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1.
Oncol Rep ; 43(3): 999-1009, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32020232

RESUMO

Acute myeloid leukemia (AML) is a hematological malignancy derived from immature myeloid cells, which have the characteristics of abnormal proliferation and differentiation. Glycolysis has been a popular topic of research in recent years, with increasing uptake and consumption of glucose. The present study aimed to investigate the glycolysis of tumor cells in patients with AML; in particular, how programmed cell death 1 ligand 1 (PD­L1) regulates tumor cells glycolysis using real time PCR (RT­PCR), western blotting and flow cytometry. PD­L1 high expression predicted poor outcome in patients with AML in the public database Gene Expression Profiling Interactive Analysis. PD­L1 expression was decreased in the samples from patients with AML with complete remission compared to that in patients with relapsed or refractory AML. In AML cell lines, glycolysis­associated genes ALDOA, PGK1, LDHA and HK2 were highly expressed in a PD­L1 high­expressed cell line. Overexpressed PD­L1 enhanced glucose consumption and the extracellular acidification rate, accompanied by decreased apoptosis and accumulation of cells in the S phase. In contrast, the apoptosis rate of tumor cells and the percentage of cells in the S phase were significantly increased following PD­L1 knockdown in the THP1 cell line. HK2 and LDHA expression decreased after AML tumor cells were treated with Akt inhibitor or rapamycin. In addition, the PD­L1­overexpressed cell line (PD­L1­OV) MOLM­13 exhibited rapid tumor progression. Glycolysis­associated genes were highly expressed in tumor tissues of PD­L1­OV MOLM­13, with increased Ki67. Based on these findings, PD­L1 may be considered as a suitable marker for prognosis and treatment in the clinical setting.

2.
Inorg Chem ; 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32064866

RESUMO

Mn-based ZrCuSiAs-type pnictides ThMnPnN (Pn = P, As) containing PbO-type Th2N2 layers were synthesized. The crystal and magnetic structures are determined using X-ray and neutron powder diffraction. While neutron diffraction indicates a C-type antiferromagnetic state at 300 K, the temperature dependence of the magnetic susceptibility shows cusps at 36 and 52 K respectively for ThMnPN and ThMnAsN. The susceptibility cusps are ascribed to a spontaneous antiferromagnetic-to-antiferromagnetic transition for Mn2+ moments, which is observed for the first time in Mn-based ZrCuSiAs-type compounds. In addition, measurements of the resistivity and specific heat suggest an abnormal increase in the density of states at the Fermi energy. The result is discussed in terms of the internal chemical pressure effect.

3.
Am J Transl Res ; 12(1): 308-309, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32051755

RESUMO

[This corrects the article on p. 1295 in vol. 10, PMID: 29887946.].

4.
Eur J Med Chem ; 190: 112079, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-32028140

RESUMO

A series of novel triptolide/furoxans hybrids were designed and synthesized as analogues of triptolide, which is a naturally derived compound isolated from the thunder god vine (Tripterygium wilfordii Hook. F). Some of these synthesized compounds exhibited antiproliferative activities in the nanomolar range. Among them, compound 33 exhibited both good antiproliferative activity and NO-releasing ability and the acute toxicity of compound 33 decreased more than 160 times (LD50 = 160.9 mg/kg) than triptolide. Moreover, compound 33 significantly inhibited the growth of melanoma at a low dose (0.3 mg/kg) and showed strong anti-inflammatory activity in vitro and in vivo. These results indicate that compound 33 could be a promising candidate for further study.

