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1.
Cancer Cell Int ; 21(1): 556, 2021 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-34689774

RESUMO

BACKGROUND: Brain metastasis is an important cause of increased mortality in patients with non-small cell lung cancer (NSCLC). In brain metastasis, the blood-brain barrier (BBB) is frequently impaired, forming blood-tumor barrier (BTB). The efficacy of chemotherapy is usually very poor. However, the characteristics of BTB and the impacts of BTB on chemotherapeutic drug delivery remain unclear. The present study investigated the structure of BTB, as well as the distribution of routine clinical chemotherapeutic drugs in both brain and peripheral tumors. METHODS: Bioluminescent image was used to monitor the tumor load after intracranial injection of lung cancer Lewis cells in mice. The permeability of BBB and BTB was measured by fluorescent tracers of evans blue and fluorescein sodium. Transmission electron microscopy (TEM), immunohistochemistry and immunofluorescence were performed to analyze structural differences between BBB and BTB. The concentrations of chemotherapeutic drugs (gemcitabine, paclitaxel and pemetrexed) in tissues were assayed by liquid chromatography with tandem mass spectrometry (LC-MS/MS). RESULTS: Brain metastases exhibited increased BTB permeability compared with normal BBB detected by fluorescence tracers. TEM showed abnormal blood vessels, damaged endothelial cells, thick basement membranes, impaired intercellular endothelial tight junctions, as well as increased fenestrae and pinocytotic vesicles in metastatic lesions. Immunohistochemistry and immunofluorescence revealed that astrocytes were distributed surrounded the blood vessels both in normal brain and the tumor border, but no astrocytes were found in the inner metastatic lesions. By LC-MS/MS analysis, gemcitabine showed higher permeability in brain metastases. CONCLUSIONS: Brain metastases of lung cancer disrupted the structure of BBB, and this disruption was heterogeneous. Chemotherapeutic drugs can cross the BTB of brain metastases of lung cancer but have difficulty crossing the normal BBB. Among the three commonly used chemotherapy drugs, gemcitabine has the highest distribution in brain metastases. The permeability of chemotherapeutic agents is related to their molecular weight and liposolubility.

2.
BMC Infect Dis ; 21(1): 629, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210287

RESUMO

BACKGROUND: Along with the medical development, organ transplant patients increase dramatically. Since these transplant patients take immunosuppressants for a long term, their immune functions are in a suppressed state, prone to all kinds of opportunistic infections and cancer. However, it is rarely reported that the kidney transplant recipients (KTRs) have pulmonary tuberculosis and lung cancer simultaneously. CASE PRESENTATION: A 60-year-old male was admitted because of persistent lung shadow for 2 years without any obvious symptom 8 years after renal transplant. T-SPOT test was positive but other etiological examinations for Mycobacterium tuberculosis were negative. Chest CT scan revealed two pulmonary lesions in the right upper and lower lobe respectively. 18F-fluorodesoxyglucose positron-emission tomography (FDG-PET) CT found FDG intake increased in both pulmonary consolidation lesions. CT-guided percutaneous transthoracic needle biopsy revealed lung adenocarcinoma and tuberculosis. The video-assisted thoracoscopic surgery was operated to resect the malignancy lesions. The patient received specific anti-tuberculosis therapy and was discharged. At the follow-up of 6 months post drug withdrawal, the patient was recovered very well. CONCLUSIONS: We for the first time reported co-existence of smear-negative pulmonary TB and lung adenocarcinoma in a KTR, which highlighted the clinical awareness of co-occurrence of TB and malignancy after renal transplant and emphasized the value of biopsy and 18F-FDG-PET in early diagnosis of TB and cancer.


Assuntos
Adenocarcinoma/complicações , Transplante de Rim , Neoplasias Pulmonares/complicações , Tuberculose Pulmonar/complicações , Adenocarcinoma/cirurgia , China/epidemiologia , Etambutol/uso terapêutico , Fluordesoxiglucose F18 , Humanos , Biópsia Guiada por Imagem , Isoniazida/uso terapêutico , Pulmão/diagnóstico por imagem , Pulmão/patologia , Pulmão/cirurgia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Moxifloxacina/uso terapêutico , Mycobacterium tuberculosis/isolamento & purificação , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Cirurgia Torácica Vídeoassistida , Resultado do Tratamento , Tuberculose Pulmonar/tratamento farmacológico
3.
Cancer Manag Res ; 13: 4299-4307, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34103985

