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1.
PLoS One ; 15(3): e0230247, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32182268

RESUMO

Granulocyte-colony stimulating factor (G-CSF), a pleiotropic cytokine, belongs to the hematopoietic growth factor family. Recent studies have reported that G-CSF is a predictive biomarker of oocyte and embryo developmental competence in humans. The aim of our study was to determine whether CSF3 and its receptor (CSF3R) were expressed in porcine maternal reproductive tissues (oviduct and uterus), cumulus cells, and embryos and to investigate the effects of human recombinant G-CSF (hrG-CSF) supplementation during in vitro culture (IVC) on the developmental competence of pre-implantation embryos. To do this, we first performed reverse-transcription polymerase chain reaction (RT-PCR). Second, we performed parthenogenetic activation (PA), in vitro fertilization (IVF), and somatic cell nuclear transfer (SCNT) to evaluate the embryonic developmental potential after hrG-CSF supplementation based on various concentrations (0 ng/mL, 10 ng/mL, 50 ng/mL, and 100 ng/mL) and durations (Un-treated, Days 0-3, Days 4-7, and Days 0-7) of IVC. Finally, we examined transcriptional levels of several marker genes in blastocysts. The results of our study showed that CSF3 transcript was present in all samples we assessed. CSF3-R was also detected, except in cumulus cells and blastocysts from PA. Furthermore, 10 ng/mL and Days 0-7 were the optimal concentration and duration for the viability of in vitro embryonic development, especially for SCNT-derived embryos. The rate of blastocyst formation and the total cell number of blastocysts were significantly enhanced, while the number and index of apoptotic nuclei were significantly decreased in optimal condition groups compared to others. Moreover, the transcriptional levels of anti-apoptotis- (BCL2), proliferation- (PCNA), and pluripotency- (POU5F1) related genes were dramatically upregulated. In conclusion, for the first time, we demonstrated that CSF3 and CSF3R were expressed in porcine reproductive organs, cells, and embryos. Additionally, we determined that hrG-CSF treatment improved porcine embryonic development capacity in vitro.


Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Proteínas Recombinantes/farmacologia , Animais , Apoptose/efeitos dos fármacos , Blastocisto/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células do Cúmulo/efeitos dos fármacos , Técnicas de Cultura Embrionária/métodos , Feminino , Fertilização In Vitro/métodos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Técnicas de Transferência Nuclear , Oócitos/efeitos dos fármacos , Gravidez , Suínos
2.
PLoS One ; 15(3): e0228878, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32134938

RESUMO

We studied a cohort of 367 healthy related donors who volunteered to donate their hematopoietic stem cells for allogeneic transplantation. All donors were homogeneously cared for at a single institution, and received rhG-CSF as a mobilization treatment prior to undergoing apheresis. Peripheral blood CD34+ cell counts were used as the main surrogate marker for rhG-CSF induced mobilization. We searched whether inter-individual variations in known genetic polymorphisms located in genes whose products are functionally important for mobilization, could affect the extent of CD34+ mobilization, either individually or in combination. We found little or no influence of individual SNPs or haplotypes for the SDF1, CXCR4, VCAM and VLA4 genes, whether using CD34+ cell counts as a continuous or a categorical variable. Simple clinical characteristics describing donors such as body mass index, age and possibly sex are more potent predictors of stem cell mobilization. The size of our cohort remains relatively small for genetic analyses, however compares favorably with cohorts analyzed in previously published reports suggesting associations of genetic traits to response to rhG-CSF; notwithstanding this limitation, our data do not support the use of genetic analyses when the choice exists of several potential donors for a given patient.


Assuntos
Quimiocina CXCL12/genética , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Integrina alfa4beta1/genética , Polimorfismo de Nucleotídeo Único , Receptores CXCR4/genética , Molécula 1 de Adesão de Célula Vascular/genética , Adulto , Idoso , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Transplante Homólogo , Adulto Jovem
3.
J Biomed Sci ; 27(1): 19, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31907023

