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1.
J Thorac Dis ; 12(10): 5934-5954, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33209426

RESUMO

Background: Surgery and stereotactic body radiotherapy (SBRT) are both suitable treatment options for early stage Non-small cell lung cancer (NSCLC), which accounts for the majority of lung cancer. This study compared the outcomes of sublobar resection (SLR) and SBRT in patients with stage T1-2N0M0 NSCLC with tumor size ≤5 cm. Methods: Patients with T1-2N0M0 lung cancer who underwent SLR or SBRT between January, 2012 and December, 2016 were included in this retrospective study. The survival outcomes and toxicity of the SLR and SBRT cohorts were compared using Kaplan-Meier survival plots. In a second exploratory analysis, propensity score matching (PSM) was applied to reduce selection bias between the two groups of patients. Results: A total of 121 SLR and 109 SBRT cases were included. The average follow-up was 49.4 months. Prior to PSM, the 5-year overall survival (OS) and cancer-specific survival (CSS) rates in the SLR group (82.8% and 89.0%, respectively) were superior to those in the SBRT group (67.0% and 75.3%; P=0.001 and P=0.013, respectively). There were no statistically significant differences in the five-year locoregional control and disease-free survival (DFS) rates between the groups. PSM identified 40 patients from each treatment group who shared similar characteristics. At 5 years, the OS rates in the SLR and SBRT groups were comparable (79.9% vs. 66.5%, respectively; P=0.154). After PSM, the rates of CSS, locoregional control, and DFS were also similar between the groups (P=0.458, 0.369, and 0.698, respectively). In the SBRT group, one patient developed grade 3 radioactive pneumonitis. No grade >3 toxicities or treatment-related deaths occurred in either group. Conclusions: SBRT may be an alternative option to SLR for patients who cannot tolerate lobectomy because of medical comorbidities and has a similar level of effectiveness.

2.
Strahlenther Onkol ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33231712

RESUMO

PURPOSE: Proliferating cell nuclear antigen-associated factor (PAF) is involved in cancer cell growth and associated with cell death induced by ultraviolet (UV) radiation. However, the contribution of PAF to radiotherapy sensitivity in non-small cell lung cancer (NSCLC) is unknown. The aim of this study was to investigate the relationship between PAF expression and radiotherapy response in NSCLC. METHODS: Associations between PAF expression and patient survival outcomes were evaluated using publicly available online gene expression datasets. RNA interference was performed to knockdown PAF expression in the NSCLC cells. The effects of PAF knockdown on cell proliferation, migration, apoptosis, DNA damage, and activation of MEK/ERK and Wnt/ß-catenin signaling pathways following X­ray irradiation were evaluated in vitro. RESULTS: PAF was found to be overexpressed in lung cancer tissues compared with normal samples, and elevated PAF expression was significantly correlated with inferior patient survival. In vitro, knockdown of PAF inhibited cell proliferation, cell apoptosis, and migration induced by X­ray irradiation. Moreover, X­ray-induced intracellular DNA strand damage was more obvious following PAF knockdown. Additionally, PAF knockdown inhibited activation of the MEK/ERK and Wnt/ß-catenin signaling pathways in X­ray-irradiated A549 cells. CONCLUSION: These data demonstrate that reduced expression of PAF enhances radiosensitivity in NSCLC cells. Mechanistically, inhibition of the MEK/ERK and Wnt/ß-catenin signaling pathways caused by PAF interference may lead to impaired cell function and enhance sensitivity to X­rays. Targeting PAF may therefore serve as a potential therapeutic strategy to increase the efficiency of radiotherapy in NSCLC patients, ultimately improving patient survival.