RESUMO

Background: A growing interest exists in identifying reliable and low-cost biomarkers or factors that could predict the therapeutic response, prognosis, recurrence, and survival in small-cell lung cancer (SCLC). This study aimed to investigate the better predictors of chemotherapy efficacy and prognosis in patients with SCLC receiving first-line chemotherapy and radiotherapy. Materials and Methods: This study retrospectively retrieved the medical records of patients with SCLC treated with first-line platinum-based chemotherapy and radiotherapy from January 2016 to June 2019 in the First Affiliated Hospital of Nanjing Medical University. Plasma biochemical parameters, clinical features, and overall survival (OS) time were collected. The independent effects of plasma parameters on patient survival were assessed by conducting univariate and multivariate Cox regression analyses. The optimal cut-off values of independent risk factors in the ROC curve and Kaplan-Meier survival analysis were determined using MedCalc software. Results: Statistically significant differences in lactate dehydrogenase (LDH) and fibrinogen (Fbg) were found between the complete remission + partial remission group and the non-responders, which consisted of stable-disease and progressive-disease groups, after first-line chemotherapy. Multivariate Cox regression analysis showed that LDH and Fbg were independent risk factors in predicting PFS (LDH HR: 1.013, 95% CI: 1.002-1.030, P = 0.037; Fbg HR: 1.622, 95% CI: 1.094-2.526, P = 0.017) and OS (LDH HR: 1.021, 95% CI: 1.008-1.034, P = 0.001; Fbg HR: 2.168, 95% CI: 1.324-3.550, P = 0.002). The AUC of LDH and Fbg was 0.77 and 0.745, respectively. The cut-off value of LDH and Fbg in predicting OS was 263 U/L and 4.03 g/L. When these two data were combined, the AUC reached 0.832, better than that of LDH and Fbg alone. The objective response rate (ORR) and OS were significantly different among these three different groups according to the addition of the assigned value (P < 0.05). Conclusion: Combined retreatment serum LDH and Fbg levels may be a better potential biomarker for predicting the clinical efficacy of chemotherapy and the prognosis of individuals with SCLC. Combining these two parameters could improve prediction efficacy.

4.
Am J Transl Res ; 12(3): 959-973, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32269727

RESUMO

Chronic thromboembolic pulmonary hypertension (CTEPH) is similar to pulmonary arterial hypertension (PAH) in its pathogenesis. Changed hemodynamic parameters in acute vasoreactivity testing (AVT) have proved to be prognostic predictors of PAH. We wanted to determine whether these changed indices also impacted the prognosis of CTEPH. Data was retrieved for 86 CTEPH patients who underwent right heart catheterization (RHC) with AVT at Shanghai Pulmonary Hospital from 2009 to 2018 and following up for 20 ± 15 months for event. Cox proportional hazards models were performed to determine the predictors of independent event-free survival. Receiver operating characteristic curve was plotted to determine the cut-off value of independent parameters in CTEPH. Kaplan-Meier method and log-rank test were used to perform the Survival analyses. Forty seven patients had an event. Many hemodynamic indices improved after AVT. The event-free group had better mean right atrial pressure, mean pulmonary arterial pressure, pulmonary vascular resistance (PVR) and oxygen saturation of mixed venous blood (SvO2) both at baseline and after AVT. The event-free group also showed higher cardiac output (CO) and cardiac index (CI) after AVT. Among the changed hemodynamic parameters during the AVT, ΔCO, ΔCO/baseline CO, ΔCI, ΔCI/baseline CI and ΔPVR/baseline PVR were significantly higher in the event-free group. Foremost, ΔPVR/baseline PVR, PVR after AVT and baseline SvO2 were independent predictors for event-free survival. Patients with SvO2 ≥ 61.65% at baseline or PVR < 8.09 WU after AVT or ΔPVR/baseline PVR ≥ 0.054 had significantly better survival. Hemodynamic indices both at baseline and after AVT as well as the changes in these indices reflected the severity of CTEPH. Baseline SvO2, PVR after AVT, and ΔPVR/baseline PVR could be used as independent predictors to estimate the outcomes of CTEPH patients.