5.
Food Chem ; 316: 126336, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32066070

RESUMO

Disodium succinate (WSA) contributes to umami taste in seafoods and it is abundantly found in scallops. However, the actual application of WSA in foods is limited due to a lack of understanding of its taste characteristics and stability. In this study, two-alternative forced choice method was used to determine the relative umami intensity of WSA compared to monosodium glutamate, as well as the relative umami intensity under different conditions (pH and temperature). WSA concentration-taste intensity curve was established, which fitted well with a logarithmic-linear regression (R2 = 0.96). WSA exhibited the strongest umami intensity at 25 °C, 0.1% Na+ addition, and pH 7.5. It also had a good thermal stability, which met the needs of high temperature heating during food processing. In conclusion, this research provided useful information on umami characteristics of WSA and the results widen the application of WSA in the food industry.

6.
Mutagenesis ; 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32067034

RESUMO

The European Regulation on Cosmetics (no. 1223/2009) has prohibited the use of animals in safety testing since March 2009 for ingredients used in cosmetics. Irreversible events at the chromosome level (clastogenesis and aneugenesis) are commonly evaluated by scoring either micronuclei or chromosome aberrations using cell-based genotoxicity assays. Like most in vitro genotoxicity assays, the 2D in vitro micronucleus assay exhibits a poor specificity and does not mimic the dermal route. To address these limitations, the current project aims to develop and validate a 3D micronucleus assay using the EpiSkin™ model. This project is scientifically supported by the Cosmetics Europe Genotoxicity Task Force. In a first step, two key criteria for the development of micronucleus assay, namely, the sufficient yield of cells from the EpiSkin™ model and an acceptable proliferation rate of the basal layer, were assessed and demonstrated. Subsequently, six chemicals (vinblastine, n-ethylnitrosourea, ß-butyrolactone, 2-acetylaminofluorene, 2,4-dichlorophenoland d-limonene) were evaluated in the EpiSkin™ Micronucleus Assay. At least two independent experiments using 48- and 72-h incubations were performed for each chemical. Results showed good inter-experimental reproducibility, as well as the correct identification of all six tested chemicals. The metabolism of 2-acetylaminofluorene on the EpiSkin™ model was also investigated and confirmed by the formation of an intermediate metabolite (2-aminofluorene). These preliminary results from the EpiSkin™ Micronucleus Assay indicate that it is a promising in vitro assay for assessing genotoxicity. The availability and suitability of this test method contribute significantly to the development of non-animal testing methods in China and its impact on the worldwide field.

7.
Food Funct ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32016208

RESUMO

Branched-chain amino acids (BCAAs) are reduced in various protein restricted models, while the detailed role of BCAAs in protein restricted response is still obscure. Thus, the current study mainly investigated the amino acid metabolism in protein restricted piglets and the effects of BCAA balance in a low-protein diet on growth performance, amino acid metabolism, intestinal structure, and gut microbiota with focus on which BCAAs contributed to the protein restricted response. The results showed that protein restriction increased serum Ser, Thr, Ala, Lys, and Trp but reduced His, Cys, Val, and Ile levels. Intestinal amino acid transporters mainly mediated the mechanism of amino acid uptake. The BCAA balance refreshed the serum BCAA pool, which further improved growth performance in protein restricted piglets. Leu, Val, and Ile balances increased serum BCAA concentrations, respectively, and Leu and Val but not Ile enhanced the feed intake and weight gain in protein restricted piglets. In addition, protein restriction impaired the villus structure and increased the number of goblet cells in the ileum. Also, gut microbiota (Spirochaetales, Gammaproteobacteria, Lactobacillales at the order level) were altered in protein restricted pigs, while the BCAA balance markedly improved Gammaproteobacteria, Lactobacillales, and Aeromonadales proliferation, which might mediate growth promotion and amino acid metabolism. In conclusion, protein restriction markedly affected the host amino acid metabolism (i.e., Ser, Thr, Lys, His, BCAAs). The BCAA balance (especially for supplementation with Leu and Val) improved the amino acid metabolism, growth performance, and gut microbiota communities.