3.
Zhongguo Fei Ai Za Zhi ; 23(10): 837-844, 2020 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-33070512

RESUMO

BACKGROUND: Tumor microenvironment is a complex and dynamic community, which plays a crucial role in tumor progression via the co-evolution of cancer cells and tumor stroma. Among them, tumor-associated macrophages (TAMs) and tumor neo-vessels are two key components in the tumor microenvironment during cancer invasion. In addition, programmed cell death ligand 1/programmed cell death ligand 1 (PD-1/PD-L1) also plays an important role in tumorigenesis and development, and the clinical strategies to block PD-1/PD-L1 pathway could have great benefits for cancer patients. This study was aimed at analyzing the quantitative expression and prognostic significance of TAMs, tumor neo-vessels and PD-L1 in tumor microenvironment and exploring the relations between the expression of above components with the patients' prognosis of non-small cell lung cancer (NSCLC). METHODS: Clinico-pathological data and surgical specimens of 92 patients with NSCLC were collected, and immunohistochemistry was used to stain the expression of TAMs, tumor neo-vessels and PD-L1 on tumor tissue and peri-tumor tissues. The inverted microscopy was used to take pictures and Image-pro Plus 6.0 software was used for quantitative analysis. The clinicopathological characteristics and overall survival (OS) were analyzed. RESULTS: The median OS of 92 NSCLC cases was 22.5 month. The expression of TAMs, tumor neo-vessels and PD-L1 in tumor tissue and peri-tumor tissues were not statistically significant (P>0.05). According to the cutoff of above key three components in tumor microenvironment, all the cases could be classified into high, middle and low expression groups. The survival analysis demonstrated that the OS in high expression group of TAMs (P=0.016) and PD-L1 (P=0.002) was shorter than the other two groups, respectively, with statistical significance. The OS in high tumor neo vessels group was shorter than the other two groups. However, there was no statistical significance between these three group (P=0.626). Combined with above the three components, all the cases could be classified into low, middle and high density groups. The survival analysis demonstrated that the median OS of combined high density group was shorter than the other two groups (P=0.001). Multivariate analysis by Cox regression indicated that pathological type, TAMs and PD-L1 expression were the independent prognostic factors. CONCLUSIONS: The key components of TAMs and PD-L1 in tumor microenvironment are closely related to the prognosis of NSCLC patients.

5.
Radiat Oncol ; 14(1): 195, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699115

RESUMO

BACKGROUND: The optimal treatment for elderly patients with early-stage non-small cell lung cancer (NSCLC) remains inconclusive. Previous studies have shown that stereotactic body radiotherapy (SBRT) provides encouraging local control though higher incidence of toxicity in elderly than younger populations. The objective of this study was to compare the outcomes of SBRT and surgical treatment in elderly patients with clinical stage I-II NSCLC. METHODS: This retrospective analysis included 205 patients aged ≥70 years with clinical stage I NSCLC who underwent SBRT or surgery at Zhejiang Cancer Hospital (Hangzhou, China) from January 2012 to December 2017. A propensity score matching analysis was performed between the two groups. In addition, we compared outcomes and related toxicity in both study arms. RESULTS: Each group included 35 patients who met the inclusion criteria. Median follow-up was 50.1 (0.8-74.4) months for surgery and 35.5 (11.5-71.4) months for SBRT. The rate of cancer-specific survival was similar between the two treatment arms (p = 0.958). In patients who underwent surgery, the corresponding 3- and 5-year cancer-specific survival rates were 85.3 and 81.7%, respectively. In those who received radiotherapy, these rates were 91.3 and 74.9%, respectively. Moreover, the 3- and 5-year locoregional control in patients who underwent surgery were 90.0 and 80.0%, respectively. In those who received radiotherapy, these rates were 91.1 and 84.1%, respectively. Notably, the observed differences in progression-free survival were not statistically significant (p = 0.934). In the surgery group, grade 1-2 complications were observed in eleven patients (31%). One patient died due to perioperative infection within 30 days following surgery. There was no grade 3-5 toxicity observed in the SBRT group. CONCLUSIONS: The outcomes of surgery and SBRT in elderly patients with early-stage NSCLC were similar.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Radiocirurgia , Carcinoma de Pequenas Células do Pulmão/radioterapia , Carcinoma de Pequenas Células do Pulmão/cirurgia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Pesquisa Comparativa da Efetividade , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Masculino , Prevalência , Pontuação de Propensão , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/mortalidade , Resultado do Tratamento
6.
Oncol Lett ; 15(4): 4805-4812, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29552120