5.
Am J Hypertens ; 33(8): 775-783, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32301965

RESUMO

BACKGROUND: Aberrant activation of epidermal growth factor receptor (EGFR) signaling pathway is associated with the pathogenesis of pulmonary hypertension (PH). However, the effect of icotinib, a first generation of EGFR tyrosine kinase inhibitor (EGFR-TKI), on PH remains to be elucidated. METHODS: PH rat model was established by a single intraperitoneal injection of monocrotaline (MCT, 60 mg/kg). Icotinib (15, 30, and 60 mg/kg/day) was administered by oral gavage from the day of MCT injection. After 4 weeks, hemodynamic parameters and histological changes of the pulmonary arterial vessels were assessed, and the phenotypic switching of pulmonary arterial smooth muscle cells (PASMCs) was determined in vivo. Moreover, the effects of icotinib (10 µM) on epidermal growth factor (EGF, 50 ng/ml)-stimulated proliferation, migration, and phenotypic switching of human PASMCs were explored in vitro. RESULTS: Icotinib significantly reduced the right ventricular systolic pressure and right ventricle hypertrophy index in rats with MCT-induced PH. Moreover, icotinib improved MCT-induced pulmonary vascular remodeling. The expression of contractile marker (smooth muscle 22 alpha (SM22α)) and synthetic markers (osteopontin (OPN) and vimentin) in pulmonary artery was restored by icotinib treatment. In vitro, icotinib suppressed EGF-induced PASMCs proliferation and migration. Meanwhile, icotinib inhibited EGF-induced downregulation of α-smooth muscle actin and SM22α and upregulation of OPN and Collagen I in PASMCs, suggesting that icotinib could inhibit EGF-induced phenotypic switching of PASMCs. Mechanistically, these effects of icotinib were associated with the inhibition of EGFR-Akt/ERK signaling pathway. CONCLUSIONS: Icotinib can attenuate MCT-induced pulmonary vascular remodeling and improve PH. This effect of icotinib might be attributed to preventing PASMC dysfunction by inhibiting EGFR-Akt/ERK signaling pathway.

6.
Clin Respir J ; 14(7): 611-621, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32090459

RESUMO

BACKGROUND: Acute vasoreactivity testing (AVT) which reflects the compliance of the pulmonary vascular bed has been proven to be of prognostic value. The purpose of the present study is to explore the sex differences of hemodynamics during the AVT and their impact on event-free survival in patients with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: Eighty-six patients underwent a right heart catheterization and AVT at Shanghai Pulmonary Hospital from February 2009 to February 2018. Univariate and multiple stepwise regression analysis were performed to determine the predictors of independent event-free survival, and receiver operating characteristic curve was plotted to determine the cut-off value of independent parameters in CTEPH. RESULTS: There were no significant differences in both demographics and hemodynamics between male and female patients with CTEPH. Except ΔPVR/PVR showed a significantly higher difference in female than male patients (P = 0.034). Male patients had higher mRAP of pre- and post-AVT than female patients in the event-free subgroup, while, female patients showed higher PVR of pre-AVT than male patients in the event subgroup (P < 0.05). The mRAP and SvO2 were independent predictors of event-free survival in female patients both before and after the AVT, whereas ΔSvO2 was an independent predictor of event-free survival in male patients. CONCLUSION: Hemodynamics during the AVT varied between male and female patients with CTEPH. Both sexes displayed unique hemodynamic responses that were independently able to predict event-free survival. Therefore, better estimates of prognosis in CTEPH can be made when sex differences are also taken into consideration.


Assuntos
Hemodinâmica/fisiologia , Hipertensão Pulmonar/fisiopatologia , Pulmão/fisiopatologia , Embolia Pulmonar/fisiopatologia , Administração por Inalação , Adulto , Idoso , Cateterismo Cardíaco/métodos , China/epidemiologia , Doença Crônica , Feminino , Humanos , Iloprosta/administração & dosagem , Iloprosta/farmacologia , Pulmão/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Intervalo Livre de Progressão , Pressão Propulsora Pulmonar/fisiologia , Curva ROC , Análise de Regressão , Caracteres Sexuais , Vasodilatadores/administração & dosagem , Vasodilatadores/farmacologia
7.
Infect Drug Resist ; 12: 1265-1276, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190914