RESUMO

BACKGROUND: The FDA approved drug granulocyte-colony stimulating factor (G-CSF) displays anti-apoptotic and immunomodulatory properties with neurogenesis and angiogenic functions. It is known to demonstrate neuroprotective mechanisms against ischemic global stroke. Autophagy is a method for the degradation of intracellular components and in particular, unrestrained autophagy may lead to uncontrolled digestion of affected neurons as well as neuronal death in cerebral ischemia. Mitochondrial dynamics is vital for the regulation of cell survival and death after cerebral ischemia and an early upstream event in neuronal death is mitochondrial fission. We examined the pro-survival mechanisms of G-CSF against apoptosis resulting from autophagy, mitochondrial stress and endoplasmic reticulum (ER) stress. METHODS: Male Swiss Webster mice (20 weeks of age) were subjected to bilateral common carotid artery occlusion (BCAO) for 30 min. After occlusion, mice were injected with G-CSF (50 µg/kg) subcutaneously for 4 days. Behavioral analysis was carried out using the corner test and locomotor activity test before animals were sacrificed on day 4 or day 7. Key proteins in ER stress, autophagy and mitochondrial stress induced apoptosis were analyzed by immunoblotting. RESULTS: G-CSF improved neurological deficits and improved behavioral performance on corner and locomotor test. G-CSF binds to G-CSF receptors and its activation leads to upregulation of Akt phosphorylation (P-Akt) which in turn decreases levels of the ER stress sensor, GRP 78 and expression of proteins involved in ER stress apoptosis pathway; ATF6, ATF4, eIF2α, XBP1, Caspase 12 and CHOP. G-CSF treatment significantly decreased Beclin-1, an autophagy marker, and decreased mitochondrial stress biomarkers DRP1 and P53. G-CSF also up-regulated the mitochondrial fusion protein, OPA1 and anti-apoptotic protein Bcl-2 while down-regulating the pro-apoptotic proteins Bax, Bak and PUMA. CONCLUSIONS: G-CSF is an endogenous ligand in the CNS that has a dual activity that is beneficial both in reducing acute neuronal degeneration and adding to long-term plasticity after cerebral ischemia. G-CSF treatment exerts neuroprotective effects on damaged neurons through the suppression of the ER stress and mitochondrial stress and maintains cellular homeostasis by decreasing pro-apoptotic proteins and increasing of anti-apoptotic proteins.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Acidente Vascular Cerebral , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/biossíntese , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Dinâmica Mitocondrial/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Fator Estimulador de Colônias de Granulócitos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
4.
Cancer Immunol Immunother ; 69(2): 199-213, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31982939

RESUMO

Neutrophils play a major role in tumor biology. Among other functions, neutrophils can release extracellular traps (NETs), mesh-like structures of decondensed chromatin fibers, in a process termed NETosis. Originally characterized as an antimicrobial mechanism, NETosis has been described in cancer, but cancer-related predisposition is not clear. In the current study, we investigated the predisposition of circulating neutrophils to release NETs in lung cancer and the impact of G-CSF on this function, comparing circulating neutrophils isolated from cancer patients to the LLC and AB12 mouse models. We find that neutrophils from both healthy donors and cancer patients display high NETotic potential, with 30-60% of cells undergoing NETosis upon PMA stimulation. In contrast, neutrophils isolated from tumor-bearing mice displayed only 4-5% NETotic cells, though significantly higher than naive controls (1-2%). Despite differential mechanisms of activation described, Ionomycin and PMA mainly triggered suicidal rather than vital NETosis. G-CSF secreting tumors did not increase NETotic rates in murine neutrophils, and direct G-CSF stimulation did not promote their NET release. In contrast, human neutrophils strongly responded to G-CSF stimulation resulting also in a higher response to PMA + G-CSF stimulation. Our data show clear differences in NETotic potentials between human and murine neutrophils. We do not find a predisposition of neutrophils to release NETs in lung cancer patients compared to healthy controls, whereas cancer may modulate neutrophils' NETotic potential in mice. G-CSF secreted from tumors differentially affects murine and human NETosis in cancer. These important differences should be considered in future studies of NETosis in cancer.


Assuntos
Armadilhas Extracelulares/fisiologia , Neoplasias Pulmonares/imunologia , Neutrófilos/fisiologia , Animais , Linhagem Celular Tumoral , Armadilhas Extracelulares/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Humanos , Ionomicina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Acetato de Tetradecanoilforbol/farmacologia
5.
Support Care Cancer ; 28(2): 691-699, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31127438

RESUMO

PURPOSE: The guidelines suggest using granulocyte-colony stimulating factor (G-CSF) for febrile neutropenia (FN) as prophylaxis in chemotherapy protocols with the risk of 10-20% after assessment of patient's risk factors. Therefore, the aim of this study is to assess the risk of FN by using the Patient Risk Score (PRS) and evaluating G-CSF use and its side effects by a clinical pharmacist at an outpatient clinic. METHODS: The study was conducted from May 2017 until November 2017 at the University Hospital oncology outpatient clinic. Patients who receive chemotherapy protocols with FN risk of 10-20% and > 20% and were initiated G-CSF were included. The patients' risk factors were assessed by the PRS, and the side effects were monitored for 3 months by a clinical pharmacist via a patient self-reported monitoring card. RESULTS: A total of 118 patients were included (286 interviews) in the study. There was a significant increase between the first and third visits on the PRS total scores of patients (p = 0.034). The patterns of G-CSF use showed that 34.7% undertreated, 22.8% overtreated, and 42.3% of patients were correctly treated for the prophylaxis. The severity of G-CSF-related musculoskeletal pain was increased on the second and third days of treatment. CONCLUSIONS: The use of G-CSFs for FN prophylaxis is recommended; however, there may be a group of patients who are inadequately or unnecessarily treated. Therefore, patients should be assessed for the risk of developing FN in each cycle of chemotherapy and a regular risk assessment by using the PRS can be implemented in the monitoring process.


