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2.
Clin Sci (Lond) ; 134(2): 273-287, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31957803

RESUMO

The current main treatment for coronary artery disease (CAD) is to reduce low-density lipoprotein cholesterol (LDL-C) by statins, which could decrease the incidence of major adverse cardiovascular events (MACEs) by 30%. However, many residual risks still remain. To clarify the mechanism involved, we studied patients with acute myocardial infarction (AMI) with low LDL-C levels. Lymphocytes were isolated, and it was found that despite no difference in plasma LDL-C level, the lymphocyte cholesterol content was higher in AMI patient than those in non-CAD patients; thus, the decrease in intracellular cholesterol content was inconsistent with that in the plasma. Additionally, [3H]-cholesterol efflux rates were lower and mRNA levels of the inflammatory factors tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) higher in AMI lymphocytes. It was found that sulphotransferase 2B1b (SULT2B1b) expression was higher in AMI lymphocytes. Further research using Jurkat T lymphocytes confirmed that SULT2B1b knockdown increased cholesterol efflux capacity and decreased mRNA levels of TNF-α and IFN-γ by increasing liver X receptor (LXR)-ß levels. Furthermore, the degree of CpG island methylation in the SULT2B1b promoter was reduced in cells from AMI patients. In conclusion, SULT2B1b up-regulation due to hypomethylation of its promoter promotes cholesterol accumulation and inflammation by inhibiting LXR-ß in lymphocytes of AMI patients with low LDL-C levels. Therefore, reducing intracellular cholesterol is also important as plasma cholesterol levels. Therapeutic approaches to decrease SULT2B1b expression might be potentially beneficial for CAD prevention by decreasing intracellular cholesterol.


Assuntos
Colesterol/metabolismo , Interferon gama/metabolismo , Linfócitos/metabolismo , Sulfotransferases/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Transporte Biológico , Colesterol/sangue , LDL-Colesterol/metabolismo , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/prevenção & controle , Metilação de DNA , Humanos , Mediadores da Inflamação/metabolismo , Interferon gama/genética , Células Jurkat , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/prevenção & controle , Regiões Promotoras Genéticas/genética , Sulfotransferases/genética , Fator de Necrose Tumoral alfa/genética
3.
Medicine (Baltimore) ; 99(4): e18607, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31977852

RESUMO

Systemic inflammatory response markers are associated with poor survival in many types of malignances. This study aimed to evaluate the prognostic value of preoperative neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and C-reactive protein (CRP) in patients with non-small cell lung cancer (NSCLC).We retrospectively evaluated 254 NSCLC patients who underwent radical surgery between January 2012 and April 2014 in the Sichuan Provincial Cancer Hospital. The cut-off values of NLR, PLR, LMR, and CRP were determined according to the receiver operating characteristic curve, and the correlation of NLR, PLR, LMR, and CRP with prognosis was analyzed based on the cut-off value.The cut-off value for NLR, PLR, LMR, and CRP were 3.18, 122, 4.04, and 8.8, respectively. Univariate analysis showed that age (P = .022), tumor-node-metastasis (TNM) stage (P < .001), T stage (P = .001), and N stage (P < .001) were significantly correlated with disease-free survival (DFS), while age (P = .011), TNM stage (P < .001), T stage (P = .008), N stage (P < .001), and PLR (P = .001) were significantly correlated with overall survival (OS). In multivariate analysis, age (hazard ratio [HR]: 1.564, 95% confidence interval [CI]: 1.087-2.252, P = .016) and TNM stage (HR: 1.704, 95% CI: 1.061-2.735, P = .027) remained independent risk factors affecting DFS, while age (HR: 1.721, 95% CI: 1.153-2.567, P = .008), TNM stage (HR: 2.198, 95% CI: 1.263-3.824, P = .005), and PLR (HR: 1.850, 95% CI: 1.246-2.746, P = .002) were independent risk factors affecting OS.The preoperative PLR is superior to NLR, LMR, and CRP as a biomarker for evaluating the prognosis of patients undergoing curative surgery for NSCLC.


