Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.137
Filtrar
1.
Scand J Immunol ; 92(1): e12883, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32243617

RESUMO

Monocytes are important cells of the innate system. They are a heterogeneous type of cells consisting of phenotypically and functionally distinct subpopulations, which play a specific role in the control, development and escalation of the immunological processes. Based on the expression of superficial CD14 and CD16 in flow cytometry, they can be divided into three subsets: classical, intermediate and non-classical. Variation in the levels of human monocyte subsets in the blood can be observed in patients in numerous pathological states, such as infections, cardiovascular and inflammatory diseases, cancer and autoimmune diseases. The aim of this review is to summarize current knowledge of human monocyte subsets and their significance in homeostasis and in pathological conditions.


Assuntos
Imunidade Inata/imunologia , Monócitos/classificação , Monócitos/imunologia , Fatores Estimuladores de Colônias/biossíntese , Fatores Estimuladores de Colônias/imunologia , Humanos , Macrófagos/citologia , Macrófagos/imunologia , Monócitos/citologia , Receptores de Superfície Celular/imunologia
2.
Immunol Lett ; 212: 6-13, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31154052

RESUMO

In the last decade several studies employing stem cells-based therapies have been investigated as an optional treatment for multiple sclerosis. Several preclinical and few clinical studies tested the efficacy of mesenchymal stem cells as a potent candidate for such therapies. Here we suggest the option of "neuralization" of classical mesenchymal stem cells as a cellular structure that resembles neural stem cells as well as there differentiation by a unique procedure towards terminally differentiated neural cells suggesting that this cell population may be appropriate for clinical application in the CNS. We investigated whether neuralized MSC (NMSC) could promote repair and recovery after injection into mice with EAE. Injection of NMSC and differentiated NMSC starting at the onset of the chronic phase of disease improved neurological function compared to controls as well as compared to naïve MSC. Injection of NMSC and mainly differentiated correlated with a reduction in the inflammation as well as in the axonal loss/damage and reduced area of demyelination. These observations suggest that NMSC and differentiated NMSC may suggest a more potent cell-based therapy that naïve MSC in the treatment arsenal of multiple sclerosis.


Assuntos
Transdiferenciação Celular/imunologia , Fatores Estimuladores de Colônias/farmacologia , Encefalomielite Autoimune Experimental/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Esclerose Múltipla/terapia , Animais , Técnicas de Cultura de Células , Transdiferenciação Celular/efeitos dos fármacos , Células Cultivadas , Encefalomielite Autoimune Experimental/imunologia , Feminino , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/imunologia , Camundongos , Esclerose Múltipla/imunologia , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Glicoproteína Mielina-Oligodendrócito/imunologia , Células-Tronco Neurais/imunologia , Esferoides Celulares , Resultado do Tratamento
4.
PLoS Biol ; 17(3): e2006859, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30921319

RESUMO

Brain metastases are prevalent in various types of cancer and are often terminal, given the low efficacy of available therapies. Therefore, preventing them is of utmost clinical relevance, and prophylactic treatments are perhaps the most efficient strategy. Here, we show that systemic prophylactic administration of a toll-like receptor (TLR) 9 agonist, CpG-C, is effective against brain metastases. Acute and chronic systemic administration of CpG-C reduced tumor cell seeding and growth in the brain in three tumor models in mice, including metastasis of human and mouse lung cancer, and spontaneous melanoma-derived brain metastasis. Studying mechanisms underlying the therapeutic effects of CpG-C, we found that in the brain, unlike in the periphery, natural killer (NK) cells and monocytes are not involved in controlling metastasis. Next, we demonstrated that the systemically administered CpG-C is taken up by endothelial cells, astrocytes, and microglia, without affecting blood-brain barrier (BBB) integrity and tumor brain extravasation. In vitro assays pointed to microglia, but not astrocytes, as mediators of CpG- C effects through increased tumor killing and phagocytosis, mediated by direct microglia-tumor contact. In vivo, CpG-C-activated microglia displayed elevated mRNA expression levels of apoptosis-inducing and phagocytosis-related genes. Intravital imaging showed that CpG-C-activated microglia cells contact, kill, and phagocytize tumor cells in the early stages of tumor brain invasion more than nonactivated microglia. Blocking in vivo activation of microglia with minocycline, and depletion of microglia with a colony-stimulating factor 1 inhibitor, indicated that microglia mediate the antitumor effects of CpG-C. Overall, the results suggest prophylactic CpG-C treatment as a new intervention against brain metastasis, through an essential activation of microglia.