Assuntos
Neutropenia Febril/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neoplasias/complicações , Adulto , Idoso , Estudos Transversais , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco , Adulto Jovem
6.
Bull Cancer ; 107(1S): S44-S51, 2020 Jan.
Artigo em Francês | MEDLINE | ID: mdl-31570213

RESUMO

The modalities of mobilization of hematopoietic stem cells in autologous transplantation have evolved in recent years. The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 9th hematopoietic stem cell transplantation clinical practices harmonization workshop series in September 2018 in Lille, France, to conduct a review of current practices of the society centers and of international recommendations. The cell dose objectives have been revised. The modalities of mobilization including the use of plerixafor have been specified allowing reaching the objectives of collection while limiting the number of apheresis. Collections failures have become exceptional.


Assuntos
Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas , Algoritmos , Antígenos CD34/análise , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Remoção de Componentes Sanguíneos/métodos , Medula Óssea/efeitos dos fármacos , Contagem de Células , Separação Celular/métodos , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fatores de Crescimento de Células Hematopoéticas/farmacologia , Mobilização de Células-Tronco Hematopoéticas/normas , Compostos Heterocíclicos/farmacologia , Humanos , Padrões de Prática Médica , Fatores de Risco , Transplante Autólogo
7.
Int J Cancer ; 146(5): 1457-1467, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31344264

RESUMO

It remains unclear whether there is a relationship between therapeutic effects of hypomethylating agents (HMAs) and epigenetic modifier gene mutations (EMMs) in patients with cytogenetically intermediate-risk acute myeloid leukemia (IR-AML). Based on targeted-capture sequencing, we retrospectively analyzed the correlation between EMMs and prognosis in 83 IR-AML patients treated with decitabine in combination with cytarabine, aclarubicin hydrochloride and granulocyte colony-stimulating factor (DCAG, n = 35) or "7 + 3" induction regimens (n = 48). In the multivariate analyses, EMM (+) patients did not show any statistically significant difference in remission rates from EMM (-) patients in the DCAG group (p > 0.05), but achieved inferior complete remission (CR; p = 0.03) and overall remission rates (ORR; p = 0.04) after the first course of standard induction regimens (p < 0.05). In the EMM (-) cohort, the DCAG group showed the tendency of adverse total CR (p = 0.06). Besides, DCAG group with EMMs achieved the best survival outcome independent of baseline characteristics, whereas it was opposite in EMM (+) patients receiving standard induction regimens (p < 0.05). Additionally, in the EMM (+) cohort, the survival rate of isolated DCAG group was statistically similar to that of the combination of standard chemotherapies and allogeneic hematopoietic stem cell transplantation (allo-HSCT) (p > 0.40), whereas patients who received only standard regimens had the worst survival rate (0.0%, p < 0.01). It can be concluded that the EMMs might be regarded as the potentially predictive biomarkers of better response to DCAG in IR-AML patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética/genética , Genes Modificadores/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Aclarubicina/farmacologia , Aclarubicina/uso terapêutico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/farmacologia , Citarabina/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Decitabina/farmacologia , Decitabina/uso terapêutico , Intervalo Livre de Doença , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Cariotipagem , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Indução de Remissão/métodos , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
8.
Radiol Med ; 125(3): 280-287, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31823293

RESUMO

OBJECTIVE: To report our experience with the use of intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) and dynamic contrast-enhanced (DCE)-MRI in bone marrow before and after administration of granulocyte colony-stimulating factor (GCSF). Moreover, a small series of patients with bone metastases from breast cancer have been evaluated by IVIM DW-MRI and DCE-MRI before and after GCSF administration. MATERIALS AND METHODS: We studied with IVIM-MRI and DCE-MRI 14 patients with rectal or uterine cervix cancer studied before and 4-18 days after administration of GCSF; the second MR examination was obtained after three chemotherapy courses. IVIM perfusion fraction (f), pseudo-diffusion coefficient (D*), true diffusion coefficient (D) and apparent diffusion coefficient (ADC) as well area under the curve at 60 s (AUC60) were calculated for bone marrow before and after GCSF administration. Moreover, two different IVIM parametric maps (i.e., ADC and ADClow) were generated by selecting two different intervals of b values (0-1000 and 0-80, respectively). Furthermore, four patients affected by pelvic bone metastases from breast adenocarcinoma who received GCSF administration were also qualitatively evaluated for evidence of lesions on ADC maps, ADClow maps and DCE-MRI. RESULTS: ADC, D, D*, f and AUC60 values were significantly higher in hyperplastic bone marrow than in untreated bone marrow (p values < 0.0001, < 0.0001, < 0.001, < 0.001, < 0.0001, respectively). All bone metastases were clearly differentiable from hyperplastic bone marrow on ADClow maps, but not on ADC maps and DCE-MRI. CONCLUSION: MR functional imaging techniques, such as DW-, IVIM DW- and DCE-MRI are effective tools in assessing the response of bone marrow to the administration of growth factors. Although an overlap between signal of hyperplastic bone marrow and lytic bone metastases can occur on ADC maps and DCE-MRI, evaluation of ADClow maps by IVIM DW-MRI could permit to differentiate hyperplastic bone marrow from lytic bone metastases. Further studies are needed to confirm our data.