RESUMO

Purpose: Multidrug-resistant tuberculosis (MDR-TB) remains a challenge of global TB control, with difficulty in early detection of drug-sensitive tuberculosis (DS-TB). We investigate the diagnostic significance of IDO as a potential biomarker to discriminate MDR patients among the TB patients. Patients and methods: Plasma indoleamine 2,3-dioxygenase (IDO) was measured by the ratio of kynurenine (Kyn) to tryptophan (Trp) concentrations, using high performance liquid chromatography-mass spectrometry (LC-MS/MS). Chest computed tomography (CT) imaging signs from TB patients were collected and analyzed in 18 DS-TB patients, 16 MDR-TB patients, 6 lung cancer (LC) patients, and 11 healthy individuals. Lung imaging signs from TB patients were collected and analyzed. Results: We found that plasma IDO activity was significantly higher in the MDR-TB patients than in the DS-TB patients (p=0.012) and in the LC patients (p=0.003). We evaluated the diagnostic significance of plasma IDO activity in discriminating the MDR-TB group from the DS-TB group using a receiver operating characteristic (ROC) curve. With a cutoff level of 46.58 uM/mM, the diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for IDO activity were 87.50%, 72.22%, 73.68%, and 86.67%, respectively. Plasma IDO activity was higher in cavity cases than in non-cavity cases (p=0.042), proving a positive correlation between lung cavity number and cavity size (p<0.05, separately) among all the TB patients studied. Conclusion: Our findings confirmed that plasma IDO activity might have an auxiliary diagnosis value for early discrimination of MDR-TB patients from DS-TB patients. Among the TB patients with cavitary lung lesions, higher plasma IDO activity can indicate a higher risk of MDR-TB.

8.
Onco Targets Ther ; 12: 985-992, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30774384

RESUMO

Background: Hypertension (HTN) is a common adverse event of the vascular endothelial growth factor pathway inhibitor apatinib. This study was conducted to evaluate the association of apatinib-induced HTN with clinical outcomes in patients with advanced non-small-cell lung cancer (NSCLC). Methods: We retrospectively analyzed 110 consecutive patients with advanced NSCLC who were treated with apatinib from August 2014 to January 2018. All patients were classified as normotensive or hypertensive based on blood pressure measurements after initiating therapy. Therapeutic response, progression-free survival (PFS), and overall survival (OS) were evaluated. Univariate and multivariate analyses were performed using the Cox proportional hazards method. Results: A total of 46 patients (42%) were diagnosed with HTN. The median PFS for the hypertensive and normotensive groups were 5.6 months and 4.2 months, respectively (P=0.0027). The median OS times for the hypertensive and normotensive groups were 9.9 months and 7.8 months, respectively (P=0.005). Thirty percent of patients who experienced HTN showed partial response to apatinib as compared with 6.3% of non-hypertensive patients (P=0.002). HTN was independently associated with improved PFS and OS on both univariate and multivariate analyses. Conclusion: Apatinib-induced HTN may be an inexpensive, valid, and easily measurable biomarker for apatinib antitumor efficacy in patients with advanced NSCLC.

9.
J Biomed Res ; 33(3): 156-163, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-28963443

RESUMO

Fasudil, a selective rho kinase (ROCK) inhibitor, has been reported to play a beneficial role in systemic inflammation in acute lung injury, but its mechanism for ameliorating pulmonary edema and inflammation remains unclear. Using hematoxylin-and-eosin (H&E) staining, immunohistochemistry, enzyme-linked immunosorbent assay, quantitative real time PCR and Western blotting, we found that fasudil attenuated LPS-induced lung injury, decreased lung edema, and suppressed inflammatory responses including leukocyte infiltration and IL-6 production. Further, fasudil upregulated LPS-induced aquaporin 5 reduction and inhibited NF-kB activation in the lungs of mice. Our results suggest that fasudil could restore the expression of aquaporin 5 to eliminate LPS-induced lung edema and prevent LPS-induced pulmonary inflammation by blocking the inflammatory pathway. Collectively, blockade of the ROCK pathway by fasudil may be a potential strategy for the treatment of acute lung injury.

10.
J Immunol Res ; 2018: 6212410, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29850635

RESUMO

Good's syndrome (GS) is often accompanied by recurrent respiratory infections and chronic diarrhea. The main purpose was to evaluate the peripheral immune status of a GS patient after thymoma resection. Twenty healthy volunteers were recruited as healthy controls (HCs). Flow cytometry was applied to determine the proportions of circuiting CD4+ T cells, CD8+ T cells, γδT cells, and regulatory T (Treg) cells in our GS patient. We also examined the proliferation capability of ex vivo CD4+ T cells and detected the levels of cytokines interferon- (IFN-) γ and interleukin-17A secreted by ex vivo immune cells from this GS patient. Compared with healthy control subjects, this GS patient had fewer B cells, an inverted ratio of CD4+/CD8+ cells, and more Treg cells in his peripheral blood. Additionally, the patient's Vδ2 T cell levels were significantly decreased despite having a normal percentage of γδT cells. Ex vivo peripheral CD4+ T cells from the patient showed insufficient proliferation and division potential as well as excessive expression of PD-1. Moreover, IFN-γ was predominantly derived from CD8+ T cells in this GS patient, rather than from CD4+ T cells and γδT cells. This GS patient had impaired T and B cell immunological alternations and cytokine disruptions after thymectomy. Detailed research should focus on therapies that can adjust the immune status in such patients for a better outcome.


