To evaluate the diagnostic performances of detecting circulating tumor cells (CTCs) and tumor cells in bronchoalveolar lavage fluid (BALF) for peripheral lung cancer.
A total of 247 patients with ...lung cancer and 70 cases with benign lung disease were recruited in this study. Peripheral blood and BALF samples were collected, in which the tumor cells were enriched by negative immunomagnetic selection and detected by fluorescence in situ hybridization (FISH) of chromosome enumeration probe 8 (CEP8). The levels of tumor-associated markers (e.g., CEA, CA125, and NSE) in peripheral blood plasma were measured by using electrochemiluminescence.
The numbers of CTCs detected in peripheral blood were significantly higher in patients with lung cancer than those with benign lung disease (5.78±0.57
1.13±0.39, Z=-8.64, P<0.01). Similarly, tumor cells count in BALF of malignancy were higher than that of benign lesions (6.76±0.89
0.89±0.23, Z=-6.254, P<0.01). However, as for patients with lung cancer and benign lung disease, the numbers of tumor cells in peripheral blood were comparable with those in BALF (both P>0.05). Detecting CTCs and tumor cells in BALF had similar areas under curves (AUC =0.871 and 0.963, respectively; P>0.05) in discriminating benign lesions from lung cancer (sensitivity 83.8% and 92.6%, specificity 86.5% and 99.9%, respectively), both of which were larger than those of NSE, CEA, and CA125 (AUC =0.564, 0.512 and 0.554, respectively; all P<0.05). The diagnostic performances of discriminating benign lesions and lung cancer in BALF and peripheral blood were both in concordance with that of histopathology (kappa values 0.662 and 0.569, respectively; both P<0.001).
Detecting tumor cells in peripheral blood and BALF may sensitive to identify benign and malignant peripheral lung lesions and be of value for early diagnosis of lung cancer.
Homocysteine (Hcy) could induce apoptosis of endothelial cells (ECs). Dimethylarginine dimethylaminohydrolase 2 (DDAH2) is recognized as a protective factor to improve the endothelial function. ...Defect of DDAH2 has been confirmed to be involved in the Hcy-induced dysfunction of endothelial NO system. This study was to determine whether Hcy could inhibit DDAH2 expression and induce apoptosis of ECs via increasing DNA methylation level of DDAH2 promoter and whether DNA methylation inhibitor 5-azacytidine (5-aza) could attenuate the effect of Hcy on ECs. Firstly, human umbilical vein endothelial cells (HUVECs) were treated by Hcy with or without 5-aza for 48 h. MTT assay showed that Hcy reduced the viability of HUVECs in a dose-dependent manner. The level of asymmetric dimethylarginine (ADMA) and the apoptosis rate of HUVECs treated with Hcy at 1.0 mM were increased significantly compared with that of control. Moreover, we found that mRNA level of DDAH2 was down-regulated and DNA methylation level of DDAH2 promoter was increased significantly in HUVECs treated with Hcy, in concomitance with up-regulated protein level of DNA methyltransferase 1 (DNMT1). Furthermore, we also found that 5-aza could neutralize the effect of Hcy on ECs through up-regulating mRNA level of DDAH2 and inducing demethylation of DDAH2 promoter. In conclusion, hypermethylation of DDAH2 contributes to Hcy induced apoptosis of ECs. Modulating DNA methylation status of DDAH2 promoter may be a potential strategy for treatment of endothelial dysfunction.
Recent studies suggested that endothelium is a main source of reactive oxygen species (ROS) and the major source was via NADPH oxidase pathway. Various stimuli including lysophosphatidylcholine ...(LPC), a major component of oxidized low-density lipoprotein (ox-LDL), can enhance the activity of NADPH oxidase and lead to a marked ROS generation. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) synthase (NOS) inhibitor, which is synthesized by protein arginine methyltransferase I (PRMT I) and degraded by dimethylarginine dimethylaminohydrolase (DDAH) in endothelial cells. Much evidence showed that ADMA was closely related to endothelial dysfunction. Our previous study showed that LPC elevated ADMA level in endothelial cells via increasing oxidative stress, but the precise cellular mechanism is not defined yet. The present study was to explore the mechanism of NADPH oxidase in LPC-induced elevation of ADMA. In LPC-treated endothelial cells, the ROS production, cell viability, ADMA and NO levels, the activity of DDAH and expression of PRMT I were detected. Treatment with LPC (10 μg/ml) for 24 h markedly increased intracellular ROS production, the expression of PRMT I, level of ADMA, decreased the concentration of NO and the activity of DDAH. These effects were attenuated by diphenyliodonium, the NADPH oxidase inhibitor. In summary, the present results suggested that LPC-induced elevation of ADMA was due to reduction of DDAH activity and the up-regulation of PRMT expression by stimulation of ROS production via NADPH oxidase pathway.
