reported time published by previous studies. Conclusions. Simultaneous use of chlorpromazine and TMP/SMX is a possible toxic combination that could induce severe agranulocytosis. Further reports are needed to confirm this observation. PMID:27829837

  11. Granulocyte and granulocyte macrophage colony-stimulating factors as therapy in human and veterinary medicine.

    PubMed

    Fernández-Varón, Emilio; Villamayor, Lucía

    2007-07-01

    Granulocyte colony-stimulating factors (G-CSFs) and granulocyte macrophage colony-stimulating factors (GM-CSFs) are endogenous cytokines that regulate granulocyte colonies and play a major role in the stimulation of granulopoiesis (neutrophils, basophils and eosinophils) and in the regulation of microbicidal functions. There are numerous pathological conditions in which neutrophils are decreased, the most common being neutropenia associated with cancer chemotherapy, which increases the risk of serious microbial infections developing with the potential for high morbidity and mortality. New methods in molecular biology have led to the identification and cloning of CSF genes and biopharmaceutical production. Since then, CSFs have been widely used for the prevention and treatment of neutropenia associated with cancer chemotherapy, for mobilising haematopoietic cell precursors, and for other neutropenia-related pathologies. This review focuses on the use of CSFs within both human and veterinary medicine. Clinical applications, pharmacology, tolerability and the potential role of these factors in veterinary medicine are considered.

  12. Modulation of colony stimulating factor release and apoptosis in human colon cancer cells by anticancer drugs

    PubMed Central

    Calatayud, S; Warner, T D; Mitchell, J A

    2002-01-01

    Modulation of the immune response against tumour cells is emerging as a valuable approach for cancer treatment. Some experimental studies have shown that secretion of colony stimulating factors by cancer cells reduces their tumorigenicity and increases their immunogenicity probably by promoting the cytolitic and antigen presenting activities of leukocytes. We have observed that human colon cancer cells (HT-29) are able to secrete granulocyte-macrophage-colony stimulating factor, granulocyte-colony stimulating factor and macrophage-colony stimulating factor when stimulated with cytokines (IL-1β and TNF-α). In this study we assessed, for the first time, the effects of several anticancer drugs on colony stimulating factor release or apoptosis in HT-29 cells. Cytokine-induced release of granulocyte-macrophage-colony stimulating factor, granulocyte-colony stimulating factor and macrophage-colony stimulating factor was significantly increased by cisplatin and 6-mercaptopurine. Taxol only increased macrophage-colony stimulating factor release while reduced that of granulocyte-colony stimulating factor. No changes in colony stimulating factor secretion were observed after treatment with methotrexate. Only cisplatin and taxol induced apoptosis in these cells. Secretion of colony stimulating factors by colon cancer cells may contribute to the immune host response against them. Anticancer drugs such as cisplatin and 6-mercaptopurine increase colony stimulating factor secretion by cytokine stimulated cancer cells probably through mechanisms different to those leading to cell apoptosis, an effect that may contribute to their anti-neoplasic action. British Journal of Cancer (2002) 86, 1316–1321. DOI: 10.1038/sj/bjc/6600240 www.bjcancer.com © 2002 Cancer Research UK PMID:11953891

  13. Physiological Mechanisms in Combined Electric-Acoustic Stimulation.

    PubMed

    Sato, Mika; Baumhoff, Peter; Tillein, Jochen; Kral, Andrej

    2017-09-01

    Electrical stimulation is normally performed on ears that have no hearing function, i.e., lack functional hair cells. The properties of electrically-evoked responses in these cochleae were investigated in several previous studies. Recent clinical developments have introduced cochlear implantation (CI) in residually-hearing ears to improve speech understanding in noise. The present study documents the known physiological differences between electrical stimulation of hair cells and of spiral ganglion cells, respectively, and reviews the mechanisms of combined electric and acoustic stimulation in the hearing ears. Literature review from 1971 to 2016. Compared with pure electrical stimulation the combined electroacoustic stimulation provides additional low-frequency information and expands the dynamic range of the input. Physiological studies document a weaker synchronization of the evoked activity in electrically stimulated hearing ears compared with deaf ears that reduces the hypersynchronization of electrically-evoked activity. The findings suggest the possibility of balancing the information provided by acoustic and electric input using stimulus intensity. Absence of distorting acoustic-electric interactions allows exploiting these clinical benefits of electroacoustic stimulation.

  14. Exploring Erythropoietin and G-CSF Combination Therapy in Chronic Stroke Patients

    PubMed Central

    Shin, Yoon-Kyum; Cho, Sung-Rae

    2016-01-01

    Erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) are known to have neuroprotective actions. Based on previous reports showing the synergistic effects of EPO+G-CSF combination therapy in experimental models, we investigated the safety of EPO+G-CSF combination therapy in patients with chronic stroke. In a pilot study, 3 patients were treated with EPO and G-CSF for 5 consecutive days, with follow-up on day 30. In an exploratory double-blind study, 6 patients were allocated to treatment with either EPO+G-CSF or placebo. Treatment was applied once a day for 5 days per month over 3 months. Participants were followed up for 6 months. To substantiate safety, vital signs, adverse events, and hematological values were measured on days 0, 5, and 30 in each cycle and on day 180. Functional outcomes were determined on day 0 and 180. In the laboratory measurements, EPO+G-CSF combination therapy significantly elevated erythropoietin, CD34+ hematopoietic stem cells, white blood cells, and neutrophils on day 5 of each cycle. There were no observations of serious adverse events. In the functional outcomes, the grip power of the dominant hand was increased in the EPO+G-CSF treatment group. In conclusion, this exploratory study suggests a novel strategy of EPO+G-CSF combination therapy for stroke patients. PMID:27043535

  15. Combined Dextroamphetamine and Transcranial Direct Current Stimulation in Poststroke Aphasia.

    PubMed

    Keser, Zafer; Dehgan, Michelle Weber; Shadravan, Shaparak; Yozbatiran, Nuray; Maher, Lynn M; Francisco, Gerard E

    2017-10-01

    There is a growing need for various effective adjunctive treatment options for speech recovery after stroke. A pharmacological agent combined with noninvasive brain stimulation has not been previously reported for poststroke aphasia recovery. In this "proof of concept" study, we aimed to test the safety of a combined intervention consisting of dextroamphetamine, transcranial direct current stimulation, and speech and language therapy in subjects with nonfluent aphasia. Ten subjects with chronic nonfluent aphasia underwent two experiments where they received dextroamphetamine or placebo along with transcranial direct current stimulation and speech and language therapy on two separate days. The Western Aphasia Battery-Revised was used to monitor changes in speech performance. No serious adverse events were observed. There was no significant increase in blood pressure with amphetamine or deterioration in speech and language performance. Western Aphasia Battery-Revised aphasia quotient and language quotient showed a statistically significant increase in the active experiment. Comparison of proportional changes of aphasia quotient and language quotient in active experiment with those in placebo experiment showed significant difference. We showed that the triple combination therapy is safe and implementable and seems to induce positive changes in speech and language performance in the patients with chronic nonfluent aphasia due to stroke.

  16. Pegfilgrastim prophylaxis is associated with a lower risk of hospitalization of cancer patients than filgrastim prophylaxis: a retrospective United States claims analysis of granulocyte colony-stimulating factors (G-CSF)

    PubMed Central

    2013-01-01

    Background Myelosuppressive chemotherapy can lead to dose-limiting febrile neutropenia. Prophylactic use of recombinant human G-CSF such as daily filgrastim and once-per-cycle pegfilgrastim may reduce the incidence of febrile neutropenia. This comparative study examined the effect of pegfilgrastim versus daily filgrastim on the risk of hospitalization. Methods This retrospective United States claims analysis utilized 2004–2009 data for filgrastim- and pegfilgrastim-treated patients receiving chemotherapy for non-Hodgkin’s lymphoma (NHL) or breast, lung, ovarian, or colorectal cancers. Cycles in which pegfilgrastim or filgrastim was administered within 5 days from initiation of chemotherapy (considered to represent prophylaxis) were pooled for analysis. Neutropenia-related hospitalization and other healthcare encounters were defined with a “narrow” criterion for claims with an ICD-9 code for neutropenia and with a “broad” criterion for claims with an ICD-9 code for neutropenia, fever, or infection. Odds ratios (OR) for hospitalization and 95% confidence intervals (CI) were estimated by generalized estimating equation (GEE) models and adjusted for patient, tumor, and treatment characteristics. Per-cycle healthcare utilization and costs were examined for cycles with pegfilgrastim or filgrastim prophylaxis. Results We identified 3,535 patients receiving G-CSF prophylaxis, representing 12,056 chemotherapy cycles (11,683 pegfilgrastim, 373 filgrastim). The mean duration of filgrastim prophylaxis in the sample was 4.8 days. The mean duration of pegfilgrastim prophylaxis in the sample was 1.0 day, consistent with the recommended dosage of pegfilgrastim - a single injection once per chemotherapy cycle. Cycles with prophylactic pegfilgrastim were associated with a decreased risk of neutropenia-related hospitalization (narrow definition: OR = 0.43, 95% CI: 0.16–1.13; broad definition: OR = 0.38, 95% CI: 0.24–0.59) and all-cause hospitalization (OR = 0.50, 95% CI: 0.35–0.72) versus cycles with prophylactic filgrastim. For neutropenia-related utilization by setting of care, there were more ambulatory visits and hospitalizations per cycle associated with filgrastim prophylaxis than with pegfilgrastim prophylaxis. Mean per-cycle neutropenia-related costs were also higher with prophylactic filgrastim than with prophylactic pegfilgrastim. Conclusions In this comparative effectiveness study, pegfilgrastim prophylaxis was associated with a reduced risk of neutropenia-related or all-cause hospitalization relative to filgrastim prophylaxis. PMID:23298389

  17. Prophylactic administration of vector-encoded porcine granulocyte-colony stimulating factor reduces Salmonella shedding,tonsil colonization,& microbiota alterations of the gastrointestinal tract in Salmonella-challenged swine

    USDA-ARS?s Scientific Manuscript database

    Salmonella colonization of food animals is a concern for animal health and public health as a food safety risk. Various obstacles impede the effort to reduce asymptomatic Salmonella carriage in food animals, including the existence of numerous serovars and the ubiquitous nature of Salmonella. To d...

  18. Pegfilgrastim prophylaxis is associated with a lower risk of hospitalization of cancer patients than filgrastim prophylaxis: a retrospective United States claims analysis of granulocyte colony-stimulating factors (G-CSF).

    PubMed

    Naeim, Arash; Henk, Henry J; Becker, Laura; Chia, Victoria; Badre, Sejal; Li, Xiaoyan; Deeter, Robert

    2013-01-08

    Myelosuppressive chemotherapy can lead to dose-limiting febrile neutropenia. Prophylactic use of recombinant human G-CSF such as daily filgrastim and once-per-cycle pegfilgrastim may reduce the incidence of febrile neutropenia. This comparative study examined the effect of pegfilgrastim versus daily filgrastim on the risk of hospitalization. This retrospective United States claims analysis utilized 2004-2009 data for filgrastim- and pegfilgrastim-treated patients receiving chemotherapy for non-Hodgkin's lymphoma (NHL) or breast, lung, ovarian, or colorectal cancers. Cycles in which pegfilgrastim or filgrastim was administered within 5 days from initiation of chemotherapy (considered to represent prophylaxis) were pooled for analysis. Neutropenia-related hospitalization and other healthcare encounters were defined with a "narrow" criterion for claims with an ICD-9 code for neutropenia and with a "broad" criterion for claims with an ICD-9 code for neutropenia, fever, or infection. Odds ratios (OR) for hospitalization and 95% confidence intervals (CI) were estimated by generalized estimating equation (GEE) models and adjusted for patient, tumor, and treatment characteristics. Per-cycle healthcare utilization and costs were examined for cycles with pegfilgrastim or filgrastim prophylaxis. We identified 3,535 patients receiving G-CSF prophylaxis, representing 12,056 chemotherapy cycles (11,683 pegfilgrastim, 373 filgrastim). The mean duration of filgrastim prophylaxis in the sample was 4.8 days. The mean duration of pegfilgrastim prophylaxis in the sample was 1.0 day, consistent with the recommended dosage of pegfilgrastim - a single injection once per chemotherapy cycle. Cycles with prophylactic pegfilgrastim were associated with a decreased risk of neutropenia-related hospitalization (narrow definition: OR = 0.43, 95% CI: 0.16-1.13; broad definition: OR = 0.38, 95% CI: 0.24-0.59) and all-cause hospitalization (OR = 0.50, 95% CI: 0.35-0.72) versus cycles with prophylactic filgrastim. For neutropenia-related utilization by setting of care, there were more ambulatory visits and hospitalizations per cycle associated with filgrastim prophylaxis than with pegfilgrastim prophylaxis. Mean per-cycle neutropenia-related costs were also higher with prophylactic filgrastim than with prophylactic pegfilgrastim. In this comparative effectiveness study, pegfilgrastim prophylaxis was associated with a reduced risk of neutropenia-related or all-cause hospitalization relative to filgrastim prophylaxis.

  19. Characterization of recombinant human granulocyte colony-stimulating factor expression by FT-IR spectroscopy: Studies on thermal induction and media formulation on the stability of the protein secondary structure.

    PubMed

    Vemula, Sandeep; Vemula, Sushma; Dedaniya, Akshay; Kante, Rajesh Kumar; Ronda, Srinivasa Reddy

    2016-08-17

    The Fourier-transform infrared (FT-IR) spectroscopic approach has been employed to understand the recombinant human G-CSF (rhG-CSF) protein accumulation, secondary structure, and thermal stability in Escherichia coli grown under a temperature shift strategy (37 and 28°C) in various media formulations. The choline + sodium pyruvate (37°C) and sodium pyruvate (28°C) formulations have shown the highest inclusion body (IB) accumulation of 0.41 and 0.46 mg/mL, respectively. Furthermore, insights on the structure of the rhG-CSF within IBs and intact cells have been investigated through secondary structure analysis. Thermal stability experiments were also carried out to explain the pattern of the second derivative structure of rhG-CSF. The studies showed that choline + sodium pyruvate formulation has preserved the protein secondary structure even at 82°C. Overall, the FT-IR spectroscopic technique can also be adopted to accelerate the characterization of other recombinant therapeutic proteins of E. coli origin.

  20. Problems in early diagnosis of bladder cancer in a spinal cord injury patient: Report of a case of simultaneous production of granulocyte colony stimulating factor and parathyroid hormone-related protein by squamous cell carcinoma of urinary bladder

    PubMed Central

    Vaidyanathan, Subramanian; Mansour, Paul; Ueno, Munehisa; Yamazaki, Kazuto; Wadhwa, Meenu; Soni, Bakul M; Singh, Gurpreet; Hughes, Peter L; Watson, Ian D; Sett, Pradipkumar

    2002-01-01

    Background Typical symptoms and signs of a clinical condition may be absent in spinal cord injury (SCI) patients. Case presentation A male with paraplegia was passing urine through penile sheath for 35 years, when he developed urinary infections. There was no history of haematuria. Intravenous urography showed bilateral hydronephrosis. The significance of abnormal outline of bladder was not appreciated. As there was large residual urine, he was advised intermittent catheterisation. Serum urea: 3.5 mmol/L; creatinine: 77 umol/L. A year later, serum urea: 36.8 mmol/l; creatinine: 632 umol/l; white cell count: 22.2; neutrophils: 18.88. Ultrasound: bilateral hydronephrosis. Bilateral nephrostomy was performed. Subsequently, blood tests showed: Urea: 14.2 mmol/l; Creatinine: 251 umol/l; Adjusted Calcium: 3.28 mmol/l; Parathyroid hormone: < 0.7 pmol/l (1.1 – 6.9); Parathyroid hormone-related protein (PTHrP): 2.3 pmol/l (0.7 – 1.8). Ultrasound scan of urinary bladder showed mixed echogenicity, which was diagnosed as debris. CT of pelvis was interpreted as vesical abscess. Urine cytology: Transitional cells showing mild atypia. Bladder biopsy: Inflamed mucosa lined by normal urothelial cells. A repeat ultrasound scan demonstrated a tumour arising from right lateral wall; biopsy revealed squamous cell carcinoma. In view of persistently high white cell count and high calcium level, immunohistochemistry for G-CSF and PTHrP was performed. Dense staining of tumour cells for G-CSF and faintly positive staining for C-terminal PTHrP were observed. This patient expired about five months later. Conclusion This case demonstrates how delay in diagnosis of bladder cancer could occur in a SCI patient due to absence of characteristic symptoms and signs. PMID:12201902

  1. Idarubicin, intermediate-dose cytarabine, etoposide, and granulocyte-colony-stimulating factor are able to recruit CD34+/HLA-DR- cells during early hematopoietic recovery in accelerated and chronic phases of chronic myeloid leukemia.

    PubMed

    Carella, A M; Frassoni, F; Podestá, M; Pungolino, E; Pollicardo, N; Ferrero, R; Soracco, M

    1994-01-01

    A group of 46 patients with chronic myelogenous leukemia (CML) [chronic phase (CP), 24 patients; accelerated phase (AP), 22 patients] ineligible for allogeneic bone marrow transplantation were given an intensive chemotherapy regimen consisting of idarubicin, intermediate-dose cytarabine, and etoposide. All patients had previously received interferon-alpha and only 2 had shown a partial cytogenetic response. During early recovery from chemotherapy-induced aplasia, peripheral blood progenitor cells (PBPC) were harvested by leukapheresis. All metaphases were found to be Philadelphia chromosome (Ph) negative in the collection from 17 of 46 (37%) patients [CP, 12 of 24 (50%); AP, 5 of 22 (23%)], and a decrease to less than 50% Ph-positive metaphases was seen in an additional 6 (CP, 3 patients; AP, 3 patients). The percentage of patients showing complete Ph disappearance was 64% in those receiving this procedure within the first year of diagnosis. In vitro studies were performed to assess the behavior of the Ph-negative PBPC. In clonogenic cultures they responded to stem cell factor and were able to grow as mixed colonies. Moreover, long-term culture initiating cells (LTCIC) were present in many Ph-negative collections but rarely in Ph-positive PBPC. In 4 females, clonality was studied by analyzing X chromosome inactivation and methylation patterns of the DXS255 locus with the probe M27 beta. Hematopoiesis was polyclonal in all 4 patients tested. Thus far, the Ph-negative collections have been used for autografting in 16 patients (CP, 11 patients; PA, 5 patients) after conditioning with total-body irradiation, etoposide, and cyclophosphamide or idarubicin.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Combined transcranial alternating current stimulation and continuous theta burst stimulation: a novel approach for neuroplasticity induction.

    PubMed

    Goldsworthy, Mitchell R; Vallence, Ann-Maree; Yang, Ruiting; Pitcher, Julia B; Ridding, Michael C

    2016-02-01

    Non-invasive brain stimulation can induce functionally relevant plasticity in the human cortex, making it potentially useful as a therapeutic tool. However, the induced changes are highly variable between individuals, potentially limiting research and clinical utility. One factor that might contribute to this variability is the level of cortical inhibition at the time of stimulation. The alpha rhythm (~ 8-13 Hz) recorded with electroencephalography (EEG) is thought to reflect pulsatile cortical inhibition; therefore, targeting non-invasive brain stimulation to particular phases of the alpha rhythm may provide an approach to enhance plasticity induction. Transcranial alternating current stimulation (tACS) has been shown to entrain cortical oscillations in a frequency-specific manner. We investigated whether the neuroplastic response to continuous theta burst stimulation (cTBS) was enhanced by timing bursts of stimuli to the peak or the trough of a tACS-imposed alpha rhythm. While motor evoked potentials (MEPs) were unaffected when cTBS was applied in-phase with the peak of the tACS-imposed oscillation, MEP depression was enhanced when cTBS was applied in-phase with the trough. This enhanced MEP depression was dependent on the individual peak frequency of the endogenous alpha rhythm recorded with EEG prior to stimulation, and was strongest in those participants classified as non-responders to standard cTBS. These findings suggest that tACS may be used in combination with cTBS to enhance the plasticity response. Furthermore, the peak frequency of endogenous alpha, as measured with EEG, may be used as a simple marker to pre-select those individuals likely to benefit from this approach. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  3. Combined Spinal Cord Stimulation and Peripheral Nerve Stimulation for Brachial Plexopathy: A Case Report.

    PubMed

    Choi, Ji Hye; Choi, Shu Chung; Kim, Dong Kyu; Sung, Choon Ho; Chon, Jin Young; Hong, Sung Jin; Lee, Ji Young; Moon, Ho Sik

    2016-03-01

    Brachial plexopathy usually results from an iatrogenic brachial plexus injury and can sometimes cause severe chronic pain and disability. There are a number of possible treatments for this condition, including medication, physical therapy, nerve blocks, and neuromodulation, but they are not always successful. Recently, combined spinal cord stimulation (SCS) and peripheral nerve stimulation (PNS) have been tried for various chronic pain diseases because of their different mechanisms of action.Here, we describe the case of a 54-year-old man who was diagnosed with brachial plexopathy 8 years ago. He underwent video-assisted thoracoscopic surgery to remove a superior mediastinal mass. However, his brachial plexus was damaged during the surgery. Although he had received various treatments, the pain did not improve. For the management of intractable severe pain, he underwent SCS 2 years ago, which initially reduced his pain from numeric rating scale (NRS) 10/10 to NRS 4 - 5/10, but the pain then gradually increased, reaching NRS 8/10, 6 months ago. At that time, he was refractory to other treatments, and we therefore applied PNS in combination with SCS. The PNS electrode was positioned on the radial nerve under ultrasound guidance. After combined PNS and SCS, his background pain disappeared, although a breakthrough pain (NRS 3 - 4/10) was caused intermittently by light touch. Furthermore, the patient's need for analgesics decreased, and he was satisfied with the outcome of this combined treatment. We concluded that combined SCS and PNS is a very useful treatment modality, which can stimulate the target nerve both directly and indirectly, and hence, relieve pain from brachial plexopathy.