Assuntos
Linfócitos B/imunologia , Síndromes de Imunodeficiência/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Proliferação de Células , Separação Celular , Células Cultivadas , Diarreia , Citometria de Fluxo , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Infecções Respiratórias , Timoma
11.
Sci Rep ; 7(1): 17854, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29259310

RESUMO

It is urgent to find an optimised therapy regimen for the control of MDR-TB globally. This study aimed to evaluate the efficiacy and safety of a combined regimen of rhIL-2 injection and standard chemotherapy within 18-month duration in a randomized controlled trial conducted in 14 centres in eastern China. From Jan. 2009 to July. 2016, 271 MDR-TB cases were enrolled and followed up in two groups, 142 cases in study group while 129 cases in control group. Clinical efficacy, safety and immune activity (Th1, Th17, Treg, IFN-γ, IL-17) among the two groups were evaluated and compared. After 24-month following up, cure rate in IL-2 group show higher than that in control group (56% VS 36%, P < 0.01). Rate of mycobacterium clearance (sputum negative) within 3 months was significantly higher in IL-2 group (74% VS 59%, P < 0.05) with no adverse events raised. Patients after rhIL-2 treatment showed increasing of Th1 populations and decreasing of Th17 and Regulatory T cells (Treg) populations, while levels of IL-17A, ROR-γt, and Foxp3 mRNA decreased and level of IFN-γ mRNA increased in PBMCs. Thus, rhIL-2 combined regimen within shorter duration achieved high conversion and success rates and improved Th1/Th17 immune responses, with no safety concerns emerging in MDR-TB patients.


Assuntos
Antituberculosos/imunologia , Antituberculosos/uso terapêutico , Interleucina-2/imunologia , Interleucina-2/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/imunologia , Tuberculose Pulmonar/imunologia , Grupo com Ancestrais do Continente Asiático , Feminino , Humanos , Interferon gama/imunologia , Interleucina-17/imunologia , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/imunologia , Estudos Prospectivos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Resultado do Tratamento , Tuberculose Pulmonar/tratamento farmacológico
12.
Oncotarget ; 8(30): 49217-49223, 2017 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-28514746

RESUMO

Over-expressed endothelial-cell-specific molecule-1 (ESM-1) in tumor vascular endothelium contributes to tumor angiogenesis, metastasis, and poor prognosis. However, the content of ESM-1 in pleural effusion is unclear. A retrospective study was carried out to investigate the diagnostic and prognostic values of ESM-1 with malignant pleural effusions in patients with non-small cell lung cancer (NSCLC). ESM-1 levels in malignant pleural effusion (MPE) from 70 patients with NSCLC and 50 cases of benign pleural effusion (BPE) were measured using enzyme-linked immunosorbent assay. Receiver operating characteristic (ROC) curve was calculated to assess the diagnostic value of ESM-1. Survival curves were performed by Kaplan-Meier method and survival characteristics were compared by log-rank test. Univariable and multivariate Cox proportional hazards model were carried out to analysis the significance of different prognostic factors for overall survival (OS). ESM-1 levels were significantly higher in MPE than those in BPE (p < 0.001). By ROC curve analysis, with a cutoff level of 19.58 ng/ml, the accuracy, sensitivity, and specificity for ESM-1 diagnosis MPE were 82.5%, 81.4%, and 84.0%, respectively. Moreover, NSCLC patients with pleural fluid ESM-1 levels below 19.58 ng/ml had significant longer OS than those patients with higher levels (22.09 months vs. 11.49 months, p = 0.003). Multivariate survival analysis showed that high MPE ESM-1 level was an independent prognostic factor (HR, 1.007; p = 0.039) for the OS of NSCLC patients. This study showed that ESM-1 level in pleural effusion could be a potential diagnostic and prognostic marker in NSCLC patients with MPE.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/metabolismo , Derrame Pleural Maligno/metabolismo , Derrame Pleural Maligno/patologia , Proteoglicanas/metabolismo , Biomarcadores , Biomarcadores Tumorais , Biópsia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Expressão Gênica , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Prognóstico , Proteoglicanas/genética , Curva ROC
13.
Cancer Cell Int ; 17: 40, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28360820