Assuntos
Plaquetas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Inflamação/metabolismo , Neoplasias Pulmonares/patologia , Linfócitos/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Proteína C-Reativa/metabolismo , Carcinoma Pulmonar de Células não Pequenas/sangue , Feminino , Humanos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Neutrófilos/metabolismo , Análise de Sobrevida
4.
Medicine (Baltimore) ; 99(2): e18545, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914029

RESUMO

This study aimed to determine the impact of the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) on the prognosis of nasopharyngeal carcinoma (NPC) before and after intensity modulated radiotherapy (IMRT).Pre/post-treatment and changes in inflammatory biomarker levels of 207 patients who were diagnosed with NPC and received IMRT between January 2012 and December 2014 were analyzed, and the cellular biomarker analyses were from patient blood. ROC (receiver operating characteristic) analysis was used to decide the optimal cutoff values of NLR and changes in NLR (ΔNLR) and PLR (ΔPLR). The Kaplan-Meier and logarithmic rank methods were used to compare overall survival times between groups. Univariate analysis was used to investigate the effects of age, gender, histology, Karnofsky performance score (KPS), TNM stage, clinical stage, course of disease and lymphocyte, neutrophil and platelet counts as well as alkaline phosphatase (ALP) levels on the prognosis of NPC. The independent predictors of OS were determined by Cox multivariate regression analysis.The optimal cut-off values of NLR, PLR, ΔNLR and ΔPLR were 2.49, 155.82, 1.80, and 100.00, respectively. These were used to classify patients into high (NLR > 2.49) and low NLR groups (NLR < 2.49); high (PLR>155.82) and low (PLR < 155.82) PLR groups; high (ΔNLR>1.80) and low ΔNLR groups (ΔNLR < 1.80); high (ΔPLR > 100.00) and low ΔPLR groups (ΔPLR < 100.00). TNM stage, clinical stage and ALP levels were highly correlated with high NLR and PLR. Cox multivariate regression analysis suggested that the ΔNLR (HR = 2.89, 95% CI: 1.33∼2.78) was independent of the characteristics for NPC.As a novel inflammatory index, ΔNLR appears to have some predictive power for the prognosis of patients with NPC.


Assuntos
Linfócitos/efeitos da radiação , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/radioterapia , Neutrófilos/efeitos da radiação , Radioterapia de Intensidade Modulada/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Fosfatase Alcalina/sangue , Contagem de Células Sanguíneas , Plaquetas/patologia , Plaquetas/efeitos da radiação , Feminino , Humanos , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Estadiamento de Neoplasias/métodos , Neutrófilos/patologia , Valor Preditivo dos Testes , Prognóstico , Radioterapia de Intensidade Modulada/métodos , Estudos Retrospectivos
5.
J Exp Med ; 217(4)2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-31985756

RESUMO

In a forward genetic screen of N-ethyl-N-nitrosourea (ENU)-induced mutant mice for aberrant immune function, we identified mice with a syndromic disorder marked by growth retardation, diabetes, premature death, and severe lymphoid and myeloid hypoplasia together with diminished T cell-independent (TI) antibody responses. The causative mutation was in Pdia6, an essential gene encoding protein disulfide isomerase A6 (PDIA6), an oxidoreductase that functions in nascent protein folding in the endoplasmic reticulum. The immune deficiency caused by the Pdia6 mutation was, with the exception of a residual T cell developmental defect, completely rescued in irradiated wild-type recipients of PDIA6-deficient bone marrow cells, both in the absence or presence of competition. The viable hypomorphic allele uncovered in these studies reveals an essential role for PDIA6 in hematopoiesis, but one extrinsic to cells of the hematopoietic lineage. We show evidence that this role is in the proper folding of Wnt3a, BAFF, IL-7, and perhaps other factors produced by the extra-hematopoietic compartment that contribute to the development and lineage commitment of hematopoietic cells.