Assuntos
Medula Óssea/efeitos dos fármacos , Medula Óssea/diagnóstico por imagem , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/secundário , Imagem de Difusão por Ressonância Magnética/métodos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Adulto , Idoso , Área Sob a Curva , Medula Óssea/patologia , Neoplasias da Mama/patologia , Meios de Contraste , Feminino , Humanos , Hiperplasia/diagnóstico por imagem , Hiperplasia/patologia , Masculino , Pessoa de Meia-Idade , Ossos Pélvicos/diagnóstico por imagem , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Fatores de Tempo , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia
9.
Biomed Res Int ; 2019: 8298192, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31687401

RESUMO

Background/Aim: Treatment with growth factors could be beneficial in both inflammatory bowel disease and experimental colitis. The aim of this study was to investigate the effect of Colony Stimulating Factor (CSF), and Recombinant Human (rHu) Granulocyte Stimulating Factor (GSF) in experimental colitis in rats. Methods: Experimental colitis was induced in 62 male Wistar rats, divided into 9 groups, using 2,4,6-trinitrobenzensulfonic acid (TNBS). Group 1: Ten rats with colitis without treatment (control group). Euthanasia after 15 days. Group 2: Ten animals with colitis without treatment (control group). Euthanasia after 30 days. Group 3: Six animals with colitis. Immediate treatment with CSF. Euthanasia after 19 days. Group 4: Six animals with colitis. Treatment started 7 days after the induction of colitis. Animals were kept for 19 days. Group 5: Six animals with colitis. Treatment started 2 weeks after the induction of colitis. Group 6: Six animals with colitis, the same as in group 3. Treatment with GSF. Group 7: Six animals with colitis, the same as in group 4. Treatment with GSF. Group 8: Six animals with colitis, the same as in group 5. Treatment with GSF. Group 9: Six animals with colitis. Immediate treatment with prednisolone. Euthanasia after 15 days. Results: CSF and GSF administration significantly improved the histological score (P < 0.05) and reduced malondialdehyde contents (P < 0.05), compared to control groups in all animals. CSF was superior to GSF and to prednisolone. Conclusion: Administration of both CSF and GSF could significantly improve the histological score and oxidative stress in experimental colitis in rats.


Assuntos
Colite/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Lenograstim/farmacologia , Fator Estimulador de Colônias de Macrófagos/farmacologia , Animais , Modelos Animais de Doenças , Granulócitos/efeitos dos fármacos , Humanos , Masculino , Ratos , Ratos Wistar , Proteínas Recombinantes/farmacologia
10.
J Craniofac Surg ; 30(8): e776-e780, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31689739

RESUMO

OBJECTIVE: Granulocyte colony-stimulating factor (G-CSF) is the critical regulator of the proliferation, differentiation, and survival of granulocytes. Recently, it has been shown that G-CSF can adversely affect bone health in both animal models and patients. Here, the authors aimed to investigate whether G-CSF could inhibit the growth of osteoblasts and osteocytes by regulating nitric oxide. METHODS: The C57BL/6 mice were divided into the control group, G-CSF treatment group and recovery group (G-CSF+L-NAME). The morphology of femurs was assessed by histology and immunohistochemistry. The expression of apoptosis-related molecules in femurs was detected by immunohistochemistry and quantitative RT-PCR, respectively. To examine if neutrophil-secreted factors can induce apoptosis in osteoblasts, Gr1-positive (Gr1+) neutrophils from the bone marrow of wild-type mice were sorted and co-cultured with MC3T3 pre-osteoblasts for 2 days. RESULTS: The number of osteoblasts and newly embedding osteocytes significantly decreased and markers related to osteoblasts and osteocytes were downregulated in the G-CSF treatment compared to the control group. Moreover, G-CSF treatment did not change proliferation markers but induced apoptosis in osteoblast-lineage cells. The combined treatment of mice with G-CSF and a nitric oxide inhibitor partially restored the number of osteoblasts and osteocyte parameters. CONCLUSIONS: The G-CSF can inhibit osteoblasts and osteocytes by upregulating nitric oxide.


