RESUMO
PURPOSE: Cytokines are vital pro-inflammatory factors and involved in tumor immune infiltration, and immune infiltration is closely related to PD-1/PD-L1 blockades immunotherapy. This study aims to explore the associations between cytokines and prognosis and also PD-1/PD-L1 expression in early lung adenocarcinoma, which is seldom reported. METHODS: 324 early lung adenocarcinoma patients with prior surgical resection were included and the associations between overall survival time and clinical factors and also cytokines including IL-1ß, IL-6 and TNF-α were analyzed by multivariate cox regression and Kaplan-Meier curve (log-rank test). Resected tumor samples were randomly obtained to detect the PD-1/PD-L1 expression by immunohistochemistry, and Chi square test was used for relations between cytokines and PD-1/PD-L1 expression. RESULTS: In this study group, 26.2% patients showed a high level of IL-1ß and patients with high IL-1ß level showed 19 months shortened mOS than those with normal IL-1 ß expression (mOS: 24.00, 95%CI 11.98-36.02 vs 43.00, 95% CI 37.37-48.63, p = 0.017). Among detected samples, the positive rate of PD-1 was 25.0% (13/52), and the positive rate of PD-L1 was 37.3% (19/52). The positive rate of PD-1 was 36.1% higher in high-IL-1 ß-level group as compared to normal-IL-1ß-level group (50.0% vs 13.9%, p = 0.012). No significant association was found between IL-1 ß and PD-L1 expression. CONCLUSION: High expression level of IL-1ß was correlated with poor prognosis and higher positive rate of PD-1 expression, which gave us insights into biomarkers of survival prediction and immunotherapy in lung adenocarcinoma. Further studies were still needed.
Assuntos
Adenocarcinoma de Pulmão/metabolismo , Antígeno B7-H1/metabolismo , Interleucina-1beta/metabolismo , Neoplasias Pulmonares/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Distribuição de Qui-Quadrado , Feminino , Humanos , Interleucina-6/metabolismo , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Prognóstico , Análise de Regressão , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVE: Using RGD10-NGR9 dual-targeting superparamagnetic iron oxide nanoparticles to evaluate their potential value in tumor angiogenesis magnetic resonance imaging (MRI) and the biodistribution in vitro and in vivo. MATERIALS AND METHODS: Dual-targeting RGD10-NGR9 ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles were designed and synthesized in our previous study. In vitro, prussian blue staining and phenanthroline colorimetry were conducted to evaluate binding affinity and adsorption of dual-targeting USPIO nanoparticles to αvß3-integrin/APN positive cells. In vivo, a xenograft mouse tumor model was used to evaluate the potential of the dual-targeting nanoparticles as an MRI contrast agent. After intravenous injection, the contrast-to-noise ratio (CNR) values of MR images obtained were calculated at predetermined time-points. The iron level was detected to access the biodistribution and plasma half-time. RESULTS: In vitro, dual-targeting USPIO nanoparticles bound to proliferating human umbilical vein endothelia cells with high specificity. In vivo, contrast MRI of xenograft mice using dual-targeting nanoparticles demonstrated a significant decrease in signal intensity and a greater increase in CNR than standard MRI and facilitated the imaging of tumor angiogenesis in T2*WI. In terms of biodistribution, dual-targeting USPIO nanoparticles increased to 1.83 times in tumor lesions as compared to the control. And the plasma half-time was about 6.2 h. CONCLUSION: A novel RGD10-NGR9 dual-targeting USPIO has a great potential value as a contrast agent for the identification of tumor angiogenesis on MRI, according to the high specific affinity in vitro and in vivo.