Assuntos
Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/metabolismo , Microglia/metabolismo , Microglia/patologia , Oligodesoxirribonucleotídeos/uso terapêutico , Receptor Toll-Like 9/agonistas , Receptor Toll-Like 9/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Fatores Estimuladores de Colônias/antagonistas & inibidores , Fatores Estimuladores de Colônias/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/metabolismo , Masculino , Melanoma/complicações , Melanoma/metabolismo , Camundongos , Minociclina/metabolismo , Fagocitose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
5.
J Dairy Sci ; 102(4): 3439-3451, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30799104

RESUMO

The objective of this study was to evaluate the effect of pegbovigrastim (PEG) treatment of peripartum Holstein cows on the microbiome found in the vagina postpartum using sequencing of the 16S rRNA gene. A subset of cows was randomly sampled from a larger study where cows had been randomly assigned to 1 of 2 treatments: pegbovigrastim (PEG) or untreated control (CTR). The PEG-treated cows received a subcutaneous injection containing 15 mg of pegbovigrastim 7 d before expected calving and a second injection within 24 h of calving. Vaginal samples from 97 PEG-treated and 98 CTR cows were collected at calving, 7 ± 3, and 35 ± 3 d in milk (0, 7, and 35 DIM). Metritis was diagnosed at 7 ± 3 DIM and purulent vaginal discharge (PVD) at 35 ± 3 DIM. The PEG treatment did not alter the vaginal microbiome. Principal coordinate analysis (PCoA) showed that metritic cows had a dissimilar vaginal microbiome compared with cows that did not develop metritis, particularly at 7 but also at 35 DIM. This difference was characterized by higher relative abundance of Porphyromonas and Bacteroides and a lower relative abundance of Ureaplasma, Ruminococcaceae, and Clostridiales at 7 DIM, and a higher relative abundance of Ureaplasma and a lower relative abundance of Pasteurellaceae at 35 DIM. Based on PCoA, we observed that cows that developed PVD had a dissimilar vaginal microbiome compared with cows that did not develop PVD, particularly at 35 DIM but also at 7 DIM. This difference was characterized by a higher relative abundance of Bacteroides at 7 DIM and higher relative abundance of Fusobacterium and Bacteroides at 35 DIM. Cows that developed metritis and PVD also had higher relative abundance of Fusobacterium and Bacteroides at 0 DIM. Furthermore, the Chao1 and Shannon indices were decreased in metritic cows at 7 DIM and in PVD cows at 7 and 35 DIM. In summary, PEG treatment had no effect on the vaginal microbiome, and uterine disease was associated with major changes in the microbiome found in the vagina postpartum.


Assuntos
Doenças dos Bovinos/prevenção & controle , Fatores Estimuladores de Colônias/farmacologia , Endometrite/veterinária , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Microbiota/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Vagina/microbiologia , Animais , Bacteroides , Bovinos , Doenças dos Bovinos/microbiologia , Endometrite/prevenção & controle , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Período Pós-Parto , RNA Ribossômico 16S , Distribuição Aleatória , Proteínas Recombinantes/farmacologia , Doenças Uterinas
6.
Eur Neuropsychopharmacol ; 29(3): 384-396, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30630651

RESUMO

Cognitive deterioration and symptom progression occur in schizophrenia over the course of the disorder. A dysfunction of the immune system/neuroinflammatory pathways has been linked to schizophrenia (SZ). These altered processes in the dorsolateral prefrontal cortex (DLPFC) could contribute to the worsening of the deficits. However, limited studies are available in this brain region in elderly population with long-term treatments. In this study, we explore the possible deregulation of 21 key genes involved in immune homeostasis, including pro- and anti-inflammatory cytokines, cytokine modulators (toll-like receptors, colony-stimulating factors, and members of the complement system) and microglial and astroglial markers in the DLPFC in elderly chronic schizophrenia. We used quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) on extracts from postmortem DLPFC of elderly subjects with chronic SZ (n = 14) compared to healthy control individuals (n = 14). We report that CSF1R, TLR4, IL6, TNFα, TNFRSF1A, IL10, IL10RA, IL10RB, and CD68 were down-regulated in elderly SZ subjects. Moreover, we found that the expression levels of all the altered inflammatory genes in SZ correlated with the microglial marker CD68. However, no associations were found with the astroglial marker GFAP. This study reveals a decrease in the gene expression of cytokines and immune response/inflammation mediators in the DLPFC of elderly subjects with chronic schizophrenia, supporting the idea of a dysfunction of these processes in aged patients and its possible relationship with active microglia abundance. These findings include elements that might contribute to the cognitive decline and symptom progression linked to DLPFC functioning at advanced stages of the disease.