  4. nab-Paclitaxel in Combination with Carboplatin for a Previously Treated Thymic Carcinoma

    PubMed Central

    Makimoto, Go; Fujiwara, Keiichi; Watanabe, Hiromi; Kameyama, Nobuhisa; Matsushita, Mizuho; Rai, Kammei; Sato, Ken; Yonei, Toshiro; Sato, Toshio; Shibayama, Takuo

    2014-01-01

    We present the case of a 40-year-old man with previously treated thymic carcinoma, complaining of gradually worsening back pain. Computed tomography scans of the chest showed multiple pleural disseminated nodules with a pleural effusion in the right thorax. The patient was treated with carboplatin on day 1 plus nab-paclitaxel on day 1 and 8 in cycles repeated every 4 weeks. Objective tumor shrinkage was observed after 4 cycles of this regimen. In addition, the elevated serum cytokeratin 19 fragment level decreased, and the patient's back pain was relieved without any analgesics. Although he experienced grade 4 neutropenia and granulocyte colony-stimulating factor (G-CSF) injection, the severity of thrombocytopenia and nonhematological toxicities such as reversible neuropathy did not exceed grade 1 during the treatment. To our knowledge, this is the first report to demonstrate the efficacy of combination chemotherapy consisting of carboplatin and nab-paclitaxel against thymic carcinoma. This case report suggests that nab-paclitaxel in combination with carboplatin can be a favorable chemotherapy regimen for advanced thymic carcinoma. PMID:24575009

  5. A Combined Anterior Pituitary Stimulation Test: Experience With 285 Individuals

    PubMed Central

    Elias, Alan N.; Valenta, Lubomir J.

    1987-01-01

    A pituitary reserve test was performed in 285 individuals. Eighteen were healthy volunteers without any endocrine disease, 25 suffered from a presumed hypothalamic abnormality, 22 from hypopituitarism, 10 from acromegaly, 65 from the amenorrhea-galactorrhea syndrome, 2 from Nelson's syndrome, 32 from borderline primary hypothyroidism, 15 from borderline hyperthyroidism, 20 were on chronic levothyroxine therapy for primary hypothyroidism, and 15 had severe uncorrected primary hypothyroidism. Sixteen postmenopausal women were also included, as well as 15 patients with idiopathic ovarian failure and six with ovarian dysgenesis. Twelve male patients with hypergonadotropic and 12 with hypogonadotropic hypogonadism were also examined. The pituitary reserve test consisted of intravenous administration of a mixture of the thyrotropin-releasing hormone (TRH), gonadotropin-releasing hormone (GnRH), and regular insulin. The following tests were obtained prior to the injection only (time 0): serum thyroxine (T4), tri-iodothyronine (T3), T3 resin uptake or thyroxine-binding globulin, total and free testosterone in men, estradiol and progesterone in women, and sex hormone binding globulin. At times 0, 20, 30, and 60 minutes, serum concentrations of the following compounds were obtained: glucose, adrenocorticotropic hormone, cortisol, growth hormone, prolactin, thyroid-stimulating hormone, luteinizing hormone, and follicle-stimulating hormone. Normal responses were established in a large number of cases. More or less typical patterns were demonstrated in the above-listed disease categories. Poor correlations between basal and stimulated values were observed, which emphasizes the diagnostic importance of the stimulation test. Maximum data were obtained using a combined test that has negligible morbidity, may be performed within an hour in an outpatient setting, and which examines the anterior pituitary function in a comprehensive fashion. PMID:3121862

  6. [Examination of the safety of docetaxel/cyclophosphamide combination therapy for advanced recurrent breast cancer].

    PubMed

    Yoneyama, Kimiyasu; Koshida, Yoshitomo; Toriumi, Fumiki; Murayama, Takaya; Toeda, Hiroyuki; Imazu, Yoshihiro; Motegi, Katsuhiko; Akamatsu, Hidetoshi; Ohyama, Renpei

    2006-10-01

    In the treatment of recurrent breast cancer in patients previously treated with anthracycline drugs, taxane drugs are generally used. This time, we retrospectively studied the safety of docetaxel/cyclophosphamide combination therapy (hereinafter referred to as TC therapy). Ten patients (mean age: 52.8 years old) were included in the study. Metastatic/recurrent sites included 3 skin, 2 each of contralateral breast, lung and bone, and 1 each of liver, carcinomatous pleurisy and supraclavicular lymph node. Seven patients had a history of anthracycline treatment. The patients received TC at doses of 60 mg/m(2) and 500 mg/m(2), respectively, every 3 weeks. With regard to adverse events, non-hematotoxic events included alopecia in all the patients, generalized malaise in 5, and abnormal nail in 1. Hematotoxic events were grades 2 and 3 decreased neutrophil count in 5 patients. One patient had grade 4 pyrexia associated with oral candida. The patient was admitted and treated with fluid replacement and granulocyte colony-stimulating factor (G-CSF). There were no other patients in whom the treatment was prolonged or dosage was reduced due to adverse reactions. TC therapy is considered to be a beneficial treatment method in terms of safety since it can be instituted on an outpatient basis.

  7. The potential role of recombinant hematopoietic colony-stimulating factors in preventing infections in the immunocompromised host

    PubMed Central

    Rusthoven, James

    1991-01-01

    Hematopoietic colony-stimulating factors coordinate the proliferation and maturation of bone marrow and peripheral blood cells during normal hematopoiesis. Most of these factors are now available as recombinant human colony-stimulating factors, and preclinical and clinical testing is proceeding rapidly. Granulocyte and granulocyte/macrophage colony-stimulating factors have been the most extensively studied to date. In human clinical trials, granulocyte colony-stimulating factor improves neutrophil counts and function, reduces episodes of febrile neutropenia, improves neutrophil recovery after disease- or treatment-induced myelosuppression, and reduces the number of serious infections in several neutropenic disease states. Granulocyte/macrophage colony-stimulating factor has similar biological properties but may also improve eosinophil proliferation and function, and platelet cell recovery after myelotoxic bone marrow injury, Interleukin-1 boosts the effects of granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor, but also may promote the resolution of established infections in conjunction with antibiotics. The therapeutic realities and future therapeutic implications of these agents for the therapy of infections, cancer and hemopoietic disorders are discussed. PMID:22529714

  8. Mimicking Isovolumic Contraction with Combined Electromechanical Stimulation Improves the Development of Engineered Cardiac Constructs

    PubMed Central

    Morgan, Kathy Ye

    2014-01-01

    Electrical and mechanical stimulation have both been used extensively to improve the function of cardiac engineered tissue as each of these stimuli is present in the physical environment during normal development in vivo. However, to date, there has been no direct comparison between electrical and mechanical stimulation and current published data are difficult to compare due to the different systems used to create the engineered cardiac tissue and the different measures of functionality studied as outcomes. The goals of this study were twofold. First, we sought to directly compare the effects of mechanical and electrical stimulation on engineered cardiac tissue. Second, we aimed to determine the importance of the timing of the two stimuli in relation to each other in combined electromechanical stimulation. We hypothesized that delaying electrical stimulation after the beginning of mechanical stimulation to mimic the biophysical environment present during isovolumic contraction would improve construct function by improving proteins responsible for cell–cell communication and contractility. To test this hypothesis, we created a bioreactor system that would allow us to electromechanically stimulate engineered tissue created from neonatal rat cardiac cells entrapped in fibrin gel during 2 weeks in culture. Contraction force was higher for all stimulation groups as compared with the static controls, with the delayed combined stimulation constructs having the highest forces. Mechanical stimulation alone displayed increased final cell numbers but there were no other differences between electrical and mechanical stimulation alone. Delayed combined stimulation resulted in an increase in SERCA2a and troponin T expression levels, which did not happen with synchronous combined stimulation, indicating that the timing of combined stimulation is important to maximize the beneficial effect. Increases in Akt protein expression levels suggest that the improvements are at least in

  9. Mimicking isovolumic contraction with combined electromechanical stimulation improves the development of engineered cardiac constructs.

    PubMed

    Morgan, Kathy Ye; Black, Lauren Deems

    2014-06-01

    Electrical and mechanical stimulation have both been used extensively to improve the function of cardiac engineered tissue as each of these stimuli is present in the physical environment during normal development in vivo. However, to date, there has been no direct comparison between electrical and mechanical stimulation and current published data are difficult to compare due to the different systems used to create the engineered cardiac tissue and the different measures of functionality studied as outcomes. The goals of this study were twofold. First, we sought to directly compare the effects of mechanical and electrical stimulation on engineered cardiac tissue. Second, we aimed to determine the importance of the timing of the two stimuli in relation to each other in combined electromechanical stimulation. We hypothesized that delaying electrical stimulation after the beginning of mechanical stimulation to mimic the biophysical environment present during isovolumic contraction would improve construct function by improving proteins responsible for cell-cell communication and contractility. To test this hypothesis, we created a bioreactor system that would allow us to electromechanically stimulate engineered tissue created from neonatal rat cardiac cells entrapped in fibrin gel during 2 weeks in culture. Contraction force was higher for all stimulation groups as compared with the static controls, with the delayed combined stimulation constructs having the highest forces. Mechanical stimulation alone displayed increased final cell numbers but there were no other differences between electrical and mechanical stimulation alone. Delayed combined stimulation resulted in an increase in SERCA2a and troponin T expression levels, which did not happen with synchronous combined stimulation, indicating that the timing of combined stimulation is important to maximize the beneficial effect. Increases in Akt protein expression levels suggest that the improvements are at least in

  10. A neuroprotective function for the hematopoietic protein granulocyte-macrophage colony stimulating factor (GM-CSF).

    PubMed

    Schäbitz, Wolf-Rüdiger; Krüger, Carola; Pitzer, Claudia; Weber, Daniela; Laage, Rico; Gassler, Nikolaus; Aronowski, Jaroslaw; Mier, Walter; Kirsch, Friederike; Dittgen, Tanjew; Bach, Alfred; Sommer, Clemens; Schneider, Armin

    2008-01-01

    Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic cytokine responsible for the proliferation, differentiation, and maturation of cells of the myeloid lineage, which was cloned more than 20 years ago. Here we uncovered a novel function of GM-CSF in the central nervous system (CNS). We identified the GM-CSF alpha-receptor as an upregulated gene in a screen for ischemia-induced genes in the cortex. This receptor is broadly expressed on neurons throughout the brain together with its ligand and induced by ischemic insults. In primary cortical neurons and human neuroblastoma cells, GM-CSF counteracts programmed cell death and induces BCL-2 and BCL-Xl expression in a dose- and time-dependent manner. Of the signaling pathways studied, GM-CSF most prominently induced the PI3K-Akt pathway, and inhibition of Akt strongly decreased antiapoptotic activity. Intravenously given GM-CSF passes the blood-brain barrier, and decreases infarct damage in two different experimental stroke models (middle cerebral artery occlusion (MCAO), and combined common carotid/distal MCA occlusion) concomitant with induction of BCL-Xl expression. Thus, GM-CSF acts as a neuroprotective protein in the CNS. This finding is remarkably reminiscent of the recently discovered functionality of two other hematopoietic factors, erythropoietin and granulocyte colony-stimulating factor in the CNS. The identification of a third hematopoietic factor acting as a neurotrophic factor in the CNS suggests a common principle in the functional evolution of these factors. Clinically, GM-CSF now broadens the repertoire of hematopoietic factors available as novel drug candidates for stroke and neurodegenerative diseases.

  11. Combination of endogenous neural stem cell mobilization and lithium chloride treatment for hydrocephalus following intraventricular hemorrhage.

    PubMed

    Yuan, Qiang; Bu, Xing-Yao; Yan, Zhao-Yue; Liu, Xian-Zhi; Wei, Zhen-Yu; Ma, Chun-Xiao; Qu, Ming-Qi

    2016-11-01

    As there are multiple factors causing hydrocephalus subsequent to intraventricular hemorrhage (IVH), it is difficult to achieve the best treatment effect using a single drug alone. In the present study, the protective effect of combination treatment with granulocyte-colony stimulating factor (G-CSF) and lithium chloride against hydrocephalus after IVH was investigated. A total of 130 adult male Sprague-Dawley rats were divided into five groups, including the IVH control, G-CSF treatment, lithium chloride treatment, combination treatment and sham surgery groups. An IVH rat model was established in order to examine the effect of combination treatment on hydrocephalus incidence. A TUNEL assay was performed to detect neuronal apoptosis in the five groups. In addition, the protein expression levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) were detected by western blot analysis. The differentiation of nerve cells in the brain tissue obtained from the five rat groups was also determined with double immunofluorescence staining. The results demonstrated that administration of G-CSF or lithium chloride alone was able to only partly relieve the incidence of hydrocephalus after IVH. By contrast, combination treatment with G-CSF and lithium chloride significantly attenuated the development of hydrocephalus following IVH. TUNEL assay showed that neuronal apoptosis was significantly reduced by the combination treatment with G-CSF and lithium chloride. Furthermore, the expression of Bcl-2 was upregulated, whereas Bax expression was downregulated in the combination treatment group. The results also detected the highest expression of BrdU/GFAP, BrdU/NeuN and BrdU/PSA-NCAM in the combination treatment group. In conclusion, the combination of endogenous neural stem cell mobilization (using G-CSF) and lithium chloride treatment resulted in highly reduced incidence of hydrocephalus after IVH by inhibiting neuronal apoptosis.

  12. Combination treatment of flag with non-pegylated liposomal doxorubicin (MYOCET(TM)) in elderly patients with acute myeloid leukemia: a single center experience.

    PubMed

    Melillo, Lorella; Valente, D; D'Arena, G; Dell'Olio, M; Falcone, A; Minervini, M M; Nobile, M; Rossi, G; Sanpaolo, G; Scalzulli, P R; Cascavilla, N

    2011-01-01

    The incidence of acute myeloid leukemia (AML) increases with age, but results of intensive chemotherapy in elderly patients are disappointing. Non-pegylated liposomal formulations of doxorubicin (Myocet™) have been developed with the aim of reducing systemic and cardiac toxicity especially in the elderly. We evaluated the efficacy and toxicity profiles of fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) regimen given in association with Myocet™ in 35 patients with AML, median age 69 years (range 61-83 years). Nineteen (54.3%) had newly-diagnosed AML, twelve (34.3%) patients had secondary AML (ten with Myelodisplastic Syndrome, two with Primary Myelofibrosis) and 4 (11.4%) patients had had a late relapse (>12 months) of AML. Complete remission (CR) and partial remission (PR) were obtained in twenty-two (63%) and 3 (8.5%) patients, respectively. Seven (20%) patients showed a resistant disease. There were 3 early deaths (8.5%). Six patients (17%) experienced severe cardiovascular toxicity. The median overall survival (OS) was 12 months (range 1-52 months) with a median disease-free survival (DFS) of 20 months (range 1-48 months). One-year and two-year DFS were 78.9% and 26.7%, respectively. This study demonstrates that in elderly patients with AML, FLAG-Myocet combination shows promising efficacy response with acceptable toxicity, enabling most patients to receive further treatments, including transplantation procedures.

  13. Combined motor point associative stimulation (MPAS) and transcranial direct current stimulation (tDCS) improves plateaued manual dexterity performance.

    PubMed

    Hoseini, Najmeh; Munoz-Rubke, Felipe; Wan, Hsuan-Yu; Block, Hannah J

    2016-10-28

    Motor point associative stimulation (MPAS) in hand muscles is known to modify motor cortex excitability and improve learning rate, but not plateau of performance, in manual dexterity tasks. Central stimulation of motor cortex, such as transcranial direct current stimulation (tDCS), can have similar effects if accompanied by motor practice, which can be difficult and tiring for patients. Here we asked whether adding tDCS to MPAS could improve manual dexterity in healthy individuals who are already performing at their plateau, with no motor practice during stimulation. We hypothesized that MPAS could provide enough coordinated muscle activity to make motor practice unnecessary, and that this combination of stimulation techniques could yield improvements even in subjects at or near their peak. If so, this approach could have a substantial effect on patients with impaired dexterity, who are far from their peak. MPAS was applied for 30min to two right hand muscles important for manual dexterity. tDCS was simultaneously applied over left sensorimotor cortex. The motor cortex input/output (I/O) curve was assessed with transcranial magnetic stimulation (TMS), and manual dexterity was assessed with the Purdue Pegboard Test. Compared to sham or cathodal tDCS combined with MPAS, anodal tDCS combined with MPAS significantly increased the plateau of manual dexterity. This result suggests that MPAS has the potential to substitute for motor practice in mediating a beneficial effect of tDCS on manual dexterity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. Cochlear dead regions constrain the benefit of combining acoustic stimulation with electric stimulation.

    PubMed

    Zhang, Ting; Dorman, Michael F; Gifford, Rene; Moore, Brian C J

    2014-01-01

    The aims of this study were to (1) detect the presence and edge frequency (fe) of a cochlear dead region in the ear with residual acoustic hearing for bimodal cochlear implant users, and (2) determine whether amplification based on the presence or absence of a dead region would improve speech understanding and sound quality. Twenty-two listeners with a cochlear implant in one ear and residual acoustic hearing in the nonimplanted ear were tested. Eleven listeners had a cochlear dead region in the acoustic-hearing ear and 11 did not. Dead regions were assessed with the threshold-equalizing noise (TEN) and the sweeping noise, psychophysical tuning curve tests. Speech understanding was assessed with monosyllabic words and the AzBio sentences at +10 dB signal-to-noise ratio. Speech- and music-quality judgments were obtained with the Judgment of Sound Quality questionnaire. Using shifted tips of the psychophysical tuning curve as a basis for diagnosis, the TEN had high sensitivity (0.91) and poor specificity (0.55) for this population. The value of fe was lower when estimated with the sweeping noise, psychophysical tuning curve test than with the TEN test. For the listeners with cochlear dead regions, speech understanding, speech quality and music quality were best when no amplification was applied for frequencies within the dead region. For listeners without dead regions, speech understanding was best with full-bandwidth amplification and was reduced when amplification was not applied when the audiometric threshold exceeded 80 dB HL. The data from this study suggest that, to improve bimodal benefit for listeners who combine electric and acoustic stimulation, audiologists should routinely test for the presence of cochlear dead regions and determine amplification bandwidth accordingly.

  15. Cochlear dead regions constrain the benefit of combining acoustic stimulation with electric stimulation

    PubMed Central

    Zhang, Ting; Dorman, Michael F.; Gifford, Rene; Moore, Brian C.J.

    2014-01-01

    Objective The aims of this study were to (i) detect the presence and edge frequency (fe) of a cochlear dead region in the ear with residual acoustic hearing for bimodal cochlear implant (CI) users, and (ii) determine whether amplification based on the presence or absence of a dead region would improve speech understanding and sound quality. Design Twenty two listeners with a CI in one ear and residual acoustic hearing in the non-implanted ear were tested. Eleven listeners had a cochlear dead region in the acoustic-hearing ear and eleven did not. Dead regions were assessed with the threshold equalizing noise (TEN) and the sweeping noise, psychophysical tuning curve (SWPTC) tests. Speech understanding was assessed with monosyllabic words and the AzBio sentences at +10 dB signal-to-noise ratio. Speech and music quality judgments were obtained with the Judgment of Sound Quality questionnaire. Results For this population, using shifted tips of the PTCs as a basis for diagnosis, the TEN had high sensitivity (0.91) and poor specificity (0.55). The value of fe was lower when estimated with the SWPTC test than with the TEN test. For the listeners with cochlear dead regions, speech understanding, speech quality and music quality were best when no amplification was applied for frequencies within the dead region. For listeners without dead regions, speech understanding was best with full-bandwidth amplification and was reduced when amplification was not applied when the audiometric threshold exceeded 80 dB HL. Conclusion Our data suggest that, to improve bimodal benefit for listeners who combine electric and acoustic stimulation, audiologists should routinely test for the presence of cochlear dead regions and determine amplification bandwidth accordingly. PMID:24950254

  16. Frequency overlap between electric and acoustic stimulation and speech-perception benefit in patients with combined electric and acoustic stimulation

    PubMed Central

    Zhang, Ting; Spahr, Anthony J.; Dorman, Michael F.

