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1.
Toxicol In Vitro ; 62: 104698, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31669364

RESUMO

Both PM2.5 and respiratory viruses are part of the atmospheric constituents. Respiratory viruses are often associated with PM2.5 exposure, but the mechanism of toxicity remains to be explored. The vitro models that adequately reproduce healthy cells or diseased cells exposing to PM2.5 and infecting VSV can provide a useful tool for studying innate immune mechanisms and investigating new therapeutic focus. In the environment of PM2.5, an infection model in which VSV infected A549 cells was established, that mimics the state in which the antiviral innate immune pathways are activated after the respiratory system is infected with RNA viruses. Subsequently, the model was exposed to PM2.5 for 24 h. PM2.5 could be ingested by A549 cells and synergize with VSV to inhibit cell viability and promote apoptosis. The expression of VSV-G were more abundant after VSV-infected A549 cells were exposed to PM2.5. Furthermore, PM2.5 inhibits VSV-induced IFN-ß expression in A549 cells. ISG15, CCL-5, and CXCL-10 had the same expression tendency with IFN-ß mRNA, consistently. Interestingly, when MG132 was applied, the expression of p-IRF-3 and IFN-ß proteins reduced by PM2.5 were refreshed. Conversely, the expression of VSV-G proteins were decreased. PM2.5 could degrade p-IRF-3 proteins by ubiquitination pathway to inhibit VSV-induced IFN-ß expression in A549 cells. Therefore, replication of the VSV viruses was promoted.

2.
J Org Chem ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31670948

RESUMO

An efficient and operationally simple method for the synthesis of N-acyl sulfamates from fluorosulfonates and potassium trimethylsilyloxyl imidates as amide precursor is reported. This approach showed broad substrate scope, mild and base-free reaction conditions, short reaction time, and high to excellent yields. Notably, we demonstrated the power of this reaction in the rapid late-stage functionalization of three complex phenol-containing bioactive molecules. Given the prevalence of phenol-containing drugs and building blocks, this method is applicable toward a diversity-oriented drug discovery.

4.
Chemosphere ; 242: 124959, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31669990

RESUMO

Long-term exposure to arsenic can cause liver injury and fibrosis. The activation of hepatic stellate cells (HSCs) plays an essential role in the process of liver fibrosis. We found that NaAsO2 caused liver damage and fibrosis in vivo, accompanied by excessive collagen deposition and HSCs activation. In addition, NaAsO2 upregulated autophagy flux, elevated the level of cytoplasmic cathepsin B (CTSB), and activated the NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasome in a subtle way. Consistent with these findings in vivo, we demonstrated that NaAsO2-induced activation of HSCs depended on CTSB-mediated NLRP3 inflammasome activation in HSC-t6 cells and rats primary HSCs. Moreover, inhibition of autophagy decreased the cytoplasmic CTSB and alleviated the activation of the NLRP3 inflammasome, thereby attenuating the NaAsO2-induced HSCs activation. In summary, these results indicated that NaAsO2 induced HSCs activation via autophagic-CTSB-NLRP3 inflammasome pathway. These findings may provide a novel insight into the potential mechanism of NaAsO2-induced liver fibrosis.

5.
Hepatology ; 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31721246

RESUMO

As conversion from calcineurin inhibitor (CNI) to sirolimus (SRL), an mTOR-inhibitor (mTOR-I), has been shown to enhance immunoregulatory profiles in liver transplant recipients (LTR), mTOR-I therapy might allow for increased success with immunosuppression withdrawal. Our aim was to determine if operational tolerance could be observed in LTR withdrawn from SRL and if blood/graft tolerance biomarkers were predictive of successful withdrawal. We performed a prospective trial of SRL monotherapy withdrawal in non-immune, non-viremic LTR > 3 years post-LT. Sirolimus was weaned over ~6 months and biopsies performed 12 months post-weaning or at concern for acute rejection (AR). Twenty-one LTR were consented; 6 were excluded due to subclinical AR on baseline biopsy or other reasons; 15 underwent weaning (age 61.3±8.8 yrs; LT to SRL weaning 6.7±3 yrs). Eight (53%) achieved operational tolerance (TOL). Of the 7 non-TOL, 6 had mild AR on biopsy near the end of weaning or at study end; 1 was removed due to liver cancer recurrence. At baseline preweaning, there were statistically higher blood tolerogenic dendritic cells, regulatory B cells, and cell phenotypes correlating with chronic antigen presentation in the TOL vs. non-TOL groups. At baseline preweaning, a previously identified biopsy gene signature accurately predicted TOL vs. non-TOL in 12/14 LTR. At study end, biopsy staining revealed statistically significant increases in antigen presenting cell:leukocyte pairings, Foxp3+CD4+ T cells, T-bet+CD8+ T cells, and lobular dendritic cells in the non-TOL group. CONCLUSION: This study is the first to evaluate IS withdrawal directly from mTOR-I therapy in LTR and achieved >50% operational tolerance. Pre-weaning blood/graft gene expression and PBMC profiling may be useful as predictors of successful mTOR-I therapy withdrawal. NCT02062944.