Assuntos
Citocinas/metabolismo , Regulação para Baixo/fisiologia , Encefalite/complicações , Córtex Pré-Frontal/metabolismo , Esquizofrenia/complicações , Esquizofrenia/patologia , Idoso , Idoso de 80 Anos ou mais , Fatores Estimuladores de Colônias/genética , Fatores Estimuladores de Colônias/metabolismo , Citocinas/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Estatísticas não Paramétricas , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo
7.
Curr Med Res Opin ; 35(6): 1073-1080, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30550346

RESUMO

BACKGROUND: Guidelines recommend primary prophylactic use of colony-stimulating factor (PP-CSF) when risk of febrile neutropenia (FN) - based on chemotherapy and patient risk factors - is high. Whether and how PP-CSF use may have changed over time (e.g. due to guideline revisions, increasing use of myelosuppressive regimens, controversy regarding inappropriate CSF use), and whether there has been a concomitant change in the incidence of FN, is unknown. METHODS: A retrospective cohort design and data from two US healthcare claims repositories were employed. The study population included patients who had non-metastatic cancer of the breast, colon/rectum, lung or ovaries, or non-Hodgkin's lymphoma (NHL), and who received myelosuppressive chemotherapy regimens with an intermediate/high risk for FN. For each patient, the first cycle of the first course was characterized in terms of PP-CSF use and FN episodes. Crude incidence proportions for PP-CSF and FN during the first cycle were estimated by calendar quarter (2010-2016); multivariable logistic regression models were used to estimate quarter-specific adjusted mean probabilities of FN by PP-CSF use. RESULTS: The study population totaled 142,730 patients with breast cancer (61%), colorectal cancer (14%), NHL (11%), ovarian cancer (10%) or lung cancer (5%). PP-CSF use increased from 52% in 1Q2010 to 58% in 4Q2016; pegfilgrastim was the most commonly used agent (>96% across quarters). PP-CSF administration on the same day as chemotherapy ranged from 8 to 11% until 1Q2015, and increased to 64% by 4Q2016. Adjusted incidence proportions for FN in the first chemotherapy cycle ranged from 2.7% (95% CI: 2.3-3.0) to 3.7% (95% CI: 3.1-4.3) among those who did not receive PP-CSF, and was 2.6% (95% CI: 2.5-2.7) across quarters among those who received PP-CSF. CONCLUSIONS: Although the use of PP-CSF is commonplace in current US clinical practice, underutilization in cancer patients receiving chemotherapy regimens with an intermediate/high risk for FN may still be an issue. Use of same-day PP-CSF increased markedly from the end of 2015, although this finding reflects (at least in part) increased uptake of pegfilgrastim delivered via an on-body injector as well as the recent change in clinical practice guidelines. Overall, patients receiving PP-CSF appear to have a lower risk of FN during the first cycle of chemotherapy.


Assuntos
Fatores Estimuladores de Colônias/uso terapêutico , Neutropenia Febril/prevenção & controle , Neoplasias/tratamento farmacológico , Adulto , Idoso , Neutropenia Febril/epidemiologia , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prevenção Primária , Estudos Retrospectivos , Fatores de Tempo
8.
Proc Natl Acad Sci U S A ; 116(4): 1361-1369, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30545915

RESUMO

Interleukin-1ß (IL-1ß) is abundant in the tumor microenvironment, where this cytokine can promote tumor growth, but also antitumor activities. We studied IL-1ß during early tumor progression using a model of orthotopically introduced 4T1 breast cancer cells. Whereas there is tumor progression and spontaneous metastasis in wild-type (WT) mice, in IL-1ß-deficient mice, tumors begin to grow but subsequently regress. This change is due to recruitment and differentiation of inflammatory monocytes in the tumor microenvironment. In WT mice, macrophages heavily infiltrate tumors, but in IL-1ß-deficient mice, low levels of the chemokine CCL2 hamper recruitment of monocytes and, together with low levels of colony-stimulating factor-1 (CSF-1), inhibit their differentiation into macrophages. The low levels of macrophages in IL-1ß-deficient mice result in a relatively high percentage of CD11b+ dendritic cells (DCs) in the tumors. In WT mice, IL-10 secretion from macrophages is dominant and induces immunosuppression and tumor progression; in contrast, in IL-1ß-deficient mice, IL-12 secretion by CD11b+ DCs prevails and supports antitumor immunity. The antitumor immunity in IL-1ß-deficient mice includes activated CD8+ lymphocytes expressing IFN-γ, TNF-α, and granzyme B; these cells infiltrate tumors and induce regression. WT mice with 4T1 tumors were treated with either anti-IL-1ß or anti-PD-1 Abs, each of which resulted in partial growth inhibition. However, treating mice first with anti-IL-1ß Abs followed by anti-PD-1 Abs completely abrogated tumor progression. These data define microenvironmental IL-1ß as a master cytokine in tumor progression. In addition to reducing tumor progression, blocking IL-1ß facilitates checkpoint inhibition.