Assuntos
Meios de Contraste/farmacocinética , Dextranos/farmacocinética , Imageamento por Ressonância Magnética/métodos , Neoplasias Experimentais/diagnóstico por imagem , Neovascularização Patológica/diagnóstico por imagem , Células A549 , Animais , Dextranos/química , Xenoenxertos , Humanos , Nanopartículas de Magnetita/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Peptídeos , Distribuição TecidualRESUMO
PURPOSE: To investigate the role of miR-585 in the development and progression of non-small-cell lung cancer (NSCLC). METHODS: The expression levels of miR-585 in NSCLC cell lines and clinical samples were measured by quantitative PCR. NSCLC cells, A549 and H1299, were stably transfected with lentiviral vectors of miR-585 mimics or negative control. The effects of miR-585 on cell proliferation were detected both in vitro and in vivo. Cell migration and invasion were evaluated using wound healing assay and Transwell assay. Furthermore, luciferase reporter assay was used to identify the direct regulation of hSMG-1 by miR-585. RESULTS: Our results showed that miR-585 was downregulated in NSCLC cell lines and tumor tissues. Ectopic expression of miR-585 inhibited the ability of cell proliferation, migration, and invasion in vitro. In addition, miR-585 also decreased the growth rate of xenografted tumor in nude mice. Mechanically, miR-585 directly targeted the 3'-untranslated region (UTR) of hSMG-1 gene, which likely resulted in a dysfunction of mRNA surveillance and nonsense-mediated mRNA decay. CONCLUSION: Taken together, miR-585 probably has an inhibitory effect on tumor growth and is a prognostic biomarker of NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Pulmonares/patologia , Metaloendopeptidases/biossíntese , MicroRNAs/genética , Animais , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/genética , Movimento Celular/genética , Proliferação de Células/genética , Genes Supressores de Tumor , Xenoenxertos , Humanos , Neoplasias Pulmonares/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Reação em Cadeia da PolimeraseRESUMO
The differentiation deficiencies of osteoclast precursors (pre-OCs) may contribute to osteoporosis. Research on osteoporosis has recently focused on microRNAs (miRNAs) that play crucial roles in pre-OC differentiation. In the current study, we aimed to analyze the expression and function of the glucocorticoid (GC)-associated miRNA-338-3p (miR-338-3p) in osteoclast formation. We found that dexamethasone induced osteoclast differentiation and inhibited miR-338-3p expression. Overexpression of an miR-338-3p mimic in osteoclast precursor cells attenuated GC-induced osteoclast formation and bone resorption, whereas inhibition of miR-338-3p reversed these effects. The expression of the nuclear factor κB ligand RANKL, a potential target gene of miR-338-3p, was inversely correlated with miR-338-3p expression in pre-OCs. Furthermore, we demonstrated that RANKL was directly regulated by miR-338-3p and re-introduction of RANKL reversed the inhibitory effects of miR-338-3p on osteoclast formation and bone resorption. Taken together, these findings demonstrate that miR-338-3p may play a significant role in GC-induced osteoclast differentiation and function by targeting RANKL in osteoclasts.
Assuntos
Reabsorção Óssea/genética , Dexametasona/farmacologia , Glucocorticoides/farmacologia , MicroRNAs/genética , Osteoclastos/efeitos dos fármacos , Ligante RANK/genética , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Bovinos , Diferenciação Celular/efeitos dos fármacos , Técnicas de Cocultura , Feminino , Fêmur/efeitos dos fármacos , Fêmur/metabolismo , Fêmur/patologia , Regulação da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Modelos Biológicos , Oligorribonucleotídeos Antissenso/genética , Oligorribonucleotídeos Antissenso/metabolismo , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteoclastos/patologia , Cultura Primária de Células , Ligante RANK/metabolismo , Transdução de SinaisRESUMO
Milk fat globule epidermal growth factor 8 (MFG-E8) is an opsonin involved in the phagocytosis of apoptotic cells. In patients with chronic obstructive pulmonary disease (COPD), apoptotic cell clearance is defective. However, whether aberrant MFG-E8 expression is involved in this defect is unknown. In this study, we examined the expression of MFG-E8 in COPD patients. MFG-E8, interleukin (IL)-1β and transforming growth factor (TGF)-β levels were measured in the plasma of 96 COPD patients (93 males, 3 females; age range: 62.12±10.39) and 87 age-matched healthy controls (85 males, 2 females; age range: 64.81±10.11 years) using an enzyme-linked immunosorbent assay. Compared with controls, COPD patients had a significantly lower plasma MFG-E8 levels (P<0.01) and significantly higher plasma TGF-β levels (P=0.002), whereas there was no difference in plasma IL-1β levels between the two groups. Moreover, plasma MFG-E8 levels decreased progressively between Global Initiative for Chronic Obstructive Lung Disease (GOLD) I and GOLD IV stage COPD. Multiple regression analysis showed that the forced expiratory volume in 1 s (FEV1 % predicted) and smoking habit were powerful predictors of MFG-E8 in COPD (P<0.01 and P=0.026, respectively). MFG-E8 was positively associated with the FEV1 % predicted and negatively associated with smoking habit. The area under the receiver operating characteristic curve was 0.874 (95% confidence interval: 0.798-0.95; P<0.01). Our findings demonstrated the utility of MFG-E8 as a marker of disease severity in COPD and that cigarette smoke impaired MFG-E8 expression in these patients.
