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1.
Food Chem ; 339: 127863, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32871299

RESUMO

In this work, one kind of zeolite imidazole frameworks containing bovine serum albumin stabilized Au nanoclusters (AuNCs), ß-galactosidase (ß-Gal) and glucose oxidase (GOx) (AuNCs/ß-Gal/GOx@ZIF-8) were obtained to detect lactose. Compared with other fluorescent nano-materials, AuNCs show distinct advantages as a guest species in ZIF-8, specifically their extremely small size (<1 nm), simple synthesis, excellent biocompatibility and high stability. Furthermore, the bovine serum albumin on their surfaces can promote the formation of ZIF-8 coating; thus, AuNCs were co-encapsulated in ZIF-8 with the enzymes together. X-ray diffraction (XRD) analysis indicates the composite possesses the similar crystalline structure with pure ZIF-8. Fluorescence microscope images, Fourier transform infrared spectra and energy dispersive X-ray spectroscopy indicate the presence of AuNCs in the composite. Owing to the high local concentrations of the fluorescent probe and the quenching agent in AuNCs/ß-Gal/GOx@ZIF-8, the quenching rate was enhanced 3.4-fold that of free AuNCs and enzymes in solution.

2.
J Hazard Mater ; 401: 123408, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32763700

RESUMO

Flexible reverse osmosis (FLERO) is a newly proposed technology for purifying and saving water simultaneously by recycling brine to inlet water. However, it is unknown if and how much FLERO may compromise micropollutant treatment efficiency. Hence, this study examined FLERO in removing twenty disinfection byproducts (DBPs) from simulated water under a constant 80% water recovery condition. The results achieved ≥ 80.8% removals for most of DBPs while varying ionic strength, methanol content, and water matrix affected only small DBPs. From chemical structure perspective, the removals of DBPs were ranked as tetra- ≥ tri- ≥ di- ≥ mono- DBPs for compounds containing identical functional groups (FGs) and halogen types, iodinated ≥ bromated ≥ chlorinated DBPs for compounds with identical FG and halogenation degrees, and HAAs ≥ HALs ≈ HMs for compounds with identical halogenation types and degrees. From chemical property viewpoint, the rejections of DBPs were modeled well (R2 = 0.76) by a quantitative structure-activity relationship model that incorporates four parameters (i.e., molecular volume, octanol-water partitioning coefficient, steric and electronic effects). From membrane-pollutant interaction standpoint, we for the first time revealed membrane trapping/sorption as another important mechanism for DBPs removal besides previously-known mechanisms like size exclusion and electrostatic repulsion.

3.
PLoS One ; 15(11): e0240909, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33151975

RESUMO

Speakers' memory of sentence structure can persist and modulate the syntactic choices of subsequent utterances (i.e., structural priming). Much research on structural priming posited a multifactorial account by which an implicit learning process and a process related to explicit memory jointly contribute to the priming effect. Here, we tested two predictions from that account: (1) that lexical repetition facilitates the retrieval of sentence structures from memory; (2) that priming is partly driven by a short-term explicit memory mechanism with limited resources. In two pairs of structural priming and sentence structure memory experiments, we examined the effects of structural priming and its modulation by lexical repetition as a function of cognitive load in native Dutch speakers. Cognitive load was manipulated by interspersing the prime and target trials with easy or difficult mathematical problems. Lexical repetition boosted both structural priming (Experiments 1a-2a) and memory for sentence structure (Experiments 1b-2b) and did so with a comparable magnitude. In Experiment 1, there were no load effects, but in Experiment 2, with a stronger manipulation of load, both the priming and memory effects were reduced with a larger cognitive load. The findings support an explicit memory mechanism in structural priming that is cue-dependent and attention-demanding, consistent with a multifactorial account of structural priming.

4.
Nat Prod Res ; : 1-6, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33183086

RESUMO

The chemical profile and phytotoxic activity of the essential oil extracted from Artemisia sieversiana was investigated. In total 17 compounds were identified by GC/MS, representing 99.17% of the entire oil, among which α-thujone (64.46%) and eucalyptol (10.15%) were the most abundant constituents. The major components, their mixture as well as the essential oil exhibited significant phytotoxic activity against Amaranthus retroflexus, Medicago sativa, Poa annua and Pennisetum alopecuroides, with their IC50 values ranged from 1.55 ∼ 6.21 mg/mL (α-thujone), 1.42 ∼ 17.81 mg/mL (eucalyptol), 0.23 ∼ 1.05 mg/mL (the mixture), and 1.89 ∼ 4.69 mg/mL (the essential oil) on the four tested species. The mixture of the major constituents exerted more potent effect compared with each individual compound, indicating the possible involvement of synergistic effect of these two compounds.