Assuntos
Anticorpos Monoclonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Interleucina-1beta/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Antígeno CD11b/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Fatores Estimuladores de Colônias/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Feminino , Granzimas/farmacologia , Humanos , Imunossupressão/métodos , Inflamação/metabolismo , Interferon gama/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
9.
Dental Press J Orthod ; 23(5): 41-46, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30427492

RESUMO

INTRODUCTION: The search for more aesthetic and comfortable orthodontic devices has led to an increase in the use of clear aligners. OBJECTIVE: To increase knowledge on biological mechanisms of orthodontic tooth movement using Invisalign aligners. METHODS: This study included 11 patients with a mean age of 23.6 ± 4.8 years. Cases planning included alignment and leveling of lower incisors using Invisalign aligners. Gingival crevicular fluid samples were collected from the lower incisors on the day of delivery of aligner number 1 (T0) and after 1 (T24h), 7 (T7d), and 21 (T21d) days. During the observation period of the study, the patients used only the aligner number 1. Levels of nine cytokines were quantified using Luminex's multi-analysis technology. Non-parametric tests were used for comparisons between cytokine expression levels over time. RESULTS: Cytokine expression levels remained constant after 21 days of orthodontic activation, except those of MIP-1ß, which presented a statistical difference between T24h and T21d with a decrease in the concentration levels. IL-8, GM-CSF, IL-1ß, MIP-1ß, and TNF-α showed the highest concentrations over time. CONCLUSIONS: The different behavior in the levels of the investigated cytokines indicates a role of these biomarkers in the tissue remodeling induced by Invisalign.


Assuntos
Citocinas/análise , Líquido do Sulco Gengival/química , Técnicas de Movimentação Dentária , Quimiocina CCL2/análise , Quimiocina CCL4/análise , Fatores Estimuladores de Colônias/análise , Citocinas/metabolismo , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/análise , Humanos , Incisivo , Interleucina-17/análise , Interleucina-1beta/análise , Interleucina-7/análise , Interleucina-8/análise , Masculino , Aparelhos Ortodônticos Removíveis , Fator de Necrose Tumoral alfa/análise , Adulto Jovem
10.
Cytokine ; 111: 334-341, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30269030

RESUMO

BACKGROUND: Unregulated inflammatory and thrombotic responses have been proposed to be important causes of early brain injury and worse clinical outcomes after subarachnoid hemorrhage (SAH). OBJECTIVE: We hypothesize that SAH is characterized by an increased inflammatory and thrombotic state and disruption of associations between these states. METHODS: This is a retrospective cohort study of 60 patients with SAH. 23 patients with unruptured aneurysms (UA) and 77 patients with traumatic brain injury (TBI) were chosen as controls. Plasma cytokine levels were measured using a 41-plex human immunoassay kit, and cytokine patterns associated with SAH, UA and TBI were identified using statistical and informatics methods. RESULTS: SAH was characterized by an increase in several cytokines and chemokines, platelet-derived factors, and growth factors. Cluster analysis identified several cytokine clusters common in SAH, UA and TBI groups - generally grouped as platelet-derived, vascular and pro-inflammatory clusters. In the UA group, the platelet-derived cluster had an inverse relationship with the inflammatory cluster which was absent in SAH. Additionally, a cluster comprising of growth and colony stimulating factors was unique to SAH. CONCLUSIONS: A cluster of cytokines involved in growth and colony stimulation was unique to SAH. Negative associations between the thrombotic and inflammatory molecules were observed in UA but not in SAH. Further studies to examine the pathophysiology behind the cluster unique to SAH and the associations between the thrombotic and inflammatory cytokines are required.