8.
Artigo em Inglês | MEDLINE | ID: mdl-32019674

RESUMO

Hypereosinophilic syndrome (HES) is a rare multisystem disease that predominantly includes skin with severe and persistent itching. A lack of understanding about the pathological condition and mechanism of dermatosis caused by HES hinders its treatment. In the present study, we applied a quantitative proteomics approach to characterize the cellular responses of skin tissue to idiopathic HES (IHES) at the proteome level. We identified hundreds of skin tissue proteins that were differentially expressed between IHES patients and healthy individuals. IHES patients display severely damaged microenvironment, including extracellular matrix (ECM) organization and disassembly, immune disorders, decreased metabolic capacity, and susceptibility to microbial infection. Moreover, there was abnormal proliferation of basal epidermal stem cells, which was closely related to high expression of the epigenetic regulator, histone deacetylase 2, providing mechanistic insight into the abnormal epidermal thickening of IHES skin tissues. Overall, our study provides a comprehensive framework for a system-level understanding of IHES-induced dermatosis (IHESiD) tissues at the protein and cell pathway levels. Our findings may facilitate a new approach to diagnosis and treatment to alleviate skin clinical symptoms, monitor the activity of IHES, and determine therapeutic effects.

9.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 12-17, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32027246

RESUMO

OBJECTIVE: To compare the gene mutational spectrum between elderly and young adults with acute myeloid leukemia(AML) based on next generation sequencing(NGS). METHODS: The specimens of 250 AML patients in first affiliated hospital of Zhengzhou University from January 2018 to November 2018 were collected and analyzed retrospectively. The mutation of 22 related genes were detected by using AML NGS chips. Then, the differences between elderly (≥60 years old) and young adults (<60 years old) were compared. RESULTS: The most frequent mutations of 250 patients were as follows: NPM1(22.4%), FLT3-ITD(18.8%), NRAS(17.2%), DNMT3A(14.4%), TET2(11.6%), IDH2(9.6%), Biallelic CEBPA(8.8%), Moallelic CEBPA(8.4%), KIT(8.4%), RUNX1(7.6%), IDH1(7.6%), ASXL1(6.0%), U2AF1(5.2%), SRSF2 (3.2%), SF3B1(3.2%), TP53(2.4%), KRAS(2.0%). The NPM1, CEBPA, DNMT3A mutation significantly increased in intermediate prognosis group while KIT significantly increased in favourable prognosis group. The TET2 and IDH2 mutation rate in elderly patients were significantly higher than that in young patients (21.8% vs 8.7%) (χ2=7.180, P=0.007) and (20.0% vs 6.7%) ( χ2=8.788, P=0.003) respectively. Compared with young patients, the frequencies of DNA methylation and demethylation mutations (including DNMT3A, TET2, IDH1, IDH2) and RNA splicing enzyme mutations (inc-luding SRSF2, SF3B1, U2AF1, ZRSR2) in elderly patients significantly increased(67.3% vs 36.4%) (χ2=16.653, P=0.000) and (23.6% vs 8.7%)(χ2=9.041, P=0.003) respectively. CONCLUSION: The gene mutational spectrum in elderly and young adult AML shows heterogeneity. Compared with young adults, the frequencies of DNA methylation and demethylation mutations and RNA splicing enzyme mutations in elderly patients significantly increase.

10.
Oncotarget ; 11(1): 115, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-32002128

RESUMO

[This corrects the article DOI: 10.18632/oncotarget.16892.].