Assuntos
Linfócitos/imunologia , Células Mieloides/imunologia , Isomerases de Dissulfetos de Proteínas/imunologia , Animais , Fator Ativador de Células B/imunologia , Linhagem Celular , Feminino , Células HEK293 , Hematopoese/imunologia , Humanos , Interleucina-7/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/imunologia , Proteína Wnt3A/imunologia
6.
Anticancer Res ; 40(1): 451-458, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892600

RESUMO

BACKGROUND/AIM: We evaluated the clinical implications of pre- and post-treatment hematological parameters as prognostic factors in patients with locally advanced cervical cancer (LACC) who received definitive concurrent chemoradiotherapy (CCRT). PATIENTS AND METHODS: We retrospectively analyzed 125 patients with LACC (FIGO stage IIB to IIIB) who received definitive CCRT. Clinical factors and hematological parameters, including neutrophil-to-lymphocyte ratio (NLR) were assessed pre- and post-CCRT. Univariate and multivariate analysis for disease-free survival (DFS) and overall survival (OS) were performed using clinicopathological and hematological parameters. RESULTS: Disease recurred in 46 (36.8%) patients, and 24 patients (19.2%) died. On multivariate analysis, post-treatment NLR, ΔNLR (pre-treatment NLR/post-treatment NLR) and ΔPLR (platelet-to-lymphocyte ratio) (pretreatment PLR/post-treatment PLR) were significant prognostic factors for DFS, and only post-treatment NLR was a significant prognostic factor for OS (p<0.001). However, pre-treatment hematological parameters were not associated with prognosis. CONCLUSION: Post-treatment hematological parameters, particularly NLR, may serve as a prognostic indicator in patients with LACC who received definitive CCRT.


Assuntos
Quimiorradioterapia , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/terapia , Intervalo Livre de Doença , Feminino , Humanos , Linfócitos/patologia , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neutrófilos/patologia , Prognóstico , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/patologia
7.
Life Sci ; 240: 117071, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31783051

RESUMO

AIMS: AML (Acute myeloid leukemia) is characterized as a heterogeneous cancer. Chemokines play fundamental roles in the onset, progression cellular, migration, survival and improvement of AML therapy outcomes. The CCR5 receptors together with their ligands have indirect effects on the progression of cancer. In the present study, we have decided to investigate the impact of chemotherapy on the expression of CCR5 and its related ligands (CCL5, CCL4 and CCL3). MAIN METHODS: In this study, peripheral blood and bone marrow specimens were collected prior and post the first stage of (7 + 3) chemotherapy from 25 AML-M4/M5 patients. The expression of CCR by Lymphocytes in peripheral blood was examined by flow cytometry and QRT-PCR. The serum levels of chemokines were measured by ELISA. KEY FINDINGS: There was not observed leukemic blast cells in peripheral blood smear at post first stage of chemotherapy. We found that the expression of CCR5 was attenuated in patients post the first stage of chemotherapy and the healthy control subjects. We have also observed that the serum levels of chemokines were elevated in AML patients prior to chemotherapy. Although in post-chemotherapy stage, only CCL3 was found to reach to the baseline level, CCL5 and CCL4 have not returned to the basal level and were significantly higher than healthy control subjects. SIGNIFICANCE: The current chemotherapy protocol was not able to completely inhibit CCL5 and CCL4. In conclusion, our findings in harmony with previous studies suggest that inhibition of chemokines along with chemotherapy in AML patients may aid therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimiocina CCL3/efeitos dos fármacos , Quimiocina CCL4/efeitos dos fármacos , Quimiocina CCL5/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Monócitos/patologia , Receptores CCR5/efeitos dos fármacos , Adulto , Medula Óssea/metabolismo , Medula Óssea/patologia , Linhagem da Célula , Quimiocina CCL3/biossíntese , Quimiocina CCL4/biossíntese , Quimiocina CCL5/biossíntese , Quimiocinas/sangue , Progressão da Doença , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Contagem de Leucócitos , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Receptores CCR5/biossíntese
8.
Scand J Immunol ; 91(1): e12839, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31630416