6.
Theranostics ; 9(24): 7345-7358, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695772

RESUMO

Rationale: Hepatitis B virus (HBV) is a leading cause of liver diseases. HBV covalently closed circular DNA (cccDNA) is a critical obstacle of complete elimination by anti-HBV therapy. HBV cccDNA accumulates in nucleus as a chromatin-like cccDNA minichromosome assembled by histones and non-histones. However, the underlying mechanism of modulation of cccDNA minichromosome in hepatocytes is poorly understood. Methods: A human liver-chimeric mouse model was established. The cccDNA-ChIP, Southern blot analysis, confocal assays, RIP assays and RNA pull-down assays, et al. were performed to assess the mechanism of assembly and epigenetic regulation of cccDNA minichromosome in human liver-chimeric mouse model, human primary hepatocytes (PHH), dHepaRG, HepG2-NTCP cell lines and clinical liver tissues. Results: Importantly, the expression levels of HAT1, CAF-1 and lncRNA HULC were significantly elevated in the liver from HBV-infected human liver-chimeric mice. Strikingly, the depletion of HAT1 reduced HBV replication and cccDNA accumulation, and impaired the assembly of histone H3/H4 and the deposition of HBx and p300 onto cccDNA to form cccDNA minichromosome in the cells. Mechanically, chromatin assembly factor-1 (CAF-1) was involved in the events. Interestingly, HAT1 modified the acetylation of histone H3K27/H4K5/H4K12 on cccDNA minichromosome. Moreover, lncRNA HULC-scaffold HAT1/HULC/HBc complex was responsible for the modification on cccDNA minichromosome. Additionally, HBV activated HAT1 through HBx-co-activated transcriptional factor Sp1 in a positive feedback manner. Conclusion: HAT1 signaling contributes to assembly and epigenetic regulation of HBV cccDNA minichromosome.

7.
Acta Biomater ; 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31672583

RESUMO

Protein-templated gold nanoclusters have attracted attention in fluorescence imaging due to their simple synthesis and good biocompatibility. However, limitations still exist such as poor colloid stability and undesirable fluorescence intensity. Here we describe the self-assembly of keratin-templated gold nanoclusters via a simple and mild preparation process, including keratin-templated synthesis of gold nanoclusters (AuNCs@Keratin), silver ions modification of AuNCs@Keratin (AuNCs-Ag@Keratin), and gadolinium ions-induced aggregation of AuNCs-Ag@Keratin (AuNCs-Ag@Keratin-Gd). It was demonstrated that the AuNCs-Ag@Keratin-Gd obtained an enhanced fluorescence intensity (6.5 times that of AuNCs@Keratin), high colloid stability for more than 4 months, and good biocompatibility. Moreover, the AuNCs-Ag@Keratin-Gd holds promise in multifunctional applications such as near-infrared (NIR) fluorescence imaging, magnetic resonance (MR) imaging, and redox-responsive drug delivery, extending the applicability of fluorescent gold nanoclusters, especially in biomedical fields. STATEMENT OF SIGNIFICANCE: Assembly-induced fluorescence enhancement has been rarely reported on as it relates to the protein-templated gold nanoclusters (AuNCs). In this work, self-assembly of protein-templated AuNCs was developed for enhanced fluorescence intensity and multifunctional applications, including bioimaging and responsive drug delivery. A cysteine-rich protein, keratin, was utilized as the template to synthesize AuNCs, which underwent silver ion modification and gadolinium ion-induced aggregation. The silver modification of the keratin-templated AuNCs facilitated the formation of a dense aggregate after gadolinium ion-induced assembly, thus generating an enhanced fluorescence intensity. Such a mechanism was confirmed by fluorescence correlation spectroscopy analysis. We believe that this work will extend the applicability of the fluorescent gold nanoclusters, especially in biomedical fields, and provided an effective approach for the mechanism analysis of the assembly-induced fluorescence enhancement via fluorescence correlation spectroscopy.