RESUMO

BACKGROUND: Non-small cell lung cancer comprises the majority of lung cancer cases and is insensitive to chemotherapy. Most patients develop drug resistance. Recently, tetrandrine (TET), a bis-benzylisoquinoline alkaloid, was identified as a novel anti-cancer agent. However, the effect of tetrandrine combined with cisplatin on lung cancer has not yet been studied. We aimed to identify a possible synergistic effect between tetrandrine and cisplatin, besides, to investigate the effects of TET in combination with DDP on proliferation and apoptosis in cisplatin-resistant and cisplatin-sensitive A549 cell lines, and to study the underlying mechanism. METHODS: Cell viability was confirmed with CCK8 assays, and the IC50 values for each treatment group were calculated. The synergistic interaction of these drugs was evaluated using an isobolographic analysis. Proliferation was assessed by EDU staining. Hoechst staining and flow cytometry were used to assess apoptosis. Apoptosis- and autophagy-associated proteins were analyzed by western blot. Transmission electron microscopy was used to detect autophagy, RFP-GFP-LC3 lentivirus was used to perform autophagic flux assay. RESULTS: Tetrandrine and cisplatin exerted synergistic cytotoxic effects on both cisplatin-resistant and cisplatin-sensitive A549 cell lines. The combination of tetrandrine and cisplatin induced apoptosis and inhibited proliferation in a synergistic manner. The formation of autophagosomes was evident by transmission electron microscopy. The autophagic flux of combination treatment was increased. CONCLUSIONS: Tetrandrine synergized with cisplatin to reduce the viability of cisplatin-resistant and cisplatin-sensitive A549 cells, tetrandrine could reverse the resistance of A549 cells to cisplatin. Tetrandrine combined with cisplatin could induce autophagy. Therefore, tetrandrine is a potent autophagy agonist and may be a promising drug for the treatment of non-small cell lung cancer.

14.
Onco Targets Ther ; 10: 447-452, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28176910

RESUMO

In the absence of a driver mutation, chemotherapy is the standard treatment option as first- and second-line therapy for advanced non-small-cell lung cancer (NSCLC). Though a large number of patients are suitable for post second-line therapies, the quality and quantity of the available drugs in this setting is poor. Apatinib, a small molecule vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, is a first-generation oral antiangiogenesis drug approved in the People's Republic of China for use as a subsequent line of treatment for advanced gastric cancer. Herein, we report three cases of advanced NSCLC with epidermal growth factor receptor wild-type and anaplastic lymphoma kinase-negative status, wherein the patients showed partial response to apatinib. Moreover, the three patients have achieved a progression-free survival of 2.8, 5.8, and 6 months, respectively. The main toxicities were hypertension, proteinuria, and hand-foot syndrome. Apatinib may provide an additional option for the treatment of advanced NSCLC, especially for advanced lung adenocarcinoma without a driver mutation.

15.
J Cell Mol Med ; 21(3): 609-620, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27709781

RESUMO

Accumulating data, including those from our laboratory, have shown that the opening of ATP-sensitive potassium channels (KATP ) plays a protective role in pulmonary vascular diseases (PVD). As maintainers of the endothelial framework, endothelial colony-forming cells (ECFCs) are considered excellent candidates for vascular regeneration in cases of PVD. Although KATP openers (KCOs) have been demonstrated to have beneficial effects on endothelial cells, the impact of KATP on ECFC function remains unclear. Herein, this study investigated whether there is a distribution of KATP in ECFCs and what role KATP play in ECFC modulation. By human ECFCs isolated from adult peripheral blood, KATP were confirmed for the first time to express in ECFCs, comprised subunits of Kir (Kir6.1, Kir6.2) and SUR2b. KCOs such as the classical agent nicorandil (Nico) and the novel agent iptakalim (Ipt) notably improved the function of ECFCs, promoting cell proliferation, migration and angiogenesis, which were abolished by a non-selective KATP blocker glibenclamide (Gli). To determine the underlying mechanisms, we investigated the impacts of KCOs on CaMKII, Akt and endothelial nitric oxide synthase pathways. Enhanced levels were detected by western blotting, which were abrogated by Gli. This suggested an involvement of Ca2+ signalling in the regulation of ECFCs by KATP . Our findings demonstrated for the first time that there is a distribution of KATP in ECFCs and KATP play a vital role in ECFC function. The present work highlighted a novel profile of KATP as a potential target for ECFC modulation, which may hold the key to the treatment of PVD.