Assuntos
Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antígenos de Superfície/sangue , Apoptose/fisiologia , Proteínas do Leite/sangue , Doença Pulmonar Obstrutiva Crônica/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Volume Expiratório Forçado , Interleucina-1beta/sangue , Valor Preditivo dos Testes , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Análise de Regressão , Curva ROC , Índice de Gravidade de Doença , Fumar/sangue , Fator de Crescimento Transformador beta/sangueRESUMO
Milk fat globule epidermal growth factor 8 (MFG-E8) is an opsonin involved in the phagocytosis of apoptotic cells. In patients with chronic obstructive pulmonary disease (COPD), apoptotic cell clearance is defective. However, whether aberrant MFG-E8 expression is involved in this defect is unknown. In this study, we examined the expression of MFG-E8 in COPD patients. MFG-E8, interleukin (IL)-1ß and transforming growth factor (TGF)-ß levels were measured in the plasma of 96 COPD patients (93 males, 3 females; age range: 62.12±10.39) and 87 age-matched healthy controls (85 males, 2 females; age range: 64.81±10.11 years) using an enzyme-linked immunosorbent assay. Compared with controls, COPD patients had a significantly lower plasma MFG-E8 levels (P<0.01) and significantly higher plasma TGF-ß levels (P=0.002), whereas there was no difference in plasma IL-1ß levels between the two groups. Moreover, plasma MFG-E8 levels decreased progressively between Global Initiative for Chronic Obstructive Lung Disease (GOLD) I and GOLD IV stage COPD. Multiple regression analysis showed that the forced expiratory volume in 1 s (FEV1 % predicted) and smoking habit were powerful predictors of MFG-E8 in COPD (P<0.01 and P=0.026, respectively). MFG-E8 was positively associated with the FEV1 % predicted and negatively associated with smoking habit. The area under the receiver operating characteristic curve was 0.874 (95% confidence interval: 0.798-0.95; P<0.01). Our findings demonstrated the utility of MFG-E8 as a marker of disease severity in COPD and that cigarette smoke impaired MFG-E8 expression in these patients.
Assuntos
Antígenos de Superfície/sangue , Apoptose/fisiologia , Proteínas do Leite/sangue , Doença Pulmonar Obstrutiva Crônica/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Fatores de Confusão Epidemiológicos , Ensaio de Imunoadsorção Enzimática , Feminino , Volume Expiratório Forçado , Humanos , Interleucina-1beta/sangue , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Curva ROC , Análise de Regressão , Índice de Gravidade de Doença , Fumar/sangue , Fator de Crescimento Transformador beta/sangueRESUMO
Stroke is a non-communicable disease of increasing socioeconomic importance in aging populations. This study compared the risk factors implicated in two subtypes of ischemic stroke: lacunar stroke (LS) and non-lacunar stroke (NLS). A retrospective case control study was conducted on a total of 368 patients [220 cases (59.8%) of NLS and 148 cases (40.2%) of LS] with first-time onset of ischemic stroke. Multivariate logistic regression was performed to compare multiple non-cerebrovascular risk factors between the two groups. More patients with a history of diabetes were found in the NLS than the LS group (40.5 vs 26.4%), and that both fasting glucose and HbA1C levels before the onset of stroke were higher in NLS than LS patients. Multivariate analysis revealed that patients with a history of diabetes were 1.57 times more likely to have NLS than LS (OR = 1.57, 95%CI = 0.95-3.26). Moreover, male patients were more likely to develop NLS than females (OR = 1.46, 95%CI = 0.79-2.69), and patients with elevated fibrinogen levels were 1.4 times more likely to develop NLS than LS (OR = 1.40, 95%CI = 1.09-1.80). Additionally, patients who were heavy drinkers (OR = 1.39, 95%CI = 0.68-2.84) or smokers (OR = 1.62, 95%CI = 0.91-2.89) were more likely to develop NLS than LS. Other risk factors, such as hypertension, dyslipidemia, age, and average blood pressure, did not differ between the two types of stroke. Thus, distinct non-cerebrovascular risk factors (male gender, long history of diabetes, elevated fibrinogen, heavy smoking, and heavy drinking) are associated with a higher risk of developing non-lacunar stroke than lacunar stroke.
Assuntos
Isquemia Encefálica/complicações , Acidente Vascular Cerebral Lacunar/etiologia , Acidente Vascular Cerebral/etiologia , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Glicemia/metabolismo , Estudos de Casos e Controles , Complicações do Diabetes/sangue , Complicações do Diabetes/etiologia , Dislipidemias/complicações , Jejum/sangue , Feminino , Fibrinogênio/metabolismo , Hemoglobinas Glicadas/metabolismo , Humanos , Hipertensão/complicações , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Fumar/efeitos adversos , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral Lacunar/sangueRESUMO
This study aims to investigate the association of peroxisome proliferator-activated receptor (PPAR) delta -87T/C polymorphism with several sugar metabolism indices and tumor necrosis factor α (TNF α) level. The body mass index (BMI), waist size, and levels of fasting plasma glucose, serum lipid, fasting insulin, TNFα, and PPAR delta -87T/C of 286 patients with type 2 diabetes mellitus (T2DM) and 158 subjects with normal fasting glucose (NFG) were measured in a Dalian population. The distribution of genotypic frequencies between T2DM and NFG were not significantly different (χ(2) = 0.012, P = 0.994). BMI, fasting blood glucose (FBG), homeostasis model assessment-estimated insulin resistance (HOMA-IR), triglyceride, and TNFα levels were significantly different among different T2DM genotypes. HOMA-IR and FBG were significantly different among different NFG genotypes. The PPAR delta -87T/C polymorphism is known to be closely related with glucose levels and lipid metabolism. A close relationship was also found between HOMA-IR and TNFα levels and HOMA-IR and FBG in T2DM and NFG, respectively.