11.
Sci Total Environ ; 715: 136968, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32014782

RESUMO

Microplastic (MP) pollution is a significant environmental concern due to the persistence of MPs and their potential adverse effects on biota. Most scientific studies have examined the distribution, ingestion, fate, behavior, amount, and effect of MPs. However, few studies have described the development of methods for the removal and remediation of MPs. Therefore, in this review, we summarize the recent literature regarding the microbial-mediated degradation of MPs and discuss the associated degradation characteristics and mechanisms. Different types and combinations of microorganisms, such as bacteria, fungi, bacterial consortia, and biofilms, that can degrade different MPs are categorized. This article summarizes approximately 50 recent papers. Twelve and 6 papers reported that bacteria and fungi, respectively, can degrade MPs. Nine articles indicated that bacterial consortia have the ability to degrade MPs, and 6 articles found that biofilms can also utilize MPs. Furthermore, to evaluate their associated degradation effects, the corresponding structural changes (i.e., macro size, surface morphology, and functional groups) in MPs after microbial degradation are examined. In addition, MP biodegradation is affected by microbial characteristics and environmental factors; therefore, the environmental factors (i.e., temperature, pH and strain activity) influencing MP degradation and the associated degradation effects (i.e., weight loss, degradation rate, and molecular weight change) are generalized. Furthermore, the mechanisms associated with the microbial-mediated degradation of MPs are briefly discussed. Finally, prospects for the degradation of MPs using microbes and future research directions are envisioned. This review provides the first systematic summary of the microbial-mediated degradation of MPs and provides a reference for future studies investigating effective means of MP pollution control.

12.
Eur Radiol ; 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32006174

RESUMO

OBJECTIVES: To develop a dual-modal neural network model to characterize ultrasound (US) images of breast masses. MATERIALS AND METHODS: A combined US B-mode and color Doppler neural network model was developed to classify US images of the breast. Three datasets with breast masses were originally detected and interpreted by 20 experienced radiologists according to Breast Imaging-Reporting and Data System (BI-RADS) lexicon ((1) training set, 103212 masses from 45,433 + 12,519 patients. (2) held-out validation set, 2748 masses from 1197 + 395 patients. (3) test set, 605 masses from 337 + 78 patients). The neural network was first trained on training set. Then, the trained model was tested on a held-out validation set to evaluate agreement on BI-RADS category between the model and the radiologists. In addition, the model and a reader study of 10 radiologists were applied to the test set with biopsy-proven results. To evaluate the performance of the model in benign or malignant classifications, the receiver operating characteristic curve, sensitivities, and specificities were compared. RESULTS: The trained dual-modal model showed favorable agreement with the assessment performed by the radiologists (κ = 0.73; 95% confidence interval, 0.71-0.75) in classifying breast masses into four BI-RADS categories in the validation set. For the binary categorization of benign or malignant breast masses in the test set, the dual-modal model achieved the area under the ROC curve (AUC) of 0.982, while the readers scored an AUC of 0.948 in terms of the ROC convex hull. CONCLUSION: The dual-modal model can be used to assess breast masses at a level comparable to that of an experienced radiologist. KEY POINTS: • A neural network model based on ultrasonic imaging can classify breast masses into different Breast Imaging-Reporting and Data System categories according to the probability of malignancy. • A combined ultrasonic B-mode and color Doppler neural network model achieved a high level of agreement with the readings of an experienced radiologist and has the potential to automate the routine characterization of breast masses.

13.
Medicine (Baltimore) ; 99(3): e18703, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32011445

RESUMO

BACKGROUND: Obesity has become a serious public health issue. The role of Helicobacter pylori (H. pylori) infection in overweight or obesity is inconsistent and controversial. It is very necessary to conduct a systematic review and meta-analysis for determining whether H. pylori infection was associated with risk of overweight/obesity. METHODS: Four databases (PubMed, Web of Science, The Cochrane Library, and EMBASE) will be searched from the inception to January 15, 2019. All observational studies (including cross-sectional, case-control or longitudinal studies) reporting the association between H. pylori infection and overweight/obesity will be included. The primary outcome was the presence and incidence of overweight/obesity in conjunction with H. pylori infection. Study selection, data extraction, and assessment of quality will be conducted independently by 2 reviewers. RevMan 5.3 and STATA 14.0 software will be used for data synthesis. RESULTS: The results of this study will provide a better understanding of the role of H. pylori infection in overweight/obesity among overall population. CONCLUSION: This systematic review and meta-analysis will generate evidence of the association between H. pylori infection and overweight/obesity, and the findings of this study will be published in a peer-reviewed journal.PROSPERO registration number: CRD42019121939.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31919633