RESUMO

The present study was performed to quantify tumor neo-vessels, macrophages and fibroblasts in the tumor microenvironment of hepatocellular carcinoma (HCC) and explore the prognostic factors of HCC. The distribution of tumor neo-vessels, macrophages and fibroblasts was quantified by immunohistochemistry and inverted microscopy with the CRi Nuance multispectral imaging system, and the correlation of these parameters with the clinico-pathological characteristics and overall survival of the patients was analyzed. The number of tumor neo-vessels and macrophages, and density of the fibroblasts, as calculated by the thickness of the tumor stroma in the tumor microenvironment, ranged from 51-429 (median, 218), 110-555 (median, 259) and 35.6-555.5 µm (median, 247.0), respectively. Using the median values as a cutoff, the cases were stratified into high- and low-density groups. Survival analysis demonstrated that the high-density groups regarding macrophages (χ2=5.249, P=0.022) and fibroblasts (χ2=18.073, P<0.001) had a significantly shorter disease-free survival (DFS) than the low-density groups. The high-density tumor neo-vessel group had a shorter DFS with a median of 5 months than the low-density group with a median of 7 months; however, there was no statistical significance between these two groups (χ2=1.663, P=0.197). Regarding the above three stromal components combined, all of the cases were classified into low-, middle- and high-density groups. Survival analysis demonstrated that the high-density group of stromal components had a shorter DFS than the other two groups with a median of 3 months (χ2=14.439, P=0.001). Multivariate analysis by Cox regression indicated that cirrhosis, metastasis stage, as well as macrophage and fibroblast density were independent prognostic factors. In conclusion, the key elements in the tumor microenvironment, including tumor neo-vessels, macrophages and fibroblasts, were heterogenic in HCC tissues and have significant roles in HCC invasion and metastasis. Stromal components are associated with the prognosis of patients with HCC; the higher the density of stromal components, the poorer the prognosis of patients with HCC.

7.
Proc Natl Acad Sci U S A ; 112(5): 1535-40, 2015 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-25605927

RESUMO

Inflammation is critical for host defense, but without appropriate control, it can cause chronic disease or even provoke fatal responses. Here we identify a mechanism that limits the inflammatory response. Probing the responses of macrophages to the key sensory Toll-like receptors, we identify that the Broad-complex, Tramtrack and Bric-a-brac/poxvirus and zinc finger (BTB/POZ), transcriptional regulator promyelocytic leukemia zinc finger (PLZF) limits the expression of inflammatory gene products. In accord with this finding, PLZF-deficient animals express higher levels of potent inflammatory cytokines and mount exaggerated inflammatory responses to infectious stimuli. Temporal quantitation of inflammatory gene transcripts shows increased gene induction in the absence of PLZF. Genome-wide analysis of histone modifications distinguish that PLZF establishes basal activity states of early response genes to maintain immune homeostasis and limit damaging inflammation. We show that PLZF stabilizes a corepressor complex that encompasses histone deacetylase activity to control chromatin. Together with our previous demonstration that PLZF promotes the antiviral response, these results suggest a strategy that could realize one of the major goals of immune therapy to retain immune resistance to pathogens while curbing damaging inflammation.


Assuntos
Cromatina/metabolismo , Inflamação/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Transdução de Sinais , Animais , Infecções Bacterianas/metabolismo , Imunoprecipitação da Cromatina , Transferência Ressonante de Energia de Fluorescência , Histona Desacetilases/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteína com Dedos de Zinco da Leucemia Promielocítica , Reação em Cadeia da Polimerase em Tempo Real
8.
J Immunol ; 194(3): 1239-51, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25520401

RESUMO

A polarized macrophage response is presumed to have a pivotal role in a variety of immunological pathophysiology. However, the molecular mechanism underlying macrophage functional shaping remains largely unknown. In this study, we reveal a pivotal role of miR-127 in macrophage development and thereby the pathogenesis of inflammation and lung injury. In particular, miR-127 was demonstrated to be prominently induced upon TLR engagement and repressed by the M2-prone cytokines. Enforced expression of miR-127 in macrophages resulted in significantly increased production of proinflammatory cytokines, whereas deletion of miR-127 impaired M1 gene expression and led to a M2-biased response. Accordingly, intratracheal administration of miR-127 resulted in an exaggerated pulmonary inflammation and injury. Conversely, antagonizing of miR-127 suppressed production of the proinflammatory cytokines and rendered the mice more refractory to the inflammation-associated pathology. Mechanistically, miR-127 demonstrated to target B cell lymphoma 6 (Bcl6) and remarkably downregulated its expression and subsequently dual specificity phosphatase 1 (Dusp1), which in turn enhanced the activation of JNK kinase and hence the development of proinflammatory macrophages. Thereby, reconstitution with the expression of Bcl6 or Dusp1 or inhibition of JNK activity impaired miR-127-mediated skewing of M1 proinflammatory macrophages, whereas interference of Bcl6 or Dusp1 expression abrogated the anti-inflammatory property of anti-miR-127. Together, these data establish miR-127 as a molecular switch during macrophage development and as a potential target for treatment of inflammatory diseases.