Assuntos
Diabetes Mellitus Tipo 2/genética , Obesidade/genética , PPAR delta/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Fator de Necrose Tumoral alfa/genética , Idoso , Alelos , Glicemia/metabolismo , Índice de Massa Corporal , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Jejum , Feminino , Frequência do Gene , Genótipo , Humanos , Insulina/sangue , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Obesidade/patologia , PPAR delta/metabolismo , Triglicerídeos/sangue , Fator de Necrose Tumoral alfa/metabolismoRESUMO
INTRODUCTION: Neovasculature imaging is a promising approach for tumor diagnosis. We constructed tumor neovasculature targeted paramagnetic nanoliposomes with RGD10, F56, and K237 peptides, which can bind to Integrin αvß3 and VEGFR-1, VEGFR-2, respectively, and compared their potential value as MRI contrast agents for detecting small tumors in animal models. MATERIALS AND METHODS: Peptide-Ahx-palmitic acid conjugate was synthesized using Fmoc solid-phase synthesis chemistry. Targeted paramagnetic nanoliposomes were prepared by the thin film dispersion-sonication method. The tumor signal enhancements of liposome particles were evaluated by MRI in a xenograft mice model. RESULTS: The apparent affinity constants of RGD10, K237, and F56 peptides binding to their cell receptors were 9.15 × 10(7), 6.01 × 10(7), and 3.85 × 10(7) mol/L, respectively. RGD10 and K237 targeted paramagnetic nanoliposomes have shown much greater tumor-specific MRI signal enhancement in xenograft of the nude mice compared to F56 targeted paramagnetic nanoliposome. Tumor signal enhancement rate (SER %) increased 2.21 ± 0.09 and 1.82 ± 0.05 fold, respectively, for RGD10 and K237 compared to non-targeted control in T1 weighted MR image. CONCLUSION: RGD10 and K237 targeted paramagnetic nanoliposomes can be developed as potential tumor-specific MRI contrast agents and are helpful for tumor detection.
Assuntos
Diagnóstico por Imagem/métodos , Lipossomos , Imageamento por Ressonância Magnética/métodos , Nanopartículas Metálicas , Neoplasias Experimentais/patologia , Neovascularização Patológica , Animais , Sistemas de Liberação de Medicamentos/métodos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
AIM: To evaluate the efficacy of postoperative serial assay of carcinoembryonic antigen (CEA) and cytokeratins for the detection of recurrent disease in patients with colorectal adenocarcinoma after radical surgery. METHODS: Between 1993 and 2000, 120 patients with colorectal adenocarcinoma underwent radical surgery in the Department of Surgical Gastroenterology, Federal University of Sao Paulo-Escola Paulista de Medicina, Sao Paulo, Brazil. Periodic postoperative evaluation was performed by assaying markers in peripheral serum, colonoscopy and imaging examination. Presence of CEA was detected using the Delfia method with 5 microg/L threshold, and cytokeratins using the LIA-mat TPA-M Prolifigen method with 72 U/L threshold. RESULTS: In the first postoperative year, patients without recurrent disease had normal levels of CEA (1.5 +/- 0.9 microg/L) and monoclonal tissue polypeptide antigen-M (TPA-M, 64.4 +/- 47.8 U/L), while patients with recurrences had high levels of CEA (6.9 +/- 9.8 microg/L, P < 0.01) and TPA-M (192.2 +/- 328.8 U/L, P < 0.05). During the second postoperative year, patients without tumor recurrence had normal levels of CEA (2.0 +/- 1.8 microg/L) and TPA-M (50.8 +/- 38.4 U/L), while patients with recurrence had high levels of CEA (66.3 +/- 130.8 microg/L, P < 0.01) and TPA-M (442.7 +/- 652.8 U/L, P < 0.05). The mean follow-up time was 22.3 mo. There was recurrence in 23 cases. Five reoperations were performed without achieving radical excision. Rises in tumor marker levels preceded identification of recurrences: CEA in seven (30%) and TPA-M in eleven individuals (48%). CONCLUSION: Intensive follow-up by serial assay of CEA and cytokeratins allows early detection of colorectal neoplasm recurrence.