    2010-01-01

    Objectives Our aim was to assess, for patients with a cochlear implant in one ear and low-frequency acoustic hearing in the contralateral ear, whether reducing the overlap in frequencies conveyed in the acoustic signal and those analyzed by the cochlear implant speech processor would improve speech recognition. Design The recognition of monosyllabic words in quiet and sentences in noise was evaluated in three listening configurations: electric stimulation alone, acoustic stimulation alone, and combined electric and acoustic stimulation. The acoustic stimuli were either unfiltered or low-pass (LP) filtered at 250 Hz, 500 Hz, or 750 Hz. The electric stimuli were either unfiltered or high-pass (HP) filtered at 250 Hz, 500 Hz or 750 Hz. In the combined condition the unfiltered acoustic signal was paired with the unfiltered electric signal, the 250 LP acoustic signal was paired with the 250 Hz HP electric signal, the 500 Hz LP acoustic signal was paired with the 500 Hz HP electric signal and the 750 Hz LP acoustic signal was paired with the 750 Hz HP electric signal. Results For both acoustic and electric signals performance increased as the bandwith increased. The highest level of performance in the combined condition was observed in the unfiltered acoustic plus unfiltered electric condition. Conclusions Reducing the overlap in frequency representation between acoustic and electric stimulation does not increase speech understanding scores for patients who have residual hearing in the ear contralateral to the implant. We find that acoustic information below 250 Hz significantly improves performance for patients who combine electric and acoustic stimulation and accounts for the majority of the speech-perception benefit when acoustic stimulation is combined with electric stimulation. PMID:19915474

  17. Synergistic combination of near-infrared irradiation and targeted gold nanoheaters for enhanced photothermal neural stimulation

    PubMed Central

    Eom, Kyungsik; Im, Changkyun; Hwang, Seoyoung; Eom, Seyoung; Kim, Tae-Seong; Jeong, Hae Sun; Kim, Kyung Hwan; Byun, Kyung Min; Jun, Sang Beom; Kim, Sung June

    2016-01-01

    Despite a potential of infrared neural stimulation (INS) for modulating neural activities, INS suffers from limited light confinement and bulk tissue heating. Here, a novel methodology for an advanced optical stimulation is proposed by combining near-infrared (NIR) stimulation with gold nanorods (GNRs) targeted to neuronal cell membrane. We confirmed experimentally that in vitro and in vivo neural activation is associated with a local heat generation based on NIR stimulation and GNRs. Compared with the case of NIR stimulation without an aid of GNRs, combination with cell-targeted GNRs allows photothermal stimulation with faster neural response, lower delivered energy, higher stimulation efficiency and stronger behavior change. Since the suggested method can reduce a requisite radiant exposure level and alleviate a concern of tissue damage, it is expected to open up new possibilities for applications to optical neuromodulations for diverse excitable tissues and treatments of neurological disorders. PMID:27446678

  18. [Epirubicin-based combination chemotherapy combined with G-CSF for the elderly patients with non-Hodgkin's lymphoma].

    PubMed

    Miyata, A; Fujii, S; Kikuchi, T; Kibata, M

    2000-02-01

    We devised a new epirubicin-based combination chemotherapy (Epi-COP) regimen for the patients with elderly non-Hodgkin's lymphoma and have treated 30 patients aged 66 years and older who had measurable diseases. In Epi-COP therapy, epirubicin was used as a substitute for doxorubicin in the CHOP regimen, and some dose modifications were made for the other agents. Combined modality treatment (CMT; chemotherapy plus radiotherapy) was adopted for 9 patients with localized disease. Complete response was obtained in 21 of all the 30 patients (70%), 8 in 9 (89%) of the CMT group and 13 in 21 (62%) of the patients with chemotherapy only (chemotherapy group). The median follow up time is 350 days, ranging from 2 to 77 months. The 2 year survival rate was 56% in all patients, 67% in the CMT group and 52% in the chemotherapy group. Granulocyte colony-stimulating factor (G-CSF) was administered when the leucocyte count decreased below 2,000/microliter, and 16 patients received it in the first course. The regimen could be repeated every three weeks in most cases. Although we encountered two early deaths, the overall toxicity level seemed to be acceptable. Even when we take account of the small number of patients and the short observation period, it might be concluded that Epi-COP was effective in inducing a good remission rate with moderate toxic effect in elderly patients with non-Hodgkin's lymphoma and CMT should be adopted if it is localized. A randomized comparative study with the CHOP regimen is necessary.

  19. Anti-Inflammatory Effect of Combination of Scutellariae Radix and Liriopis Tuber Water Extract

    PubMed Central

    So, Mi-Hye; Choi, You-Kyung

    2015-01-01

    Scutellariae Radix and Liriopis Tuber have been used to treat the inflammatory diseases in traditional Korean medicine and anti-inflammatory effect of each herb has been shown partially in several articles. However, the combined extract of these medicinal herbs (SL) has not been reported for its anti-inflammatory effects. In this study, we investigated the effects of SL on the creation of several proinflammatory mediators in RAW 264.7 cell mouse macrophages induced by Lipopolysaccharide (LPS). SL inhibited significantly the increase of NO, the release of intracellular calcium, the increase of interleukin-6 (IL-6), macrophage inflammatory proteins (MIP-1α, MIP-1β, and MIP-2), and granulocyte colony-stimulating factor (G-CSF) in LPS-induced RAW 264.7 cell at the concentrations of 25, 50, and 100 μg/mL, and SL inhibited significantly the increase of macrophage colony-stimulating factor (M-CSF) at the concentrations of 25 and 50 μg/mL, and tumor necrosis factor (TNF) at the concentration of 25 μg/mL. These results implicate that SL has anti-inflammatory effects by suppressing the production of various inflammatory mediators in macrophages. But SL did not inhibit significantly the increase of granulocyte macrophage colony-stimulating factor (GM-CSF), leukemia inhibitory factor (LIF), and Regulated on Activation, Normal T cell Expressed and Secreted (RANTES); therefore, further study is demanded for the follow-up research to find out the possibility of SL as a preventive and therapeutic medicine for various inflammatory diseases. PMID:26604969

  20. Action of granulopoiesis-stimulating cytokines rhG-CSF, rhGM-CSF, and rmGM-CSF on murine haematopoietic progenitor cells for granulocytes and macrophages (GM-CFC).

    PubMed

    Hofer, M; Vacek, A; Weiterová, L

    2005-01-01

    The aim of this study was to provide new data to the knowledge of mechanisms by which recombinant human granulocyte colony-stimulating factor (rhG-CSF), recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) and recombinant murine granulocyte-macrophage colony-stimulating factor (rmGM-CSF) enhance the numbers of colonies growing from hematopoietic progenitor cells for granulocytes and macrophages (GM-CFC) in the murine bone marrow. The in vitro technique for cultivating GM-CFC from normal bone marrow cells was used. For evaluation of stimulatory actions of the drugs studied, the factors themselves or sera of mice given these factors were added to the cultures. The factors or the sera were present in the cultures either as the only potentially stimulatory agents or acted jointly with a suboptimum concentration of recombinant murine interleukin-3 (rmIL-3). It was found that both rhG-CSF and rmGM-CSF stimulate the proliferation of GM-CFC by a combination of direct mechanisms (direct actions on the target cells) and indirect effects (effects mediated through the induction of other cytokines and/or growth factors in the murine organism). The rhGM-CSF exhibited somewhat weaker in vitro effects in comparison with the other two factors and only indirect effects were noted. Additional in vivo experiments documented that, in spite of differences in mechanisms of action of the individual drugs studied on murine bone marrow cells in vitro, equal in vivo doses of the factors induce quantitatively similar effects on the production of GM-CFC in vivo.

  1. Combined noninvasive language mapping by navigated transcranial magnetic stimulation and functional MRI and its comparison with direct cortical stimulation.

    PubMed

    Ille, Sebastian; Sollmann, Nico; Hauck, Theresa; Maurer, Stefanie; Tanigawa, Noriko; Obermueller, Thomas; Negwer, Chiara; Droese, Doris; Zimmer, Claus; Meyer, Bernhard; Ringel, Florian; Krieg, Sandro M

    2015-07-01

    Repetitive navigated transcranial magnetic stimulation (rTMS) is now increasingly used for preoperative language mapping in patients with lesions in language-related areas of the brain. Yet its correlation with intraoperative direct cortical stimulation (DCS) has to be improved. To increase rTMS's specificity and positive predictive value, the authors aim to provide thresholds for rTMS's positive language areas. Moreover, they propose a protocol for combining rTMS with functional MRI (fMRI) to combine the strength of both methods. The authors performed multimodal language mapping in 35 patients with left-sided perisylvian lesions by using rTMS, fMRI, and DCS. The rTMS mappings were conducted with a picture-to-trigger interval (PTI, time between stimulus presentation and stimulation onset) of either 0 or 300 msec. The error rates (ERs; that is, the number of errors per number of stimulations) were calculated for each region of the cortical parcellation system (CPS). Subsequently, the rTMS mappings were analyzed through different error rate thresholds (ERT; that is, the ER at which a CPS region was defined as language positive in terms of rTMS), and the 2-out-of-3 rule (a stimulation site was defined as language positive in terms of rTMS if at least 2 out of 3 stimulations caused an error). As a second step, the authors combined the results of fMRI and rTMS in a predefined protocol of combined noninvasive mapping. To validate this noninvasive protocol, they correlated its results to DCS during awake surgery. The analysis by different rTMS ERTs obtained the highest correlation regarding sensitivity and a low rate of false positives for the ERTs of 15%, 20%, 25%, and the 2-out-of-3 rule. However, when comparing the combined fMRI and rTMS results with DCS, the authors observed an overall specificity of 83%, a positive predictive value of 51%, a sensitivity of 98%, and a negative predictive value of 95%. In comparison with fMRI, rTMS is a more sensitive but less specific

  2. Effects of combined mechanical stimulation on the proliferation and differentiation of pre-osteoblasts

    PubMed Central

    Kang, Kyung Shin; Lee, Seung-Jae; Lee, Haksue; Moon, Wonkyu

    2011-01-01

    We observed how combined mechanical stimuli affect the proliferation and differentiation of pre-osteoblasts. For this research, a bioreactor system was developed that can simultaneously stimulate cells with cyclic strain and ultrasound, each of which is known to effectively stimulate bone tissue regeneration. MC3T3-E1 pre-osteoblasts were chosen for bone tissue engineering due to their osteoblast-like characteristics. 3-D scaffolds were fabricated with polycaprolactone and poly-L-lactic acid using the salt leaching method. The cells were stimulated by the bioreactor with cyclic strain and ultrasound. The bioreactor was set at a frequency of 1.0 Hz and 10% strain for cyclic strain and 1.0 MHz and 30 mW/cm2 for ultrasound. Three experimental groups (ultrasound, cyclic strain, and combined stimulation) and a control group were examined. Each group was stimulated for 20 min/day. Mechanical stimuli did not affect MC3T3-E1 cell proliferation significantly up to 10 days when measured with the cell counting kit-8. However, gene expression analysis of collagen type-I, osteocalcin, RUNX2, and osterix revealed that the combined mechanical stimulation accelerated the matrix maturation of MC3T3-E1 cells. These results indicate that the combined mechanical stimulation can enhance the differentiation of pre-osteoblasts more efficiently than simple stimuli, in spite of no effect on cell proliferation. PMID:21532314

  3. Combined application of neuromuscular electrical stimulation and voluntary muscular contractions.

    PubMed

    Paillard, Thierry

    2008-01-01

    Electromyostimulation (EMS) and voluntary muscle contraction (VC) constitute different modes of muscle activation and induce different acute physiological effects on the neuromuscular system. Long-term application of each mode of muscle activation can produce different muscle adaptations. It seems theoretically possible to completely or partially cumulate the muscle adaptations induced by each mode of muscle activation applied separately. This work consisted of examining the literature concerning the muscle adaptations induced by long-term application of the combined technique (CT) [i.e. EMS is combined with VC - non-simultaneously] compared with VC and/or EMS alone in healthy subjects and/or athletes and in post-operative knee-injured subjects. In general, CT induced greater muscular adaptations than VC whether in sports training or rehabilitation. This efficiency would be due to the fact that CT can facilitate cumulative effects of training completely or partially induced by VC and EMS practiced alone. CT also provides a greater improvement of the performance of complex dynamic movements than VC. However, EMS cannot improve coordination between different agonistic and antagonistic muscles and thus does not facilitate learning the specific coordination of complex movements. Hence, EMS should be combined with specific sport training to generate neuromuscular adaptations, but also allow the adjustment of motor control during a voluntary movement. Likewise, in a therapeutic context, CT was particularly efficient to accelerate recovery of muscle contractility during a rehabilitation programme. Strength loss and atrophy inherent in a traumatism and/or a surgical operation would be more efficiently compensated with CT than with VC. Furthermore, CT also restored more functional abilities than VC. Finally, in a rehabilitation context, EMS is complementary to voluntary exercise because in the early phase of rehabilitation it elicits a strength increase, which is necessary

  4. Mandarin Speech Perception in Combined Electric and Acoustic Stimulation

    PubMed Central

    Li, Yongxin; Zhang, Guoping; Galvin, John J.; Fu, Qian-Jie

    2014-01-01

    For deaf individuals with residual low-frequency acoustic hearing, combined use of a cochlear implant (CI) and hearing aid (HA) typically provides better speech understanding than with either device alone. Because of coarse spectral resolution, CIs do not provide fundamental frequency (F0) information that contributes to understanding of tonal languages such as Mandarin Chinese. The HA can provide good representation of F0 and, depending on the range of aided acoustic hearing, first and second formant (F1 and F2) information. In this study, Mandarin tone, vowel, and consonant recognition in quiet and noise was measured in 12 adult Mandarin-speaking bimodal listeners with the CI-only and with the CI+HA. Tone recognition was significantly better with the CI+HA in noise, but not in quiet. Vowel recognition was significantly better with the CI+HA in quiet, but not in noise. There was no significant difference in consonant recognition between the CI-only and the CI+HA in quiet or in noise. There was a wide range in bimodal benefit, with improvements often greater than 20 percentage points in some tests and conditions. The bimodal benefit was compared to CI subjects’ HA-aided pure-tone average (PTA) thresholds between 250 and 2000 Hz; subjects were divided into two groups: “better” PTA (<50 dB HL) or “poorer” PTA (>50 dB HL). The bimodal benefit differed significantly between groups only for consonant recognition. The bimodal benefit for tone recognition in quiet was significantly correlated with CI experience, suggesting that bimodal CI users learn to better combine low-frequency spectro-temporal information from acoustic hearing with temporal envelope information from electric hearing. Given the small number of subjects in this study (n = 12), further research with Chinese bimodal listeners may provide more information regarding the contribution of acoustic and electric hearing to tonal language perception. PMID:25386962

  5. Contributions to muscle force and EMG by combined neural excitation and electrical stimulation.

    PubMed

    Crago, Patrick E; Makowski, Nathaniel S; Cole, Natalie M

    2014-10-01

    Stimulation of muscle for research or clinical interventions is often superimposed on ongoing physiological activity without a quantitative understanding of the impact of the stimulation on the net muscle activity and the physiological response. Experimental studies show that total force during stimulation is less than the sum of the isolated voluntary and stimulated forces, but the occlusion mechanism is not understood. We develop a model of efferent motor activity elicited by superimposing stimulation during a physiologically activated contraction. The model combines action potential interactions due to collision block, source resetting, and refractory periods with previously published models of physiological motor unit recruitment, rate modulation, force production, and EMG generation in human first dorsal interosseous muscle to investigate the mechanisms and effectiveness of stimulation on the net muscle force and EMG. Stimulation during a physiological contraction demonstrates partial occlusion of force and the neural component of the EMG, due to action potential interactions in motor units activated by both sources. Depending on neural and stimulation firing rates as well as on force-frequency properties, individual motor unit forces can be greater, smaller, or unchanged by the stimulation. In contrast, voluntary motor unit EMG potentials in simultaneously stimulated motor units show progressive occlusion with increasing stimulus rate. The simulations predict that occlusion would be decreased by a reverse stimulation recruitment order. The results are consistent with and provide a mechanistic interpretation of previously published experimental evidence of force occlusion. The models also predict two effects that have not been reported previously--voluntary EMG occlusion and the advantages of a proximal stimulation site. This study provides a basis for the rational design of both future experiments and clinical neuroprosthetic interventions involving either

  6. Contributions to muscle force and EMG by combined neural excitation and electrical stimulation

    NASA Astrophysics Data System (ADS)

    Crago, Patrick E.; Makowski, Nathaniel S.; Cole, Natalie M.

    2014-10-01

    Objective. Stimulation of muscle for research or clinical interventions is often superimposed on ongoing physiological activity without a quantitative understanding of the impact of the stimulation on the net muscle activity and the physiological response. Experimental studies show that total force during stimulation is less than the sum of the isolated voluntary and stimulated forces, but the occlusion mechanism is not understood. Approach. We develop a model of efferent motor activity elicited by superimposing stimulation during a physiologically activated contraction. The model combines action potential interactions due to collision block, source resetting, and refractory periods with previously published models of physiological motor unit recruitment, rate modulation, force production, and EMG generation in human first dorsal interosseous muscle to investigate the mechanisms and effectiveness of stimulation on the net muscle force and EMG. Main results. Stimulation during a physiological contraction demonstrates partial occlusion of force and the neural component of the EMG, due to action potential interactions in motor units activated by both sources. Depending on neural and stimulation firing rates as well as on force-frequency properties, individual motor unit forces can be greater, smaller, or unchanged by the stimulation. In contrast, voluntary motor unit EMG potentials in simultaneously stimulated motor units show progressive occlusion with increasing stimulus rate. The simulations predict that occlusion would be decreased by a reverse stimulation recruitment order. Significance. The results are consistent with and provide a mechanistic interpretation of previously published experimental evidence of force occlusion. The models also predict two effects that have not been reported previously—voluntary EMG occlusion and the advantages of a proximal stimulation site. This study provides a basis for the rational design of both future experiments and clinical

  7. Combination of Static Magnetic Fields and Peripheral Nerve Stimulation Can Alter Focal Cortical Excitability.

    PubMed

    Nojima, Ippei; Koganemaru, Satoko; Mima, Tatsuya

    2016-01-01

    For clinical application of transcranial static magnetic stimulation (tSMS), it is important to achieve a focal target cortical stimulation. Previous study suggested that the associative stimulation combining non-invasive stimulation of the motor cortex (M1) and the peripheral nerve stimulation (PNS) may be useful to produce cortical excitability change. To test this hypothesis, we measured the M1 excitability and intracortical circuits by using transcranial magnetic stimulation (TMS) before and after the tSMS of short duration (5 min) combined with PNS. Thirty-three normal volunteers were participated; tSMS+PNS (n = 11), sham+PNS (n = 11), and tSMS alone (n = 11). We found the transient suppression of the motor-evoked potential (MEP) of the right abductor pollicis brevis (APB) muscle, but not of the abductor digiti minimi (ADM) muscle, when combining tSMS with PNS over median nerve at the wrist. The lack of suppressive effect on APB in tSMS alone with short duration is in accord with the previous observation. In addition, the tendency of transient enhancement of the short-latency intracortical inhibition was observed immediately after intervention in the tSMS±PNS group. These findings show that the combination of tSMS and PNS can induce the cortical excitability change in target cortical motor area and potentiate the suppression effect.