RESUMO

PURPOSE: Glioma treatment planning requires precise tumor delineation, which is typically performed with contrast-enhanced (CE) MRI. However, CE MRI fails to reflect the entire extent of glioma. O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) PET may detect tumor volumes missed by CE MRI. We investigated the clinical value of simultaneous FET-PET and CE MRI in delineating tumor extent before treatment planning. Guided stereotactic biopsy was used to validate the findings. METHODS: Conventional MRI and 18F-FET PET were performed simultaneously on a hybrid PET/MR in 33 patients with histopathologically confirmed glioma. Tumor volumes were quantified using a tumor-to-brain ratio ≥ 1.6 (VPET) and a visual threshold (VCE). We visually assessed abnormal areas on FLAIR images and calculated Dice's coefficient (DSC), overlap volume (OV), discrepancy-PET, and discrepancy-CE. Additionally, several stereotactic biopsy samples were taken from "matched" or "mismatched" FET-PET and CE MRI regions. RESULTS: Among 31 patients (93.94%), FET-PET delineated significantly larger tumor volumes than CE MRI (77.84 ± 51.74 cm3 vs. 34.59 ± 27.07 cm3, P < 0.05). Of the 21 biopsy samples obtained from regions with increased FET uptake, all were histopathologically confirmed as glioma tissue or tumor infiltration, whereas only 13 showed enhancement on CE MRI. Among all patients, the spatial similarity between VPET and VCE was low (average DSC 0.56 ± 0.22), while the overlap was high (average OV 0.95 ± 0.08). The discrepancy-CE and discrepancy-PET were lower than 10% in 28 and 0 patients, respectively. Eleven patients showed VPET partially beyond abnormal signal areas on FLAIR images. CONCLUSION: The metabolically active biodistribution of gliomas delineated with FET-PET significantly exceeds tumor volume on CE MRI, and histopathology confirms these findings. Our preliminary results indicate that combining the anatomic and molecular information obtained from conventional MRI and FET-PET would reveal a more accurate glioma extent, which is critical for individualized treatment planning.

15.
Obes Facts ; : 1-16, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31962332

RESUMO

OBJECTIVE: In obese individuals, chronic low-grade inflammation resulting from adipocyte-macrophage interactions is a major cause of adipose tissue dysfunction and metabolic disease. This study investigated the role of MAP kinase phosphatase-5 (MKP-5) in obesity-induced inflammation during macrophage and adipocyte interactions. METHODS: High-fat diet-induced obese mice were used to explore the role of MKP-5 in obesity-induced adipose tissue inflammation. Macrophage polarization was determined by inflammatory cytokine expression in MKP-5-overexpressed or -silenced Raw264.7 cells exposed to palmitate (PA) or M1/M2 macrophage inducers. To uncover the role of MKP-5 during macrophage-adipocyte interactions, a coculture system composed of differentiated 3T3-L1 and Raw264.7 cells was employed. MAPK inhibitors were used to investigate the involvement of MAPK signaling. RESULTS: Increased MKP-5 expression was observed in adipose stromal vascular cells (SVCs) of obese mice. In Raw264.7 cells, MKP-5 promoted the switching of M1 macrophages to an M2 phenotype. Notably, MKP-5 reduced inflammation during the interaction of macrophages and adipocytes. MKP-5 overexpression in primary SVCs attenuated the expression of inflammatory mediators and increased the number of obesity-induced adipose tissue macrophages. MKP-5 suppressed PA-induced inflammation through the inactivation of P38, JNK, and ERK MAPKs. CONCLUSIONS: MKP-5 promotes macrophages to switch from the M1 to the M2 phenotype and is an inflammatory inhibitor involved in obesity-induced adipose tissue inflammation and PA-triggered macrophage inflammation via the P38, JNK, and ERK MAPK pathways. MKP-5 may be developed into a potential therapeutic target for obesity-related diseases, including type 2 diabetes mellitus and insulin resistance.