Assuntos
Citocinas/metabolismo , Inflamação/metabolismo , Hemorragia Subaracnóidea/metabolismo , Plaquetas/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Fatores Estimuladores de Colônias/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
11.
Invest Ophthalmol Vis Sci ; 59(12): 4986-4997, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30326070

RESUMO

Purpose: Lens epithelial cell (LEC) conversion to myofibroblast is responsible for fibrotic cataract surgery complications including posterior capsular opacification. While transforming growth factor beta (TGFß) signaling is important, the mechanisms by which the TGFß pathway is activated post cataract surgery (PCS) are not well understood. Methods: RNA-seq was performed on LECs obtained from a mouse cataract surgery model at the time of surgery and 24 hours later. Bioinformatic analysis was performed with iPathwayGuide. Expression dynamics were determined by immunofluorescence. Results: The LEC transcriptome is massively altered by 24 hours PCS. The differentially expressed genes included those important for lens biology, and fibrotic markers. However, the most dramatic changes were in the expression of genes regulating the innate immune response, with the top three altered genes exhibiting greater than 1000-fold upregulation. Immunolocalization revealed that CXCL1, S100a9, CSF3, COX-2, CCL2, LCN2, and HMOX1 protein levels upregulate in LECs between 1 hour and 6 hours PCS and peak at 24 hours PCS, while their levels sharply attenuate by 3 days PCS. This massive upregulation of known inflammatory mediators precedes the infiltration of neutrophils into the eye at 18 hours PCS, the upregulation of canonical TGFß signaling at 48 hours PCS, and the infiltration of macrophages at 3 days PCS. Conclusions: These data demonstrate that LECs produce proinflammatory cytokines immediately following lens injury that could drive postsurgical flare, and suggest that inflammation may be a major player in the onset of lens-associated fibrotic disease PCS.


Assuntos
Opacificação da Cápsula/metabolismo , Extração de Catarata , Citocinas/genética , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/fisiologia , Inflamação/metabolismo , Cristalino/metabolismo , Animais , Calgranulina B/genética , Quimiocina CCL2/genética , Quimiocina CXCL1/genética , Fatores Estimuladores de Colônias/genética , Ciclo-Oxigenase 2/genética , Técnica Indireta de Fluorescência para Anticorpo , Perfilação da Expressão Gênica , Heme Oxigenase-1/genética , Lipocalina-2/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Infiltração de Neutrófilos/fisiologia , Análise de Sequência de RNA , Transcriptoma/genética
12.
J Mol Cell Cardiol ; 125: 6-17, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30336142

RESUMO

Endothelial cell derived secretive factors play pivotal roles maintaining the homeostasis by influencing the behaviors of other cells. When dysregulated, these factors may contribute to the disruption of physiological integrity and promote disease genesis in a number of different tissues and organs. In the present study we investigated how targeted deletion of brahma related gene 1 (Brg1), a chromatin remodeling protein, in endothelium might affect the pathogenesis of abdominal aortic aneurysm (AAA) induced by calcium chloride (CaCl2). We report here that compared to the wild type (WT) littermates, endothelial conditional Brg1 knockout (ecKO) mice exhibited an attenuated phenotype of AAA. Immunostaining and quantitative PCR analyses showed that vascular inflammation was suppressed in ecKO mice as opposed to WT mice likely due to diminished recruitment of macrophages. Further examination revealed that Brg1 deficiency led to a reduction in colony stimulating factor 1 (CSF1) levels. In cultured endothelial cells, Brg1 cooperated with histone H3K9 demethylase KDM3A to activate CSF1 transcription and macrophage recruitment thereby perpetuating vascular inflammation. Depletion of BRG1 or KDM3A in endothelial cells dampened CSF1 production and attenuated macrophage chemotaxis. Therefore, our data suggest that epigenetic activation of CSF1 transcription by Brg1 may contribute to AAA pathogenesis.


Assuntos
Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/metabolismo , Cloreto de Cálcio/toxicidade , DNA Helicases/metabolismo , Endotélio/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Imunoprecipitação da Cromatina , Fatores Estimuladores de Colônias , DNA Helicases/genética , Feminino , Fator Estimulador de Colônias de Macrófagos , Masculino , Camundongos , Camundongos Knockout , Proteínas Nucleares/genética , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição/genética
14.
J Natl Compr Canc Netw ; 16(2): 162-169, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29439177