RESUMO

The humanized IgG1κ monoclonal antibody siplizumab and its rat parent monoclonal IgG2b antibody BTI-322 are directed against the CD2 antigen. Siplizumab is species-specific, reacting with human and chimpanzee cells but not with cells from any other species, including other non-human primates. Because siplizumab treatment has recently shown great potential in clinical transplantation, we now present the results of our previous pharmacokinetic, pharmacodynamic and safety studies of both antibodies. Fourteen chimpanzees received 1-3 doses of 0.143 to 5.0 mg/kg iv The effects were followed with flow cytometry on peripheral lymphocytes and staining of lymph nodes. Side effects were recorded. Serum antibody concentrations were followed. Across the doses, a rapid, transient depletion of CD2, CD3, CD4 and CD8 lymphocytes and NK cells was observed for both antibodies. Immune reconstitution was more rapid for BTI-322 compared to siplizumab. Paracortical lymph node T cell depletion was moderate, estimated at 45% with doses of >0.6 mg/kg. Restoration of lymph node architecture was seen after two weeks to two months for all animals. All four subjects receiving BTI-322 experienced AEs on the first dosing day, while the eight subjects dosed with siplizumab experienced few mild, transient AEs. Infusion with siplizumab and BTI-322 resulted in rapid depletion of CD2+ cells in circulation and tissue. Siplizumab had a longer t1/2 and fewer AEs compared to BTI-322.


Assuntos
Anticorpos Monoclonais/farmacocinética , Antígenos CD2/antagonistas & inibidores , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores , Biópsia , Citocinas/sangue , Feminino , Imunoglobulina G/administração & dosagem , Imunoglobulina G/farmacologia , Imunofenotipagem , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Depleção Linfocítica , Linfócitos/imunologia , Linfócitos/metabolismo , Masculino , Pan troglodytes , Ratos
9.
J Surg Res ; 246: 535-543, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31711613

RESUMO

BACKGROUND: A growing body of evidences shows that systemic inflammatory responses are involved in patient prognosis in multiple cancers. Combinations of peripheral leukocyte fractions have been shown to be useful markers for the inflammatory responses. However, significance of such systemic inflammatory responses is still unknown in thyroid cancer. Accordingly, we aimed to clarify clinical impact of peripheral leukocyte fractions in papillary thyroid cancer (PTC). METHODS: Clinicopathological analyses were performed including preoperative leukocyte fractions in 570 patients with curatively resected PTC. Receiver operating characteristic curves were used to determine cutoffs of leukocyte fraction or inflammation indexes such as lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio. A Kaplan-Meier analysis and a Cox's proportional hazard model were used to conduct prognostic analysis. A multivariable logistic regression analysis was performed for correlation assay. RESULTS: Preoperative low LMR predicted recurrence with high sensitivity (63.3%) and specificity (68.7%) (P = 0.002). The multivariable prognostic analyses revealed that preoperative low LMR (P = 0.025), pathological N1b (P = 0.019), high metastatic lymph node ratio (node density) (P = 0.014), and high thyroglobulin level (P = 0.002) independently predicted worse prognosis. The combination of these independent parameters clearly enriched high-risk patients (P < 0.001). Of note, low LMR was dramatically associated with recurrence especially in patients with advanced PTC. CONCLUSIONS: Preoperative low LMR dramatically predicts high-risk patients for recurrences. The results in this study give rational to focusing on immune cell profiles to tackle advanced PTC.


Assuntos
Linfócitos , Monócitos , Recidiva Local de Neoplasia/diagnóstico , Câncer Papilífero da Tireoide/sangue , Neoplasias da Glândula Tireoide/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/prevenção & controle , Período Pré-Operatório , Prognóstico , Curva ROC , Estudos Retrospectivos , Câncer Papilífero da Tireoide/mortalidade , Câncer Papilífero da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Adulto Jovem
10.
HNO ; 68(1): 8-13, 2020 Jan.
Artigo em Alemão | MEDLINE | ID: mdl-31511908