6.
Clin Chim Acta ; 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33181148

RESUMO

Atherosclerosis is one of the chronic progressive diseases, which is caused by vascular injury and promoted by the interaction of various inflammatory factors and inflammatory cells. In recent years, kruppel-like factor 4 (KLF4), a significant transcription factor that participated in cell growth, differentiation and proliferation, has been proved to cause substantial impacts on regulating cardiovascular disease. This paper will give a comprehensive summary to highlight KLF4 as a crucial regulator of foam cell formation, vascular smooth muscle cells (VSMCs) phenotypic transformation, macrophage polarization, endothelial cells inflammation, lymphocyte differentiation and cell proliferation in the process of atherosclerosis. Recent studies show that KLF4 may be an important "molecular switch" in the process of improving vascular injury and inflammation under harmful stimulation, suggesting that KLF4 is a latent disease biomarker for the therapeutic target of atherosclerosis and vascular disease.

7.
J Clin Neurosci ; 81: 421-425, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33222954

RESUMO

INTRODUCTION: The efficacy of vagus nerve stimulation (VNS) for the rehabilitation of stroke remains controversial. We conduct a systematic review and meta-analysis to explore the influence of VNS on the rehabilitation of stroke. METHODS: We search PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through March 2020 for randomized controlled trials (RCTs) assessing the effect of VNS on the rehabilitation of stroke. This meta-analysis is performed using the random-effect model. RESULTS: Three RCTs are included in the meta-analysis. Overall, compared with control group in stroke, VNS is associated with significantly improved FMA-UE (SMD = 3.86; 95% CI = 1.19 to 6.52; P = 0.005) and Motor Function Test (SMD = 0.33; 95% CI = 0.04 to 0.62; P = 0.03), but has no obvious impact on Box and Block Test (SMD = -0.31; 95% CI = -3.48 to 2.86; P = 0.85), Nine-Hole Peg Test (SMD = 8.35; 95% CI = -40.59 to 57.28; P = 0.74), atrial fibrillation (RR = 3.46; 95% CI = 0.39 to 30.57; P = 0.26) or adverse events (RR = 0.59; 95% CI = 0.21 to 1.61; P = 0.30). CONCLUSIONS: VNS may be beneficial to the rehabilitation of stroke.

8.
Aging (Albany NY) ; 122020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33226370

RESUMO

In this meta-analysis, we systematically investigated the correlation between single nucleotide polymorphisms (SNPs) and pancreatic cancer (PC) risk. We searched PubMed, Network Science, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Science and Technology Periodical Database (VIP), and Wanfang databases up to January 2020 for studies on PC risk-associated SNPs. We identified 45 case-control studies (36,360 PC patients and 54,752 non-cancer individuals) relating to investigations of 27 genes and 54 SNPs for this meta-analysis. Direct meta-analysis followed by network meta-analysis and Thakkinstian algorithm analysis showed that homozygous genetic models for CTLA-4 rs231775 (OR =0.326; 95% CI: 0.218-0.488) and VDR rs2228570 (OR = 1.976; 95% CI: 1.496-2.611) and additive gene model for TP53 rs9895829 (OR = 1.231; 95% CI: 1.143-1.326) were significantly associated with PC risk. TP53 rs9895829 was the most optimal SNP for diagnosing PC susceptibility with a false positive report probability < 0.2 at a stringent prior probability value of 0.00001. This systematic review and meta-analysis suggests that TP53 rs9895829, VDR rs2228570, and CTLA-4 rs231775 are significantly associated with PC risk. We also demonstrate that TP53 rs9895829 is a potential diagnostic biomarker for estimating PC risk.