RESUMO

Background: White blood cell colony-stimulating factors (CSFs) decrease the incidence of chemotherapy-induced febrile neutropenia (FN). Widespread use of CSFs that is not guideline-concordant has been reported. Among patients with breast cancer receiving chemotherapy, the ability of evidence-based decision support tools to promote risk-appropriate reductions in CSF use without increased incidence of FN has not been examined. Methods: A retrospective cohort design and US commercial claims data were used. The impact of CSF decision support was analyzed among women with breast cancer receiving first-cycle chemotherapy from April 1, 2013, to March 30, 2015. The tool was implemented as part of a prior authorization process in 9 states starting July 1, 2014. Patients were assigned to intervention (ie, states where the decision support tool had been implemented) or nonintervention states (ie, 39 states where the tool had not been implemented). CSF use and subsequent incidence of FN were compared using difference-in-difference (DID) regressions adjusting for baseline differences in FN risk factors such as comorbidities and various infections. Results: The study sample of 7,224 patients (intervention states: pre-implementation, 1,991 and post-implementation, 2,010; nonintervention states: pre-implementation, 1,569 and post-implementation, 1,654) showed no significant difference in risk factors. Before and after implementation, a significant decrease in the proportion of patients with CSF use was observed in the intervention states (75% to 69%) compared with no significant change in the nonintervention (72% to 71%) states (DID, -5.4%; 95% CI, -6.0% to -4.7%; P=.006). No significance increase in FN incidence occurred in intervention (5.0% to 5.5%) and nonintervention (5.4% to 4.8%) states (DID, 0.2%; 95% CI, -0.20 to 0.30; P=.78). Similar results were obtained in subgroups by comorbidities and in sensitivity analyses by claims-based FN definitions. Conclusions: CSF use decreased modestly after implementation of the decision support tool, with no observed changes in FN rates. Such tools can reduce practice variation to improve care standards.


Assuntos
Neoplasias da Mama/complicações , Neoplasias da Mama/epidemiologia , Neutropenia Febril Induzida por Quimioterapia/epidemiologia , Neutropenia Febril Induzida por Quimioterapia/etiologia , Fatores Estimuladores de Colônias , Técnicas de Apoio para a Decisão , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Neutropenia Febril Induzida por Quimioterapia/diagnóstico , Neutropenia Febril Induzida por Quimioterapia/tratamento farmacológico , Fatores Estimuladores de Colônias/administração & dosagem , Fatores Estimuladores de Colônias/uso terapêutico , Terapia Combinada , Medicina Baseada em Evidências , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
15.
Dev Comp Immunol ; 84: 181-192, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29408047

RESUMO

Considering that macrophage functions are strongly impacted by the local tissue environment and the type of immune response, the aim of this study was to carefully set the methodological baseline for phenotype and functions of polarized porcine monocyte-derived macrophages. To this end, macrophages were generated in autologous serum alone or with colony-stimulating factor (CSF)-1 or CSF-2, and subsequently polarized with interferon (IFN)γ, interleukin-4 or IFNß. IFNγ promoted expression of MHC class I, MHC class II, CD11a, and CD40 as well as LPS-induced IL-6 and IL-12. A hallmark of interleukin-4 was Arginase 1 and CD203a upregulation, without abrogating pro-inflammatory cytokine production. IFNß induced CD169, MHC class I, CD40, CD80/86, but suppressed IL-6, IL-12 and tumor-necrosis-factor secretion. CSF-2 alone altered macrophage differentiation and promoted an IFNγ-like polarization. Altogether, the results provide a comprehensive overview of porcine macrophage polarization, and demonstrate commonalities with other species as well as peculiarities of the pig.


Assuntos
Interferon beta/metabolismo , Interferon gama/metabolismo , Macrófagos/imunologia , Monócitos/imunologia , Suínos/imunologia , Animais , Antígenos CD/metabolismo , Arginase/metabolismo , Diferenciação Celular , Células Cultivadas , Fatores Estimuladores de Colônias/metabolismo , Citocinas/metabolismo , Antígenos de Histocompatibilidade/metabolismo , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Interleucina-4/metabolismo , Especificidade da Espécie
16.
Expert Rev Hematol ; 11(2): 155-168, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29285951

RESUMO

INTRODUCTION: The rapid spread of severe infections mainly due to resistant pathogens, justifies the search for therapies aiming to restore immune functions severely compromised in patients with hematologic malignancies. Areas covered: The present review summarizes the current knowledge on the role of granulocyte transfusions and colony-stimulating factors as treatment strategy for hematologic patients with serious infectious complications. In addition, a survey among 21 hematologic centers, to evaluate the clinical practice for the use of G-CSF originator and biosimilars was performed. Expert commentary: Granulocyte transfusions with a target dose of at least 1.5-3 × 108 cells/kg, may be considered as an approach to bridge the gap between marrow suppression and recovery of granulocytes. G-CSF shortens the period of neutropenia, the hospitalization, the use of antibiotics and the rate of febrile neutropenia (FN) in adult and pediatric patients with non-Hodgkin lymphoma, and in adults with acute myeloid leukemia where these advantages nevertheless, did not translate into a clinical benefit. G-CSF biosimilar showed equivalence or non-inferiority to filgrastim. There are no data supporting the use of GM-CSF, eltrombopag and erythropoietin for preventing or treating infectious complications in patients with hematologic disorders.