RESUMO

BACKGROUND: While an abundant number of studies concerning tobacco smoke and chewing tobacco show carcinogenic potential, there is little data on the consequences of snuff, especially on the cellular level. Therefore, the mutagenic effect of snuff is difficult to estimate and the WHO assessment of snuff being not carcinogenic is based on very limited data. OBJECTIVES: This paper investigates the potential cytotoxic and genotoxic effects of snuff on human lymphocytes and nasal mucosa cells. MATERIALS AND METHODS: Two types of snuff were used: one without menthol and one with a high degree of menthol. The necessary nasal mucosa cells and lymphocytes were collected from 10 subjects undergoing nasal obstruction surgery and incubated for one hour with a snuff-DMSO mixture (range 0.01-2000 µg/ml). Methods included the trypan blue test, the comet assay, and the micronucleus test. RESULTS: The trypan blue test showed no decrease in cell viability for either cell type. The comet assay revealed a significant increase in the Olive Tail Moment for lymphocytes starting at 100 µg/ml and at 1000 µg/ml for nasal mucosa cells. There was no significant increase in micronuclei according to the micronucleus test. No differences between these two types of tobacco were observed. CONCLUSION: The present study demonstrated genotoxic damage, such as DNA strand breaks, which may be repaired, but no non-repairable elevated micronuclei. The present findings cast doubts on the WHO assessment that snuff is not carcinogenic. However, for a sound assessment of the risk potential of snuff, further research on various genotoxic endpoints in human cells is warranted.


Assuntos
Linfócitos , Mucosa Nasal , Tabaco sem Fumaça , Ensaio Cometa , Dano ao DNA , Humanos , Linfócitos/efeitos dos fármacos , Mucosa Nasal/efeitos dos fármacos , Tabaco sem Fumaça/efeitos adversos
12.
Int J Radiat Biol ; 96(1): 57-66, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30507310

RESUMO

PURPOSE: We introduce and evaluate a high throughput biodosimetry test system (REDI-Dx) suitable for testing of thousands of potential radiation victims following a mass scale nuclear event caused by detonation of a nuclear device or a nuclear accident, as part of an overall strategy for effective medical management of the crisis. MATERIALS AND METHODS: The performance of a high throughput biodosimetry test was evaluated by collecting samples of both non-irradiated presumed healthy donors as well as irradiated subjects collected as part of either cancer treatment regimens or banked from previous studies. The test measures the gene expression of a set of radiation responsive genes based on the DxDirect® genomic platform. The potential diagnostic accuracy of REDI-Dx was evaluated as a predictor of actual dose of radiation. While the REDI-Dx test has been calibrated to provide a quantitative measure of actual absorbed dose, we compared the performance of the REDI-Dx test (sensitivity and specificity) as a qualitative result at the most commonly applied thresholds 2.0 Gy and 6.0 Gy. RESULTS: The test demonstrated high specificity and lack of effect of medical conditions. Using receiver operating characteristic (ROC) curve analysis, REDI-Dx was shown to be a good predictor of actual dose for determining treatment category based on either 2.0 or 6.0 Gy, with a 98.5% sensitivity and 90% specificity for 2.0 Gy, and 92% sensitivity and 84% specificity for 6.0 Gy. Results were reproducible between clinical laboratories with an SD of 0.2 Gy for samples ≤2.0 Gy and a CV of 10.3% for samples from 2.0 to 10.0 Gy. CONCLUSIONS: Use of a biodosimetry test, like REDI-Dx test system would provide valuable information that would improve the ability to assign patients to the correct treatment category when combined with currently available biodosimetry tools, as compared to the use of existing tools alone. The REDI-Dx biodosimetry test system is for investigational use only in the U.S.A. The performance characteristics of this product have not been established.


Assuntos
Seleção de Pacientes , Lesões por Radiação/terapia , Liberação Nociva de Radioativos , Relação Dose-Resposta à Radiação , Humanos , Linfócitos/efeitos da radiação , Lesões por Radiação/complicações , Lesões por Radiação/etiologia , Radiometria , Vômito/complicações
13.
Biochem Med (Zagreb) ; 30(1): 010701, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31839721