9.
Med Sci Monit ; 26: e924266, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33144554

RESUMO

BACKGROUND Spinal cord injury (SCI) is a devastating trauma of the central nervous system (CNS), with high levels of morbidity, disability, and mortality. One week after SCI may be a critical time for treatment. Changes in protein expression have crucial functions in nervous system diseases, although the effects of changes occurring 1 week after SCI on patient outcomes are unclear. MATERIAL AND METHODS Protein expression was examined in a rat contusive SCI model 1 week after SCI. Differentially expressed proteins (DEPs) were identified by isobaric tagging for relative and absolute protein quantification (iTRAQ)-coupled liquid chromatography tandem-mass spectrometry (LC-MS/MS) proteomics analysis. Gene Ontology (GO) analysis was performed to identify the biological processes, molecular functions, and cellular component terms of the identified DEPs, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) was used to identify key enriched pathways. Protein-protein interaction (PPI) networks were analyzed to identify the top 10 high-degree core proteins. RESULTS Of the 295 DEPs identified, 204 (69.15%) were upregulated and 91 (30.85%) were downregulated 1 week after injury. The main cellular components, molecular functions, biological processes, and pathways identified may be crucial mechanisms involved in SCI. The top 10 high-degree core proteins were complement component C3 (C3), alpha-2-HS-glycoprotein (Ahsg), T-kininogen 1 (Kng1), Serpinc1 protein (Serpinc1), apolipoprotein A-I (Apoa1), serum albumin (Alb), disulfide-isomerase protein (P4hb), transport protein Sec61 subunit alpha isoform 1 (Sec61a1), serotransferrin (Tf), and 60S ribosomal protein L15 (Rpl15). CONCLUSIONS The proteins identified in this study may provide potential targets for diagnosis and treatment 1 week after SCI.

10.
Clin Interv Aging ; 15: 2109-2115, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33204076

RESUMO

Background: There were few studies on the case mortality of severe community-acquired pneumonia (CAP) in elderly people. Improved outcomes with XueBiJing (XBJ) injection vs placebo have been shown in overall trial populations. We investigated the efficacy and safety of XBJ vs placebo in subjects with severe CAP stratified by age (<65 and ≥65 years). Methods: This post hoc analysis of a large randomized trial compared data from elderly and nonelderly patients with XBJ, 100 mL, q 12 h, or a visually indistinguishable placebo for five-to-seven days. Results: Among subjects ≥65 years (n=291), 23 (16.0%) XBJ recipients and 41 (27.9%) placebo recipients (P=0.014) died within 28 days. Among subjects <65 years (n=360), XBJ still had lower mortality (XBJ 15.6% vs placebo 22.8%; P=0.082), without significantly statistical difference. Total duration of ICU stay and the time of mechanical ventilation were similar in both groups (P>0.05). XBJ also had a favorable safety profile, with no clinically relevant differences between the two groups. The overall incidence of adverse events was similar in both groups. Conclusion: XBJ was safe and effective for reduction in 28-day mortality among elderly patients with severe CAP. Additional confirmatory trials involving elderly patients are needed to further confirm the present results. Trial Registration: http://www.chictr.org.cn/index.aspx. ChiCTR-TRC-13003534.

11.
Aging (Albany NY) ; 122020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33206628

RESUMO

Heart failure (HF) affects over 26 million people worldwide, yet the pathologies of this complex syndrome have not been completely understood. Here, we investigated the involvement of deacetylase Sirtuin 1 (Sirt1) in HF and its downstream signaling pathways. A HF model was induced by the ligation of the left coronary artery in rats, where factors associated with left ventricular echocardiography, heart hemodynamics and ventricular mass indexes were recorded. Collagen volume fraction in heart tissues was determined by Masson's trichrome staining. Cell models of HF were also established (H2O2, 30 min) in cardiomyocytes harvested from suckling rats. HF rats presented with downregulated expressions of Sirt1, brain-derived neurotrophic factor (BDNF) and exhibited upregulated expressions of NF-κB p65 and miR-155. Repressed Sirt1 expression increased acetylation of NF-κB p65, resulting in the elevation of NF-κB p65 expression. NF-κB p65 silencing improved heart functions, decreased ventricular mass and reduced apoptosis in cardiomyocytes. MiR-155 inhibition upregulated its target gene BDNF, thereby reducing cardiomyocyte apoptosis. Sirt1 overexpression upregulated BDNF, improved heart function, and reduced apoptosis in cardiomyocytes. In conclusion, Sirt1 alleviates HF in rats through the NF-κB p65/miR-155/BDNF signaling cascade.