Abstract Asymmetric dimethylarginine (ADMA), a major endogenous nitric oxide (NO) synthase inhibitor, is thought to be a key contributor for endothelial dysfunction. Decrease in activity of ...dimethylarginine dimethylaminohydrolase (DDAH), a major hydrolase of ADMA, causes accumulation of ADMA in some risk factors of atherosclerosis, including hypercholesterolemia. Taurine is a semiessential amino acid that has previously been shown to have endothelial protective effects. The present study was to test whether the protective effect of taurine on endothelial function is related to modulation of the DDAH/ADMA pathway. A single injection of native LDL (4 mg/kg, i.v.) markedly reduced endothelium-dependent vasorelaxation and the plasma level of NO, and increased plasma concentrations of ADMA, malondialdehyde (MDA) and tumor necrosis factor-α (TNF-α). Treatment with taurine in vivo (60 or 180 mg/kg) significantly attenuated the inhibition of endothelium-dependent vasorelaxation and the reduced level of NO, and decreased the elevated levels of ADMA, MDA, and TNF-α. Incubation human umbilical vein endothelial cells (HUVECs) with ox-LDL (100 μg/ml) for 24 h markedly increased the medium levels of lactate dehydrogenase (LDH), ADMA, TNF-α and MDA, and decreased the level of NO in the medium and the intracellular activity of DDAH. Taurine (1 or 5 μg/ml) significantly attenuated the increases in the levels of LDH, ADMA, TNF-α and MDA, and the decrease in the level of NO and the activity of DDAH induced by ox-LDL in HUVECs. The present results suggested that taurine protected against endothelial dysfunction induced by native LDL in vivo or by ox-LDL in endothelial cells, and the protective effect of taurine on the endothelium is related to decrease in ADMA level by increasing of DDAH activity.
CD38 contains an ADP ribosylcyclase domain that mediates intracellular Ca(2+) signaling by the production of cyclic ADP-ribose (cADPR), but the mechanisms by which the agonists activate this enzyme ...remain unclear. The present study tested a hypothesis that a special lipid-raft (LR) form, ceramide-enriched lipid platform, contributes to CD38 activation to produce cADPR in response to muscarinic type 1 (M(1)) receptor stimulation in bovine coronary arterial myocytes (CAMs). By confocal microscopic analysis, oxotremorine (Oxo), an M(1) receptor agonist, was found to increase LR clustering on the membrane with the formation of a complex of CD38 and LR components such as GM(1), acid sphingomyelinase (ASMase), and ceramide, a typical ceramide-enriched macrodomain. At 80 microM, Oxo increased LR clustering by 78.8%, which was abolished by LR disruptors, methyl-beta-cyclodextrin (MCD), or filipin. With the use of a fluorescence resonance energy transfer (FRET) technique, 15.5+/-1.9% energy transfer rate (vs. 5.3+/-0.9% of control) between CD38 and LR component, ganglioside M(1) was detected, further confirming the proximity of both molecules. In the presence of MCD or filipin, there were no FRET signals detected. In floated detergent-resistant membrane fractions, CD38 significantly increased in LR fractions of CAMs treated by Oxo. Moreover, MCD or filipin attenuated Oxo-induced production of cADPR via CD38. Functionally, Oxo-induced intracellular Ca(2+) release and coronary artery constriction via cADPR were also blocked by LR disruption or ASMase inhibition. These results provide the first evidence that the formation of ceramide-enriched lipid macrodomains is crucial for Oxo-induced activation of CD38 to produce cADPR in CAMs, and these lipid macrodomains mediate transmembrane signaling of M(1) receptor activation to produce second messenger cADPR.
Aim It has been reported that Ginkgo biloba extract (GBE) is an inducer or inhibitor of microsomal cytochrome P450 (CYP) 2C19, and diazepam is a substrate of CYP2C19. Thus, it could be expected that ...GBE may alter the metabolism of diazepam. Methods The pharmacokinetic parameters of diazepam and one of its metabolites, N-demethyldiazepam, were compared after oral administration of diazepam (10 mg) in the absence or presence of oral GBE (120 mg bid, for 28 days) in 12 healthy volunteers. The pharmacokinetic analysis was performed using a noncompartmental method. Results The 90% confidence intervals (CIs) of the ratios of mean pharmacokinetic parameters of diazepam presence and absence of GBE were well within the 80-125% bioequivalence range, indicating no pharmacokinetic interaction. The ratio of AUC₀₋₄₀₈ with GBE to AUC₀₋₄₀₈ without GBE was 95.2 (90%CI: 91.6-98.8) and 101.8 (90%CI: 99.4-104.1) for diazepam and N-desmethyldiazepam, respectively. The two drugs were well tolerated, and no drug-related serious adverse events were reported. Conclusion The above data suggest that GBE, when taken in normally recommended doses over a 4-week time period, may not affect the pharmacokinetics of diazepam via CYP2C19 and the excretion of N-desmethyldiazepam in healthy volunteers. No drug-drug interaction was observed between GBE and diazepam.