Assuntos
Sistema de Sinalização das MAP Quinases , Macrófagos/imunologia , Macrófagos/metabolismo , MicroRNAs/genética , Pneumonia/genética , Pneumonia/metabolismo , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/metabolismo , Animais , Linhagem Celular , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Suscetibilidade a Doenças , Fosfatase 1 de Especificidade Dupla/genética , Fosfatase 1 de Especificidade Dupla/metabolismo , Endotoxinas/efeitos adversos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ligantes , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Camundongos , Pneumonia/imunologia , Proteínas Proto-Oncogênicas c-bcl-6 , Interferência de RNA , Sepse/genética , Sepse/imunologia , Sepse/metabolismo , Receptores Toll-Like/metabolismo , Transcrição Genética , Transcriptoma
9.
Int Immunopharmacol ; 21(1): 1-9, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24747094

RESUMO

Daphnetin, a natural coumarin derivative, is known to display anti-inflammatory properties and has been used to treat inflammatory diseases. A novel finding suggested that daphnetin might have a neuroprotective effect in stressed mice, leading us to explore its role in the microglial inflammatory response, as well as its underlying mechanism of action. We found that the production of pro-inflammatory mediators, including interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α), induced by lipopolysaccharide (LPS) or ß-amyloid (Aß) was significantly suppressed by daphnetin in a dose-dependent manner in BV2 microglia. Also, daphnetin inhibited LPS-induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression and NO formation by microglia. Mechanistically, daphnetin blunted the transcriptional activity of nuclear factor-kappa B (NF-κB), which was associated with the down-regulation of the phosphorylation and nuclear translocation of RelA/p65. Inhibitors of kappa B (IκB) phosphorylation and degradation were also affected by daphnetin, which was likely due to the reduced activation of IκB kinase (IKK). Additionally, LPS-induced activation of mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK, were, to a varying extent, altered by daphnetin. Finally, daphnetin blocked phosphatidylinositol-3 kinase (PI-3K)/protein kinase B (Akt) signaling in LPS-activated microglia, which appeared to at least partially account for the reduction in NF-κB transcriptional activity. Thus, daphnetin inhibited microglial activation and proinflammatory responses by modulating a series of intracellular signaling pathways, including IKK/IκB, MAPKs and PI-3K/Akt.


Assuntos
Daphne/imunologia , Microglia/efeitos dos fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Umbeliferonas/farmacologia , Peptídeos beta-Amiloides/imunologia , Animais , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/imunologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Microglia/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
10.
J Immunol ; 191(1): 386-94, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23729445

RESUMO

Chlamydia pneumonia (C. pneumonia) remains one of the leading causes of bacterial pneumonia and has been implicated in the pathogenesis of some inflammation-related diseases, such as asthma, chronic obstructive pulmonary disease, and vascular diseases. Heat shock protein 60 is one of the pathogenic components of C. pneumonia that is closely associated with the inflammatory disorders. However, the molecular basis for the immunopathologic property of chlamydial heat shock protein (cHSP60) has not been elucidated. In this article, we report that MAPK kinase 3 (MKK3) is essential for cHSP60-induced lung inflammation, because MKK3-knockout mice displayed significantly reduced lung neutrophil accumulation and decreased production of proinflammatory mediators, correlating with the alleviated inflammatory response in lung tissues. Mechanistically, p38 kinase was selectively activated by MKK3 in response to cHSP60 and activated NF-κB by stimulating the nuclear kinase, mitogen- and stress-activated protein kinase 1. The specific knockdown of mitogen- and stress-activated protein kinase 1 in macrophages resulted in a defective phosphorylation of NF-κB/RelA at Ser(276) but had no apparent effect on RelA translocation. Furthermore, TGF-ß-activated kinase 1 was found to relay the signal to MKK3 from TLR4, the major receptor that sensed cHSP60 in the initiation of the inflammatory response. Thus, we establish a critical role for MKK3 signaling in cHSP60 pathology and suggest a novel mechanism underlying C. pneumonia-associated inflammatory disorders.


Assuntos
Chaperonina 60/fisiologia , Chlamydophila pneumoniae/enzimologia , Chlamydophila pneumoniae/imunologia , Inflamação/imunologia , Proteína Quinase 3 Ativada por Mitógeno/fisiologia , NF-kappa B/metabolismo , Animais , Linhagem Celular , Chaperonina 60/biossíntese , Chaperonina 60/genética , Infecções por Chlamydophila/enzimologia , Infecções por Chlamydophila/imunologia , Infecções por Chlamydophila/metabolismo , Chlamydophila pneumoniae/efeitos dos fármacos , Relação Dose-Resposta Imunológica , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/imunologia , Inflamação/enzimologia , Inflamação/genética , Camundongos , Camundongos Knockout , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/deficiência , NF-kappa B/fisiologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética
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