Assuntos
Trifosfato de Adenosina/metabolismo , Cálcio/metabolismo , Células Endoteliais/metabolismo , Canais KATP/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Canais de Potássio/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Humanos , Neovascularização Fisiológica/fisiologia , Transdução de Sinais/fisiologia
16.
Huan Jing Ke Xue ; 38(7): 2718-2727, 2017 Jul 08.
Artigo em Chinês | MEDLINE | ID: mdl-29964610

RESUMO

A continuous measurement was conducted in Yixing city urban area from 24th August to 15th September using TH-300B continuous online GC-MS instrument during G20 summit in Hangzhou, 2016. The VOCs average mass concentrations of alkane, alkene, aromatic, acetylene, haloalkane hydrocarbons, OVOC and acetonitrile were 11.00×10-9, 1.93×10-9, 5.78×10-9, 1.23×10-9, 4.16×10-9, 10.37×10-9, 0.27×10-9, respectively. The photochemical reaction activity was calculated by using the maximum potential coefficient of Ozone Formation Potential. Alkene and aromatic hydrocarbons were the most active components of OFP. By applying the positive matrix factorization(PMF)model, five major factors were extracted to identify the sources of NMHCs in Yixing city, including industry(42.2%),vehicle exhaust(17.9%), fuel evaporation(20.8%), paint/solvent usage(7.0%)and plant(12.1%). Combined with the conditional probability function(CPF) analysis, source of anthropogenic pollution was related to the distribution of industrial enterprises in the northwest and southeast, while the plant source was related to the forest hilly region of Southwest Yixing city. The effect of air pollutant emission reduction showed that the primary emission air pollutants had declined significantly during the strict control period from 1th to 6th September in G20 summit,2016, and the industry proportion was reduced to 30.5%, whereas the plant proportion increased to 16.8%.

17.
Cardiovasc Drugs Ther ; 30(6): 587-598, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27844183

RESUMO

PURPOSE: Endoplasmic reticulum (ER) stress contributes to pulmonary artery hypertension (PAH). However, the exact roles of ER stress in right ventricular (RV) dysfunction, which is strongly associated with PAH, are largely unknown. Here, we aimed to explore how ER stress affects RV function in a rat PAH model and evaluated the effects of an ER stress inhibitor on RV dysfunction. METHODS: We examined expression changes of an ER marker: chaperone glucose-regulated protein 78 (GRP78), three ER stress sensor proteins: activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1), and protein kinase RNA-like endoplasmic reticulum kinase (PERK), and a key ER stress-induced apoptosis indicator: CCAAT/enhancer-binding protein homologous protein (CHOP), with inflammation indicators: interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and matrix metalloproteinases (MMPs) in RV at 3, 7, 14 and 28 days following a single dose of monocrotaline (MCT) injection, with or without a preventive treatment [4-phenylbutyric acid (PBA)]. RV function was evaluated by histological, molecular and echocardiographic analysis. RESULTS: 1) GRP78 protein expression started to increase (1.5 ± 0.06 fold change) at 3d post MCT injection, even before the formation of PAH. 2) ATF6, IRE1, and PERK showed distinctive expression patterns post MCT injection. 3) CHOP expression remained low at day 3 & 7, but significantly increased at day 14 (p < 0.05), along with the peak of RV cardiomyocytes apoptosis. 4) PBA inhibited ER stress and alleviated remodeling and dysfunction in the RV. CONCLUSIONS: The early phase of ER stress might benefit RV function, whereas the extended phase led to RV cardiomyocyte apoptosis and dysfunction. Inhibition of ER stress by PBA during PAH directly improved RV function.


Assuntos
Estresse do Retículo Endoplasmático , Ventrículos do Coração/fisiopatologia , Hipertensão Pulmonar/fisiopatologia , Disfunção Ventricular Direita/fisiopatologia , Fator 6 Ativador da Transcrição/genética , Fator 6 Ativador da Transcrição/metabolismo , Animais , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Monocrotalina , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Fenilbutiratos/farmacologia , Fenilbutiratos/uso terapêutico , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , Disfunção Ventricular Direita/induzido quimicamente , Disfunção Ventricular Direita/tratamento farmacológico , Disfunção Ventricular Direita/metabolismo , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo
18.
Rev Sci Instrum ; 86(11): 113508, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26628136