8.
Sensors (Basel) ; 19(22)2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31703380

RESUMO

Rapid detection of illicit opium poppy plants using UAV (unmanned aerial vehicle) imagery has become an important means to prevent and combat crimes related to drug cultivation. However, current methods rely on time-consuming visual image interpretation. Here, the You Only Look Once version 3 (YOLOv3) network structure was used to assess the influence that different backbone networks have on the average precision and detection speed of an UAV-derived dataset of poppy imagery, with MobileNetv2 (MN) selected as the most suitable backbone network. A Spatial Pyramid Pooling (SPP) unit was introduced and Generalized Intersection over Union (GIoU) was used to calculate the coordinate loss. The resulting SPP-GIoU-YOLOv3-MN model improved the average precision by 1.62% (from 94.75% to 96.37%) without decreasing speed and achieved an average precision of 96.37%, with a detection speed of 29 FPS using an RTX 2080Ti platform. The sliding window method was used for detection in complete UAV images, which took approximately 2.2 sec/image, approximately 10× faster than visual interpretation. The proposed technique significantly improved the efficiency of poppy detection in UAV images while also maintaining a high detection accuracy. The proposed method is thus suitable for the rapid detection of illicit opium poppy cultivation in residential areas and farmland where UAVs with ordinary visible light cameras can be operated at low altitudes (relative height < 200 m).

9.
Blood Adv ; 3(21): 3360-3374, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31698464

RESUMO

MYD88 L265P is the most common mutation in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) and one of the most frequent in poor-prognosis subtypes of diffuse large B-cell lymphoma (DLBCL). Although inhibition of the mutated MYD88 pathway has an adverse impact on LPL/WM and DLBCL cell survival, its role in lymphoma initiation remains to be clarified. We show that in mice, human MYD88L265P promotes development of a non-clonal, low-grade B-cell lymphoproliferative disorder with several clinicopathologic features that resemble human LPL/WM, including expansion of lymphoplasmacytoid cells, increased serum immunoglobulin M (IgM) concentration, rouleaux formation, increased number of mast cells in the bone marrow, and proinflammatory signaling that progresses sporadically to clonal, high-grade DLBCL. Murine findings regarding differences in the pattern of MYD88 staining and immune infiltrates in the bone marrows of MYD88 wild-type (MYD88WT) and MYD88L265P mice are recapitulated in the human setting, which provides insight into LPL/WM pathogenesis. Furthermore, histologic transformation to DLBCL is associated with acquisition of secondary genetic lesions frequently seen in de novo human DLBCL as well as LPL/WM-transformed cases. These findings indicate that, although the MYD88L265P mutation might be indispensable for the LPL/WM phenotype, it is insufficient by itself to drive malignant transformation in B cells and relies on other, potentially targetable cooperating genetic events for full development of lymphoma.

10.
Drug Discov Today ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31705979

RESUMO

Undesirable pharmacokinetic (PK) properties or unacceptable toxicity are the main causes of the failure of drug candidates at the clinical trial stage. Since the concept of drug-likeness was first proposed, it has become an important consideration in the selection of compounds with desirable bioavailability during the early phases of drug discovery. Over the past decade, online resources have effectively facilitated drug-likeness studies in an economical and time-efficient manner. Here, we provide a comprehensive summary and comparison of current accessible online resources, in terms of their key features, application fields, and performance for in silico drug-likeness studies. We hope that the assembled toolbox will provide useful guidance to facilitate future in silico drug-likeness research.

11.
J Hazard Mater ; : 121390, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31735470

RESUMO

Chronic arsenic exposure is a significantly risk factor for pancreatic dysfunction and type 2 diabetes (T2D). Ferroptosis is a newly identified iron-dependent form of oxidative cell death that relies on lipid peroxidation. Previous data have indicated that ferroptosis is involved in various diseases, including cancers, neurodegenerative diseases, and T2D. However, the concrete effect and mechanism of ferroptosis on pancreatic dysfunction triggered by arsenic remains unknown. In this study, we verified that ferroptosis occurred in animal models of arsenic-induced pancreatic dysfunction through assessing proferroptotic markers and morphological changes in mitochondria. In vitro, arsenic caused execution of ferroptosis in a dose-dependent manner, which could be significantly reduced by ferrostatin-1. Additionally, arsenic damaged mitochondria manifested as diminishing of mitochondrial membrane potential, reduced cytochrome c level and production of mitochondrial reactive oxygen species (MtROS) in MIN6 cells. Using the Mito-TEMPO, we found the autophagy level and subsequent ferroptotic cell death induced by arsenic were both alleviated. With autophagy inhibitor chloroquine, we further revealed that ferritin regulated ferroptosis through the MtROS-autophagy pathway. Collectively, NaAsO2-induced ferroptotic cell death is relied on the MtROS-dependent autophagy by regulating the iron homeostasis. Ferroptosis is involved in pancreatic dysfunction triggered by arsenic, and arsenic-induced ferroptosis involves MtROS, autophagy, ferritin.