Assuntos
Fator Estimulador de Colônias de Granulócitos/farmacologia , Neutrófilos/efeitos dos fármacos , Óxido Nítrico/biossíntese , Osteoblastos/efeitos dos fármacos , Osteócitos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/citologia , Neutrófilos/metabolismo , Osteoblastos/citologia , Osteócitos/citologia , Osteócitos/metabolismo , Regulação para Cima/efeitos dos fármacos
11.
J Dairy Sci ; 102(10): 9312-9327, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31378494

RESUMO

In the present study, we aimed to investigate the side effects of pegbovigrastim, injected approximately 7 d before parturition and on the day of calving, on a panel of plasma biomarkers to evaluate energy, inflammatory, oxidative, and liver function status. We also addressed treatment responses in different breeds during the transition period. Holstein and Simmental cows were randomly assigned into 2 groups based on expected calving date and according to parity: the treated group (PEG; 14 Holstein and 12 Simmental cows) received pegylated recombinant bovine granulocyte colony stimulating factor (pegbovigrastim, Imrestor; Elanco Animal Health, Greenfield, IN), and the control group (CTR; 14 Holstein and 14 Simmental cows) received saline solution. The PEG or CTR treatments were administered via subcutaneous injection in the scapular region at approximately 7 d (mean 7.80 ± 5.50 d) before expected parturition and within 24 h after calving. Blood samples were collected at -21, -7 (before injection), 1, 3, and 28 d relative to calving. Milk production was recorded at 7, 15, 21, 30, and 42 d. A mixed model with repeated measures was fitted to the normalized data using Proc MIXED of SAS (SAS Institute Inc., Cary, NC). Simmental PEG cows showed higher plasma protein concentrations at 1 and 3 d after calving compared with Simmental CTR and Holstein PEG cows, whereas no differences were detected between Holstein PEG and CTR cows. Albumin was greater at 1 d in Simmental PEG compared with Simmental CTR cows. In contrast, γ-glutamyl transferase was higher overall (across breed) in PEG than in CTR. The PEG group had higher values throughout the postcalving period compared with CTR. Cows treated with pegbovigrastim had also higher alkaline phosphatase (ALP) activity at 1 and 3 d after calving. The Holstein PEG group had higher ALP activity at 3 d compared with the Holstein CTR and Simmental PEG groups, and higher ALP at 1 d compared with the Simmental CTR group. The PEG group had higher levels of IL-6 at 3 and 28 d but higher IL-1ß only at 28 d after calving compared with the CTR group. Overall, Holstein cows were characterized by a greater response in the production of inflammation biomarkers (cytokines, haptoglobin, and ceruloplasmin). In addition, PEG cows had higher values of zinc at 1 and 3 d after calving compared with CTR cows. The response observed in plasma biomarkers for energy metabolism and liver functionality after pegbovigrastim treatment in Simmental and Holstein cows was not different from that in control cows. However, our data shed light on the different metabolic adaptations during the transition period between Simmental and Holstein cows, characterized by different energy, inflammatory, and oxidative pattern responses. For the first time, we have highlighted the effect of pegbovigrastim in maintaining stable cytokine levels during the first month after parturition, reflecting greater regulation of neutrophil recruitment, trafficking, and maturation during the inflammatory response. These results provide evidence of the immunomodulatory action of pegbovigrastim around parturition, when dairy cows are highly immunosuppressed. At the same time, these data demonstrate that increasing release of cytokines after parturition is not linked to exacerbation of a systemic inflammation evaluated based on haptoglobin and ceruloplasmin levels.


Assuntos
Bovinos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Leite , Proteínas Recombinantes/farmacologia , Animais , Indústria de Laticínios , Metabolismo Energético , Feminino , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Haptoglobinas/metabolismo , Inflamação/metabolismo , Inflamação/veterinária , Lactação/fisiologia , Leite/metabolismo , Paridade , Parto , Gravidez , Distribuição Aleatória , Proteínas Recombinantes/efeitos adversos
12.
Drug Dev Res ; 80(6): 807-813, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31294492

RESUMO

Neutropenia is a condition of an abnormally low number of neutrophils which render patients more susceptible to infections, especially to bacterial infections, as the condition may become life threatening and deadly without prompt medical attention. Various factors such as, anticancer drugs, radiotherapy, infectious diseases, congenital defects, or vitamin B12/B9 deficiency can trigger neutropenia. GX-G3, a human hybrid (hy) Fc-fused granulocyte colony stimulating factor (G-CSF), was developed as next-generation G-CSF for the treatment of cancer therapy-induced neutropenia. In this study, with the aim of investigating this promising potential next-generation G-CSF, comparative pharmacokinetic and pharmacodynamic studies were conducted in healthy and neutropenia-induced rats. It was found that t1/2 of GX-G3 is longer than same mass injection of filgrastim and pegfilgrastim and AUEClast (area under theeffect-time curve from time zero to the last measurable ANC level) of absolute neutrophil count showed a significant increase after GX-G3 injection compared with filgrastim and pegfilgrastim in healthy rats. Besides, in duration of neutropenia after the same mass injection GX-G3 showed about 3.3 days of reduction effect compared with that of filgrastim, and 1.3 days of reduction effect compared with that of pegfilgrastim in neutropenia-induced rats. These results demonstrate that the half-life of GX-G3 is longer than pegfilgrastim and GX-G3 is more effective than filgrastim and pegfilgrastim in neutropenia-induced rats.


Assuntos
Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos/farmacocinética , Neutropenia/imunologia , Neutropenia/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/farmacocinética , Animais , Meia-Vida , Injeções Subcutâneas , Contagem de Leucócitos , Masculino , Neutrófilos/efeitos dos fármacos , Ratos
13.
J Dairy Sci ; 102(10): 9389-9395, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31326166

RESUMO

In periparturient dairy cows, immune suppression, resulting in decreased neutrophil numbers and function, leads to increased susceptibility to postpartum conditions such as mastitis, retained placenta, and metritis. Administration of polyethylene glycol-conjugated bovine granulocyte colony stimulating factor (pegbovigrastim, Imrestor; Elanco Animal Health, Greenfield, IN) 7 d before and within 24 h of calving, effectively improves granulocyte production and function in vivo as well as in milk. A recently developed coculture assay was adapted for use with endometrial epithelial cells to assess the effects of pegbovigrastim application on directed granulocyte migration and bactericidal activity in vitro on a per-cell basis in endometrial cell cultures. Granulocytes from treated and untreated periparturient cows (6 and 5 per group, respectively) were evaluated for their ability to migrate to and kill bacteria after treatment, in context of the infected endometrium. We hypothesized that in addition to increasing the absolute concentration of circulating neutrophil granulocytes, pegbovigrastim treatment in vivo alters the ability of granulocytes to migrate to endometrial cells in vitro. The results clearly show a marked increase in the total concentration of granulocytes and monocytes between the 2 treatment groups as early as 2 d after the first injection, and this increased between the samples taken 2 d after calving. No migratory or killing differences were identified between granulocytes of both groups, suggesting that pegbovigrastim-induced granulocytes were as effective as non-induced cells. This may also be due to the absence of negative energy balance in the study animals and leads us to conclude that the positive effects seen in vivo are most likely based on the larger number of granulocytes present rather than a direct effect of pegbovigrastim treatment on the functionality of cells for the parameters tested in this study.


Assuntos
Bactérias/imunologia , Bovinos/imunologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Endométrio/citologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Granulócitos/efeitos dos fármacos , Proteínas Recombinantes/farmacologia , Animais , Endométrio/imunologia , Metabolismo Energético , Feminino , Granulócitos/imunologia , Contagem de Leucócitos , Leite , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Período Pós-Parto/efeitos dos fármacos , Gravidez , Distribuição Aleatória
14.
Vox Sang ; 114(6): 622-627, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31168814

RESUMO

BACKGROUND AND OBJECTIVES: Many consider volunteer blood donors as ideal candidates for unrelated haematopoietic progenitor cell (HPC) donation. However, frequent blood donations could influence the results of HPC mobilization. To our best knowledge, there are no data on the possible impact of repeated blood donation on efficiency of subsequent HPC mobilization by granulocyte colony-stimulating factor (G-CSF). MATERIALS AND METHODS: We compared outcomes of HPC mobilization in unrelated donors with and without a history of blood donation. We conducted a prospective study on 287 consecutive donors admitted to the Department of Hematology since January 2016. The final analysis included 153 donors who agreed to take part in the study and had undergone stem cell mobilization with G-CSF. RESULTS: History of blood donations prior to haematopoietic stem cell mobilization with G-CSF does not have a significant impact on the number of collected CD34+ cells in the first leucocytapheresis (516.2 x 106 (170-1148) in blood donors vs 490.5 x 106 (101-1154) in non-donors) (P = 0.32). In all donors, in this study mobilization of HPC was successful: 87.5% of blood donors and 85.6% of non-donors collected the required cell number in a single apheresis. In blood donors, a higher number of blood donations within 2 and 5 years prior to HPC mobilization correlated significantly with successful donation within one leucocytapheresis (P = 0.014 and P = 0.024, respectively). CONCLUSION: Multiple blood donations do not significantly influence the outcome of HPC collection in unrelated donors. Blood donors and non-donors have similar results of HPC collection, so there is no reason to favour either group.


Assuntos
Remoção de Componentes Sanguíneos , Doadores de Sangue , Fator Estimulador de Colônias de Granulócitos/farmacologia , Mobilização de Células-Tronco Hematopoéticas , Leucaférese , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
15.
Methods Mol Biol ; 2017: 41-58, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31197767

RESUMO

Peripheral blood stem cells (PBSCs) are preferentially used as a hematopoietic stem cell source for autologous blood stem cell transplantation (ABSCT) upon high-dose chemotherapy (HDT) in a variety of hemato-oncologic diseases. As a prerequisite, hematopoietic stem cells have to be mobilized into the peripheral blood (PB) and collected by leukapheresis (LP). Despite continuous improvements, e.g., the introduction of plerixafor, current challenges are the further optimization regarding the leukapheresis procedure, preventing collection failures, as well as benchmarking and harmonization of mobilization approaches between institutions.This chapter summarizes the current PBSC mobilization and collection approaches and is focusing on timely orchestration of mobilization therapy, granulocyte colony-stimulating factor (G-CSF) application, and peripheral blood (PB) CD34+ cell assessment. Moreover, strategies for prediction and performance assessment of the PBSC collection yield are discussed.