16.
Obesity (Silver Spring) ; 28(2): 315-322, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31970910

RESUMO

OBJECTIVE: This study aimed to investigate the potential antiobesity effect of genetically modified Escherichia coli Nissle 1917 (EcN-GM) in mice fed a high-fat diet (HFD). METHODS: The mice were randomly divided into six groups: a normal diet group (ND), a HFD group, a HFD + EcN group, and three HFD + EcN-GM groups. The effects of EcN-GM on body weight, food intake, fat pad and organ weight, and an oral glucose tolerance test were measured, in addition to hepatic biochemistry and histological analysis. The mRNA expression of neuropeptides related to food intake regulation in the hypothalamus was also detected. RESULTS: The results showed that EcN-GM decreased body weight, body weight gain, food intake, fat pad weight, and hepatic weight of HFD mice. There were beneficial effects of EcN-GM on blood glucose, hepatic biochemistry, and hepatic histological alterations. A dramatic switch of food intake-regulating gene expression in the hypothalamus was also observed in mice. CONCLUSIONS: This work has revealed that a modified live bacterial therapeutic, EcN-GM, has potential beneficial effects on obesity. This effect may be related to the regulating of the neuropeptide expression of energy intake and expenditure in the hypothalamus. This study demonstrates a successful example of engineered EcN-GM as a novel approach for weight management.

17.
ACS Nano ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31909977

RESUMO

Carbon nanomaterial-based cancer therapy has flourished for decades. However, their practical applications on clinical bases still pose a challenge to address the dilemma of metabolism in vivo. In this study, an attempt is made to design a degradable carbon-silica nanocomposite (CSN) with immunoadjuvant property, which could undergo an enzyme-free degradation process into small particles (~5 nm) and facilitate its clinical application. CSN harbors photothermal and photodynamic properties, and meanwhile as an immunoadjuvant, would help to generate the tumor-associated antigens and mature dendritic cells (DCs). Potent antitumor effects have been achieved in both 4T1 and patient-derived xenograft (PDX) tumor models with tumor inhibition efficiencies of 93.2% and 92.5%, respectively. We believe that this strategy will benefit to the possible clinical translation and carbon-silica nanomaterial-based cancer therapy.

18.
Mol Immunol ; 117: 110-121, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31765840

RESUMO

Although granulocyte colony-stimulating factor(G-CSF) has pathogenic roles in several immune inflammatory diseases, its role in periodontitis has not been investigated. Here we detected local expression of G-CSF using public datasets in the Gene Expression Omnibus (GEO) database, and immune cell infiltration into gingival tissue was estimated based on single-sample gene set enrichment analysis (ssGSEA). G-CSF expression and neutrophil infiltration were also confirmed by human gingival biopsies analysis. Moreover, anti-G-CSF neutralizing antibody was locally administrated to investigate the effects of G-CSF neutralization on neutrophils infiltration and periodontal tissue destruction in periodontitis mice model. Two public datasets (GSE10334 and GSE16134), which included 424 patients with periodontitis and 133 health controls, were used in the analysis. Markedly increased immune cell infiltration and G-CSF expression in gingival tissues were found in the periodontitis group as compared to the control group. The higher expression of G-CSF was correlated with higher infiltration of immune cells, especially with neutrophil infiltration. Analysis of gingival biopsies further confirmed high neutrophil infiltration and G-CSF expression. In addition, anti-G-CSF antibody-treated mice with periodontitis showed significantly reduced alveolar bone resorption and neutrophil infiltration when compared with periodontitis mice treated with isotype control antibody. Also, anti-G-CSF antibody treatment significantly reduced mRNA expression of CXC chemokines (CXCL1, CXCL2 and CXCL3), interleukin 1ß (IL-1ß), IL-6, matrix metalloproteinases 9, receptor activator of nuclear factor κB ligand/osteoprotegerin (RANKL/OPG) ratio and osteoclasts number in periodontal tissues. In summary, neutrophil infiltration and G-CSF expression levels were significantly increased in inflamed gingival tissues. G-CSF neutralization in periodontal inflammation could alleviate neutrophil infiltration and periodontal tissue destruction in experimental periodontitis.