  8. Combination of Static Magnetic Fields and Peripheral Nerve Stimulation Can Alter Focal Cortical Excitability

    PubMed Central

    Nojima, Ippei; Koganemaru, Satoko; Mima, Tatsuya

    2016-01-01

    For clinical application of transcranial static magnetic stimulation (tSMS), it is important to achieve a focal target cortical stimulation. Previous study suggested that the associative stimulation combining non-invasive stimulation of the motor cortex (M1) and the peripheral nerve stimulation (PNS) may be useful to produce cortical excitability change. To test this hypothesis, we measured the M1 excitability and intracortical circuits by using transcranial magnetic stimulation (TMS) before and after the tSMS of short duration (5 min) combined with PNS. Thirty-three normal volunteers were participated; tSMS+PNS (n = 11), sham+PNS (n = 11), and tSMS alone (n = 11). We found the transient suppression of the motor-evoked potential (MEP) of the right abductor pollicis brevis (APB) muscle, but not of the abductor digiti minimi (ADM) muscle, when combining tSMS with PNS over median nerve at the wrist. The lack of suppressive effect on APB in tSMS alone with short duration is in accord with the previous observation. In addition, the tendency of transient enhancement of the short-latency intracortical inhibition was observed immediately after intervention in the tSMS±PNS group. These findings show that the combination of tSMS and PNS can induce the cortical excitability change in target cortical motor area and potentiate the suppression effect. PMID:27932966

  9. Combination of Foot Stimulation and Tramadol Treatment Reverses Irritation Induced Bladder Overactivity in Cats

    PubMed Central

    Mally, Abhijith D.; Zhang, Fan; Matsuta, Yosuke; Shen, Bing; Wang, Jicheng; Roppolo, James R.; de Groat, William C.; Tai, Changfeng

    2013-01-01

    Purpose We determined whether transcutaneous electrical foot stimulation combined with a low dose of tramadol (Sigma-Aldrich®) could completely suppress bladder overactivity. Materials and Methods Repeat cystometrograms were performed in 18 α-chloralose anesthetized cats by infusing the bladder with saline or 0.25% acetic acid. Transcutaneous electrical stimulation (5 Hz) of the cat hind foot at 2 to 4 times the threshold intensity needed to induce observable toe movement was applied to suppress acetic acid induced bladder overactivity. Tramadol (1 to 3 mg/kg intravenously) was administered to enhance foot inhibition. Results Acetic acid irritated the bladder, induced bladder overactivity and significantly decreased bladder capacity to a mean ± SE of 26% ± 5% of saline control capacity (p <0.01). Without tramadol, foot stimulation at 2 and 4 threshold intensity applied during acetic acid cystometrograms significantly increased bladder capacity to a mean of 47% ± 5% and 62% ± 6% of saline control capacity, respectively (p <0.05). Without foot stimulation, tramadol (1 mg/kg) only slightly changed bladder capacity to a mean of 39% ± 2% of saline control capacity (p >0.05), while 3 mg/kg significantly increased capacity to 85% ± 14% that of control (p <0.05). However, 1 mg/kg tramadol combined with foot stimulation increased bladder capacity to a mean of 71% ± 18% (2 threshold intensity) and 84% ± 14% (4 threshold intensity), respectively, which did not significantly differ from saline control capacity. In addition, long lasting (greater than 1.5 to 2 hours) post-stimulation inhibition was induced by foot stimulation combined with 3 mg/kg tramadol treatment. Conclusions This study suggests a new treatment strategy for overactive bladder by combining foot stimulation with a low dose of tramadol, which is noninvasive and has potentially high efficacy and fewer adverse effects. PMID:23088991

  10. Complete inhibition of food-stimulated gastric acid secretion by combined application of pirenzepine and ranitidine.

    PubMed Central

    Londong, W; Londong, V; Ruthe, C; Weizert, P

    1981-01-01

    In a double-blind, placebo controlled and randomised secretory study the effectiveness of pirenzepine, ranitidine, and their combination was compared intraindividually in eight healthy subjects receiving intravenous bolus injections. Pirenzepine (0.15 mg/kg) plus ranitidine (0.6 mg/kg) suppressed peptone-stimulated gastric acid secretion from 69 +/- 11 to 2 +/- 0.4 mmol H+/3 h; the mean percentage inhibition was 97%. Postprandial gastrin was unaffected. There were only minor side-effects in a few experiments (reduction of salivation, brief blurring of vision), but no prolactin stimulation after ranitidine or ranitidine plus pirenzepine. The combined application of ranitidine and pirenzepine inhibited meal-stimulated acid secretion more effectively and produced fewer side-effects than the combination of cimetidine plus pirenzepine studied previously. PMID:6114900

  11. Combination Pharmacotherapies for Stimulant Use Disorder: A Review of Clinical Findings and Recommendations for Future Research

    PubMed Central

    Stoops, William W.; Rush, Craig R.

    2014-01-01

    Despite concerted efforts to identify a pharmacotherapy for managing stimulant use disorders, no widely effective medications have been approved. Innovative strategies are necessary to develop successful pharmacotherapies for stimulant use disorders. This manuscript reviews human laboratory studies and clinical trials to determine whether one such strategy, use of combination pharmacotherapies, holds promise. The extant literature shows that combination pharmacotherapy produced results that were better than placebo treatment, especially with medications shown to have efficacy as monotherapies. However, many studies did not compare individual constituents to the combination treatment, making it impossible to determine whether combination treatment is more effective than monotherapy. Future research should systematically compare combined treatments with individual agents using medications showing some efficacy when tested alone. PMID:24716825

  12. Combined Effects of Acrobatic Exercise and Magnetic Stimulation on the Functional Recovery after Spinal Cord Lesions

    PubMed Central

    Wieraszko, Andrzej

    2008-01-01

    Abstract The objective of the study was to determine whether physical exercise combined with epidural spinal cord magnetic stimulation could improve recovery after injury of the spinal cord. Spinal cord lesioning in mice resulted in reduced locomotor function and negatively affected the muscle strength tested in vitro. Acrobatic exercise attenuated the behavioral effects of spinal cord injury. The exposure to magnetic fields facilitated further this improvement. The progress in behavioral recovery was correlated with reduced muscle degeneration and enhanced muscle contraction. The acrobatic exercise combined with stimulation with magnetic fields significantly facilitates behavioral recovery and muscle physiology in mice following spinal cord injury. PMID:18986227

  13. Stretchable Silver Nanowire Microelectrodes for Combined Mechanical and Electrical Stimulation of Cells.

    PubMed

    Hosseini, Vahid; Gantenbein, Silvan; Avalos Vizcarra, Ima; Schoen, Ingmar; Vogel, Viola

    2016-08-01

    The use of stretchable electrodes interfaced with the human body has enabled a new frontier in biomedical engineering, and the miniaturization of such electrodes can allow for a more precise spatial control to monitor or stimulate tissues. The understanding of the response of cells or tissues to combined electromechanical stimulation, as made possible by stretchable electrodes, is essential to improve medical devices and therapies. Cheap to produce and easy to use platforms for in vitro cell studies are thus urgently needed. This study reports the successful implementation of silver nanowires (AgNWs) into an integrated miniaturized electromechanical stimulator, which is compatible with cell culture. The innovative steps include a lithography-based lift-off method to micropattern AgNWs onto an elastic silicone membrane. These stretchable microelectrodes are then integrated into a microfluidic device for cell culture, which enables the synchronous electromechanical stimulation of cells. In a proof-of-concept study, it is furthermore shown that fibroblasts respond uniquely to mechanical stretching, electrical stimulation, and combined electromechanical stimulations in terms of cell alignment and morphology, as well as by producing the extracellular matrix protein collagen. This proof-of-concept study illustrates the functionality and usability of these stretchable AgNWs microelectrodes for either basic research or future biomedical applications. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Exploration and Modulation of Brain Network Interactions with Noninvasive Brain Stimulation in Combination with Neuroimaging

    PubMed Central

    Shafi, Mouhsin M.; Westover, M. Brandon; Fox, Michael D.; Pascual-Leone, Alvaro

    2012-01-01

    Much recent work in systems neuroscience has focused on how dynamic interactions between different cortical regions underlie complex brain functions such as motor coordination, language, and emotional regulation. Various studies using neuroimaging and neurophysiologic techniques have suggested that in many neuropsychiatric disorders, these dynamic brain networks are dysregulated. Here we review the utility of combined noninvasive brain stimulation and neuroimaging approaches towards greater understanding of dynamic brain networks in health and disease. Brain stimulation techniques, such as transcranial magnetic stimulation and transcranial direct current stimulation, use electromagnetic principles to noninvasively alter brain activity, and induce focal but also network effects beyond the stimulation site. When combined with brain imaging techniques such as functional MRI, PET and EEG, these brain stimulation techniques enable a causal assessment of the interaction between different network components, and their respective functional roles. The same techniques can also be applied to explore hypotheses regarding the changes in functional connectivity that occur during task performance and in various disease states such as stroke, depression and schizophrenia. Finally, in diseases characterized by pathologic alterations in either the excitability within a single region or in the activity of distributed networks, such techniques provide a potential mechanism to alter cortical network function and architectures in a beneficial manner. PMID:22429242

  15. Model study of combined electrical and near-infrared neural stimulation on the bullfrog sciatic nerve.

    PubMed

    You, Mengxian; Mou, Zongxia

    2017-07-01

    This paper implemented a model study of combined electrical and near-infrared (808 nm) neural stimulation (NINS) on the bullfrog sciatic nerve. The model includes a COMSOL model to calculate the electric-field distribution of the surrounding area of the nerve, a Monte Carlo model to simulate light transport and absorption in the bullfrog sciatic nerve during NINS, and a NEURON model to simulate the neural electrophysiology changes under electrical stimulus and laser irradiation. The optical thermal effect is considered the main mechanism during NINS. Therefore, thermal change during laser irradiation was calculated by the Monte Carlo method, and the temperature distribution was then transferred to the NEURON model to stimulate the sciatic nerve. The effects on thermal response by adjusting the laser spot size, energy of the beam, and the absorption coefficient of the nerve are analyzed. The effect of the ambient temperature on the electrical stimulation or laser stimulation and the interaction between laser irradiation and electrical stimulation are also studied. The results indicate that the needed stimulus threshold for neural activation or inhibition is reduced by laser irradiation. Additionally, the needed laser energy for blocking the action potential is reduced by electrical stimulus. Both electrical and laser stimulation are affected by the ambient temperature. These results provide references for subsequent animal experiments and could be of great help to future basic and applied studies of infrared neural stimulation (INS).

  16. The benefits of combining acoustic and electric stimulation for the recognition of speech, voice and melodies.

    PubMed

    Dorman, Michael F; Gifford, Rene H; Spahr, Anthony J; McKarns, Sharon A

    2008-01-01

    Fifteen patients fit with a cochlear implant in one ear and a hearing aid in the other ear were presented with tests of speech and melody recognition and voice discrimination under conditions of electric (E) stimulation, acoustic (A) stimulation and combined electric and acoustic stimulation (EAS). When acoustic information was added to electrically stimulated information performance increased by 17-23 percentage points on tests of word and sentence recognition in quiet and sentence recognition in noise. On average, the EAS patients achieved higher scores on CNC words than patients fit with a unilateral cochlear implant. While the best EAS patients did not outperform the best patients fit with a unilateral cochlear implant, proportionally more EAS patients achieved very high scores on tests of speech recognition than unilateral cochlear implant patients. (c) 2007 S. Karger AG, Basel

  17. Time-dependent changes in motor cortical excitability by electrical stimulation combined with voluntary drive.

    PubMed

    Sugawara, Kenichi; Yamaguchi, Tomofumi; Tanabe, Shigeo; Suzuki, Tomotaka; Saito, Kei; Higashi, Toshio

    2014-04-16

    Prolonged changes in primary motor cortex excitability in response to combined neuromuscular electrical stimulation (NMES) and voluntary contraction with motor evoked potentials (MEPs) were investigated by transcranial magnetic stimulation and recorded by mechanomyography. Participants included 22 healthy individuals. NMES was applied to the extensor carpi radialis (ECR) by voluntary ECR contraction with 20% maximum voluntary contraction (MVC) of wrist extension. MEPs were recorded from the flexor carpi radialis (FCR) and ECR at rest with NMES, at 20% MVC with NMES (combined), and at 20% MVC alone. Significant conditional effects were revealed in ECR and FCR. In the combined condition, MEPs showed gradual enhancement, and those in FCR were more inhibited than those in the control condition. Voluntary contraction with NMES increased primary motor cortex excitability in the agonist muscle, whereas the antagonist muscle might affect reciprocal modulation in the combined condition.

  18. Combining acoustic and electric stimulation in the service of speech recognition

    PubMed Central

    Dorman, Michael F.; Gifford, Rene H.

    2010-01-01

    The majority of recently implanted, cochlear implant patients can potentially benefit from a hearing aid in the ear contralateral to the implant. When patients combine electric and acoustic stimulation, word recognition in quiet and sentence recognition in noise increase significantly. Several studies suggest that the acoustic information that leads to the increased level of performance resides mostly in the frequency region of the voice fundamental, e.g. 125 Hz for a male voice. Recent studies suggest that this information aids speech recognition in noise by improving the recognition of lexical boundaries or word onsets. In some noise environments, patients with bilateral implants can achieve similar levels of performance as patients who combine electric and acoustic stimulation. Patients who have undergone hearing preservation surgery, and who have electric stimulation from a cochlear implant and who have low-frequency hearing in both the implanted and not-implanted ears, achieve the best performance in a high noise environment. PMID:20874053

  19. Combination of Foot Stimulation and Tolterodine Treatment Eliminates Bladder Overactivity in Cats

    PubMed Central

    Schwen, Zeyad; Matsuta, Yosuke; Shen, Bing; Wang, Jicheng; Roppolo, James R.; de Groat, William C.; Tai, Changfeng

    2014-01-01

    Aims To determine whether transcutaneous foot stimulation combined with a lower dose tolterodine would inhibit bladder overactivity more effectively than either treatment alone. Methods Cystometrograms were performed on α-chloralose anesthetized cats (N = 6) by infusing 0.25% acetic acid (AA) to induce bladder overactivity. Foot stimulation (5 Hz) was applied at 2 and 4 times the threshold (T) intensity in volts (i.e., 2T or 4T) for inducing toe movement to inhibit bladder overactivity. Cumulative doses of tolterodine (0.003–0.3 mg/kg, i.v.) were also administered to determine the effect of combination treatment. Results AA irritation of the bladder significantly (P < 0.0001) reduced bladder capacity to 23.6±7.1% of saline control capacity. Foot stimulation alone at 2T and 4T inhibited bladder overactivity and significantly (P < 0.0001) increased bladder capacity to 50.7±6.8% and 79.0±11.6% of saline control, respectively. Tolterodine alone at 0.3 mg/kg significantly (P < 0.05) increased bladder capacity to 65.6±15.5% of saline control. However, when tolterodine at a threshold dose (0.3 mg/kg) was combined with foot stimulation, the bladder capacity was significantly (P < 0.05) increased to 86.2±6.2% and 107.9±10.6% by 2T and 4T stimulation, respectively. Complete inhibition of bladder overactivity could be achieved at a lower tolterodine dose (0.1 mg/kg) when combined with 4T stimulation (97.0±11.2% of saline control). The amplitude of micturition contraction was not changed by tolterodine treatment. Conclusions This study suggests a novel, efficacious, non-invasive therapy by combining foot stimulation with a lower dose tolterodine to treat bladder overactivity. It also provides the first objective evidence supporting an additive therapeutic benefit of neuromodulation and antimuscarinic combination treatment. PMID:24038323

  20. Impact of Combined Subthalamic Nucleus and Substantia Nigra Stimulation on Neuropsychiatric Symptoms in Parkinson's Disease Patients

    PubMed Central

    Horn, A.; Hamel, W.; Koeppen, J. A.; Westphal, M.; Engel, A. K.; Gerloff, C.; Moll, C. K. E.

    2017-01-01

    The goal of the study was to compare the tolerability and the effects of conventional subthalamic nucleus (STN) and combined subthalamic nucleus and substantia nigra (STN+SNr) high-frequency stimulation in regard to neuropsychiatric symptoms in Parkinson's disease patients. In this single center, randomized, double-blind, cross-over clinical trial, twelve patients with advanced Parkinson's disease (1 female; age: 61.3 ± 7.3 years; disease duration: 12.3 ± 5.4 years; Hoehn and Yahr stage: 2.2 ± 0.39) were included. Apathy, fatigue, depression, and impulse control disorder were assessed using a comprehensive set of standardized rating scales and questionnaires such as the Lille Apathy Rating Scale (LARS), Modified Fatigue Impact Scale (MFIS), Becks Depression Inventory (BDI-I), Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale (QUIP-RS), and Parkinson's Disease Questionnaire (PDQ-39). Three patients that were initially assigned to the STN+SNr stimulation mode withdrew from the study within the first week due to discomfort. Statistical comparison of data retrieved from patients who completed the study revealed no significant differences between both stimulation conditions in terms of mean scores of scales measuring apathy, fatigue, depression, impulse control disorder, and quality of life. Individual cases showed an improvement of apathy under combined STN+SNr stimulation. In general, combined STN+SNr stimulation seems to be safe in terms of neuropsychiatric side effects, although careful patient selection and monitoring in the short-term period after changing stimulation settings are recommended. PMID:28246572

  1. Impact of Combined Subthalamic Nucleus and Substantia Nigra Stimulation on Neuropsychiatric Symptoms in Parkinson's Disease Patients.

    PubMed

    Hidding, U; Gulberti, A; Horn, A; Buhmann, C; Hamel, W; Koeppen, J A; Westphal, M; Engel, A K; Gerloff, C; Weiss, D; Moll, C K E; Pötter-Nerger, M

    2017-01-01

    The goal of the study was to compare the tolerability and the effects of conventional subthalamic nucleus (STN) and combined subthalamic nucleus and substantia nigra (STN+SNr) high-frequency stimulation in regard to neuropsychiatric symptoms in Parkinson's disease patients. In this single center, randomized, double-blind, cross-over clinical trial, twelve patients with advanced Parkinson's disease (1 female; age: 61.3 ± 7.3 years; disease duration: 12.3 ± 5.4 years; Hoehn and Yahr stage: 2.2 ± 0.39) were included. Apathy, fatigue, depression, and impulse control disorder were assessed using a comprehensive set of standardized rating scales and questionnaires such as the Lille Apathy Rating Scale (LARS), Modified Fatigue Impact Scale (MFIS), Becks Depression Inventory (BDI-I), Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale (QUIP-RS), and Parkinson's Disease Questionnaire (PDQ-39). Three patients that were initially assigned to the STN+SNr stimulation mode withdrew from the study within the first week due to discomfort. Statistical comparison of data retrieved from patients who completed the study revealed no significant differences between both stimulation conditions in terms of mean scores of scales measuring apathy, fatigue, depression, impulse control disorder, and quality of life. Individual cases showed an improvement of apathy under combined STN+SNr stimulation. In general, combined STN+SNr stimulation seems to be safe in terms of neuropsychiatric side effects, although careful patient selection and monitoring in the short-term period after changing stimulation settings are recommended.

  2. Effect of tactile stimulation on primary motor cortex excitability during action observation combined with motor imagery.

    PubMed

    Tanaka, Megumi; Kubota, Shinji; Onmyoji, Yusuke; Hirano, Masato; Uehara, Kazumasa; Morishita, Takuya; Funase, Kozo

    2015-07-23

    We aimed to investigate the effects of the tactile stimulation to an observer's fingertips at the moment that they saw an object being pinched by another person on the excitability of observer's primary motor cortex (M1) using transcranial magnetic stimulation (TMS). In addition, the above effects were also examined during action observation combined with the motor imagery. Motor evoked potentials (MEP) were evoked from the subjects' right first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles. Electrical stimulation (ES) inducing tactile sensation was delivered to the subjects' first and second fingertips at the moment of pinching action performed by another person. Although neither the ES nor action observation alone had significant effects on the MEP amplitude of the FDI or ADM, the FDI MEP amplitude which acts as the prime mover during pinching was reduced when ES and action observation were combined; however, no such changes were seen in the ADM. Conversely, that reduced FDI MEP amplitude was increased during the motor imagery. These results indicated that the M1 excitability during the action observation of pinching action combined with motor imagery could be enhanced by the tactile stimulation delivered to the observer's fingertips at the moment corresponding to the pinching being observed. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  3. Multiple Channel Laser Beam Combination and Phasing Using Stimulated Brillouin Scattering in Optical Fibers

    DTIC Science & Technology

    2005-12-01

    Mandel’shtam–Brillouin scattering,” JETP Lett ., 15, 109-112, 1972. 41 . Hellwarth, R. W., “Phase conjugation by stimulated backscattering,” ch. 7, Optical...wavefront-reversing mirrors,” Sov . Phys . JETP , 52, 847-851, 1980. 79. Valley, M., G. Lombardi, and R. Aprahamian, “Beam combination by stimulated...Thomas, and R. Byer, Monolithic, “Unidirectional single-mode Nd:YAG ring laser”, Opt. Lett ., 10, 65-67, 1985 . 56. Imai, M. and E. H. Hara

  4. Multiple Channel Laser Beam Combination and Phasing Using Stimulated Brillouin Scattering in Optical Fibers

    DTIC Science & Technology

    2005-12-22

    Mandel’shtam–Brillouin scattering,” JETP Lett ., 15, 109-112, 1972. 41 . Hellwarth, R. W., “Phase conjugation by stimulated backscattering,” ch. 7, Optical...wavefront-reversing mirrors,” Sov . Phys . JETP , 52, 847-851, 1980. 79. Valley, M., G. Lombardi, and R. Aprahamian, “Beam combination by stimulated...Thomas, and R. Byer, Monolithic, “Unidirectional single-mode Nd:YAG ring laser”, Opt. Lett ., 10, 65-67, 1985 . 56. Imai, M. and E. H. Hara

  5. Combined pallidal and subthalamic nucleus stimulation in sporadic dystonia-parkinsonism.

    PubMed

    Wöhrle, Johannes C; Blahak, Christian; Capelle, Hans-Holger; Fogel, Wolfgang; Bäzner, Hansjoerg; Krauss, Joachim K

    2012-01-01

    Multifocal deep brain stimulation (DBS) is a new technique that has been introduced recently. A 39-year-old man with dystonia-parkinsonism underwent the simultaneous implantation of subthalamic nucleus (STN) and globus pallidus internus (GPi) DBS electrodes. While bilateral STN DBS controlled the parkinsonian symptoms well and allowed for a reduction in levodopa, the improvement of dystonia was only temporary. Additional GPi DBS also alleviated dystonic symptoms. Formal assessment at the 1-year follow-up showed that both the parkinsonian symptoms and the dystonia were markedly improved via continuous bilateral combined STN and GPi stimulation. Sustained benefit was achieved at 3 years postoperatively.