12.
Brief Bioinform ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33230549

RESUMO

Deconvolution of mouse transcriptomic data is challenged by the fact that mouse models carry various genetic and physiological perturbations, making it questionable to assume fixed cell types and cell type marker genes for different data set scenarios. We developed a Semi-Supervised Mouse data Deconvolution (SSMD) method to study the mouse tissue microenvironment. SSMD is featured by (i) a novel nonparametric method to discover data set-specific cell type signature genes; (ii) a community detection approach for fixing cell types and their marker genes; (iii) a constrained matrix decomposition method to solve cell type relative proportions that is robust to diverse experimental platforms. In summary, SSMD addressed several key challenges in the deconvolution of mouse tissue data, including: (i) varied cell types and marker genes caused by highly divergent genotypic and phenotypic conditions of mouse experiment; (ii) diverse experimental platforms of mouse transcriptomics data; (iii) small sample size and limited training data source and (iv) capable to estimate the proportion of 35 cell types in blood, inflammatory, central nervous or hematopoietic systems. In silico and experimental validation of SSMD demonstrated its high sensitivity and accuracy in identifying (sub) cell types and predicting cell proportions comparing with state-of-the-arts methods. A user-friendly R package and a web server of SSMD are released via https://github.com/xiaoyulu95/SSMD.

13.
J Cell Physiol ; 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33230845

RESUMO

Hepatic stellate cell (HSC) activation plays an important role in the pathogenesis of liver fibrosis, and epithelial-mesenchymal transition (EMT) is suggested to potentially promote HSC activation. Superoxide dismutase 3 (SOD3) is an extracellular antioxidant defense against oxidative damage. Here, we found downregulation of SOD3 in a mouse model of liver fibrosis induced by carbon tetrachloride (CCl4 ). SOD3 deficiency induced spontaneous liver injury and fibrosis with increased collagen deposition, and further aggravated CCl4 -induced liver injury in mice. Depletion of SOD3 enhanced HSC activation marked by increased α-smooth muscle actin and subsequent collagen synthesis primarily collagen type I in vivo, and promoted transforming growth factor-ß1 (TGF-ß1)-induced HSC activation in vitro. SOD3 deficiency accelerated EMT process in the liver and TGF-ß1-induced EMT of AML12 hepatocytes, as evidenced by loss of E-cadherin and gain of N-cadherin and vimentin. Notably, SOD3 expression and its pro-fibrogenic effect were positively associated with sirtuin 1 (SIRT1) expression. SOD3 deficiency inhibited adenosine monophosphate-activated protein kinase (AMPK) signaling to downregulate SIRT1 expression and thus involving in liver fibrosis. Enforced expression of SIRT1 inhibited SOD3 deficiency-induced HSC activation and EMT, whereas depletion of SIRT1 counteracted the inhibitory effect of SOD3 in vitro. These findings demonstrate that SOD3 deficiency contributes to liver fibrogenesis by promoting HSC activation and EMT process, and suggest a possibility that SOD3 may function through modulating SIRT1 via the AMPK pathway in liver fibrosis.

14.
Nat Commun ; 11(1): 5401, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33144561

RESUMO

Petroleum-based plastics are useful but they pose a great threat to the environment and human health. It is highly desirable yet challenging to develop sustainable structural materials with excellent mechanical and thermal properties for plastic replacement. Here, inspired by nacre's multiscale architecture, we report a simple and efficient so called "directional deforming assembly" method to manufacture high-performance structural materials with a unique combination of high strength (281 MPa), high toughness (11.5 MPa m1/2), high stiffness (20 GPa), low coefficient of thermal expansion (7 × 10-6 K-1) and good thermal stability. Based on all-natural raw materials (cellulose nanofiber and mica microplatelet), the bioinspired structural material possesses better mechanical and thermal properties than petroleum-based plastics, making it a high-performance and eco-friendly alternative structural material to substitute plastics.