RESUMO

Introduction: Chronic obstructive pulmonary disease (COPD) is a complex inflammatory condition that can affect haemostasis. This study aimed to determine differences in platelet-related parameters between controls and COPD subjects. The hypothesis was that platelet indices are disturbed in COPD patients, and this would be accompanied by increased C-reactive protein (CRP), fibrinogen (Fbg) and white blood cells (WBC). Therefore, platelet count (Plt), platelet-related parameters - mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (Pct), their ratios (MPV/Plt, MPV/Pct, PDW/Plt, PDW/Pct), platelet to lymphocyte ratio (PLR), Plt index as well as CRP, Fbg and WBC were assessed. Materials and methods: Study included 109 patients with stable COPD and 95 control subjects, recruited at Clinical Department for Lung Diseases Jordanovac, University Hospital Centre Zagreb (Zagreb, Croatia). Complete blood count was performed on Sysmex XN-1000, CRP on Cobas c501, and Fbg on BCS XP analyser. Data were analysed with MedCalc statistical software. Results: Platelet (P = 0.007) and PLR (P = 0.006) were increased, while other platelet indices were decreased in COPD patients compared to controls. Combined model that included PLR, PDW and WBC showed great diagnostic performances, and correctly classified 75% of cases with an AUC of 0.845 (0.788 - 0.892), P < 0.001. Comorbidities (cardiovascular or metabolic diseases) had no effect on investigated parameters, while inhaled corticosteroids/long-acting ß2-agonists (ICS/LABA) therapy increased MPV and PDW values in COPD patients. Conclusion: Platelet indices were altered in COPD patients and they could be valuable as diagnostic markers of COPD development, especially if combined with already known inflammatory markers.


Assuntos
Biomarcadores/sangue , Plaquetas/citologia , Doença Pulmonar Obstrutiva Crônica/patologia , Corticosteroides/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Plaquetas/metabolismo , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/patologia , Estudos de Casos e Controles , Feminino , Volume Expiratório Forçado , Humanos , Leucócitos/citologia , Modelos Logísticos , Linfócitos/citologia , Masculino , Doenças Metabólicas/complicações , Doenças Metabólicas/patologia , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico
14.
Chemosphere ; 239: 124810, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31520980

RESUMO

Perfluorooctanoic acid (PFOA) is a dispersive persistent organic pollutant in the environment. Accumulating reports suggest that PFOA is toxic to human lymphocytes; however, the toxicological effects of PFOA on these cells remain largely unclear. In this study, ultra-performance liquid chromatography (UPLC)-based metabolomic analysis was employed to identify metabolites in human peripheral blood lymphocytes and to assess the metabolic alterations caused by PFOA exposure. Our comparative metabolomic analysis results demonstrated that PFOA treatment could increase the level of organic acids and reduce the level of lipid molecules. Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation further highlighted the fact that the PFOA treatment interfered with the metabolism of amino acids, carbohydrates and lipids, which may lead to disruption of the immune system.


Assuntos
Caprilatos/farmacologia , Fluorcarbonetos/farmacologia , Linfócitos/efeitos dos fármacos , Metabolômica/métodos , Aminoácidos/efeitos dos fármacos , Células Sanguíneas , Caprilatos/toxicidade , Metabolismo dos Carboidratos/efeitos dos fármacos , Células Cultivadas , Cromatografia Líquida de Alta Pressão/métodos , Poluentes Ambientais/farmacologia , Poluentes Ambientais/toxicidade , Fluorcarbonetos/toxicidade , Humanos , Metabolismo dos Lipídeos , Lipídeos/deficiência , Linfócitos/metabolismo
15.
J Enzyme Inhib Med Chem ; 35(1): 96-108, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31690133

RESUMO

A series of analogues of Amb639752, a novel diacylglycerol kinase (DGK) inhibitor recently discovered by us via virtual screening, have been tested. The compounds were evaluated as DGK inhibitors on α, θ, and ζ isoforms, and as antagonists on serotonin receptors. From these assays emerged two novel compounds, namely 11 and 20, which with an IC50 respectively of 1.6 and 1.8 µM are the most potent inhibitors of DGKα discovered to date. Both compounds demonstrated the ability to restore apoptosis in a cellular model of X-linked lymphoproliferative disease as well as the capacity to reduce the migration of cancer cells, suggesting their potential utility in preventing metastasis. Finally, relying on experimental biological data, molecular modelling studies allow us to set a three-point pharmacophore model for DGK inhibitors.