  6. Combined Fruit and Vegetable Intake Is Correlated with Improved Inflammatory and Oxidant Status from a Cross-Sectional Study in a Community Setting

    PubMed Central

    Root, Martin M.; McGinn, Megan C.; Nieman, David C.; Henson, Dru A.; Heinz, Serena A.; Shanely, R. Andrew; Knab, Amy M.; Jin, Fuxia

    2012-01-01

    Previous studies have examined the relationship between specific nutrient and food intakes with limited markers of either inflammation or oxidant status. The objective of this study was to determine if an increase in combined self-reported fruit and vegetable (F&V) intake in a community setting was associated with improved multiple markers of inflammatory and oxidant status. A community group (N = 1000, age 18–85 years, 61% female) gave two fasted blood samples separated by 12 weeks. Blood inflammatory biomarkers included total leukocytes (WBC), plasma C-reactive protein (CRP), interleukin-6 (IL-6), IL-10, tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1, and granulocyte colony stimulating factor. Measured oxidant status markers were ferric reducing ability of plasma (FRAP), oxygen radical absorbance capacity (ORAC) and plasma F2-isoprostanes. The relation of markers across categories of F&V intake was examined. In analyses controlling for other important dietary and lifestyle factors, IL-6 and TNF-α were significantly lower across categories of increasing F&V intakes (p < 0.008). FRAP and ORAC were significantly higher (p < 0.0001 and p = 0.047 respectively) while F2-isoprostanes was significantly lower (p < 0.0001) across F&V categories. In a community study, several markers of both inflammation and oxidant status were associated in a putatively salutary direction by higher intake of combined F&V, supporting current guidelines suggesting increased F&V consumption for the prevention of chronic diseases. PMID:22347616

  7. A model-based analysis of the "combined-stimulation advantage".

    PubMed

    Seldran, Fabien; Micheyl, Christophe; Truy, Eric; Berger-Vachon, Christian; Thai-Van, Hung; Gallego, Stéphane

    2011-12-01

    Improvements in speech-recognition performance resulting from the addition of low-frequency information to electric (or vocoded) signals have attracted considerable interest in recent years. An important question is whether these improvements reflect a form of constructive perceptual interaction-whereby acoustic cues enhance the perception of electric or vocoded signals-or whether they can be explained without assuming any interaction. To address this question, speech-recognition performance was measured in 24 normal-hearing listeners using lowpass-filtered, vocoded, and "combined" (lowpass + vocoded) words presented either in quiet or in a realistic background (cafeteria noise), for different signal-to-noise ratios, different lowpass-filter cutoff frequencies, and different numbers of vocoder bands. The results of these measures were then compared to the predictions of three models of cue combination, including a "probability-summation" model and two Gaussian signal detection theory (SDT) models-one (the "independent-noises" model) involving pre-combination noises, and the other (the "late-noise" model) involving post-combination noise. Consistent with previous findings, speech-recognition performance with combined stimulation was significantly higher than performance with vocoded or lowpass stimuli alone, and it was also higher than predicted by the probability-summation model. The two Gaussian-SDT models could account quantitatively for the data. Moreover, a Bayesian model-comparison procedure demonstrated that, given the data, these two models were far more likely than the probability-summation model. Since these models do not involve any constructive-interaction mechanism, this demonstrates that constructive interactions are not needed to explain the combined-stimulation benefits measured in this study. It will be important for future studies to investigate whether this conclusion generalizes to other test conditions, including real EAS, and to further test

  8. Oncofertility: combination of ovarian stimulation with subsequent ovarian tissue extraction on the day of oocyte retrieval

    PubMed Central

    2013-01-01

    Background New anticancer treatments have increased survival rates for cancer patients, but often at the cost of sterility. Several strategies are currently available for preserving fertility. However, the chances of achieving a pregnancy with one technique are still limited. A combination of methods is therefore recommended in order to maximize women’s chances of future fertility. In this retrospective study, ovarian stimulation with subsequent ovarian tissue extraction on the day of oocyte retrieval were combined and the quality of the ovarian tissue, the numbers and quality of oocytes, time requirements, and the safety of the strategy were examined. Methods Fourteen female patients suffering from malignant diseases underwent one in vitro fertilization cycle. Different stimulation protocols were used, depending on the menstrual cycle. Transvaginal oocyte retrieval was scheduled 34–36 h after human chorionic gonadotropin administration. Immediately afterwards, ovarian tissue was extracted laparoscopically. Results A mean of 10 oocytes were retrieved per patient, and 67% of the oocytes were successfully fertilized using intracytoplasmic sperm injection. No periprocedural complications and no complications leading to postponement of the start of chemotherapy occurred. The ovarian tissues were of good quality, with a normal age-related follicular distribution and without carcinoma cell invasion. Conclusions An approach using ovarian stimulation first, followed by laparoscopic collection of ovarian tissue, is a useful strategy for increasing the efficacy of fertility preservation techniques. The ovarian tissue is not affected by prior ovarian stimulation. PMID:23510640

  9. Implantation of anterior sacral root stimulators combined with posterior sacral rhizotomy in spinal injury patients.

    PubMed

    Egon, G; Barat, M; Colombel, P; Visentin, C; Isambert, J L; Guerin, J

    1998-01-01

    Brindley-Finetech sacral anterior root stimulators combined with posterior sacral rhizotomy were implanted in 68 males and 28 females with spinal cord lesions. In 9 patients the electrodes were implanted extradurally in the sacrum, and in 90 patients they were implanted intradurally (3 patients had a second extradural implant after a first intradural implant). Three patients died from causes unrelated to the implant. Of the 93 surviving patients, 83 used their implants for micturition and 82 were fully continent. The mean bladder capacity increased from 206 ml preoperatively to 564 ml after the operation. Three patients had a preoperative vesicorenal reflux that disappeared after surgery. In all, 51 patients used the stimulator for defecation. Erection was possible with electrical stimulation in 46 males and was used for coitus by 17 couples. Secondary deafferentation at the level of the conus was performed four times. Three patients who had a cerebrospinal fluid leak were operated on again. Two implants had to be removed because of infection. Sacral anterior root stimulation combined with sacral deafferentation is a welcome addition to the treatment of neurogenic bladder in spinal cord injury patients.

  10. Improved speech recognition in noise in simulated binaurally combined acoustic and electric stimulation.

    PubMed

    Kong, Ying-Yee; Carlyon, Robert P

    2007-06-01

    Speech recognition in noise improves with combined acoustic and electric stimulation compared to electric stimulation alone [Kong et al., J. Acoust. Soc. Am. 117, 1351-1361 (2005)]. Here the contribution of fundamental frequency (F0) and low-frequency phonetic cues to speech recognition in combined hearing was investigated. Normal-hearing listeners heard vocoded speech in one ear and low-pass (LP) filtered speech in the other. Three listening conditions (vocode-alone, LP-alone, combined) were investigated. Target speech (average F0=120 Hz) was mixed with a time-reversed masker (average F0=172 Hz) at three signal-to-noise ratios (SNRs). LP speech aided performance at all SNRs. Low-frequency phonetic cues were then removed by replacing the LP speech with a LP equal-amplitude harmonic complex, frequency and amplitude modulated by the F0 and temporal envelope of voiced segments of the target. The combined hearing advantage disappeared at 10 and 15 dB SNR, but persisted at 5 dB SNR. A similar finding occurred when, additionally, F0 contour cues were removed. These results are consistent with a role for low-frequency phonetic cues, but not with a combination of F0 information between the two ears. The enhanced performance at 5 dB SNR with F0 contour cues absent suggests that voicing or glimpsing cues may be responsible for the combined hearing benefit.

  11. The hematopoietic factor GM-CSF (granulocyte-macrophage colony-stimulating factor) promotes neuronal differentiation of adult neural stem cells in vitro.

    PubMed

    Krüger, Carola; Laage, Rico; Pitzer, Claudia; Schäbitz, Wolf-Rüdiger; Schneider, Armin

    2007-10-22

    Granulocyte-macrophage colony stimulating factor (GM-CSF) is a hematopoietic growth factor involved in the generation of granulocytes, macrophages, and dendritic cells from hematopoietic progenitor cells. We have recently demonstrated that GM-CSF has anti-apoptotic functions on neurons, and is neuroprotective in animal stroke models. The GM-CSF receptor alpha is expressed on adult neural stem cells in the rodent brain, and in culture. Addition of GM-CSF to NSCs in vitro increased neuronal differentiation in a dose-dependent manner as determined by quantitative PCR, reporter gene assays, and FACS analysis. Similar to the hematopoietic factor Granulocyte-colony stimulating factor (G-CSF), GM-CSF stimulates neuronal differentiation of adult NSCs. These data highlight the astonishingly similar functions of major hematopoietic factors in the brain, and raise the clinical attractiveness of GM-CSF as a novel drug for neurological disorders.

  12. Combining stimulants with monoamine oxidase inhibitors: a review of uses and one possible additional indication.

    PubMed

    Feinberg, S Shalom

    2004-11-01

    Among antidepressant augmentation strategies, the addition of a stimulant to a monoamine oxidase inhibitor (MAOI) has received little attention in the literature in recent years because of the diminished clinical use of the latter and concerns of precipitating a hypertensive crisis or other serious complication. Despite that fact, experienced clinicians continue to use this combination for a variety of indications after other options have failed. This article reviews these reported uses and presents a case suggesting another possible indication. A MEDLINE search was conducted for articles published from 1962 to December 2003 using relevant search terms (psychostimulant, stimulant, amphetamine, dextroamphetamine, pemoline or methylphenidate, atomoxetine, bupropion, monoamine oxidase inhibitor, and selegiline). A manual search was conducted of cross-references and other relevant recent psychiatric sources (2000-2003). The described uses of the MAOI-stimulant combination have included treatment of refractory depression and the MAOI-related side effects of orthostatic hypotension and daytime sedation. No documented reports were found in the recent literature of hypertensive crises or fatalities occurring when the stimulant was cautiously added to the MAOI. Also presented here is another possible indication for this therapeutic regimen: treatment of attention-deficit/hyperactivity disorder in an adult patient whose major depression had uniquely responded to the MAOI tranylcypromine. As in other fields of medicine, potentially hazardous medication combinations are utilized in psychiatry after cautiously weighing the danger of the treatment against the morbidity and risk of not adequately addressing the illness. Particularly, as the potential arrival of the apparently safer transdermal selegiline may increase the use of MAOIs, we feel this combination deserves additional controlled study.

  13. Functional Improvement after Photothrombotic Stroke in Rats Is Associated with Different Patterns of Dendritic Plasticity after G-CSF Treatment and G-CSF Treatment Combined with Concomitant or Sequential Constraint-Induced Movement Therapy.

    PubMed

    Frauenknecht, Katrin; Diederich, Kai; Leukel, Petra; Bauer, Henrike; Schäbitz, Wolf-Rüdiger; Sommer, Clemens J; Minnerup, Jens

    2016-01-01

    We have previously shown that granulocyte-colony stimulating factor (G-CSF) treatment alone, or in combination with constraint movement therapy (CIMT) either sequentially or concomitantly, results in significantly improved sensorimotor recovery after photothrombotic stroke in rats in comparison to untreated control animals. CIMT alone did not result in any significant differences compared to the control group (Diederich et al., Stroke, 2012;43:185-192). Using a subset of rat brains from this former experiment the present study was designed to evaluate whether dendritic plasticity would parallel improved functional outcomes. Five treatment groups were analyzed (n = 6 each) (i) ischemic control (saline); (ii) CIMT (CIMT between post-stroke days 2 and 11); (iii) G-CSF (10 μg/kg G-CSF daily between post-stroke days 2 and 11); (iv) combined concurrent group (CIMT plus G-CSF) and (v) combined sequential group (CIMT between post-stroke days 2 and 11; 10 μg/kg G-CSF daily between post-stroke days 12 and 21, respectively). After impregnation of rat brains with a modified Golgi-Cox protocol layer V pyramidal neurons in the peri-infarct cortex as well as the corresponding contralateral cortex were analyzed. Surprisingly, animals with a similar degree of behavioral recovery exhibited quite different patterns of dendritic plasticity in both peri-lesional and contralesional areas. The cause for these patterns is not easily to explain but puts the simple assumption that increased dendritic complexity after stroke necessarily results in increased functional outcome into perspective.

  14. Combined effect of motor imagery and peripheral nerve electrical stimulation on the motor cortex.

    PubMed

    Saito, Kei; Yamaguchi, Tomofumi; Yoshida, Naoshin; Tanabe, Shigeo; Kondo, Kunitsugu; Sugawara, Kenichi

    2013-06-01

    Although motor imagery enhances the excitability of the corticospinal tract, there are no peripheral afferent inputs during motor imagery. In contrast, peripheral nerve electrical stimulation (ES) can induce peripheral afferent inputs; thus, a combination of motor imagery and ES may enhance the excitability of the corticospinal tract compared with motor imagery alone. Moreover, the level of stimulation intensity may also be related to the modulation of the excitability of the corticospinal tract during motor imagery. Here, we evaluated whether a combination of motor imagery and peripheral nerve ES influences the excitability of the corticospinal tract and measured the effect of ES intensity on the excitability induced during motor imagery. The imagined task was a movement that involved touching the thumb to the little finger, whereas ES involved simultaneous stimulation of the ulnar and median nerves at the wrist. Two different ES intensities were used, one above the motor threshold and another above the sensory threshold. Further, we evaluated whether actual movement with afferent input induced by ES modulates the excitability of the corticospinal tract as well as motor imagery. We found that a combination of motor imagery and ES enhanced the excitability of the motor cortex in the thenar muscle compared with the other condition. Furthermore, we established that the modulation of the corticospinal tract was related to ES intensity. However, we found that the excitability of the corticospinal tract induced by actual movement was enhanced by peripheral nerve ES above the sensory threshold.

  15. The responses of Golgi tendon organs to stimulation of different combinations of motor units.

    PubMed Central

    Gregory, J E; Proske, U

    1979-01-01

    1. Afferent discharges were recorded from stretch receptors identified as Golgi tendon organs, in the medial gastrocnemius and soleus muscles of the cat. 2. The response of a tendon organ was recorded during stimulation of one or more motor units selected for the intensity of discharge elicited from the receptor during twitch and tetanic contractions. 3. Repetitive stimulation of a single motor unit could evoke in a tendon organ a firing rate of up to 174 impulses/sec. The mean rate for a total of 90 motor units was 65 (+/- 32 S.D.) impulses/sec. No significant difference in effectiveness could be detected between motor units covering a wide range of contraction speeds, tetanic tensions and susceptibility to fatigue. 4. The response of a tendon organ to contraction of several motor units in combination was greater than from stimulating any one motor unit alone but less than predicted from the algebraic sum of individual responses. 5. The relation between firing rate and tension was plotted for combined stimulation of up to ten motor units. The relation was found to be a straight line provided the size of the response elicited by each motor unit in the stimulated bundle was similar or when responses were ranked according to their intensity. When one motor unit evoked a much more powerful response than others it tended to dominate the discharge and disturb the linearity. 6. Evidence is provided that the sites of stimulus transduction for motor units which exert their effect directly on the receptor can be relatively independent of one another. It is argued that on such occasions summation of responses may be attributed to mechanisms operating at the level of impulse generation. PMID:521931

  16. Machine learning approach to optimizing combined stimulation and medication therapies for Parkinson’s disease

    PubMed Central

    Shamir, Reuben R.; Dolber, Trygve; Noecker, Angela M.; Walter, Benjamin L.; McIntyre, Cameron C.

    2015-01-01

    Background Deep brain stimulation (DBS) of the subthalamic region is an established therapy for advanced Parkinson’s disease (PD). However, patients often require time-intensive postoperative management to balance their coupled stimulation and medication treatments. Given the large and complex parameter space associated with this task, we propose that clinical decision support systems (CDSS) based on machine learning algorithms could assist in treatment optimization. Objective Develop a proof-of-concept implementation of a CDSS that incorporates patient-specific details on both stimulation and medication. Methods Clinical data from 10 patients, and 89 post-DBS surgery visits, were used to create a prototype CDSS. The system was designed to provide three key functions: 1) information retrieval; 2) visualization of treatment, and; 3) recommendation on expected effective stimulation and drug dosages, based on three machine learning methods that included support vector machines, Naïve Bayes, and random forest. Results Measures of medication dosages, time factors, and symptom-specific preoperative response to levodopa were significantly correlated with postoperative outcomes (p<0.05) and their effect on outcomes was of similar magnitude to that of DBS. Using those results, the combined machine learning algorithms were able to accurately predict 86% (12/14) of the motor improvement scores at one year after surgery. Conclusions Using patient-specific details, an appropriately parameterized CDSS could help select theoretically optimal DBS parameter settings and medication dosages that have potential to improve the clinical management of PD patients. PMID:26140956

  17. Plasma biomarkers of clinical response during chemotherapy plus combination antiretroviral therapy (cART) in HIV+ patients with advanced Kaposi sarcoma.

    PubMed

    Tedeschi, Rosamaria; Bidoli, Ettore; Bortolin, Maria Teresa; Schioppa, Ornella; Vaccher, Emanuela; De Paoli, Paolo

    2015-10-06

    This study aimed to evaluate plasma concentration of selected cancer-associated inflammatory and immune-modulated cytokines in HIV+ patients with advanced Kaposi sarcoma (KS), and to explore candidate biomarkers capable of predicting clinical outcome in response to chemotherapy (CT) plus combination antiretroviral therapy (cART).Thirty-seven plasma cytokines/chemokines were assessed by Luminex technology in 27 consecutive HIV+ KS patients, followed-up during CT and cART of maintenance (m-cART). Associations between plasma concentration of biomarkers and patient clinical response to m-cART were evaluated by means of Hazard Ratios (HRs) and corresponding 95% Confidence Intervals (CIs).Plasma baseline concentration of Granulocyte colony-stimulating factor (G-CSF), Hepatocyte growth factor (HGF) and endoglin were found to be associated with m-cART clinical response (HR:1.56, 95%CI:1.09-2.22, p = 0.01; HR:0.32, 95% CI:0.10-0.99, p = 0.05; HR:0.72, 95% CI:0.54-0.96, p = 0.03, respectively). The multivariate analysis confirmed the associations of baseline plasma G-CSF and HGF concentration with m-cART clinical complete remission response (HR:1.78, 95% CI:1.15-2.74, p = 0.009; HR:0.19, 95% CI:0.04-0.95, p = 0.04). Our exploratory study suggested that plasma G-CSF, HGF and endoglin may be novel predictors of clinical response during m-cART in HIV+ KS patients. Nonetheless, these findings should be further validated in an independent population study.

  18. A Combination of Podophyllotoxin and Rutin Attenuates Radiation Induced Gastrointestinal Injury by Negatively Regulating NF-κB/p53 Signaling in Lethally Irradiated Mice

    PubMed Central

    Kalita, Bhargab; Ranjan, Rajiv; Singh, Abhinav; Yashavarddhan, M. H.; Bajaj, Sania; Gupta, Manju Lata

    2016-01-01

    Development of an effective radio protector to minimise radiation-inflicted damages have largely failed owing to inherent toxicity of most of the agents examined so far. This study is centred towards delivering protection to lethally irradiated mice by pre-administration of a safe formulation G-003M (combination of podophyllotoxin and rutin) majorly through regulation of inflammatory and cell death pathways in mice. Single intramuscular dose of G-003M injected 60 min prior to 9 Gy exposure rescued 89% of whole body lethally irradiated C57BL/6J mice. Studies have revealed reduction in radiation induced reactive oxygen species (ROS), nitric oxide (NO) generation, prostaglandin E2 (PGE2) levels and intestinal apoptosis in G-003M pre-treated mice intestine. Restricted nuclear translocation of redox-sensitive Nuclear factor-κB (NF-κB) and subsequent downregulation of cyclo-oxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS; EC 1.14.13.39) and tumor necrosis factor (TNF-α) levels demonstrated the anti-inflammatory effect that G-003M exerts. Support to early hematopoietic recovery was exhibited through G-003M mediated induction of granulocyte colony stimulating factor (G-CSF) and interleukin (IL-6) levels in lethally irradiated mice. Considerable attenuation in radiation induced morphological damage to the intestinal villi, crypts and mucosal layers was observed in G-003M pre-treated mice. Additionally, our formulation did not reduce the sensitivity of tumor tissue to radiation. Altogether, these results suggest that G-003M ameliorates the deleterious effects of radiation exposure by minimising ROS and NO generation and effectively regulating inflammatory and cell death pathways. Mechanism of protection elucidated in the current study demonstrates that G-003M can be used as a safe and effective radio protective agent in radiotherapy for human application. PMID:28036347

  19. Treatment of advanced soft-tissue sarcomas using a combined strategy of high-dose ifosfamide, high-dose doxorubicin and salvage therapies.

    PubMed

    Leyvraz, S; Herrmann, R; Guillou, L; Honegger, H P; Christinat, A; Fey, M F; Sessa, C; Wernli, M; Cerny, T; Dietrich, D; Pestalozzi, B

    2006-11-20

    Having determined in a phase I study the maximum tolerated dose of high-dose ifosfamide combined with high-dose doxorubicin, we now report the long-term results of a phase II trial in advanced soft-tissue sarcomas. Forty-six patients with locally advanced or metastatic soft-tissue sarcomas were included, with age <60 years and all except one in good performance status (0 or 1). The chemotherapy treatment consisted of ifosfamide 10 g m(-2) (continuous infusion for 5 days), doxorubicin 30 mg m(-2) day(-1) x 3 (total dose 90 mg m(-2)), mesna and granulocyte-colony stimulating factor. Cycles were repeated every 21 days. A median of 4 (1-6) cycles per patient was administered. Twenty-two patients responded to therapy, including three complete responders and 19 partial responders for an overall response rate of 48% (95% CI: 33-63%). The response rate was not different between localised and metastatic diseases or between histological types, but was higher in grade 3 tumours. Median overall survival was 19 months. Salvage therapies (surgery and/or radiotherapy) were performed in 43% of patients and found to be the most significant predictor for favourable survival (exploratory multivariate analysis). Haematological toxicity was severe, including grade > or =3 neutropenia in 59%, thrombopenia in 39% and anaemia in 27% of cycles. Three patients experienced grade 3 neurotoxicity and one patient died of septic shock. This high-dose regimen is toxic but nonetheless feasible in multicentre settings in non elderly patients with good performance status. A high response rate was obtained. Prolonged survival was mainly a function of salvage therapies.

  20. Allogeneic transplantation using CD34(+) selected peripheral blood progenitor cells combined with non-mobilized donor T cells for refractory severe aplastic anaemia.

    PubMed

    Purev, Enkhtsetseg; Tian, Xin; Aue, Georg; Pantin, Jeremy; Vo, Phuong; Shalabi, Reem; Reger, Robert N; Cook, Lisa; Ramos, Catalina; Cho, Elena; Worthy, Tat'yana; Khuu, Hanh; Stroncek, David; Young, Neal S; Childs, Richard W

    2017-03-01

    Allogeneic haematopoietic stem cell transplantation is curative for severe aplastic anaemia (SAA) unresponsive to immunosuppressive therapy. To reduce chronic graft-versus-host disease (GVHD), which occurs more frequently after peripheral blood stem cell (PBSC) transplantation compared to bone-marrow transplantation (BMT), and to prevent graft rejection, we developed a novel partial T-cell depleted transplant that infuses high numbers of granulocyte colony-stimulating factor-mobilized CD34(+) selected PBSCs combined with a BMT-equivalent dose of non-mobilized donor T-cells. Fifteen patients with refractory SAA received cyclophosphamide, anti-thymocyte globulin and fludarabine conditioning, and were transplanted with a median 8 × 10(6) CD34(+)  cells/kg and 2 × 10(7) non-mobilized CD3(+) T-cells/kg from human leucocyte antigen-matched sibling donors. All achieved sustained engraftment with only two developing acute and two developing chronic GVHD. With a 3·5-year median follow-up, 86% of patients survived and were transfusion-independent. When compared to a retrospective cohort of 56 bone-marrow failure patients that received the identical transplant preparative regimen and GVHD prophylaxis with the exception that the allograft contained unmanipulated PBSCs, partial T-cell depleted transplant recipients had delayed donor T-cell chimerism and relative reduction of 75% in the incidence of acute grade II-IV GVHD (13% vs. 52%; P = 0·010) and of 82% in chronic GVHD (13% vs. 72%; P = 0·0004). In multivariate analysis, partial T-cell depleted transplants remained significantly associated with a reduced risk of GVHD. In conclusion, for patients with refractory SAA, this novel transplant strategy achieves excellent engraftment and survival when compared to unmanipulated PBSC transplants and dramatically reduces the incidence of both acute and chronic GVHD. © 2017 John Wiley & Sons Ltd.

  1. A Combination of Podophyllotoxin and Rutin Attenuates Radiation Induced Gastrointestinal Injury by Negatively Regulating NF-κB/p53 Signaling in Lethally Irradiated Mice.

    PubMed

    Kalita, Bhargab; Ranjan, Rajiv; Singh, Abhinav; Yashavarddhan, M H; Bajaj, Sania; Gupta, Manju Lata

    2016-01-01

    Development of an effective radio protector to minimise radiation-inflicted damages have largely failed owing to inherent toxicity of most of the agents examined so far. This study is centred towards delivering protection to lethally irradiated mice by pre-administration of a safe formulation G-003M (combination of podophyllotoxin and rutin) majorly through regulation of inflammatory and cell death pathways in mice. Single intramuscular dose of G-003M injected 60 min prior to 9 Gy exposure rescued 89% of whole body lethally irradiated C57BL/6J mice. Studies have revealed reduction in radiation induced reactive oxygen species (ROS), nitric oxide (NO) generation, prostaglandin E2 (PGE2) levels and intestinal apoptosis in G-003M pre-treated mice intestine. Restricted nuclear translocation of redox-sensitive Nuclear factor-κB (NF-κB) and subsequent downregulation of cyclo-oxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS; EC 1.14.13.39) and tumor necrosis factor (TNF-α) levels demonstrated the anti-inflammatory effect that G-003M exerts. Support to early hematopoietic recovery was exhibited through G-003M mediated induction of granulocyte colony stimulating factor (G-CSF) and interleukin (IL-6) levels in lethally irradiated mice. Considerable attenuation in radiation induced morphological damage to the intestinal villi, crypts and mucosal layers was observed in G-003M pre-treated mice. Additionally, our formulation did not reduce the sensitivity of tumor tissue to radiation. Altogether, these results suggest that G-003M ameliorates the deleterious effects of radiation exposure by minimising ROS and NO generation and effectively regulating inflammatory and cell death pathways. Mechanism of protection elucidated in the current study demonstrates that G-003M can be used as a safe and effective radio protective agent in radiotherapy for human application.

  2. The Effect of Combined Ultrasound and Electric Field Stimulation on Wound Healing in Chronic Ulcerations.

    PubMed

    Avrahami, Ram; Rosenblum, Jonathan; Gazes, Michael; Rosenblum, Sean; Litman, Leib

    2015-07-01

    Ultrasound and electric stimulation are known therapies for the treatment of chronic ulcerations. Combined modulated ultrasound and electric field stimulation (CUSEFS) have never been studied as a single modality. The authors evaluate the results of CUSEFS (BRH Medical Ltd, Jerusalem, Israel) on a variety of wound types in a number of clinics. This retrospective analysis looked at ulcers treated with CUSEFS in 4 clinics. Wounds were evaluated by an independent assessor and data was evaluated by an independent statistician. Of the 300 wounds treated with the CUSEFS device, only those classified as diabetic foot ulcers (DFUs) or venous leg ulcers (VLUs) were evaluated. A treatment was deemed successful if the wound was 50% closed within 4 weeks. Subjects were then followed to see if their wounds completely closed within 16 weeks. Of the 27 DFUs treated, 59.3% (16) achieved 50% closure within 4 weeks. Of the 38 VLUs treated, 71.1% (27) achieved 50% closure within 4 weeks. It was found that variables such as gender, size of the wound at presentation, and longevity of the wound had no bearing on the outcome. The age of the patient had an effect on the outcome of the VLUs. The wound healing trajectory was supported in that there was a significant difference in the achievement of total closure between those subjects who had a successful trial and those who did not. Combined modulated ultrasound and electric field stimulation has a place as adjunct therapy that aids wound healing and provides an effective noninvasive treatment option.

  3. Site-specific effects of mental practice combined with transcranial direct current stimulation on motor learning.

    PubMed

    Foerster, Aguida; Rocha, Sérgio; Wiesiolek, Carine; Chagas, Anna Paula; Machado, Giselle; Silva, Evelyn; Fregni, Felipe; Monte-Silva, Katia

    2013-03-01

    Mental practice can induce significant neural plasticity and result in motor performance improvement if associated with motor imagery tasks. Given the effects of transcranial direct current stimulation (tDCS) on neuroplasticity, the current study tested whether tDCS, using different electrode montages, can increase the neuroplastic effects of mental imagery on motor learning. Eighteen healthy right-handed adults underwent a randomised sham-controlled crossover experiment to receive mental training combined with either sham or active anodal tDCS of the right primary motor cortex (M1), right supplementary motor area, right premotor area, right cerebellum or left dorsolateral prefrontal cortex (DLPFC). Motor performance was assessed by a blinded rater using: non-dominant handwriting time and legibility, and mentally trained task at baseline (pre) and immediately after (post) mental practice combined with tDCS. Active tDCS significantly enhances the motor-imagery-induced improvement in motor function as compared with sham tDCS. There was a specific effect for the site of stimulation such that effects were only observed after M1 and DLPFC stimulation during mental practice. These findings provide new insights into motor imagery training and point out that two cortical targets (M1 and DLPFC) are significantly associated with the neuroplastic effects of mental imagery on motor learning. Further studies should explore a similar paradigm in patients with brain lesions. © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  4. Targeting Neuronal Networks with Combined Drug and Stimulation Paradigms Guided by Neuroimaging to Treat Brain Disorders.

    PubMed

    Faingold, Carl L; Blumenfeld, Hal

    2015-10-01

    Improved therapy of brain disorders can be achieved by focusing on neuronal networks, utilizing combined pharmacological and stimulation paradigms guided by neuroimaging. Neuronal networks that mediate normal brain functions, such as hearing, interact with other networks, which is important but commonly neglected. Network interaction changes often underlie brain disorders, including epilepsy. "Conditional multireceptive" (CMR) brain areas (e.g., brainstem reticular formation and amygdala) are critical in mediating neuroplastic changes that facilitate network interactions. CMR neurons receive multiple inputs but exhibit extensive response variability due to milieu and behavioral state changes and are exquisitely sensitive to agents that increase or inhibit GABA-mediated inhibition. Enhanced CMR neuronal responsiveness leads to expression of emergent properties--nonlinear events--resulting from network self-organization. Determining brain disorder mechanisms requires animals that model behaviors and neuroanatomical substrates of human disorders identified by neuroimaging. However, not all sites activated during network operation are requisite for that operation. Other active sites are ancillary, because their blockade does not alter network function. Requisite network sites exhibit emergent properties that are critical targets for pharmacological and stimulation therapies. Improved treatment of brain disorders should involve combined pharmacological and stimulation therapies, guided by neuroimaging, to correct network malfunctions by targeting specific network neurons.

  5. Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer

    PubMed Central

    2013-01-01

    Introduction This Phase I study evaluated the safety, tolerability and efficacy of olaparib, a potent oral poly(ADP-ribose) polymerase (PARP) inhibitor, in combination with paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC). Methods Eligible patients who had received ≤1 prior cytotoxic regimen for mTNBC were treated with olaparib 200 mg bid continuously plus weekly paclitaxel 90 mg/m2 for three weeks per four-week cycle. Dose modifications in a large proportion of patients due to neutropenia resulted in enrollment of a second cohort of patients who, if they experienced grade ≥2 neutropenia in cycle 1, received granulocyte-colony stimulating factor, which was continued prophylactically in subsequent cycles. All patients had measurable disease; tumor responses were evaluated according to RECIST (version 1.0). Results Nineteen patients (cohort 1, n = 9; cohort 2, n = 10) received treatment; 15 had received prior taxane chemotherapy. The most frequent adverse events were diarrhea (n = 12, 63%), nausea (n = 11, 58%) and neutropenia (n = 11, 58%). Seven neutropenia events were reported in cohort 1 (four grade ≥3) and four in cohort 2 (two grade ≥3, including one event of febrile neutropenia). The median (range) dose intensity of paclitaxel was 57% (26 to 100%) in cohort 1 and 73% (29 to 100%) in cohort 2. Seven patients (37%) had a confirmed partial response; one patient remains on olaparib monotherapy without progression. Conclusions The combination of olaparib and weekly paclitaxel was complicated by a significant clinical interaction, with higher-than-expected rates of neutropenia despite secondary prophylaxis. Given the encouraging response rate, alternative scheduling and dosing strategies should be considered (funded by AstraZeneca; ClinicalTrials.gov, NCT00707707). PMID:24063698

  6. Speech Perception With Combined Electric-Acoustic Stimulation: A Simulation and Model Comparison.

    PubMed

    Rader, Tobias; Adel, Youssef; Fastl, Hugo; Baumann, Uwe

    2015-01-01

    The aim of this study is to simulate speech perception with combined electric-acoustic stimulation (EAS), verify the advantage of combined stimulation in normal-hearing (NH) subjects, and then compare it with cochlear implant (CI) and EAS user results from the authors' previous study. Furthermore, an automatic speech recognition (ASR) system was built to examine the impact of low-frequency information and is proposed as an applied model to study different hypotheses of the combined-stimulation advantage. Signal-detection-theory (SDT) models were applied to assess predictions of subject performance without the need to assume any synergistic effects. Speech perception was tested using a closed-set matrix test (Oldenburg sentence test), and its speech material was processed to simulate CI and EAS hearing. A total of 43 NH subjects and a customized ASR system were tested. CI hearing was simulated by an aurally adequate signal spectrum analysis and representation, the part-tone-time-pattern, which was vocoded at 12 center frequencies according to the MED-EL DUET speech processor. Residual acoustic hearing was simulated by low-pass (LP)-filtered speech with cutoff frequencies 200 and 500 Hz for NH subjects and in the range from 100 to 500 Hz for the ASR system. Speech reception thresholds were determined in amplitude-modulated noise and in pseudocontinuous noise. Previously proposed SDT models were lastly applied to predict NH subject performance with EAS simulations. NH subjects tested with EAS simulations demonstrated the combined-stimulation advantage. Increasing the LP cutoff frequency from 200 to 500 Hz significantly improved speech reception thresholds in both noise conditions. In continuous noise, CI and EAS users showed generally better performance than NH subjects tested with simulations. In modulated noise, performance was comparable except for the EAS at cutoff frequency 500 Hz where NH subject performance was superior. The ASR system showed similar behavior

  7. Combination and switching of stimulants in children and adolescents with attention deficit/hyperactivity disorder in quebec.

    PubMed

    Ben Amor, Leila; Sikirica, Vanja; Cloutier, Martin; Lachaine, Jean; Guerin, Annie; Carter, Valerie; Hodgkins, Paul; van Stralen, Judy

    2014-09-01

    To assess the one-year period prevalence of stimulant combination therapy and switching in children/ adolescents with attention deficit/hyperactivity disorder (ADHD) in Quebec, Canada. Patients aged 6-17 years, with at least two ADHD diagnosis codes documented in different visits and at least 30 days' supply of a stimulant during their most recent one-year observation period were selected from the Regie de l'assurance maladie du Quebec database (03/2007-02/2012). Combination therapy was defined as at least 30 consecutive days of concomitant use of multiple stimulants with different active moieties, or use of a stimulant and another psychotropic medication. Therapy switching was defined as a prescription claim for a new psychotropic medication less than 30 days before or after the end of supply of a stimulant. The one-year period prevalence of therapy combination and switching was calculated. The one-year period prevalence of combination therapy and switching among 9,431 children and adolescents with ADHD treated with stimulants was 19.8% and 18.7%, respectively. The most frequent combination categories were atypical antipsychotics (AAP: 10.8%), atomoxetine (ATX: 5.5%) and clonidine (5.3%). The most frequent switched-to categories were other stimulants (7.9%), AAP (5.5%) and ATX (4.7%). Approximately one in five children/adolescents with ADHD on a stimulant experienced combination therapy or therapy switching; however, the majority of the medications used in combination or switching were not label-indicated for the treatment of ADHD in Canada. These results highlight the need for further research to evaluate the risk-benefit of stimulant combination and switching in children and adolescents with ADHD.

  8. Combination and Switching of Stimulants in Children and Adolescents with Attention Deficit/Hyperactivity Disorder in Quebec

    PubMed Central

    Ben Amor, Leila; Sikirica, Vanja; Cloutier, Martin; Lachaine, Jean; Guerin, Annie; Carter, Valerie; Hodgkins, Paul; van Stralen, Judy

    2014-01-01

    Objective: To assess the one-year period prevalence of stimulant combination therapy and switching in children/ adolescents with attention deficit/hyperactivity disorder (ADHD) in Quebec, Canada. Method: Patients aged 6–17 years, with at least two ADHD diagnosis codes documented in different visits and at least 30 days’ supply of a stimulant during their most recent one-year observation period were selected from the Regie de l’assurance maladie du Quebec database (03/2007–02/2012). Combination therapy was defined as at least 30 consecutive days of concomitant use of multiple stimulants with different active moieties, or use of a stimulant and another psychotropic medication. Therapy switching was defined as a prescription claim for a new psychotropic medication less than 30 days before or after the end of supply of a stimulant. The one-year period prevalence of therapy combination and switching was calculated. Results: The one-year period prevalence of combination therapy and switching among 9,431 children and adolescents with ADHD treated with stimulants was 19.8% and 18.7%, respectively. The most frequent combination categories were atypical antipsychotics (AAP: 10.8%), atomoxetine (ATX: 5.5%) and clonidine (5.3%). The most frequent switched-to categories were other stimulants (7.9%), AAP (5.5%) and ATX (4.7%). Conclusions: Approximately one in five children/adolescents with ADHD on a stimulant experienced combination therapy or therapy switching; however, the majority of the medications used in combination or switching were not label-indicated for the treatment of ADHD in Canada. These results highlight the need for further research to evaluate the risk-benefit of stimulant combination and switching in children and adolescents with ADHD. PMID:25320609

  9. Combined treatment with dabrafenib and trametinib with immune-stimulating antibodies for BRAF mutant melanoma

    PubMed Central

    Homet Moreno, Blanca; Mok, Stephen; Comin-Anduix, Begonya; Hu-Lieskovan, Siwen; Ribas, Antoni

    2016-01-01

    The combination of targeted therapy with BRAF and MEK inhibitors has become the standard of care in patients with BRAFV600E mutant melanoma, but responses are not durable. In addition, the impressive clinical benefits with anti-PD-1 and anti-PD-L1 antibodies (Ab) in patients with heavily pretreated metastatic melanoma and the synergistic effect of dabrafenib, trametinib and anti-PD-1 compared with single therapy alone groups support the idea that combining dabrafenib, trametinib and immunotherapy based on PD-1 blockade could be an interesting approach in the treatment of metastatic melanoma. With our mouse model of syngeneic BRAFV600E driven melanoma (SM1), we tested whether the addition of an immunostimulatory Ab targeting CD137 (4-1BB) and/or CD134 (OX40) would enhance the antitumor effect of dabrafenib, trametinib and anti-PD-1 or anti-PD-L1 therapy. In vitro studies showed that the combination group of dabrafenib, trametinib and anti-PD-1 increases CD8+ tumor infiltrating lymphocytes (TILs), as well as CD4+ T cells and tumor-associated macrophages (TAMs). An upregulation of PD-L1 was observed in the combination of dabrafenib, trametinib and anti-PD-1 therapy. Combination of dabrafenib, trametinib and anti-PD-1, with either anti-CD137 or anti-CD134, showed a superior antitumor effect, but the five-agent combination was not superior to the four-agent combinations. In conclusion, the combination of dabrafenib, trametinib, anti-PD1 or anti-PD-L1 therapy results in robust antitumor activity, which is further improved by adding the immune-stimulating Ab anti-CD137 or anti-CD134. Our findings support the testing of these combinations in patients with BRAFV600E mutant metastatic melanoma. PMID:27622011

  10. Unilateral thalamic and pallidal deep brain stimulation for idiopathic hemidystonia: results of individual and combined stimulations. Case report.

    PubMed

    Goulenko, Victor; da Costa Cruz, Paulo Luiz; Niemeyer Filho, Paulo

    2017-07-01

    Pallidal stimulation has been the usual surgical treatment for dystonia in the last decades. The continuous investigation of the physiopathology and the motor pathways involved leads to the search for complementary targets to improve results. The authors present the case of a 37-year-old woman who had suffered from idiopathic hemidystonia with hyperkinetic and hypokinetic movements for 11 years, and who was treated with deep brain stimulation. A brief literature review is also provided. The globus pallidus internus and the ventral intermediate/ventral oral posterior complex of the thalamus were stimulated separately and simultaneously for 3 months and compared using the Burke-Fahn-Marsden Dystonia Rating Scale and the Global Dystonia Severity Rating Scale, with a 3.5-year follow-up. The synergism of multiple-target stimulation resulted in a complete improvement of the mixed dystonic symptoms.

  11. Antitumor protection from the murine T-cell leukemia/lymphoma EL4 by the continuous subcutaneous coadministration of recombinant macrophage-colony stimulating factor and interleukin-2.

    PubMed

    Vallera, D A; Taylor, P A; Aukerman, S L; Blazar, B R

    1993-09-15

    Combined continuous s.c. coadministration of macrophage-colony stimulating factor (M-CSF) plus interleukin-2 (IL-2) by osmotic pump protected mice given i.v. injections of a lethal dose of EL4 T-cell leukemia/lymphoma. Antitumor protection was significantly greater than that afforded by treatment with either cytokine alone. Since neither IL-2 receptors nor M-CSF receptors were expressed on EL4, the antitumor effect was likely attributed to murine effector cells. To determine how M-CSF+IL-2 provided this effect, we performed immunophenotypic and functional analyses as well as in vivo depletion studies of putative antitumor effector cells. Splenic phenotyping experiments revealed that the highest levels of macrophages and natural killer cells were observed in mice given the cytokine combination rather than either M-CSF or IL-2 alone. In vivo depletion of natural killer cells ablated the antitumor protective effect of M-CSF and IL-2. T-cells were also important for M-CSF+IL-2 efficacy, since adult thymectomy/T-cell depletion significantly inhibited the ability of cytokine coadministration to protect against EL4. Coadministration of the 2 cytokines significantly elevated in vivo levels of CD3+CD4+, CD3+CD8+, CD3+NK1.1+ T-cells, and CD3+CD25+ (activated) T-cells, and elevated anti-EL4 cytotoxic T-cell activity measured in vitro. Although WBC counts and fluorescence-activated cell sorter studies showed that M-CSF+IL-2 treatment significantly elevated neutrophils, s.c. delivery of granulocyte-colony stimulating factor at doses sufficient to induce neutrophilia was unable to confer anti-EL4 protection. These studies indicate that macrophages, T-cells, and natural killer cells are all important in the M-CSF+IL-2 anti-EL4 response. The superior antitumor effect of this cytokine combination along with the ability of M-CSF to diminish the toxicity of IL-2 in this model suggests that further investigations into the clinical potential of this combination treatment are warranted.

  12. Robust Stimulation of W1282X-CFTR Channel Activity by a Combination of Allosteric Modulators

    PubMed Central

    Wang, Wei; Hong, Jeong S.; Rab, Andras; Sorscher, Eric J.; Kirk, Kevin L.

    2016-01-01

    W1282X is a common nonsense mutation among cystic fibrosis patients that results in the production of a truncated Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel. Here we show that the channel activity of the W1282X-CFTR polypeptide is exceptionally low in excised membrane patches at normally saturating doses of ATP and PKA (single channel open probability (PO) < 0.01). However, W1282X-CFTR channels were stimulated by two CFTR modulators, the FDA-approved VX-770 and the dietary compound curcumin. Each of these compounds is an allosteric modulator of CFTR gating that promotes channel activity in the absence of the native ligand, ATP. Although W1282X-CFTR channels were stimulated by VX-770 in the absence of ATP their activities remained dependent on PKA phosphorylation. Thus, activated W1282X-CFTR channels should remain under physiologic control by cyclic nucleotide signaling pathways in vivo. VX-770 and curcumin exerted additive effects on W1282X-CFTR channel gating (opening/closing) in excised patches such that the Po of the truncated channel approached unity (> 0.9) when treated with both modulators. VX-770 and curcumin also additively stimulated W1282X-CFTR mediated currents in polarized FRT epithelial monolayers. In this setting, however, the stimulated W1282X-CFTR currents were smaller than those mediated by wild type CFTR (3–5%) due presumably to lower expression levels or cell surface targeting of the truncated protein. Combining allosteric modulators of different mechanistic classes is worth considering as a treatment option for W1282X CF patients perhaps when coupled with maneuvers to increase expression of the truncated protein. PMID:27007499

  13. Robust Stimulation of W1282X-CFTR Channel Activity by a Combination of Allosteric Modulators.

    PubMed

    Wang, Wei; Hong, Jeong S; Rab, Andras; Sorscher, Eric J; Kirk, Kevin L

    2016-01-01

    W1282X is a common nonsense mutation among cystic fibrosis patients that results in the production of a truncated Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel. Here we show that the channel activity of the W1282X-CFTR polypeptide is exceptionally low in excised membrane patches at normally saturating doses of ATP and PKA (single channel open probability (PO) < 0.01). However, W1282X-CFTR channels were stimulated by two CFTR modulators, the FDA-approved VX-770 and the dietary compound curcumin. Each of these compounds is an allosteric modulator of CFTR gating that promotes channel activity in the absence of the native ligand, ATP. Although W1282X-CFTR channels were stimulated by VX-770 in the absence of ATP their activities remained dependent on PKA phosphorylation. Thus, activated W1282X-CFTR channels should remain under physiologic control by cyclic nucleotide signaling pathways in vivo. VX-770 and curcumin exerted additive effects on W1282X-CFTR channel gating (opening/closing) in excised patches such that the Po of the truncated channel approached unity (> 0.9) when treated with both modulators. VX-770 and curcumin also additively stimulated W1282X-CFTR mediated currents in polarized FRT epithelial monolayers. In this setting, however, the stimulated W1282X-CFTR currents were smaller than those mediated by wild type CFTR (3-5%) due presumably to lower expression levels or cell surface targeting of the truncated protein. Combining allosteric modulators of different mechanistic classes is worth considering as a treatment option for W1282X CF patients perhaps when coupled with maneuvers to increase expression of the truncated protein.

  14. Spontaneous movement tempo can be influenced by combining action observation and somatosensory stimulation

    PubMed Central

    Bisio, Ambra; Avanzino, Laura; Lagravinese, Giovanna; Biggio, Monica; Ruggeri, Piero; Bove, Marco

    2015-01-01

    Spontaneous movement tempo (SMT) was a popular field of study of the Gestalt psychologists It can be determined from subjects freely tapping out a rhythm with their finger, and it has been found to average about 2 Hz. A previous study showed that SMT changed after the observation of rhythmical movements performed at frequency different from the SMT. This effect was long-lasting only when movement execution immediately followed action observation (AO). We recently demonstrated that only when AO was combined with peripheral nerve stimulation (AO-PNS) was it possible to induce plastic changes in the excitability of the motor cortex, whereas AO and PNS alone did not evoke any changes. Here we investigated whether the observation of rhythmical actions at a frequency higher than the SMT combined with PNS induced lasting changes in SMT even in absence of immediate movement execution. Forty-eight participants were assigned to four groups. In AO-PNS group they observed a video showing a right hand performing a finger opposition movement sequence at 3 Hz and contemporarily received an electrical stimulation at the median nerve; in AO group and PNS group participants either observed the same video or received the same electrical stimulation of the AO-PNS group, respectively; in LANDSCAPE group subjects observed a neutral video. Participants performed a finger opposition movement sequence at spontaneous movement rate before and 30 min after the conditioning protocols. Results showed that SMT significantly changed only after AO-PNS. This result suggested that the AO-PNS protocol was able to induce lasting changes in SMT due to neuroplasticity mechanisms, indicating possible application of AO-PNS in rehabilitative treatments. PMID:26441565

  15. Combination of transcranial direct current stimulation and methylphenidate in subacute stroke.

    PubMed

    Wang, Qing Mei; Cui, Huashun; Han, Soo Jeong; Black-Schaffer, Randie; Volz, Magdalena Sarah; Lee, Yong-Tae; Herman, Seth; Latif, Lydia Abul; Zafonte, Ross; Fregni, Felipe

    2014-05-21

    Noninvasive transcranial direct current stimulation (tDCS) and methylphenidate (MP) are associated with motor recovery after stroke. Based on the potentially complementary mechanisms of these interventions, we examined whether there is an interactive effect between MP and tDCS. In this preliminary study, we randomized subacute stroke subjects to receive tDCS alone, MP alone or combination of tDCS and MP. A blinded rater measured safety, hand function, and cortical excitability before and after treatment. None of the treatments caused any major or severe adverse effects or induced significant differences in cortical excitability. Analysis of variance of gain score, as measured by Purdue pegboard test, showed a significant between-group difference (F(2,6)=12.167, p=0.008). Post hoc analysis showed that the combination treatment effected greater Purdue pegboard gain scores than tDCS alone (p=0.017) or MP alone (p=0.01). Our preliminary data with nine subjects shows an interesting dissociation between motor function improvement and lack of motor corticospinal plasticity changes as indexed by transcranial magnetic stimulation in subacute stroke subjects.

  16. Swallowing is differentially influenced by retronasal compared with orthonasal stimulation in combination with gustatory stimuli.

    PubMed

    Welge-Lüssen, Antje; Ebnöther, Myriam; Wolfensberger, Markus; Hummel, Thomas

    2009-07-01

    Identical stimuli are processed differently when presented ortho- or retronasally. In contrast to orthonasal olfaction, retronasal odorant perception is strongly associated with flavor and food intake, which is usually followed by swallowing. Along with other stimuli, gustatory stimuli are known to influence the swallowing reflex. It was therefore the aim of present study to examine whether retronasal olfaction, in combination with simultaneous gustatory stimuli, influences swallowing in a manner different from that of orthonasal olfaction. Fifty normosmic and normogeusic subjects took part in the study. A sweet taste (glucose, delivered via an intraoral taste dispenser) was presented simultaneously with vanillin, a food-like odor, either ortho- or retronasally at random using a computer-controlled olfactometer. Ultrasound imaging of the mouth floor was recorded on videotape to continuously monitor swallowing activity. After retronasal stimulation, swallowing occurred significantly faster (7.49 vs. 9.42 s; P < 0.001) and also took place more frequently compared with swallowing after orthonasal stimulation (1.38 times vs. 1.14 times; P < 0.001). These results show that a food-like odorant presented retronasally in combination with a congruent taste stimulus can influence swallowing. Whether these results can be assigned to other, unfamiliar, unpleasant nonfood-like odors has yet to be determined.

  17. Combined neuromodulatory interventions in acute experimental pain: assessment of melatonin and non-invasive brain stimulation

    PubMed Central

    da Silva, Nádia Regina Jardim; Laste, Gabriela; Deitos, Alícia; Stefani, Luciana Cadore; Cambraia-Canto, Gustavo; Torres, Iraci L. S.; Brunoni, Andre R.; Fregni, Felipe; Caumo, Wolnei

    2015-01-01

    Transcranial direct current stimulation (tDCS) and melatonin can effectively treat pain. Given their potentially complementary mechanisms of action, their combination could have a synergistic effect. Thus, we tested the hypothesis that compared to the control condition and melatonin alone, tDCS combined with melatonin would have a greater effect on pain modulatory effect, as assessed by quantitative sensory testing (QST) and by the pain level during the Conditioned Pain Modulation (CPM)-task. Furthermore, the combined treatment would have a greater cortical excitability effect as indicated by the transcranial magnetic stimulation (TMS) and on the serum BDNF level. Healthy males (n = 20), (aged 18–40 years), in a blinded, placebo-controlled, crossover, clinical trial, were randomized into three groups: sublingual melatonin (0.25 mg/kg) + a-tDCS, melatonin (0.25 mg/kg) + sham-(s)-tDCS, or sublingual placebo+sham-(s)-tDCS. Anodal stimulation (2 mA, 20 min) was applied over the primary motor cortex. There was a significant difference in the heat pain threshold (°C) for melatonin+a-tDCS vs. placebo+s-tDCS (mean difference: 4.86, 95% confidence interval [CI]: 0.9 to 8.63) and melatonin+s-tDCS vs. placebo+s-tDCS (mean: 5.16, 95% CI: 0.84 to 8.36). There was no difference between melatonin+s-tDCS and melatonin+a-tDCS (mean difference: 0.29, 95% CI: −3.72 to 4.23). The mean change from the baseline on amplitude of motor evocate potential (MEP) was significantly higher in the melatonin+a-tDCS (−19.96% ± 5.2) compared with melatonin+s-tDCS group (−1.36% ± 5.35) and with placebo+s-tDCS group (3.61% ± 10.48), respectively (p < 0.05 for both comparisons). While melatonin alone or combined with a-tDCS did not significantly affect CPM task result, and serum BDNF level. The melatonin effectively reduced pain; however, its association with a-tDCS did not present an additional modulatory effect on acute induced pain. PMID:25873871

  18. The combination of radiotherapy and immunotherapy using glycated chitosan as an immunological stimulant

    NASA Astrophysics Data System (ADS)

    Chang, Chun-Yuan; Leu, Jyh-Der; Wang, Chung-Yi; Chen, Wei R.; Lee, Yi-Jang

    2015-03-01

    Immunotherapy has been reported to effectively treat various cancers. In addition, scientists are dedicated in finding whether the combination of radiotherapy and immunotherapy can efficiently suppress cancer progression and recurrence. Although radiotherapy has been widely used for breast cancer, better strategies to overcome the latestage breast cancer remains explored. The glycated chitosan (GC), a novel immunological stimulant, was demonstrated to trigger local immune response facilitating the enhancement of radiosensitivity. Our previous study also revealed that the cell mortality and invasive ability were decreased under GC treatment, but the underlying mechanism remains unclear. In this study, we used 4T1-3R-L, a derived murine breast cancer cell line from the spontaneous metastasized liver lesion. We combined ionizing radiation with GC to treat 4T1-3R-L and found the expression of DNA damage-related genes such as gamma-H2AX was more than radiation alone In addition, the cell cycle distribution and colony forming assay showed an increased sub-G1 population and decreased cell survival rate after IR combined GC treatment. Taken together, we sought to elucidate the underlying mechanism by the investigation of DNA damage repair process when IR combined with GC, and to explore another advantage of GC to aid other cancer treatments. Based on our most updated results, the GC treatment is able to effectively increase the radiosensitivity through an immune-responsive signaling transduction, indicating that GC could be a valuable therapeutic strategy for treating against advanced breast cancers.

  19. Mirror therapy combined with functional electrical stimulation for rehabilitation of stroke survivors' ankle dorsiflexion.

    PubMed

    Salhab, Ghadir; Sarraj, Ahmad Rifaii; Saleh, Soha

    2016-08-01

    This study investigates the effect of combining both mirror therapy with Electrical Stimulation (ES) on improvement of the function of lower extremity compared to conventional therapy. 18 stroke survivors (sub acute stage) were recruited, 9 of them were randomly assigned to receive conventional treatment and another 9 started the mirror therapy combined with ES treatment. Duration of each session in both interventions was 50 minutes, done 4 times per week over two weeks. After 2 weeks, subjects took one week rest before switching they type of treatment; those started with conventional therapy continued with mirror therapy combined with ES, and vice versa. The duration of this phase was 2 weeks with same schedule as the 1st one. Ankle dorsi-flexion range of motion, lower extremity sensory-motor function, and walking duration were measured at baseline, after 1st 2 weeks, and immediately after the last two weeks, and 4 weeks after end of training (retention test). Repeated Measures ANCOVA was done to compare outcome measures scores in both groups and between all testing days, and paired T-test was used measure the difference between groups. Significant increase in all outcome measures was found after the (MT+ES) training, which is higher than conventional therapy training (p<;0.0001). In conclusion, the results suggest that combination of mirror therapy and ES is more effective than conventional therapy in improving lower limb motor function after stroke.

  20. Ovulation induction and controlled ovarian stimulation using letrozole gonadotropin combination: A single center retrospective cohort study.

    PubMed

    Arya, Sushila; Kupesic-Plavsic, Sanja; Mulla, Zuber D; Dwivedi, Alok K; Crisp, Zeni; Jose, Jisha; Noble, Luis S

    2017-09-23

    To assess the effect of letrozole in combination with low dose gonadotropins for ovulation induction in anovulatory infertility from polycystic ovary syndrome (PCOS) and controlled ovarian stimulation for endometriosis, and unexplained infertility patients. Retrospective cohort study in a setting of private Reproductive Endocrinology and Infertility Clinic affiliated with the University. Three hundred couples (650 cycles) requiring OI/COS for PCOS (92 patients, 195 cycles), endometriosis (89 patients, 217 cycles), and unexplained infertility (119 patients, 238 cycles). Patients received 2.5mg or 5mg letrozole for 5days (D3-D7) and recombinant follicle-stimulating hormone on alternating D3-D7 and human menopausal gonadotropin-highly purified alternating D5-D10 until growth of ideally 2 mature follicles. Ovulation was triggered with 10,000 IU of HCG. Maximum number of cycles per patient was four. Main outcome measures were clinical pregnancy rates, multiple order pregnancy rates, miscarriage rates, number of follicles and endometrial thickness on the day of HCG administration. The cumulative incidence of pregnancy was estimated as 35% (95%CI: 29%-41%) overall and was highest in patients with PCOS (36.6%), followed by unexplained infertility (34.6%) and endometriosis (32.5%). The pregnancy rates per cycle in PCOS, endometriosis and unexplained infertility patients were 17%, 13.2% and 17.2% respectively, no statistically significant difference between the groups. There were three twin pregnancies in PCOS, and one in unexplained infertility group. Monofolliculogenesis was noted in 48% of patients. Letrozole-low dose gonadotropins combination appears to be effective across different causes of infertility for superovulation. The letrozole-low dose gonadotropin combination resulted in high rate of monofolliculogenesis, low occurrence of multiple gestations and no case of OHSS or cycle cancellation. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. A combined model of human erythropoiesis and granulopoiesis under growth factor and chemotherapy treatment

    PubMed Central

    2014-01-01

    Background Haematotoxicity of conventional chemotherapies often results in delays of treatment or reduction of chemotherapy dose. To ameliorate these side-effects, patients are routinely treated with blood transfusions or haematopoietic growth factors such as erythropoietin (EPO) or granulocyte colony-stimulating factor (G-CSF). For the latter ones, pharmaceutical derivatives are available, which differ in absorption kinetics, pharmacokinetic and -dynamic properties. Due to the complex interaction of cytotoxic effects of chemotherapy and the stimulating effects of different growth factor derivatives, optimal treatment is a non-trivial task. In the past, we developed mathematical models of thrombopoiesis, granulopoiesis and erythropoiesis under chemotherapy and growth-factor applications which can be used to perform clinically relevant predictions regarding the feasibility of chemotherapy schedules and cytopenia prophylaxis with haematopoietic growth factors. However, interactions of lineages and growth-factors were ignored so far. Results To close this gap, we constructed a hybrid model of human granulopoiesis and erythropoiesis under conventional chemotherapy, G-CSF and EPO applications. This was achieved by combining our single lineage models of human erythropoiesis and granulopoiesis with a common stem cell model. G-CSF effects on erythropoiesis were also implemented. Pharmacodynamic models are based on ordinary differential equations describing proliferation and maturation of haematopoietic cells. The system is regulated by feedback loops partly mediated by endogenous and exogenous EPO and G-CSF. Chemotherapy is modelled by depletion of cells. Unknown model parameters were determined by fitting the model predictions to time series data of blood counts and cytokine profiles. Data were extracted from literature or received from cooperating clinical study groups. Our model explains dynamics of mature blood cells and cytokines after growth-factor applications in

  2. A combined model of human erythropoiesis and granulopoiesis under growth factor and chemotherapy treatment.

    PubMed

    Schirm, Sibylle; Engel, Christoph; Loeffler, Markus; Scholz, Markus

    2014-05-26

    Haematotoxicity of conventional chemotherapies often results in delays of treatment or reduction of chemotherapy dose. To ameliorate these side-effects, patients are routinely treated with blood transfusions or haematopoietic growth factors such as erythropoietin (EPO) or granulocyte colony-stimulating factor (G-CSF). For the latter ones, pharmaceutical derivatives are available, which differ in absorption kinetics, pharmacokinetic and -dynamic properties. Due to the complex interaction of cytotoxic effects of chemotherapy and the stimulating effects of different growth factor derivatives, optimal treatment is a non-trivial task. In the past, we developed mathematical models of thrombopoiesis, granulopoiesis and erythropoiesis under chemotherapy and growth-factor applications which can be used to perform clinically relevant predictions regarding the feasibility of chemotherapy schedules and cytopenia prophylaxis with haematopoietic growth factors. However, interactions of lineages and growth-factors were ignored so far. To close this gap, we constructed a hybrid model of human granulopoiesis and erythropoiesis under conventional chemotherapy, G-CSF and EPO applications. This was achieved by combining our single lineage models of human erythropoiesis and granulopoiesis with a common stem cell model. G-CSF effects on erythropoiesis were also implemented. Pharmacodynamic models are based on ordinary differential equations describing proliferation and maturation of haematopoietic cells. The system is regulated by feedback loops partly mediated by endogenous and exogenous EPO and G-CSF. Chemotherapy is modelled by depletion of cells. Unknown model parameters were determined by fitting the model predictions to time series data of blood counts and cytokine profiles. Data were extracted from literature or received from cooperating clinical study groups. Our model explains dynamics of mature blood cells and cytokines after growth-factor applications in healthy volunteers

  3. Shifts in connectivity during procedural learning after motor cortex stimulation; a combined transcranial magnetic stimulation /functional magnetic resonance imaging study

    PubMed Central

    Steel, Adam; Song, Sunbin; Bageac, Devin; Knutson, Kristine M.; Saad, Ziad S.; Gotts, Stephen J.; Wassermann, Eric M.; Wilkinson, Leonora

    2015-01-01

    Inhibitory transcranial magnetic stimulation, of which continuous theta burst stimulation (cTBS) is a common form, has been used to inhibit cortical areas during investigations of their function. cTBS applied to the primary motor area (M1) depresses motor output excitability via a local effect and impairs procedural motor learning. This could be due to an effect on M1 itself and/or to changes in its connectivity with other nodes in the learning network. To investigate this issue, we used functional magnetic resonance imaging to measure changes in brain activation and connectivity during implicit procedural learning after real and sham cTBS of M1. Compared to sham, real cTBS impaired motor sequence learning, but caused no local or distant changes in brain activation. Rather, it reduced functional connectivity between motor (M1, dorsal premotor & supplementary motor areas) and visual (superior & inferior occipital gyri) areas. It also increased connectivity between frontal associative (superior & inferior frontal gyri), cingulate (dorsal & middle cingulate), and temporal areas. This potentially compensatory shift in coupling, from a motor-based learning network to an associative learning network accounts for the behavioral effects of cTBS of M1. The findings suggest that the inhibitory transcranial magnetic stimulation affects behavior via relatively subtle and distributed effects on connectivity within networks, rather than by taking the stimulated area “offline.” PMID:26673946

  4. PR-104 a bioreductive pre-prodrug combined with gemcitabine or docetaxel in a phase Ib study of patients with advanced solid tumours