19.
J Cancer Res Clin Oncol ; 146(2): 407-416, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31696302

RESUMO

INTRODUCTION: Next-generation sequencing (NGS)-based assays to understand various mutations and co-occurrence of genomic alterations in non-small cell lung cancer (NSCLC) have enabled understanding of treatment impact on clinical outcomes. METHODS: This retrospective study was conducted in 1353 formalin-fixed paraffin-embedded (FFPE) tissues from surgically resected, pre-TKI-treated NSCLC patients with identified gene alterations. Genomic DNA and RNA extraction was followed by NGS library preparation and sequencing using the Ion Ampliseq Colon and Lung Cancer Gene Panel V2 and the AmpliSeq RNA Lung Cancer Research Fusion Panel. RESULTS: A total of 2328 alterations in 25 genes were detected from the 1293 patients. DNA mutations and RNA fusions co-occurred in 27 patients with TP53 being the most common co-occurring DNA mutation (43.8%) with concurrent ALK fusions. Analysis of the 975 patients with EGFR mutations revealed that the incidence of dual EGFR L858R/T790M mutations was higher compared to EGFR 19del/T790M, and the mean allele fraction (MAF) of T790M was lower compared to 19del in dual EGFR 19del/T790M patients. CONCLUSION: NSCLC patients represented genetically heterogeneous subgroup with a high frequency of co-occurring mutations in cancer-associated pathways. This diverse mutational profile may have key clinical and research implications for understanding the variability of treatment outcome in pre-TKI-treated NSCLC population. The differences in the MAF of EGFR T790M may determine different responses to TKI therapy in patients harboring dual mutations.

20.
Thorac Cancer ; 11(1): 103-112, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31692283

RESUMO

BACKGROUND: Distinction in the mutational profile between the common histological types, lung adenocarcinoma (LUAD) and squamous cell lung carcinoma (LUSC) has been well-established. However, comprehensive mutation profiles of the predominant histological subtypes within LUAD and LUSC remains elusive. METHODS: We analyzed the mutational profile of 318 Chinese NSCLC patients of adenocarcinoma and squamous cell carcinoma predominant subtypes from seven hospitals using capture-based ultra-deep sequencing of 68 lung cancer-related genes. RESULTS: Of the 318 NSCLC patients, 215 were diagnosed with LUAD and 103 with LUSC. Adenocarcinoma in situ and acinar adenocarcinoma were the most predominant subtypes of LUAD. On the other hand, keratinizing squamous cell carcinoma was the most predominant subtype of LUSC. Among the LUAD subtypes, EGFR sensitizing mutations were most prevalent in the invasive lepidic subtype. More than half of the patients with preinvasive adenocarcinoma in situ, minimally invasive, acinar, micropapillary and papillary subtypes were also EGFR-mutants. Patients with colloidal, invasive mucinous, and fetal subtypes had the least number of EGFR mutations. Moreover, KRAS mutations were prevalent in patients with invasive mucinous, colloid, enteric and solid subtypes. A total of 90% of the LUSC patients harbor mutations in TP53, wherein all patients except five with nonkeratinizing were TP53 mutants. PIK3CA amplifications were most prevalent in keratinizing, followed by basaloid and nonkeratinizing subtypes. CONCLUSION: These data suggest that the mutational profiles among the predominant histological subtypes were very distinct, which provided a reliable tool to improve treatment decisions.

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