Assuntos
Antibacterianos/uso terapêutico , Fatores Estimuladores de Colônias/uso terapêutico , Granulócitos , Neoplasias Hematológicas , Infecções , Leucemia Mieloide Aguda , Transfusão de Leucócitos , Linfoma não Hodgkin , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Humanos , Infecções/etiologia , Infecções/terapia , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/terapia , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/terapia , Masculino , Neutropenia/complicações , Neutropenia/terapia
17.
Breast J ; 24(4): 462-467, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29205665

RESUMO

While the docetaxel, carboplatin, and trastuzumab (TCH) regimen is one of the standard treatments in Her2-positive breast cancer, however, acute toxicities, especially those related to the high rate of neutropenia are consistently reported. Primary: To compare the toxicity of TCH in current clinical practice vs the toxicity observed in the pivotal study, comparing the toxicity in patients that received primary prophylaxis (PP) with colony-stimulating factors vs those that did not receive PP. Secondary: To describe the demographic and clinical characteristics of the study sample, as well as the adverse effects and survival. The data regarding 95 patients were analyzed. Observed toxicity (hematological and extra-hematological) was greater compared to the pivotal study, with the exception of neuropathy and neutropenia. Toxicities "PP" vs "no PP": Extra-hematological grade 3-4 toxicities: Significant reduction was observed in the "PP" group vs the "no PP" group referred to fatigue, stomatitis, nausea, and vomiting. Hematological grade 3-4 toxicities: Lesser neutropenia, leukopenia, and febrile neutropenia were observed in the "PP" group. Complications associated to treatment: No grade 3-4 cardiac toxicity, leukemia or deaths were recorded. DFS and OS: After a mean follow-up of 22.9 months, only one bone metastatic relapse was detected (DFS: 98.9%; OS: 100%). The combination TCH is very active and effective as adjuvant and neo-adjuvant therapy in Her2-positive breast cancer, and is currently regarded as standard treatment. However, global toxicity as well as hematological toxicity is elevated. The incorporation of PP to TCH significantly reduces hematological toxicity and some of the global toxicity, thus favoring treatment implementation and lessening the clinical complications. We therefore recommend generalization of PP with colony-stimulating factors in patients receiving TCH.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carboplatina/efeitos adversos , Docetaxel/efeitos adversos , Trastuzumab/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/efeitos adversos , Fatores Estimuladores de Colônias/efeitos dos fármacos , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Neutropenia/induzido quimicamente , Receptor ErbB-2/efeitos dos fármacos
18.
Brain Behav Immun ; 68: 248-260, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29080683

RESUMO

Accumulation of microglia occurs in the dorsal horn in the rodent model of chronic post ischemic pain (CPIP), while the mechanism how microglia affects the development of persistent pain largely remains unknown. Here, using a rodent model of CPIP induced by ischemia-reperfusion (IR) injury in the hindpaw, we observed that microglial accumulation occurred in the ipsilateral dorsal horn after ischemia 3h, and in ipsilateral and contralateral dorsal horn in the rats with ischemia 6h. The accumulated microglia released BDNF, increased neuronal excitability in dorsal horn, and produced pain behaviors in the modeled rodents. We also found significantly increased signaling mediated by astrocytic colony-stimulating factor-1 (CSF1) and microglial CSF1 receptor (CSF1R) in dorsal horn in the ischemia 6h modeled rats. While exogenous M-CSF induced microglial activation and proliferation, BDNF production, neuronal hyperactivity in dorsal horn and behavioral hypersensitivity in the naïve rats, inhibition of astrocytic CSF1/microglial CSF1R signaling by fluorocitric or PLX3397 significantly suppressed microglial activation and proliferation, BDNF upregulation, and neuronal activity in dorsal horn, as well as the mechanical allodynia and thermal hyperalgesia, in the rats with ischemia 6h. Collectively, these results demonstrated that glial CSF1/CSF1R pathway mediated the microglial activation and proliferation, which facilitated the nociceptive output and contributed to the chronic pain induced by IR injury.