Assuntos
Fator Estimulador de Colônias de Granulócitos/farmacologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco de Sangue Periférico/citologia , Adulto , Benchmarking , Antígenos CD4/metabolismo , Humanos , Leucaférese , Células-Tronco de Sangue Periférico/imunologia , Fatores de Tempo
16.
Methods Mol Biol ; 2017: 165-175, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31197776

RESUMO

It has been shown that the complement cascade is involved in the process of mobilization of hematopoietic stem cells, from their niche in the bone marrow to the peripheral blood. Based on this knowledge modulation of complement, cascade activation may enable the development of better mobilization strategies for poorly mobilizing patients. Herein we present a mobilization protocol in mice model, useful for studying the effect of the complement activation in the mobilization process.


Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/citologia , Animais , Ativação do Complemento , Técnicas de Inativação de Genes , Fator Estimulador de Colônias de Granulócitos/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos , Modelos Animais , Transdução de Sinais/efeitos dos fármacos , Nicho de Células-Tronco
17.
Rinsho Ketsueki ; 60(3): 165-170, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31068511

RESUMO

Failure of autologous peripheral blood stem cell collection (PBSCH) can affect the treatment modality for patients with hematological malignancies. The clinical efficacy of plerixafor in PBSCH was analyzed in our institution. The medical records of 61 patients were retrospectively reviewed. The use of plerixafor was determined according to the CD34+ cell count in the peripheral blood (PB CD34+) on day 4 of G-CSF administration and patients' backgrounds. A total of 47 patients received G-CSF plus plerixafor: 31 with multiple myeloma, 8 with AL amyloidosis or POEMS syndrome, and 8 with non-Hodgkin lymphoma. The median fold increase in PB CD34+ following the first dose of plerixafor was 7.18 times. The median number of collected CD34+ cells on day 5 was 4.1×106/kg and 5.3×106/kg in total. Among the 47 patients, 44 (93.6%) yielded the minimum required cell collection of 2.0×106/kg within an average of 1.3 days. Plerixafor enables rapid and efficient mobilization, and sufficient numbers of CD34+ cells were successfully collected.


Assuntos
Mobilização de Células-Tronco Hematopoéticas , Compostos Heterocíclicos/farmacologia , Células-Tronco de Sangue Periférico/citologia , Amiloidose/terapia , Antígenos CD34 , Fator Estimulador de Colônias de Granulócitos/farmacologia , Humanos , Linfoma não Hodgkin/terapia , Mieloma Múltiplo/terapia , Síndrome POEMS/terapia , Estudos Retrospectivos , Transplante Autólogo
18.
Cardiovasc Toxicol ; 19(6): 510-517, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31054117

RESUMO

Doxorubicin-induced (DXR) cardiomyopathy is a serious health issue in oncology patients. Effective treatment of this clinical situation still remains to be discovered. In this experimental animal study, we aimed to define therapeutic effects of liraglutide, oxytocin and granulocyte colony-stimulating factor in DXR-induced cardiomyopathy model. 40 male Sprague-Dawley rats were included to study. 32 rats were given doxorubicin (DXR) for cardiomyopathy model. DXR was administered intraperitonally (i.p.) at every other day of 2.5 mg/kg/day at six times. Eight rats were taken as normal group and no treatment was performed. 32 rats given doxorubicin were divided into 4 groups. Group 1 rats were assigned to a placebo group and was given with a 0.9% NaCl saline solution at a dose of 1 ml/kg/day i.p. (DXR + saline), Group 2 rats were given with 1.8 mg/kg/day of Liraglutide i.p. (DXR + LIR), Group 3 rats were given with 160 µg/kg/day oxytocin i.p. (DXR + OX), Group 4 rats were given with 100 µg/kg/day filgrastim i.p. (DXR + G-CSF). All medications were given for 15 days. On day 16, under anesthesia, ECG was recorded from derivation I. After that, blood samples were taken by tail vein puncture for biochemical analysis. Finally, the animals were euthanized and the heart removed and prepared for immunohistochemical examination. All three treatments were shown to ameliorate the toxic effect of doxorubicin in cardiac tissue with the best results in DXR + OX group. DXR + OX group had the most preserved tissue integrity examined by light microscopy, least immune expression level of CASPASE-3 (5.3 ± 0.9) (p < 0.001) the highest ECG QRS wave voltage amplitude (0.21 ± 0.008 mV) (p < 0.00001) least plasma MDA (115.3 ± 19.8 nm) (p < 0.001), TNF-alpha (26.6 ± 3.05 pg/ml) (p < 0.001), pentraxin-3 (2.7 ± 0.9 ng/ml) (p < 0.001), Troponin T (1.4 ± 0.08 pg/ml) (p < 0.001), pro-BNP (11.1 ± 3.6 pg/ml) (p < 0.001) levels among all three treatment groups. Consistent with previous literature, we found that OX treatment decreased oxidative, apoptotic and inflammatory activity in DXR-induced cardiomyopathy rat model as well as provided better tissue integrity and better results in clinically relevant measures of ECG assessment, plasma Troponin T and pro-BNP levels. LIR and G-CSF treatment caused similar results with less powerful effects. Our findings suggest that with the best results in OX treatment group, all three agents including LIR and G-CSF attenuates DXR-induced cardiomyopathy in this rat model.