The metacognitive deficit in awareness of one's own mental states is a core feature of schizophrenia (SZ). The previous studies suggested that the metacognitive deficit associates with clinical ...symptoms. However, the neural mechanisms underlying the relationship remain largely unknown. We here investigated the neural activities associated with the metacognitive deficit and the neural signatures associated with clinical symptoms in 38 patients with SZ using functional magnetic resonance imaging with a perceptual decision‐making task accompanied with metacognition, in comparison to 38 age, gender, and education matched healthy control subjects. The metacognitive deficit in patients with SZ was associated with reduced regional activity in both the frontoparietal control network (FPCN) and the default mode network. Critically, the anticorrelational balance between the two disrupted networks was substantially altered during metacognition, and the extent of alteration positively scaled with negative symptoms. Conversely, decoupling between the two networks was impaired when metacognitive monitoring was not required, and the strength of excessive neural activity positively scaled with positive symptoms. Thus, disruptions of the FPCN and the default mode network underlie the metacognitive deficit, and alternations of network balance between the two networks correlate with clinical symptoms in SZ. These findings implicate that rebalancing these networks holds important clinical potential in developing more efficacious therapeutic treatments.
•The dynamic contact displacement is very sensitive to oscillating frequency.•Piezoelectric effect increases the peak value of dynamic contact stiffness factor.•Dynamic contact stiffness is sensitive ...to elastic and dielectric constants.
Based on the perturbation method, axisymmetric contact vibration of a rigid spherical punch on a piezoelectric half-space is studied in this paper. It is assumed that the rigid punch is a perfect insulating body with zero electric charge distribution. A compressive force composed of a static force and a time-harmonic force is applied to the spherical punch normally on the top of the surface. The variable contact radius and contact pressure are caused at the contact region for this dynamic contact problem. With the aid of Hankel integral transform technique, the dynamic contact model is established and the dynamic contact stiffness is derived from different contact displacement conditions, including two-point and one-point displacement conditions. Numerical examples are provided to show the effects of the oscillating frequency, contact displacement condition, internal friction, piezoelectric effect and material constants on the dynamic contact stiffness.
We present the first results of an ensemble and systematic survey of oscillation mode variability in pulsating hot B subdwarf (sdB) and white dwarf stars observed with the original Kepler mission. ...The satellite provides uninterrupted high-quality photometric data with a time baseline that can reach up to 4 yr collected on pulsating stars. This is a unique opportunity to characterize long-term behaviors of oscillation modes. A mode modulation in amplitude and frequency can be independently inferred by its fine structure in the Fourier spectrum, from the sLSP, or with prewhitening methods applied to various parts of the light curve. We apply all these techniques to the sdB star KIC 3527751, a long-period-dominated hybrid pulsator. We find that all the detected modes with sufficiently large amplitudes to be thoroughly studied show amplitude and/or frequency variations. Components of three identified quintuplets around 92, 114, and 253 Hz show signatures that can be linked to nonlinear interactions according to the resonant mode coupling theory. This interpretation is further supported by the fact that many oscillation modes are found to have amplitudes and frequencies showing correlated or anticorrelated variations, a behavior that can be linked to the amplitude equation formalism, where nonlinear frequency corrections are determined by their amplitude variations. Our results suggest that oscillation modes varying with diverse patterns are a very common phenomenon in pulsating sdB stars. Close structures around main frequencies therefore need to be carefully interpreted in light of this finding to secure a robust identification of real eigenfrequencies, which is crucial for seismic modeling. The various modulation patterns uncovered should encourage further developments in the field of nonlinear stellar oscillation theory. It also raises a warning to any long-term project aiming at measuring the rate of period change of pulsations caused by stellar evolution, or at discovering stellar (planetary) companions around pulsating stars using timing methods, as both require very stable pulsation modes.
Comprehensive measurements were conducted in winter 2018 and combined with RMPAS-Chem model simulations to analyze the regional transport mechanisms of atmospheric pollutants over the North China ...Plain. The instruments used consisted of four Vaisala CL51 ceilometers for planetary boundary layer (PBL) heights and aerosol backscatter profiles, two wind profilers, one radiosonde for the profiles of meteorological variables, and an instrumented King-Air 350 aircraft for the profiles of atmospheric pollutants and meteorological variables. Additionally, observations from Environmental Protection Bureau stations were also analyzed, including hourly concentrations of surface PM2.5, SO2, NO2, CO, and O3. The results suggest that regional atmospheric pollutant transport is driven by a combination of topography and PBL processes. First, a mountain-induced vertical vortex forms over downwind regions; this elevates ground pollutants to form an elevated pollutant layer (EPL) at an altitude of 1.4–1.7 km. The EPL is then transported to Beijing via an enhanced southerly wind. Finally, the pollutants in the EPL are transported downward to the surface through PBL processes.
•The mountain-induced vortex elevated surface pollutants to high layer.•Pollutant in the EPL was transported downward to the surface through PBL process.•Regional atmospheric pollutant transport mechanisms over NCP are suggested.
PDF