15.
Artigo em Inglês | MEDLINE | ID: mdl-33155889

RESUMO

BACKGROUND: In Traditional Chinese Medicine (TCM), the heads and tails of Angelica sinensis (Oliv.) Diels (AS) is used in treating different diseases due to their different pharmaceutical efficacies. The underline mechanisms, however, have not been fully explored. OBJECTIVE: Novel mechanisms responsible for the discrepant activities between AS heads and tails were explored by a combined strategy of transcriptomes and metabolomics. METHOD: Six pairs of the heads and tails of AS roots were collected in Min County, China. Total RNA and metabolites, which were used for RNA-seq and untargeted metabolomics analysis, were respectively isolated from each AS sample (0.1 g) by Trizol and methanol reagent. Subsequently, differentially expressed genes (DEGs) and discrepant pharmaceutical metabolites were identified for comparing AS heads and tails. Key DEGs and metabolites were quantified by qRT-PCR and targeted metabolomics experiment. RESULTS: Comprehensive analysis of transcriptomes and metabolomics results suggested that five KEGG pathways with significant differences included 57 DEGs. Especially, fourteen DEGs and six key metabolites were relation to the metabolic regulation of Phenylpropanoid biosynthesis (PB) pathway. Results of qRT-PCR and targeted metabolomics indicated that higher levels of expression of crucial genes in PB pathway, such as PAL, CAD, COMT and peroxidase in the tail of AS were positively correlated with levels of ferulic acid-related metabolites. The average content of ferulic acid in tails (569.58162.39 nmol/g) was higher than those in the heads (168.73  67.30 nmol/g) (P˂0.01); Caffeic acid in tails (3.82  0.88 nmol/g) vs heads (1.37  0.41 nmol/g) (P˂0.01), and Cinnamic acid in tails (0.24  0.09 nmol/g) vs heads (0.14  0.02 nmol/g) (P˂0.05). CONCLUSION: Our work demonstrated that overexpressed genes and accumulated metabolites derived from PB pathway might be responsible for the discrepant pharmaceutical efficacies between AS heads and tails.

16.
Artigo em Inglês | MEDLINE | ID: mdl-33146456

RESUMO

Birefringence is a fundamental optical property for linear and nonlinear optical (NLO) materials. Thus far, it has proved to be very difficult to engineer large birefringence in optical crystals functioning in the UV region. Herein, we report the first 2D rare-earth iodate-nitrate crystal Sc(IO3)2(NO3) (SINO), which is shown to exhibit giant optical anisotropy. Air-stable SINO possesses a short UV absorption edge (298 nm), a strong NLO response (4.0 times that of benchmark KH2PO4) for the nitrate family, and the largest birefringence (Δn = 0.348 at 546 nm) of inorganic oxide optical crystals. The unusually large birefringence and NLO response can be attributed to an optimized 2D layered structure, combined with highly polarizable and anisotropic building units [IO3]- and [NO3]-. These findings will facilitate development of UV linear and NLO materials with giant optical anisotropy, and promote their potential applications in optoelectronic devices.

17.
J Clin Invest ; 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33090974

RESUMO

Diabetes mellitus (DM) is a risk factor for cancer development. However, the role of DM induced hyperglycemic stress (HG) in the development of blood cancer is poorly understood, largely due to lack of appropriate animal models. Epidemiologic studies show that individuals with DM are more likely to possess higher rate of mutations in genes found in pre-leukemic stem and progenitor cells (pre-LHSC/Ps) including in the epigenetic regulator TET2. TET2-mutant pre-LHSC/Ps require additional hits to evolve into a full-blown leukemia and/or aggressive myeloproliferative neoplasm (MPN). Cell intrinsic mutations have been shown to cooperate with Tet2 to promote leukemic transformation. However, the role of extrinsic factors is poorly understood. Utilizing a novel mouse model bearing haploinsufficiency of Tet2, to mimic the human pre-LHSC/P condition and HG stress, in the form of an Ins2Akita/+ mutation, which induces HG and Type-1 DM, we show that the compound mutant mice develop a lethal form of MPN and/or acute myeloid leukemia (AML). RNAseq revealed that this is in part due to upregulation of pro-inflammatory pathways, thereby generating a feedforward loop, including the expression of an anti-apoptotic lncRNA Morrbid. Loss of Morrbid in the compound mutants rescues the lethality and mitigates the development of MPN/AML. Our results describe a novel mouse model for age-dependent AML/MPN and suggest that HG stress acts as an environmental driver for myeloid neoplasm, which could be effectively prevented by reducing the expression of inflammation-related lncRNA Morrbid.