Assuntos
Dor Crônica/metabolismo , Fatores Estimuladores de Colônias/metabolismo , Receptores de Fator Estimulador de Colônias/metabolismo , Animais , Astrócitos/metabolismo , Comportamento Animal/fisiologia , Sensibilização do Sistema Nervoso Central/fisiologia , Modelos Animais de Doenças , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Hiperalgesia/metabolismo , Isquemia/fisiopatologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Masculino , Microglia/metabolismo , Neuralgia/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Regulação para Cima
19.
J Cell Physiol ; 233(2): 1500-1511, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28574591

RESUMO

In bone marrow (BM), hematopoietic elements are mingled with adipocytes (BM-A), which are the most abundant stromal component in the niche. BM-A progressively increase with aging, eventually occupying up to 50% of BM cavities. In this work, the role played by BM-A was explored by studying primary human BM-A isolated from hip surgery patients at the molecular level, through microarray analysis, and at the functional level, by assessing their relationship with primary human hematopoietic stem cells (HSC) by the long-term culture initiating cell (LTC-IC) assay. Findings demonstrated that BM-A are capable of supporting HSC survival in the LTC-IC assay, since after 5 weeks of co-culture, HSC were still able to proliferate and differentiate. Furthermore, critical molecules such as C-X-C motif chemokine 12 (CXCL12), interleukin (IL)-8, colony-stimulating factor 3 (CSF3), and leukaemia inhibitory factor (LIF), were expressed at similar levels in BM-A and in primary human BM mesenchymal stromal cells (BM-MSC), whereas IL-3 was higher in BM-A. Interestingly, BM-A displayed a different gene expression profile compared with subcutaneous adipose tissue adipocytes (AT-A) collected from abdominal surgery patients, especially in terms of regulation of lipid metabolism, stemness genes, and white-to-brown differentiation pathways. Accordingly, analysis of the gene pathways involved in hematopoiesis regulation showed that BM-A are more closely related to BM-MSC than to AT-A. The present data suggest that BM-A play a supporting role in the hematopoietic niche and directly sustain HSC survival.


Assuntos
Adipócitos/fisiologia , Células da Medula Óssea/fisiologia , Comunicação Celular , Células-Tronco Hematopoéticas/fisiologia , Adipócitos/metabolismo , Idoso , Idoso de 80 Anos ou mais , Células da Medula Óssea/metabolismo , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Quimiocina CXCL12/metabolismo , Técnicas de Cocultura , Fatores Estimuladores de Colônias/metabolismo , Feminino , Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Humanos , Interleucina-8/metabolismo , Fator Inibidor de Leucemia/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Transdução de Sinais , Nicho de Células-Tronco , Gordura Subcutânea/citologia , Gordura Subcutânea/fisiologia , Fatores de Tempo , Transcriptoma
20.
J Oncol Pract ; 13(12): e1040-e1045, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29136390

RESUMO

PURPOSE: Four incident reports involving missed doses of myeloid growth factors (MGFs) triggered the need for an outcome-driven initiative. From March 1, 2015, to February 29, 2016, at University of California Irvine Health Chao Infusion Center, 116 of 3,300 MGF doses were missed (3.52%), including pegfilgrastim, filgrastim, and sargramostim. We hypothesized that with the application of Lean Six Sigma methodology, we would achieve our primary objective of reducing the number of missed MGF doses to < 0.5%. METHODS: This quality improvement initiative was conducted at Chao Infusion Center as part of a Lean Six Sigma Green Belt Certification Program. Therefore, Lean Six Sigma principles and tools were used throughout each phase of the project. Retrospective and prospective medical record reviews and data analyses were performed to evaluate the extent of the identified problem and impact of the process changes. Improvements included systems applications, practice changes, process modifications, and safety-net procedures. RESULTS: Preintervention, 24 missed doses (20.7%) required patient supportive care measures, resulting in increased hospital costs and decreased quality of care. Postintervention, from June 8, 2016, to August 7, 2016, zero of 489 MGF doses were missed after 2 months of intervention ( P < .001). Chao Infusion Center reduced missed doses from 3.52% to 0%, reaching the goal of < 0.5%. CONCLUSION: The establishment of simplified and standardized processes with safety checks for error prevention increased quality of care. Lean Six Sigma methodology can be applied by other institutions to produce positive outcomes and implement similar practice changes.


Assuntos
Fatores Estimuladores de Colônias/administração & dosagem , Fatores Estimuladores de Colônias/economia , Erros de Medicação/economia , Melhoria de Qualidade/economia , Gestão da Qualidade Total/economia , Humanos , Adesão à Medicação , Estudos Prospectivos , Estudos Retrospectivos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA