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1.
Chemosphere ; 239: 124802, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31521933

RESUMO

Pesticides are usually present as mixtures in water environments. Evaluating the toxic effects of individual pesticide may not be enough for protecting ecological environment due to interactions among substances. In this study, we aimed to examine the lethal doses and gene expression changes in zebrafish (Danio rerio) upon exposure to individual and mixture pesticides [malathion (MAL), chlorpyrifos (CHL) and lambda-cyhalothrin (LCY)]. Individual pesticide toxicity evaluation manifested that the toxicity of the three pesticides to D. rerio at various developmental stages (embryonic, larval, juvenile and adult stages) followed the order of LCY > CHL > MAL. On the contrary, the least toxicity to the animals was discovered from MAL. Most of the tested pesticides displayed lower toxicities to the embryonic stage compared with other life stages of zebrafish. Synergistic effects were monitored from two binary mixtures of LCY in combination with MAL or CHL and ternary mixture of MAL + CHL + LCY. The expressions of 16 genes involved in oxidative stress, immunity system, cell apoptosis and endocrine disruption at the mRNA level revealed that embryonic zebrafish were influenced by the individual or mixture pesticides. The expressions of Tnf, P53, TRα, Crh and Cyp19a exerted greater variations upon exposure to pesticide mixtures compared with their individual compounds. Collectively, the transcriptional responses of these genes might afford early warning biomarkers for identifying pollutant exposure, and the data acquired from this study provided valuable insights into the comprehensive toxicity of pesticide mixtures to zebrafish.

2.
Phys Chem Chem Phys ; 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729504

RESUMO

The Z-type hexaferrites Ba3(Zn1-xCox)2Fe24O41 (x = 0.2, 0.4, 0.6, 0.8, defined as Z1-Z4) were synthesized by a sol-gel method. With increasing cobalt concentration, the origin of magnetoelectric (ME) coupling and the effects of crystal parameters, occupation of ions, and magnetocrystalline anisotropy (MCA) on ME current were studied systematically. The mechanism of magnetic phase transition, revealing the evolution of the magnetic order in the temperature range of 10-400 K, was discussed in detail. Our results suggest that the ferroelectricity of Z1-Z4 originates from both inverse Dzyaloshinskii Moriya (DM) interaction and p-d hybridization mechanism. In particular the ME coupling property is only dominated by p-d hybridization with spin-orbit coupling. This study provides an effective way to improve the ME coupling property of hexaferrites, which have potential applications in the design of new electronic devices.

3.
ACS Nano ; 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31715095

RESUMO

Room-temperature mid- and far-infrared photodetectors and energy harvesters meet diverse upcoming demands including health condition monitoring, industrial inspection, and miniaturized power-source for Internet of Things. However, the cryogenic cooling requirement for III-V semiconductors and the inefficient light absorption in two-dimensional (2D) materials, for example, graphene (2.3%) and black phosphorus (∼3%), have hindered mid- and far-infrared optoelectronics from widespread applications. Here, we demonstrate a self-powered infrared photodetector as well as energy harvester via employing vertical photothermoelectric (PTE) effect of a carbon nanotube forest (CNTF). In the self-assembled anti-reflecting CNTF, 99.4% reflection suppression is observed, resulting in a broadband detectivity of 1.9 × 107 cm Hz1/2 in 2.5-25 µm spectral range and peak detectivity of 2.3 × 109 cm Hz1/2 at 4.3 THz via nonlithography fabrication. By virtue of vertical architecture, this photodetector exhibits enhanced sensitivity to weak and unfocused infrared illumination, which mitigates the high actuating power density in conventional PTE or field-effect detectors and renders practical infrared detection in the real life.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31675331

RESUMO

Micro-appearance models offer state-of-the-art quality for cloth renderings. Unfortunately, they usually rely on 3D volumes or fiber meshes that are not only data-intensive but also expensive to render. Traditional surface-based models, on the other hand, are light-weight and fast to render but normally lack the fidelity and details important for design and prototyping applications. We introduce a multi-scale, hybrid model to bridge this gap for thin fabrics. Our model enjoys both the compactness and speedy rendering offered by traditional surface-based models and the rich details provided by the micro-appearance models. Further, we propose a new algorithm to convert state-of-the-art micro-appearance models into our representation while qualitatively preserving the detailed appearance. We demonstrate the effectiveness of our technique by integrating it into a real-time rendering system.