18.
Water Res ; 188: 116449, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-33075600

RESUMO

Sediments have been found to be one of the most important reservoirs for microplastics, providing abundant indigenous microbes. The processes involved in the distribution and degradation behavior of microplastics are complex. This study investigated the vertical distribution of microplastics (with the size < 5 mm) and the bacterial community assemblages colonizing microplastics in urban river sediments at a depth from 0 to 50 cm. The results showed that both microplastics and associated microbial communities presented vertical profiles in river sediments. The mean concentration of microplastics increased from the shallow layers to the deep layers of sediments, and smaller microplastic particles were dominant in deeper layers. A greater degradation of microplastics in deeper layers was confirmed by contact angle measurements, scanning electron microscopy and Fourier transform infrared spectroscopy-attenuated total reflectance analyses. Unlike the surrounding sediments, the whole bacterial communities on microplastics exhibited higher frequency of positive correlations in the bacterial co-occurrence network, which indicated a less stability of bacterial communities on microplastics. The indicative plastic-degrading bacteria with an average abundance of 4.33% was found in the surrounding sediments, while on the microplastics 21.37% was found. From shallow layers to deep layers, the indicative plastic-degrading bacteria significantly increased both in the abundance and in their betweenness centrality in the co-occurrence network, which suggested a potentially primary role of these bacteria in the degradation of microplastics in deep layers. This study provides new insight into the vertical distribution and the potential microbial degrading characteristics of microplastics in urban river sediments, which expanded our understanding of the fate of microplastics in aquatic environments. The observed results implied a great risk that microplastics might become smaller and more in deepened sediments and finally migrate into groundwater.

19.
Brief Bioinform ; 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126247

RESUMO

The triangular correlation heatmap aiming to visualize the linkage disequilibrium (LD) pattern and haplotype block structure of SNPs is ubiquitous component of population-based genetic studies. However, current tools suffered from the problem of time and memory consuming. Here, we developed LDBlockShow, an open source software, for visualizing LD and haplotype blocks from variant call format files. It is time and memory saving. In a test dataset with 100 SNPs from 60 000 subjects, it was at least 10.60 times faster and used only 0.03-13.33% of physical memory as compared with other tools. In addition, it could generate figures that simultaneously display additional statistical context (e.g. association P-values) and genomic region annotations. It can also compress the SVG files with a large number of SNPs and support subgroup analysis. This fast and convenient tool will facilitate the visualization of LD and haplotype blocks for geneticists.

20.
Cancer Chemother Pharmacol ; 86(6): 761-772, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33068176

RESUMO

PURPOSE: This study aimed to investigate the predictive and prognostic roles of circulating exosomal miRNAs in breast cancer treated with trastuzumab-based chemotherapy. METHODS: Circulating exosomal miRNAs from trastuzumab-resistant (n = 4) and -sensitive (n = 4) patients were profiled using miRNA microarray. The predictive and prognostic roles of filtered miRNAs were validated in 107 early-stage and 68 metastatic patients treated with trastuzumab-based chemotherapy through receiver-operating characteristic (ROC) curve analysis, logistic regression and Cox proportional hazards regression analysis, and Kaplan-Meier survival analysis. RESULTS: MiRNA microarray analysis revealed miR-1246 and miR-155 were the most up-regulated miRs in trastuzumab-resistant HER2-positive breast cancer patients, which were further validated in trastuzumab-resistant patient samples (n = 32) compared with trastuzumab sensitive ones (n = 36). MiR-1246 showed a ROC curve area of 0.750 with 78.1% sensitivity and 75% specificity in discriminating resistant from sensitive patients (p < 0.001), while miR-155 showed a ROC curve area of 0.877 with 68.8% sensitivity and 97.2% specificity (p < 0.001). Predictive factors and multivariate analysis showed that high levels of miR-1246 and miR-155 strongly predicted poor event-free survival (EFS) for early-stage patients, and poor progression-free survival (PFS) for metastatic patients. However, both miRNAs were revealed not to be associated with overall survival (OS). In addition, Kaplan-Meier survival analysis demonstrated that early-stage and metastatic patients with high expression of miR-1246 and miR-155 had poorer EFS or PFS, respectively, than those with decreased expression of both miRs. CONCLUSIONS: This study demonstrated the valuable roles of circulating exosomal miR-1246 and miR-155 in distinguishing trastuzumab resistant from sensitive patients.

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