12.
Eur J Med Chem ; 185: 111803, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31677447

RESUMO

A potent and novel MET inhibitor, 5-((4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)amino)-3-(4-fluorophenyl)-1,6-naphthyridin-4(1H)-ones (8), was designed and synthesized via a scaffold-hopping strategy of a 2,7-naphthyridinone MET kinase inhibitor 7. Lead compound 8 had good potency (IC50 of 9.8 nM), but unfavorable pharmacokinetic profiles (F = 12%, CL = 5.0 L/h/kg). Systematic structural optimization of compound 8 resulted in 9g (MET, IC50 = of 9.8 nM) with a comparable MET potency to that of compound 2 and a favorable pharmacokinetic profile (F = 63%, CL = 0.12 L/h/kg). Further study of the derivatization of N(1) amine group of 9g led to the discovery of 23a with good MET potency (IC50 of 7.1 nM), promising VEGFR-2 selectivity (3226-fold), and a markedly drug-likeness improvement (F = 57.7%, CL = 0.02 L/h/kg). The excellent VEGFR-2 selectivity and favorable drug-likeness of 23g suggest that the 1,6-naphthyridine moiety could be used as a new scaffold for kinase inhibitor discovery.

13.
iScience ; 21: 549-561, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31715498

RESUMO

Multi-targeted kinase inhibitors, such as sorafenib, have been used in various malignancies, but their efficacy in clinical applications varies among individuals and lacks pretherapeutic prediction measures. We applied the concept of "click chemistry" to pathological staining and established a drug-loaded probe staining assay. We stained the cells and different types of pathological sections and demonstrated that the assay was reliable. We further verified in cells, cell-derived xenograft model, and clinical level that the staining intensity of the probe could reflect drug sensitivity. The stained samples from 300 patients who suffered from hepatocellular carcinoma and used the sorafenib probe also indicated that staining intensity was closely related to clinical information and could be used as an independent marker without undergoing sorafenib therapy for prognosis. This assay provided new ideas for multi-target drug clinical trials, pre-medication prediction, and pathological research.

14.
Nanotechnology ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31751960

RESUMO

The abnormal activation of Wnt/ß-Catenin signal pathway, underlying multiple malignancies, promotes tumor progression, blocking this pathway highly attractive drug candidates for anticancer therapy. Using a peptide therapeutic derived from E-cadherin region Ⅴ (cECRⅤ), we sought to develop a potent and selective antagonist against ß-Catenin via disrupting the carcinogenic interaction between ß-Catenin and BCL9. More importantly, to overcome the pharmacological obstacle of peptide-derived therapeutics: poor nucleases stability and low membrane permeability, a gold nanoparticle (AuNP)-based nanocarrier was designed to delivery cECRⅤ into cytoplasm to modulate the intracellular ß-Catenin-Bcl9 interaction. The resultant nanoparticle pAuNP-cECRⅤ, while no cytotoxicity towards normal PBMC cells, induced cycle arrest and subsequent apoptosis of Wnt-hyperactive cancer cells by antagonizing ß-Catenin to inhibit the Wnt pathway. Our results indicated that pAuNP-cECRⅤ exhibited remarkable potential application as an efficient and safe peptide delivery vector for cancer therapy.