    PubMed Central

    2012-01-01

    Background The purpose of this phase Ib clinical trial was to determine the maximum tolerated dose (MTD) of PR-104 a bioreductive pre-prodrug given in combination with gemcitabine or docetaxel in patients with advanced solid tumours. Methods PR-104 was administered as a one-hour intravenous infusion combined with docetaxel 60 to 75 mg/m2 on day one given with or without granulocyte colony stimulating factor (G-CSF) on day two or administrated with gemcitabine 800 mg/m2 on days one and eight, of a 21-day treatment cycle. Patients were assigned to one of ten PR-104 dose-levels ranging from 140 to 1100 mg/m2 and to one of four combination groups. Pharmacokinetic studies were scheduled for cycle one day one and 18F fluoromisonidazole (FMISO) positron emission tomography hypoxia imaging at baseline and after two treatment cycles. Results Forty two patients (23 females and 19 males) were enrolled with ages ranging from 27 to 85 years and a wide range of advanced solid tumours. The MTD of PR-104 was 140 mg/m2 when combined with gemcitabine, 200 mg/m2 when combined with docetaxel 60 mg/m2, 770 mg/m2 when combined with docetaxel 60 mg/m2 plus G-CSF and ≥770 mg/m2 when combined with docetaxel 75 mg/m2 plus G-CSF. Dose-limiting toxicity (DLT) across all four combination settings included thrombocytopenia, neutropenic fever and fatigue. Other common grade three or four toxicities included neutropenia, anaemia and leukopenia. Four patients had partial tumour response. Eleven of 17 patients undergoing FMISO scans showed tumour hypoxia at baseline. Plasma pharmacokinetics of PR-104, its metabolites (alcohol PR-104A, glucuronide PR-104G, hydroxylamine PR-104H, amine PR-104M and semi-mustard PR-104S1), docetaxel and gemcitabine were similar to that of their single agents. Conclusions Combination of PR-104 with docetaxel or gemcitabine caused dose-limiting and severe myelotoxicity, but prophylactic G-CSF allowed PR-104 dose escalation with docetaxel. Dose-limiting thrombocytopenia

  5. Electrical stimulation combined with exercise increase axonal regeneration after peripheral nerve injury.

    PubMed

    Asensio-Pinilla, Elena; Udina, Esther; Jaramillo, Jessica; Navarro, Xavier

    2009-09-01

    Although injured peripheral axons are able to regenerate, functional recovery is usually poor after nerve transection. In this study we aim to elucidate the role of neuronal activity, induced by nerve electrical stimulation and by exercise, in promoting axonal regeneration and modulating plasticity in the spinal cord after nerve injury. Four groups of adult rats were subjected to sciatic nerve transection and suture repair. Two groups received electrical stimulation (3 V, 0.1 ms at 20 Hz) for 1 h, immediately after injury (ESa) or during 4 weeks (1 h daily; ESc). A third group (ES+TR) received 1 h electrical stimulation and was submitted to treadmill running during 4 weeks (5 m/min, 2 h daily). A fourth group performed only exercise (TR), whereas an untreated group served as control (C). Nerve conduction, H reflex and algesimetry tests were performed at 1, 3, 5, 7 and 9 weeks after surgery, to assess muscle reinnervation and changes in excitability of spinal cord circuitry. Histological analysis was made at the end of the follow-up. Groups that received acute ES and/or were forced to exercise in the treadmill showed higher levels of muscle reinnervation and increased numbers of regenerated myelinated axons when compared to control animals or animals that received chronic ES. Combining ESa with treadmill training significantly improved muscle reinnervation during the initial phase. The facilitation of the monosynaptic H reflex in the injured limb was reduced in all treated groups, suggesting that the maintenance of activity helps to prevent the development of hyperreflexia.

  6. Heparan sulfate mimetics can efficiently mobilize long-term hematopoietic stem cells

    PubMed Central

    Di Giacomo, Fabio; Lewandowski, Daniel; Cabannes, Eric; Nancy-Portebois, Vanessa; Petitou, Maurice; Fichelson, Serge; Romeo, Paul-Henri

    2012-01-01

    Background Although mobilization of hematopoietic stem cells and hematopoietic progenitor cells can be achieved with a combination of granulocyte colony-stimulating factor and plerixafor (AMD3100), improving approaches for hematopoietic progenitor cell mobilization is clinically important. Design and Methods Heparan sulfate proteoglycans are ubiquitous macromolecules associated with the extracellular matrix that regulates biology of hematopoietic stem cells. We studied the effects of a new family of synthetic oligosaccharides mimicking heparan sulfate on hematopoietic stem cell mobilization. These oligosaccharides were administered intravenously alone or in combination with granulocyte colony-stimulating factor and/or AMD3100 in mice. Mobilized hematopoietic cells were counted and phenotyped at different times and the ability of mobilized hematopoietic stem cells to reconstitute long-term hematopoiesis was determined by competitive transplantation into syngenic lethally irradiated mice followed by secondary transplantation. Results Mimetics of heparan sulfate induced rapid mobilization of B-lymphocytes, T-lymphocytes, hematopoietic stem cells and hematopoietic progenitor cells. They increased the mobilization of hematopoietic stem cells and hematopoietic progenitor cells more than 3-fold when added to the granulocyte colony-stimulating factor/AMD3100 association. Hematopoietic stem cells mobilized by mimetics of heparan sulfate or by the granulocyte colony-stimulating factor/AMD3100/mimetics association were as effective as hematopoietic stem cells mobilized by the granulocyte colony-stimulating factor/AMD3100 association for primary and secondary hematopoietic reconstitution of lethally irradiated mice. Conclusions This new family of mobilizing agents could alone or in combination with granulocyte colony-stimulating factor and/or AMD3100 mobilize a high number of hematopoietic stem cells that were able to maintain long-term hematopoiesis. These results strengthen

  7. Semantic Feature Training in Combination with Transcranial Direct Current Stimulation (tDCS) for Progressive Anomia

    PubMed Central

    Hung, Jinyi; Bauer, Ashley; Grossman, Murray; Hamilton, Roy H.; Coslett, H. B.; Reilly, Jamie

    2017-01-01

    We examined the effectiveness of a 2-week regimen of a semantic feature training in combination with transcranial direct current stimulation (tDCS) for progressive naming impairment associated with primary progressive aphasia (N = 4) or early onset Alzheimer’s Disease (N = 1). Patients received a 2-week regimen (10 sessions) of anodal tDCS delivered over the left temporoparietal cortex while completing a language therapy that consisted of repeated naming and semantic feature generation. Therapy targets consisted of familiar people, household items, clothes, foods, places, hygiene implements, and activities. Untrained items from each semantic category provided item level controls. We analyzed naming accuracies at multiple timepoints (i.e., pre-, post-, 6-month follow-up) via a mixed effects logistic regression and individual differences in treatment responsiveness using a series of non-parametric McNemar tests. Patients showed advantages for naming trained over untrained items. These gains were evident immediately post tDCS. Trained items also showed a shallower rate of decline over 6-months relative to untrained items that showed continued progressive decline. Patients tolerated stimulation well, and sustained improvements in naming accuracy suggest that the current intervention approach is viable. Future implementation of a sham control condition will be crucial toward ascertaining whether neurostimulation and behavioral treatment act synergistically or alternatively whether treatment gains are exclusively attributable to either tDCS or the behavioral intervention. PMID:28559805

  8. Transcranial Direct Current Stimulation Combined with Treadmill Gait Training in Delayed Neuro-psychomotor Development

    PubMed Central

    Grecco, Luanda André Collange; E Mendonça, Mariana; Duarte, Natália A. C.; Zanon, Nelci; Fregni, Felipe; Oliveira, Claudia Santos

    2014-01-01

    [Purpose] The aim of the present study was to describe the results of transcranial direct current stimulation combined with treadmill training in a child with delayed neuro-psychomotor development. [Subject and Methods] Transcranial direct current stimulation (intensity: 1 mA) was applied over the primary motor cortex for 20 minutes during simultaneous treadmill training (2.5 km/h) in ten sessions. [Results] Clinically significant improvement was found in motor development (fine motor subscale, 23 to 25; gross motor subscale, 32 to 41). Reductions in mean oscillation of the center of pressure were found in the anteroposterior (239.2 to 146.5 mm) and mediolateral (177.4 to 149.2 mm) directions. Increases occurred in cadence (106 to 123 steps/minute), step length (0.16 to 0.23 m), step width (0.09 to 0.14 m) and gait velocity with support (0.3 to 0.7 m/s). [Conclusion] After treatment, the child was able to initiate the standing position for the first time and walk without support. PMID:25013302

  9. Efficacy of Cranial Electrotherapy Stimulation Combined with Biofeedback Therapy in Patients with Functional Constipation

    PubMed Central

    Gong, Bing Yan; Ma, Hong Mei; Zang, Xiao Ying; Wang, Si Yuan; Zhang, Yi; Jiang, Nan; Zhang, Xi Peng; Zhao, Yue

    2016-01-01

    Background/Aims A large number of studies have shown that function constipation (FC) has an extremely high incidence of mental and psychological disorders. Cranial electrotherapy stimulation (CES) was applied to the treatment of psychological disorders such as anxiety and depression. We explored the effects of CES combined with biofeedback therapy (BFT) on the psychological state, clinical symptoms, and anorectal function in patients with FC. Methods A total of 74 patients with FC were randomly divided into 2 groups. The control group received BFT. CES combined with BFT was carried out in the experiment group. All patients were assessed using the self-rating anxiety scale (SAS), self-rating depression scale (SDS), and Wexner constipation score at baseline and the end of each course. Anorectal manometry and balloon expulsion tests were performed before and after treatment. Results After treatment, the participants in the experiment group had significantly lower score SAS, SDS, and Wexner constipation scores than the control group (all P < 0.05). The number of successful expulsion in the experiment group was larger than the control group (P = 0.016). Conclusions CES combined with BFT was effective in improving the psychological status of anxiety, depression, and bowel symptoms in patients with FC. PMID:26932836

  10. Facilitation of corticospinal tract excitability by transcranial direct current stimulation combined with voluntary grip exercise.

    PubMed

    Kim, Gi-Wook; Ko, Myoung-Hwan

    2013-08-26

    Previous studies have established that transcranial direct current stimulation (tDCS) is a powerful technique for the deliberate manipulation of the activity of human cerebral cortex. Moreover, it has also been shown that the non-exhausted voluntary motor exercise increases the excitability of corticospinal tract. We conducted this study to define the facilitation effect following anodal tDCS combined with the voluntary grip exercise as compared with single use of tDCS or voluntary grip exercise. Our result showed that the combination of anodal tDCS with voluntary grip exercise produced a 2-fold increase in the amplitude of MEP as compared with single use of anodal tDCS or voluntary grip exercise. In conclusion, our result could indicate that the treatment outcomes of brain and neurorehabilitation using tDCS would be better when tDCS is combined with the appropriate method of voluntary exercise as compared with single use of tDCS. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  11. Application and outcomes of therapy combining transcranial direct current stimulation and virtual reality: a systematic review.

    PubMed

    Massetti, Thais; Crocetta, Tânia Brusque; Silva, Talita Dias da; Trevizan, Isabela Lopes; Arab, Claudia; Caromano, Fátima Aparecida; Monteiro, Carlos Bandeira de Mello

    2017-08-01

    To evaluate the methods and major outcomes of transcranial direct current stimulation (tDCS) combined with virtual reality (VR) therapy in randomized controlled trials. A systematic review was performed following PRISMA guidelines using PubMed, PubMed Central, Web of Science and CAPES periodic databases, with no time restriction. The studies were screened for the following inclusion criteria: human subjects, combination of VR and tDCS methods, and randomized controlled study design. All potentially relevant articles were independently reviewed by two researchers, who reached a consensus on which articles met the inclusion criteria. The PEDro scale was used to evaluate the studies. Eleven studies were included, all of which utilized a variety of tDCS and VR application methods. The main outcomes were found to be beneficial in intervention groups of different populations, including improvements in body sway, gait, stroke recovery, pain management and vegetative reactions. The use of tDCS combined with VR showed positive results in both healthy and impaired patients. Future studies with larger sample sizes and homogeneous participants are required to confirm the benefits of tDCS and VR. Implications for Rehabilitation tDCS with VR intervention can be an alternative to traditional rehabilitation programs. tDCS with VR is a promising type of intervention with a variety of positive effects. Application of tDCS with VR is appropriated to both healthy and impaired patients. There is no consensus of tDCS with VR application.

  12. Treatment of primary progressive aphasias by transcranial direct current stimulation combined with language training.

    PubMed

    Cotelli, Maria; Manenti, Rosa; Petesi, Michela; Brambilla, Michela; Cosseddu, Maura; Zanetti, Orazio; Miniussi, Carlo; Padovani, Alessandro; Borroni, Barbara

    2014-01-01

    Primary progressive aphasia (PPA) is an untreatable neurodegenerative disorder that disrupts language functions. Previous studies have demonstrated transcranial direct current stimulation (tDCS) may improve language symptoms in patients with post stroke aphasia or neurodegenerative diseases. The present study investigated whether the application of anodal tDCS (AtDCS) to the scalp overlying the left dorsolateral prefrontal cortex (DLPFC), which may increase cortical excitability, in combination with individualized speech therapy would improve naming accuracy in the agrammatic variant of PPA (avPPA). Sixteen avPPA patients were randomly allocated into two subgroups: AtDCS (n = 8) or placebo tDCS (PtDCS). tDCS was applied over the left DLPFC (BA 8/9) 25 minutes per day for two weeks (10 days). Each patient underwent 25 minutes of individualized speech therapy with either AtDCS or PtDCS during each treatment session. Neuropsychological assessment, experimental naming, and linguistic abilities in daily living were assessed at baseline (T0), after two weeks of intervention (T1) and at a 12-week follow-up (T2). Significant improvement in experimental naming was observed in both groups at T1 and T2, but this effect was significantly greater in AtDCS than PtDCS patients. Naming correctness, as assessed using the Aachener Aphasie Test, increased selectively in the AtDCS group from T0 to T1, and this effect remained significant at T2. The analysis of daily living language abilities improved selectively in AtDCS group. Our results support the beneficial effect of targeted language training in combination with brain stimulation in avPPA patients. tDCS should be considered a useful tool for the improvement of language functions in patients with neurodegenerative diseases in future trials.

  13. Cortical changes after mental imagery training combined with electromyography-triggered electrical stimulation in patients with chronic stroke.

    PubMed

    Hong, Il Ki; Choi, Jong Bae; Lee, Jong Ha

    2012-09-01

    Paresis of the upper extremity after stroke is not effectively solved by existing therapies. We investigated whether mental imagery training combined with electromyogram-triggered electric stimulation improved motor function of the paretic upper extremity in patients with chronic stroke and induced cortical changes. Fourteen subjects with chronic stroke (≥12 months) were randomly allocated to receive mental imagery training combined with electromyogram-triggered electric stimulation (n=7) or generalized functional electric stimulation (n=7) on the forearm extensor muscles of the paretic extremity in 2 20-minute daily sessions 5 days a week for 4 weeks. The upper extremity component of the Fugl-Meyer Motor Assessment, the Motor Activity Log, the modified Barthel Index, and (18)F-fluorodeoxyglucose brain positron emission tomography were measured before and after the intervention. The group receiving mental imagery training combined with electromyogram-triggered electric stimulation exhibited significant improvements in the upper extremity component of the Fugl-Meyer Motor Assessment after intervention (median, 7; interquartile range, 5-8; P<0.05), but the group receiving functional electric stimulation did not (median, 0; interquartile range, 0-3). Differences in score changes between the 2 groups were significant. The mental imagery training combined with electromyogram-triggered electric stimulation group showed significantly increased metabolism in the contralesional supplementary motor, precentral, and postcentral gyri (P(uncorrected)<0.001) after the intervention, but the functional electric stimulation group showed no significant differences. Mental imagery training combined with electromyogram-triggered electric stimulation improved motor function of the paretic extremity in patients with chronic stroke. The intervention increased metabolism in the contralesional motor-sensory cortex. Clinical Trial Registration- URL: https://e

  14. Feasibility of Using Lokomat Combined with Functional Electrical Stimulation for the Rehabilitation of Foot Drop

    PubMed Central

    Laursen, Christian B.; Nielsen, Jørgen F.; Andersen, Ole K.; Spaich, Erika G.

    2016-01-01

    This study investigated the clinical feasibility of combining the electromechanical gait trainer Lokomat with functional electrical therapy (LokoFET), stimulating the common peroneal nerve during the swing phase of the gait cycle to correct foot drop as an integrated part of gait therapy. Five patients with different acquired brain injuries trained with LokoFET 2-3 times a week for 3-4 weeks. Pre- and post-intervention evaluations were performed to quantify neurophysiological changes related to the patients’ foot drop impairment during the swing phase of the gait cycle. A semi-structured interview was used to investigate the therapists’ acceptance of LokoFET in clinical practice. The patients showed a significant increase in the level of activation of the tibialis anterior muscle and the maximal dorsiflexion during the swing phase, when comparing the pre- and post-intervention evaluations. This showed an improvement of function related to the foot drop impairment. The interview revealed that the therapists perceived the combined system as a useful tool in the rehabilitation of gait. However, lack of muscle selectivity relating to the FES element of LokoFET was assessed to be critical for acceptance in clinical practice. PMID:27990246

  15. Best of both worlds: promise of combining brain stimulation and brain connectome

    PubMed Central

    Luft, Caroline Di Bernardi; Pereda, Ernesto; Banissy, Michael J.; Bhattacharya, Joydeep

    2014-01-01

    Transcranial current brain stimulation (tCS) is becoming increasingly popular as a non-pharmacological non-invasive neuromodulatory method that alters cortical excitability by applying weak electrical currents to the scalp via a pair of electrodes. Most applications of this technique have focused on enhancing motor and learning skills, as well as a therapeutic agent in neurological and psychiatric disorders. In these applications, similarly to lesion studies, tCS was used to provide a causal link between a function or behavior and a specific brain region (e.g., primary motor cortex). Nonetheless, complex cognitive functions are known to rely on functionally connected multitude of brain regions with dynamically changing patterns of information flow rather than on isolated areas, which are most commonly targeted in typical tCS experiments. In this review article, we argue in favor of combining tCS method with other neuroimaging techniques (e.g., fMRI, EEG) and by employing state-of-the-art connectivity data analysis techniques (e.g., graph theory) to obtain a deeper understanding of the underlying spatiotemporal dynamics of functional connectivity patterns and cognitive performance. Finally, we discuss the possibilities of using these combined techniques to investigate the neural correlates of human creativity and to enhance creativity. PMID:25126060

  16. Combined effects of fast treadmill walking and functional electrical stimulation on post-stroke gait.

    PubMed

    Kesar, Trisha M; Reisman, Darcy S; Perumal, Ramu; Jancosko, Angela M; Higginson, Jill S; Rudolph, Katherine S; Binder-Macleod, Stuart A

    2011-02-01

    Gait dysfunctions are highly prevalent in individuals post-stroke and affect multiple lower extremity joints. Recent evidence suggests that treadmill walking at faster than self-selected speeds can help improve post-stroke gait impairments. Also, the combination of functional electrical stimulation (FES) and treadmill training has emerged as a promising post-stroke gait rehabilitation intervention. However, the differential effects of combining FES with treadmill walking at the fast versus a slower, self-selected speed have not been compared previously. In this study, we compared the immediate effects on gait while post-stroke individuals walked on a treadmill at their self-selected speed without FES (SS), at the SS speed with FES (SS-FES), at the fastest speed they are capable of attaining (FAST), and at the FAST speed with FES (FAST-FES). During SS-FES and FAST-FES, FES was delivered to paretic ankle plantarflexors during terminal stance and to paretic dorsiflexors during swing phase. Our results showed improvements in peak anterior ground reaction force (AGRF) and trailing limb angle during walking at FAST versus SS. FAST-FES versus SS-FES resulted in greater peak AGRF, trailing limb angle, and swing phase knee flexion. FAST-FES resulted in further increase in peak AGRF compared to FAST. We posit that the enhancement of multiple aspects of post-stroke gait during FAST-FES suggest that FAST-FES may have potential as a post-stroke gait rehabilitation intervention.

  17. A systematic review of transcranial electrical stimulation combined with cognitive training.

    PubMed

    Elmasry, Jessica; Loo, Colleen; Martin, Donel

    2015-01-01

    Transcranial Electrical Stimulation (tES) methods have been shown to enhance performance across a range of cognitive tasks. It is thought that tES can be used to enhance the treatment-effects of cognitive training (CT), leading to lasting improvements in neurocognitive function. Recently, a small number of studies have investigated the effects of tES combined with CT in healthy and cognitively impaired subjects. To evaluate the effects of tES + CT on both CT task performance and on non-trained cognitive outcomes. A systematic review was conducted in accordance with PRISMA guidelines. Databases (PsycINFO, EMBASE, PubMed and Medline) were searched for all randomized, controlled and naturalistic prospective studies up until June 2014, combining tES and CT. 13 studies comprising 465 participants met the inclusion criteria. Findings indicated that tES + CT enhanced performance on the majority of CT tasks. The effects on non-trained tasks were mixed, with some evidence for improvements in working memory, cognitive control, approximate number sense and arithmetic processing. tES + CT enhances performance on CT tasks across a range of cognitive functions. Preliminary evidence suggests that tES may also increase transfer effects to non-trained tasks in some domains. Recommendations for future studies are provided.

  18. Mexican Biosimilar Filgrastim for Autologous Hematopoietic Stem Cell Mobilization and Transplantation.

    PubMed

    León-González, M