5.
Biosci Rep ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31713581

RESUMO

Kanglaite, a type of Chinese medicine preparation, is considered a promising complementary therapy option for advanced hepatocellular carcinoma (HCC). Although an analysis of the published literature has been performed, the exact effects and safety have yet to be systematically investigated. Therefore, we conducted a wide-ranging online search of electronic databases to provide systematic conclusions; data from 31 trials with 2,315 HCC patients were included. The results indicated that compared with conventional treatment (CT) alone, the combination of kanglaite with CT markedly prolonged patients' 6-month overall survival (OS, P = 0.003), 12-month OS (P < 0.0001), 18-month OS (P = 0.003), 24-month OS (P = 0.03) and 36-month OS (P = 0.0006) and significantly improved the overall response rate (OR = 2.57, 95% CI = 2.10-3.16, P < 0.00001) and disease control rate (OR = 3.10, 95% CI = 2.42-3.97, P < 0.00001) of patients. The quality of life, clinical symptoms and immune function of patients were also obviously improved after combined treatment. The incidence rates of nausea and vomiting (P = 0.04), hepatotoxicity (P = 0.0002), leukopenia (P < 0.00001), thrombocytopenia (P < 0.0001), gastrointestinal side effects (P = 0.01) and fever (P < 0.0009) were lower in the group receiving CT and kanglaite than in the group receiving CT alone. In summary, the combination of kanglaite and CT is safe and more effective in treating HCC than is CT alone, and its application in the clinic is worth promoting.

6.
ACS Appl Mater Interfaces ; 11(43): 40366-40371, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31595743

RESUMO

Integration of selective photodetection and signal storage in a single device, such as organic field-effect transistor (OFET) memories, meets the demands for radiation monitoring and protection. A new strategy is developed to achieve filter-free and selective light monitoring by adopting a solution-processed blend charge-trapping layer in OFET memories, where the charge-trapping layer is composed of phenyl-C61-butyric acid methyl ester (PCBM) dispersed in a polymer electret thin film. The OFET memory without PCBM shows response only to ultraviolet light, whereas the spectral response edges are extended to the visible and near-infrared regions in the corresponding devices with relatively low and high contents of PCBM in the charge-trapping layer, respectively. A set of OFET memories with different PCBM contents is used to qualitatively evaluate the light composition in an optical source. The tunable spectral response in the OFET memories is ascribed to the additional photoassisted charge-trapping paths depending on the blend ratio in the charge-trapping layer. This mechanism may inspire alternative approaches to organic-based optical sensing and monitoring in flexible and wearable electronics.

7.
J Hazard Mater ; 384: 121371, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610344

RESUMO

Highly toxic Cr(VI) poses huge threats to human health and ecosystem. This study utilized biochar obtained from apple wood which is favorable for the formation of high C content biochar for removing Cr(VI) from aqueous media. Cr(VI) removal was highly pH-dependent with the highest Cr(VI) removal efficiency (99.9%) at pH 2.0. Fourier-transform infrared spectroscopy (FTIR) results showed that the functionalities CO and CO on biochar were likely involved in Cr(VI) treatment. Results of X-ray photoelectron spectroscopy (XPS) analysis and X-ray absorption near-edge structure (XANES) spectra indicated that the majority of Cr exhibited as the reduced Cr(III) on the biochar. Confocal micro X-ray fluorescence (µ-XRF) maps confirmed the heterogeneous distribution of Cr on biochar. The electrostatic attraction, Cr(VI) reduction, Cr(III) complexation, and ion exchange likely accounted for the principal processes of Cr(VI) removal from water. These results showed that biochar can be an effective reactive medium for remediation of Cr(VI) in an aqueous solution. This study firstly integrated the Cr(VI) removal data with XANES and confocal µ-XRF mapping to obtain a deeper understanding of Cr speciation and distribution on biochar, which was critical for identifying the key role of functional groups and Cr(VI) removal mechanisms using apple wood biochar.

8.
Sci Rep ; 9(1): 14390, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591515

RESUMO

Phytase is one of the most effective feed additives to increase the availability of phosphorus and minerals by catalyzing the hydrolysis of phytic acid. A modified appA gene (mappA) was transformed into soybean (Glycine max) under the control of a seed-specific promoter from common bean (Phaselous vulgaris). The soybean recombinant phytase showed optimal activity at pH 4.5 and 70 °C. A slight increase in enzyme activity occurred when the recombinant enzyme was pre-incubated with n-hexane. In addition, the phytase activity from our transgenic soybean does not reduce even after 2 hours of extraction with n-hexane at 55~65 °C. In conclusion, the oil extraction process using n-hexane does not inactivate the phytase expressed in the mAppA transgenic soybean, and the meal derived from the transgenic soybean processing can be used as feed supplement to livestock.

9.
Sensors (Basel) ; 19(18)2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31540211

RESUMO

This paper presents microelectromechanical system (MEMS)-based electrochemical seismometers with two pairs of electrodes integrated on one chip. Both theoretical analysis and numerical simulations were conducted to reveal the working principle of the proposed electrochemical seismometers, finding that flow holes distributed on cathodes rather than anodes can produce significantly higher sensitivities. The proposed electrochemical seismometers were fabricated based on conventional micromachined processes with high fabrication repeatability. Sensitivity measurements of the proposed seismometers and their commercial counterpart of CME6011 were conducted, indicating the sensitivities of the proposed seismometer with flow holes on cathodes were two orders higher than the counterpart with flow holes on anodes and one order higher than CME6011 at dominant frequencies. Measurements of random ground motions based on the proposed seismometer with flow holes on cathodes and CME6011 were conducted, producing comparable noise levels without observable ground motions and high correlations in response to random events of ground motions. These results validated the functionality of the proposed electrochemical seismometers, which may contribute to seismic monitoring in the near future.

10.
Int J Biol Macromol ; 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31521663

RESUMO

Peri-prosthetic osteolysis (PPO) often generates after total joint arthroplasty, which can bring implant failure and following revision surgery. Wear debris shed from prostheses strongly enhances bone resorption and attenuates bone formation in osteolytic process. We previously proved that suppression of protein phosphatase 2A (PP2A), a major serine-threonine phosphatase, inhibited wear-debris-induced osteoclastogenesis and alleviated local osteolysis. Whether PP2A inhibition facilitates osteoblastogenesis and bone formation in the osteolytic sites remains unclear. Here, we observed that PP2A inhibition with a selective inhibitor attenuated particle-induced bone destruction by accelerating osteoblast differentiation and promoting bone regeneration. Meanwhile, we proved inhibition of PP2A alleviated the inhibition of osteogenic differentiation by titanium particles in MC3T3-E1 cells. In addition, PP2A inhibition increased ß-catenin expression and enhanced ß-catenin nuclear translocation, compared with that in the vehicle group. ICG-001, a specific inhibitor of ß-catenin, was further applied and was found to weaken the effect of PP2A inhibition on ß-catenin expression and nuclear translocation. Therefore, we demonstrated PP2A inhibition exerts protective effects on osteogenic differentiation mainly by activating Wnt/ß-catenin signaling pathway. Thus, all the results further revealed PP2A could be a promising target for treating PPO and other bone related diseases.

11.
Inorg Chem ; 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31498603

RESUMO

Bis[o-(trifluoromethyl)phenyl]dithiophosphinate is a sulfur-donating ligand capable of providing the largest reported trivalent lanthanide (Ln3+)-actinide (An3+) group separation factors. Literature has shown that the placement and number of the -CF3 functionalities on the aryl rings proximate to the ligating sulfur atoms can significantly impact Ln3+-An3+ extraction and separation factors, but the complexation thermodynamics of -CF3-derivatized aryldithiophosphinates have not been considered to date. This systematic study considers the complexation of three CF3-substituted aryldithiophosphinates-bis(phenyl)dithiophosphinate (LI), [o-(trifluoromethyl)phenyl](phenyl)dithiophosphinate (LII), and bis[o-(trifluoromethyl)phenyl]dithiophosphinate (LIII), with Nd3+ in an ethanolic environment. The chelating ability of NdIII by these ligands follows the order of LIII > LII > LI, which is in line with the reported extraction efficiency. The positive ΔS, as well as positive ΔH, suggests that Nd3+ chelation is entropy-driven and effective desolvation is critical to enabling Nd3+ interaction with otherwise weakly interacting sulfur-containing ligands. Extended X-ray absorption fine structure results confirm thermodynamic investigations and suggest that LI can only form up to 1:2 (M-L) complexes, while LII and LIII form up to 1:3 complexes with Nd3+. All three LIII anions have bidentate interactions with NdIII, but two LII anions have bidentate interactions with Nd3+, while the third LII anion is monodentate. The significant increase in ΔS with each o-CF3 addition suggests aiding desolvation could be central in enabling f-element interaction with weakly interacting donor groups, and this report provides an approach to controlling f-element desolvation as an innovative f-element chelating strategy.

12.
Int J Biol Macromol ; 141: 484-492, 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31479677

RESUMO

Sugarcane bagasse (SCB) was pretreated by sodium hydroxide (SH), alkaline ethanol (AE) and alkaline hydrogen peroxide (AHP), and the solid residue with similar lignin content after different pretreatment was selected. Enzymatic saccharification with different substrates was performed at 2%, 10%, and 20% (w/v) solid loading. After that, the lignin from different substrate was extracted and its structure was characterized. Furthermore, the adsorption capability of isolated lignin to cellulase and its effect on enzymatic hydrolysis were studied. The results showed that, as the substrate content increased from 2% (w/v) to 20% (w/v), the glucose yield after digestion of SH, AE, and AHP pretreated SCB reduced by 41.8%, 35.4%, and 28.7%, respectively. The inhibitory effect of different prepared lignin on the digestibility of Avicel was as follows, SH pretreated lignin (SHL) > cellulase enzymatic hydrolysis lignin (CEL) > AE pretreated lignin (AEL) > AHP pretreated lignin (AHPL), which exhibited positive correlation with its non-productive adsorption capability to cellulase. Lignin samples with low negative zeta potential, high hydrophobicity and high ration of syringyl (S) to guaiacyl (G) were unfavorable for the enzymatic saccharification of cellulose.

13.
Mol Oncol ; 13(11): 2305-2328, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31495056

RESUMO

Formalin-fixed, paraffin-embedded (FFPE), biobanked tissue samples offer an invaluable resource for clinical and biomarker research. Here, we developed a pressure cycling technology (PCT)-SWATH mass spectrometry workflow to analyze FFPE tissue proteomes and applied it to the stratification of prostate cancer (PCa) and diffuse large B-cell lymphoma (DLBCL) samples. We show that the proteome patterns of FFPE PCa tissue samples and their analogous fresh-frozen (FF) counterparts have a high degree of similarity and we confirmed multiple proteins consistently regulated in PCa tissues in an independent sample cohort. We further demonstrate temporal stability of proteome patterns from FFPE samples that were stored between 1 and 15 years in a biobank and show a high degree of the proteome pattern similarity between two types of histological regions in small FFPE samples, that is, punched tissue biopsies and thin tissue sections of micrometer thickness, despite the existence of a certain degree of biological variations. Applying the method to two independent DLBCL cohorts, we identified myeloperoxidase, a peroxidase enzyme, as a novel prognostic marker. In summary, this study presents a robust proteomic method to analyze bulk and biopsy FFPE tissues and reports the first systematic comparison of proteome maps generated from FFPE and FF samples. Our data demonstrate the practicality and superiority of FFPE over FF samples for proteome in biomarker discovery. Promising biomarker candidates for PCa and DLBCL have been discovered.

14.
Bioresour Technol ; 292: 121993, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31442837

RESUMO

Obtaining higher amount of final sugars with low cellulase dosage has great economic benefits for the industrial biorefinery of lignocellulosic biomass. The optimization of accessory enzymes and additives were performed using single factor and orthogonal experiment firstly, after that, fed-batch strategy was applied to enhance the high-solids enzymatic hydrolysis efficiency of alkali pretreated sugarcane bagasse (SCB). A novel enzymatic hydrolysis procedure with 22% (w/v) substrate content and cellulase dosage of only 4 FPU/g dry biomass (DM) was developed, after digested for 48 h, the achieved glucose titer, yield and productivity were 122 g/L, 80% and 2.54 g L-1 h-1, respectively. Results obtained in this study indicated a potential finding for the industrial application of lignocellulosic biomass.


Assuntos
Celulase , Saccharum , Álcalis , Celulose , Hidrólise
15.
Bull Environ Contam Toxicol ; 103(4): 585-589, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31428844

RESUMO

This study investigated the growth, apoptosis and oxidative stress of the cyanobacterium Microcystis viridis exposed to glyphosate. Results showed that growth parameters, namely, cell destiny, chlorophyll a content, and protein content, were affected by glyphosate. The viability of the treated cells was monitored to further investigate the toxicity of glyphosate on M. viridis. After 24 and 48 h of exposure, glyphosate enhanced superoxide dismutase (SOD) activity and decreased malondialdehyde (MDA) concentration. The decrease in the MDA concentration might be caused by the enhanced SOD activity. This study helped elucidate the toxic effects of glyphosate on cyanobacteria and contributed to environmental assessment and protection.

16.
Ying Yong Sheng Tai Xue Bao ; 30(7): 2338-2344, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31418237

RESUMO

To obtain salt-alkali tolerant strains which could be potenially used to improve the quality of saline-alkali soil, soil samples collected from Dongying, Shandong Province were diluted and spread to modified Gibbson medium with pH 9 and salt concentration of 100 g·L-1. A total of 18 bacteria strains were obtained. By increasing salt concentration and pH, an extremely salt-alkali tole-rant strain N14 was screened which could grow at pH 12 and salt concentration of 20%. We analyzed the morphological, physiological and biochemical characters and 16S rDNA sequence of N14. The strain N14 was identified as Bacillus marmarensis. N14 bacterial fertilizer significantly increased the biomass of wheat, improved shoot height, fresh weight and dry weight by 21.8%, 57.9% and 41.7%, respectively. The addition of N14 bacterial fertilizer significantly increased the chlorophyll a, chlorophyll b and total chlorophyll in wheat by 36.4%, 20.0% and 31.7%, respectively. It significantly increased the activities of invertase, urease and alkaline phosphatase in saline-alkali soil by 23.2%, 68.8% and 106.5%, respectively. It also significantly increased the activities of superoxide dismutase, peroxidase and catalase in roots by 109.6%, 17.8% and 50%, respectively. The concentration of malondialdehyde in wheat roots was significantly reduced by 39.8%. This study provided an idea for the application of extreme salt-alkali tolerant bacteria and a way for improvement of saline-alkali soil.


Assuntos
Fertilizantes , Plantas Tolerantes a Sal/fisiologia , Triticum/fisiologia , Agricultura , Álcalis , Clorofila A , Solo , Microbiologia do Solo
17.
Cell Res ; 29(9): 778, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31395957

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

18.
Ecotoxicol Environ Saf ; 183: 109492, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31421534

RESUMO

Bisphenol A (BPA) is an artificial xenoestrogen widely used in consumer products containing polycarbonate plastics and epoxy resins. Exposure to BPA occurs through various channels, including ingestion of contaminated food and water. Autophagy is an important catabolic pathway that plays an important role in liver lipid metabolism. Evidence suggests that BPA exposure causes abnormal lipid droplet accumulation in liver, but the mechanism remains unknown. Here, we investigate the function of BPA in lipid metabolism and autophagy. BPA exposure increases lipid droplet and ROS accumulation which is accompanied by a defect in the fusion of the autophagosome to the lysosome. BPA exposure decreases the translocation of Stx17 to lysosome resulting in the autophagogome-lysosome fusion defect. There is no defect in the formation of the autophagosome indicated by increased LC3-II, p62 level, GFP/mRFP-LC3 ratios and decreased colocalization between LAMP2 with LC3. Mechanistically, BPA exposure reduces autophagy SNARE complex formation. Promoting autophagy by autophagy inducer (Torin2) partially reverses lipid droplet accumulation caused by BPA exposure. In summary, our results demonstrate BPA exposure inhibits autophagy resulting in decreased lipid droplet degradation and increased ROS levels. These results also provide a novel implication between autophagosome-lysosome fusion.