RESUMO

Fast z-pinch is a very efficient way of converting electromagnetic energy to radiation. With an 8-10 MA current on primary test stand facility, about 1 MJ electromagnetic energy is delivered to vacuum chamber, which heats z-pinch plasma to radiate soft x-ray. To develop a pulsed high power x-ray source, we studied the applicability of diagnosing x-ray power from tungsten wire array z-pinch with a flat spectral response x-ray diode (FSR-XRD). The detector was originally developed to diagnose radiation of a hohlraum in SG-III prototype laser facility. It utilized a gold cathode XRD and a specially configured compound gold filter to yield a nearly flat spectral response in photon energy range of 0.1-4 keV. In practice, it was critical to avoid surface contamination of gold cathode. It is illustrated that an exposure of an XRD to multiple shots caused a significant change of response. Thus, in diagnosing x-ray power and energy, we used each XRD in only one shot after calibration. In a shot serial, output of FSR-XRD was compared with output of a nickel bolometer. In these shots, the outputs agreed with each other within their uncertainties which were about 12% for FSR-XRD and about 15% for bolometer. Moreover, the ratios between the FSR-XRD and the bolometer among different shots were explored. In 8 shots, the standard deviation of the ratio was 6%. It is comparable to XRD response change of 7%.

19.
Mol Med Rep ; 12(2): 2945-52, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25936382

RESUMO

The present study aimed to investigate the protective effects of iptakalim, an adenosine triphosphate (ATP)-sensitive potassium channel opener, on the inflammation of the pulmonary artery and endothelial cell injury in a hypoxia-induced pulmonary arterial hypertension (PAH) rat model. Ninety-six Sprague-Dawley rats were placed into normobaric hypoxia chambers for four weeks and were treated with iptakalim (1.5 mg/kg/day) or saline for 28 days. The right ventricle systolic pressures (RVSP) were measured and small pulmonary arterial morphological alterations were analyzed with hematoxylin and eosin staining. Enzyme-linked immunosorbent assay (ELISA) was performed to analyze the content of interleukin (IL)-1ß and IL-10. Immunohistochemical analysis for ED1(+) monocytes was performed to detect the inflammatory cells surrounding the pulmonary arterioles. Western blot analysis was performed to analyze the expression levels of platelet endothelial cell adhesion molecule-1 (PECAM-1) and endothelial nitric oxide synthase (eNOS) in the lung tissue. Alterations in small pulmonary arteriole morphology and the ultrastructure of pulmonary arterial endothelial cells were observed via light and transmission electron microscopy, respectively. Iptakalim significantly attenuated the increase in mean pulmonary artery pressure, RVSP, right ventricle to left ventricle plus septum ratio and small pulmonary artery wall remodeling in hypoxia-induced PAH rats. Iptakalim also prevented an increase in IL-1ß and a decrease in IL-10 in the peripheral blood and lung tissue, and alleviated inflammatory cell infiltration in hypoxia-induced PAH rats. Furthermore, iptakalim enhanced PECAM-1 and eNOS expression and prevented the endothelial cell injury induced by hypoxic stimuli. Iptakalim suppressed the pulmonary arteriole and systemic inflammatory responses and protected against the endothelial damage associated with the upregulation of PECAM-1 and eNOS, suggesting that iptakalim may represent a potential therapeutic agent for PAH.


Assuntos
Hipóxia Celular , Endotélio Vascular/efeitos dos fármacos , Propilaminas/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Endotélio Vascular/patologia , Endotélio Vascular/fisiologia , Ensaio de Imunoadsorção Enzimática , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Imuno-Histoquímica , Interleucina-10/análise , Interleucina-1beta/análise , Canais KATP/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiologia , Ratos , Ratos Sprague-Dawley , Traqueia/patologia
20.
ScientificWorldJournal ; 2014: 807620, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24991647

RESUMO

The sudden stiffness reduction in a structure may cause the signal discontinuity in the acceleration responses close to the damage location at the damage time instant. To this end, the damage detection on sudden stiffness reduction of building structures has been actively investigated in this study. The signal discontinuity of the structural acceleration responses of an example building is extracted based on the discrete wavelet transform. It is proved that the variation of the first level detail coefficients of the wavelet transform at damage instant is linearly proportional to the magnitude of the stiffness reduction. A new damage index is proposed and implemented to detect the damage time instant, location, and severity of a structure due to a sudden change of structural stiffness. Numerical simulation using a five-story shear building under different types of excitation is carried out to assess the effectiveness and reliability of the proposed damage index for the building at different damage levels. The sensitivity of the damage index to the intensity and frequency range of measurement noise is also investigated. The made observations demonstrate that the proposed damage index can accurately identify the sudden damage events if the noise intensity is limited.


Assuntos
Análise Numérica Assistida por Computador , Vibração , Análise de Ondaletas
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