Assuntos
Cardiomiopatias/prevenção & controle , Doxorrubicina , Fator Estimulador de Colônias de Granulócitos/farmacologia , Liraglutida/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Ocitocina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteína C-Reativa/metabolismo , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Cardiotoxicidade , Caspase 3/metabolismo , Modelos Animais de Doenças , Frequência Cardíaca/efeitos dos fármacos , Humanos , Mediadores da Inflamação/sangue , Peroxidação de Lipídeos/efeitos dos fármacos , Malondialdeído/sangue , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Peptídeo Natriurético Encefálico/sangue , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Componente Amiloide P Sérico/metabolismo , Transdução de Sinais , Troponina T/sangue , Fator de Necrose Tumoral alfa/sangue
19.
Regen Med ; 14(6): 571-583, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31115255

RESUMO

Aim: The therapeutic effects of human wisdom teeth-derived neuronal stem cell (tNSC) cotreatment with granulocyte-colony-stimulating factor (G-CSF) were evaluated for contusion-induced spinal cord injury in rats. Materials & methods: 7 days after contusion, tNSCs were transplanted to the injury site and followed by G-CSF cotreatment for 5 days. Behavioral deficits were evaluated by the Basso, Beattie and Bresnahan test. The injury site was collected for immunohistochemistry analysis. Results: The Basso, Beattie and Bresnahan test significantly improved in the cotreated group compared with the tNSCs or G-CSF single treatment groups. However, inflammation indices did not differ among the three groups. In vitro experiment demonstrated that tNSCs express both G-CSF and its relevant receptor. G-CSF enhanced tNSC proliferation and neurotrophins secretion in vitro. Conclusion: This study demonstrated that G-CSF enhances neurotrophins secretion of tNSCs, and might help improving functional recovery from spinal cord injury in rats if they were given together.


Assuntos
Fator Estimulador de Colônias de Granulócitos/farmacologia , Células-Tronco Neurais , Traumatismos da Medula Espinal , Transplante de Células-Tronco , Animais , Xenoenxertos , Humanos , Masculino , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Células-Tronco Neurais/transplante , Ratos , Ratos Long-Evans , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia
20.
Int J Oncol ; 54(6): 2237-2249, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31081057

RESUMO

Cytotoxic chemotherapy is the standard treatment for patients with advanced bladder cancer. However, this treatment can cause transient and prolonged neutropenia, which can result in fatal infection. Three recombinant human colony­stimulating factors (CSFs), granulocyte CSF (G­CSF), granulocyte­macrophage CSF (GM­CSF), and macrophage CSF (M­CSF), are currently available to reduce the duration and degree of neutropenia. The present study investigated the pro­ and anti­tumor effects of these three CSFs and the changes in molecular profiles. Xenograft tumors in athymic mice were generated by subcutaneously inoculating the human bladder cancer cell lines MGH­U3 and UM­UC­3. A total of 2 weeks after cell inoculation, mice were randomly divided into four groups (control, G­CSF, GM­CSF and M­CSF) and treated thrice a week for 2 weeks. Tumor growth during monitoring and tumor weight at the time of euthanization were significantly higher in mice treated with G­CSF and lower in mice treated with GM­CSF compared with the control mice. Tumors were examined by immunostaining with antibodies against proteins associated tumor proliferation (Ki­67), angiogenesis [CD31 and vascular endothelial growth factor (VEGF)], anti­immunity (CD204) and epithelial­mesenchymal transition (EMT; E­cadherin). Immunohistochemical staining revealed that tumor proliferation, angiogenesis, recruitment of M2 macrophages and EMT were promoted by G­CSF, whereas lymphangiogenesis and recruitment of M2 macrophages were inhibited by GM­CSF. Treatment­associated changes in serum pro­ and anti­tumoral cytokines and chemokines were evaluated by enzyme­linked immunosorbent assay (ELISA)­based arrays. In the ELISA for serum, the levels of cytokines associated with angiogenesis (interleukin­6 and VEGF), and EMT (transforming growth factor­ß1 and ­ß2) were elevated in mice treated with G­CSF. Treatment with GM­CSF and M­CSF also affected the level of these cytokines characteristically. The current results indicate that administration of exogenous G­CSF to patients with bladder cancer promotes tumor growth through promotion of cell proliferation, angiogenesis, recruitment of M2 macrophages and enhancement of EMT through the modulation of the tumor microenvironment.


Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Macrófagos/administração & dosagem , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Interleucina-6/metabolismo , Fator Estimulador de Colônias de Macrófagos/farmacologia , Camundongos , Distribuição Aleatória , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Carga Tumoral/efeitos dos fármacos , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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