Assuntos
Indóis/farmacologia , Lipase Lipoproteica/antagonistas & inibidores , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Indóis/síntese química , Indóis/química , Lipase Lipoproteica/metabolismo , Linfócitos/efeitos dos fármacos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Monócitos/efeitos dos fármacos , Piperazinas/síntese química , Piperazinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos
16.
Immunology ; 159(1): 39-51, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31777064

RESUMO

Immunity is shaped by commensal microbiota. From early life onwards, microbes colonize mucosal surfaces of the body and thereby trigger the establishment of immune homeostasis and defense mechanisms. Recent evidence reveals that the family of innate lymphoid cells (ILCs), which are mainly located in mucosal tissues, are essential in the maintenance of barrier functions as well as in the initiation of an appropriate immune response upon pathogenic infection. In this review, we summarize recent insights on the functional interaction of microbiota and ILCs at steady-state and throughout life. Furthermore, we will discuss the interplay of ILCs and the microbiota in mucosal infections focusing on intestinal immunity.


Assuntos
Bactérias/imunologia , Microbioma Gastrointestinal/imunologia , Imunidade Inata , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Linfócitos/imunologia , Linfócitos/microbiologia , Fatores Etários , Envelhecimento/imunologia , Animais , Bactérias/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Mucosa Intestinal/metabolismo , Linfócitos/metabolismo , Neoplasias/imunologia , Neoplasias/microbiologia , Transdução de Sinais
17.
Pol J Pathol ; 70(3): 155-161, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31820858

RESUMO

Organic basis of gastrointestinal symptoms is in the scope of many specialists. In this article lymphocytic gastritis, relatively newly described and not widely-known entity is presented. The lesion is characterized by presence of numerous mature lymphocytes in the surface and foveolar epithelium, as well as lymphocytic infiltration of the lamina propria. According to the definition at least 25 lymphocytes per 100 gastric epithelial cells is now required for the diagnosis. Literature found in wide range of databases was searched for morphological features of lymphocytic gastritis and its relationship with others coexisting or predisposing conditions or lesions. A strong positive correlation between celiac disease and Helicobacter pylori infection, and occurrence and severity of lymphocytic gastritis was revealed. A relationship was also found between lymphocytic gastritis and gastric lymphomas and other conditions.


Assuntos
Doença Celíaca/complicações , Gastrite/patologia , Infecções por Helicobacter/complicações , Linfócitos , Mucosa Gástrica/patologia , Humanos
18.
Pol Merkur Lekarski ; 47(281): 177-182, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31812971

RESUMO

The pathogenesis of both chronic obstructive pulmonary disease (COPD) and arterial hypertension (AH) is closely related to oxidative stress, which is characterized by an imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense. AIM: The aim of the study was to assess the status of glutathione-based antioxidant protection system in lymphocytes of blood in patients with associated COPD and AH. MATERIALS AND METHODS: Lymphocytes were isolated from peripheral blood using A. Boyum technique. The quantification assay for reduced glutathione (GSH) level, glutathione reductase (GR), glutathione peroxidase (GP) and glutathione S transferase activities were assessed with spectrophotometry method. RESULTS: The study population included 73 patients admitted to the Ternopil University Hospital. The subjects were distributed across three groups: group 1 (25 patients with COPD), group 2 (28 patients with COPD and AH) and the group 3 (control group of 20 healthy subjects). The analysis of parameters of lymphocytic glutathione system has not revealed any significant changes in GSH in patients with COPD only and a significant (20.5%) decrease in reduced glutathione in a COPD + AH combination. The group of patients with COPD was found to have decreased GP and GST activities, as well as increased GR activities. Patients with concomitant COPD and AH had uniform changes in the enzymes of the glutathione system. These changes were seen as significant decreases in GP activity (by 31.6%), GST activity (by 28.4%) and GR activity (by 18.8%). In patients with COPD+AH, positive correlations were found between GSH and GR/GST. In this respect, GST activity was directly correlated with GR activity and inversely correlated with GP activity. CONCLUSIONS: Overall, the results of our research suggest the glutathione-based antioxidant protection system to change differently in patients with COPD (GR activity increases, GP and GST activities decreases, GSH level does not change) and in patients with COPD+AH (GSH level and activities of glutathione-based antioxidant enzymes [GR, GP and GST] decreases). The changes found in the glutathione redox system suggest an important contribution of arterial hypertension to adverse course of COPD.