19.
Obes Facts ; 12(4): 476-488, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31394543

RESUMO

BACKGROUND: Childhood overweight and obesity have become some of the most serious public health problems in the 21st century and have a significant impact on affected children as they grow into adulthood. OBJECTIVE: The purpose of this study was to evaluate the overweight and obesity status and their main influencing factors in preschool children aged 2-7 years in urban areas of China between 2011 and 2017. METHODS: A stratified cluster random sampling method was used to conduct a sample survey of children aged 2-7 years in Xiamen, one of China's five special economic zones. The 56,738 participants (29,444 boys, 27,294 girls) were examined at three time points (15,757 in 2011, 19,098 in 2014, and 21,883 in 2017), and were analyzed for factors influencing obesity. RESULTS: Between 2011 and 2017, the prevalence of overweight and obesity in preschool children between 2 and 7 years old was 10.91 and 5.66%, respectively. The overweight and obesity rates were higher in boys (11.85 and 7.11%) than in girls (9.90 and 4.09%), and the difference was statistically significant (p < 0.01). In the past 7 years, the overweight and obesity rates showed a downward trend in both boys and girls (p < 0.01). The peak ages for overweight were 6 years in boys and 2 years in girls, while the obesity rate peaked at 6 years. In those children with obesity, the proportion of those with moderate to severe obesity decreased from 40.70% in 2011 to 32.80% in 2017. Multiple stepwise regression analysis showed that children who were averse to sports activities preferred greasy foods and had earlier introduction of solid foods as infants, as well as those who were born at a high birth weight, ate fast, and those with parents with obesity were more likely to have obesity themselves (p < 0.05). CONCLUSIONS: Although preventative and control measures for childhood obesity have achieved initial results, Chinese preschool children remain to have high levels of overweight and obesity. It is therefore necessary to strengthen monitoring of overweight and obesity in preschool-aged children and implement appropriate interventions when necessary.

20.
J Thorac Oncol ; 14(11): 1912-1923, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31446140

RESUMO

BACKGROUND: Understanding the genomic landscape and immune microenvironment features of preinvasive and early invasive lung adenocarcinoma may provide critical insight and facilitate development of novel strategies for early detection and intervention. METHODS: A total of 80 tumor tissue samples and 30 paired histologically normal lung tissue samples from 30 patients with adenocarcinoma in situ (AIS) (n = 8), minimally invasive adenocarcinoma (MIA) (n = 8), and invasive adenocarcinoma (IAC) (n = 14) were subjected to multiregion whole exome sequencing and immunohistochemistry staining for CD8 and programmed death ligand 1 (PD-L1). RESULTS: All tumors, including AIS, exhibited evidence of genomic intratumor heterogeneity. Canonical cancer gene mutations in EGFR, erb-b2 receptor tyrosine kinase 2 gene (ERBB2), NRAS, and BRAF were exclusively trunk mutations detected in all regions within each tumor, whereas genes associated with cell mobility, gap junction, and metastasis were all subclonal mutations. EGFR mutation represented the most common driver alterations across AIS, MIA, and IAC, whereas tumor protein p53 gene (TP53) was identified in MIA and IAC but not in AIS. There was no difference in PD-L1 expression among AIS, MIA, and IAC, but the CD8 positivity rate was higher in IAC. Tumors positive for both PD-L1 and CD8 had a larger proportion of subclonal mutations. CONCLUSIONS: Mutations in EGFR, ERBB2, NRAS, and BRAF are early clonal genomic events during carcinogenesis of lung adenocarcinoma, whereas TP53 and cell mobility, gap junction, and metastasis-related genes may be late events associated with subclonal diversification and neoplastic progression. Genomic intratumor heterogeneity and immunoediting are common and early phenomena that may have occurred before the acquisition of invasion.

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