Assuntos
Hipertensão , Doença Pulmonar Obstrutiva Crônica , Antioxidantes , Glutationa , Glutationa Peroxidase , Humanos , Linfócitos , Estresse Oxidativo
19.
Urologiia ; (5): 60-63, 2019 Dec.
Artigo em Russo | MEDLINE | ID: mdl-31808634

RESUMO

INTRODUCTION: According to the epidemiological studies, prevalence of urolithiasis is nearly 10% worldwide. The course of the disease is often complicated by the development of pyelonephritis, the pathogenesis of which is rather multifactorial. Along with urinary tract obstruction, increasing virulence of microorganisms and immune insufficiency in patients also plays a major role. AIM: To define specific features of immune insufficiency in patients who develop pyelonephritis as a complication of urolithiasis. MATERIALS AND METHODS: A total of 150 patients with urolithiasis complicated by pyelonephritis were prospectively enrolled into our study in order to develop a novel method. All patients were divided into two clinical groups. Group I consisted of 75 patients with urolithiasis complicated by serous pyelonephritis and Group II included 75 patients with urolithiasis complicated by purulent pyelonephritis. In all patients an evaluation of the immune status with a determination of CD3, CD4, CD8, CD16, CD19 level and phagocyte activity of immune system was carried out. The state of lymphocytes plasmatic membrane was evaluated by phase contrast microscopy. RESULTS: It is established that development of pyelonephritis in patients with urolithiasis is accompanied by a lymphopenia, the decrease in relative contents T-helpers, natural killers, as well as a decrease in the immuno-regulatory index and an increase in indicators of terminal and total lymphocytes blebbing. The most pronounced changes were noted in purulent pyelonephritis, where suppressed immune status was confirmed by the high level of lymphocyte with terminal blebbing state.


Assuntos
Pielonefrite/complicações , Urolitíase/imunologia , Membrana Celular , Humanos , Linfócitos , Pielonefrite/sangue , Pielonefrite/tratamento farmacológico , Pielonefrite/etiologia , Urolitíase/sangue , Urolitíase/complicações , Urolitíase/tratamento farmacológico
20.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(6): 1831-1837, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-31839046

RESUMO

OBJECTIVE: To investigate the expression and clinical significance of chemokine receptor CXCR3 in mantle cell lymphoma (MCL). METHODS: Flow cytometry was used to detect CXCR3 in lymph nodes and extranodal tissues in 25 newly diagnosed MCL patients. The correlation of the expression of CXCR3 level with clinical features and prognostic factors was analyzed. RESULTS: Twenty-five tumor submitted specimens all expressed CXCR3 at varied degrees. The expression levels of CXCR3 in lymph nodes (LN) and bone marrow (BM) were higher than those in peripheral blood (PB), and the expression intensity in BM positively correlated with the involved tumor numbers. The absolute values of lymphocytes and hemoglobins level in PB of CXCR3high group were significantly lower than those in CXCR3low group (all P<005). The CXCR3 expression in tumor cells significantly correlated with LDH level, ß2-MG level, Ki-67 index, MIPI score and the BM involvement (all P<0.05). But, there was no correlation between the CXCR3 expression and clinical stage, histomorphology (all P>0.05). The overall response rate (ORR) in CXCR3low group was significantly higher than that in CXCR3high group (P=0.001). The expression level of CXCR3 in MCL cells of the effective group was significantly lower than that before treatment (P=0.038), and the CXCR3 expression in the ineffective group was significantly higher than that before treatment (P=0.002). After following up, it was found that the 3-year overall survival (OS) time and progression-free survival (PFS) time in CXCR3high group were significantly shorter than those in CXCR3low group (all P<0.05). CONCLUSION: The expression level of CXCR3 in MCL closely relates with early metastasis and prognosis. CXCR3 can be used as one of the indicators for clinical efficacy and prognosis evaluation.


Assuntos
Linfoma de Célula do Manto , Receptores CXCR3/metabolismo , Medula Óssea , Humanos , Linfócitos , Prognóstico , Resultado do Tratamento
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