15.
J Am Chem Soc ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31710480

RESUMO

Polymorphism has been the subject of investigation across different research disciplines. In biology, polymorphism could be interpreted in such a way that discrete biomacromolecules can adopt diversiform specific conformations/packing arrangement, and this polymorph-dependent property is essential for many biochemical processes. For example, bacterial flagellar filament, composed of flagellin, switches between different supercoiled state allowing the bacteria to swim and tumble. However, in artificial supramolecular systems, it is often challenging to achieve polymorph control and prediction, and in most cases, two or more concomitant polymorphs of similar formation energies coexist. Here, we show that a tetrameric protein with properly oriented binding sites on its surface can arrange into diverse protein tubes with distinct helical parameters by adding specifically designed inducing ligands. We examined several parameters of the ligand that would influence the protein tube formation and found that the flexibility of the ligand linker and the dimerization pose of the ligand complex is critical for the successful production of the tubes and eventually influence the specific helical polymorphs of the formed tubes. A surface lattice accommodation model was further developed to rationalize the geometrical relationship between each helical tube type. Molecular simulation was used to elucidate the interactions between ligands and SBA and molecular basis for polymorphic switching of the protein tubes. Moreover, the kinetics of structural formation was studied and the ligand design was found that can affect the kinetics of the protein polymerization pathway. In short, our designed protein tubes serves as an enlightening system for understanding how a protein polymer composed of a single protein switches among different helical states.

16.
J Am Soc Nephrol ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727850

RESUMO

BACKGROUND: GSTM1 encodes glutathione S-transferase µ-1 (GSTM1), which belongs to a superfamily of phase 2 antioxidant enzymes. The highly prevalent GSTM1 deletion variant is associated with kidney disease progression in human cohorts: the African American Study of Kidney Disease and Hypertension and the Atherosclerosis Risk in Communities (ARIC) Study. METHODS: We generated a Gstm1 knockout mouse line to study its role in a CKD model (involving subtotal nephrectomy) and a hypertension model (induced by angiotensin II). We examined the effect of intake of cruciferous vegetables and GSTM1 genotypes on kidney disease in mice as well as in human ARIC study participants. We also examined the importance of superoxide in the mediating pathways and of hematopoietic GSTM1 on renal inflammation. RESULTS: Gstm1 knockout mice displayed increased oxidative stress, kidney injury, and inflammation in both models. The central mechanism for kidney injury is likely mediated by oxidative stress, because treatment with Tempol, an superoxide dismutase mimetic, rescued kidney injury in knockout mice without lowering BP. Bone marrow crosstransplantation revealed that Gstm1 deletion in the parenchyma, and not in bone marrow-derived cells, drives renal inflammation. Furthermore, supplementation with cruciferous broccoli powder rich in the precursor to antioxidant-activating sulforaphane significantly ameliorated kidney injury in Gstm1 knockout, but not wild-type mice. Similarly, among humans (ARIC study participants), high consumption of cruciferous vegetables was associated with fewer kidney failure events compared with low consumption, but this association was observed primarily in participants homozygous for the GSTM1 deletion variant. CONCLUSIONS: Our data support a role for the GSTM1 enzyme in the modulation of oxidative stress, inflammation, and protective metabolites in CKD.

17.
Horm Behav ; : 104640, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31765661

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease that severely affects the health and lifespan of the elderly worldwide. Recently, the correlation between AD and type 2 diabetes mellitus (T2DM) has received intensive attention, and a promising new anti-AD strategy is the use of anti-diabetic drugs. Oxyntomodulin (Oxm) is a peptide hormone and growth factor that acts on neurons in the hypothalamus. OXM activates glucagon-like peptide 1 (GLP-1) and glucagon (Gcg) receptors, facilitates insulin signaling and has neuroprotective effects against Aß1-42-induced cytotoxicity in primary hippocampal neurons. Here, we tested the effects of the protease-resistant analogue (D-Ser2)Oxm on spatial memory and synaptic plasticity and the underlying molecular mechanisms in the APP/PS1 transgenic mouse model of AD. The results showed that (D-Ser2)Oxm not only alleviated the impairments of working memory and long-term spatial memory, but also reduced the number of Aß plaques in the hippocampus, and reversed the suppression of hippocampal synaptic long-term potentiation (LTP). Moreover, (D-Ser2)Oxm administration significantly increased p-PI3K/p-AKT1 expression and decreased p-GSK3ß levels in the hippocampus. These results are the first to show an in vivo neuroprotective role of (D-Ser2)Oxm in APP/PS1 mice, and this role involves the improvement of synaptic plasticity, clearance of Aß and normalization of PI3K/AKT/GSK3ß cell signaling in the hippocampus. This study suggests that (D-Ser2)Oxm holds promise for the prevention and treatment of AD.

18.
J Biomed Opt ; 24(11): 1-7, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31724344

RESUMO

Fiber bundle fluorescence endomicroscopy is an effective method for in vivo imaging of biological tissue samples. Line-scanning confocal laser endomicroscopy realizes confocal imaging at a much higher frame rate compared to the point scanning system, but with reduced optical sectioning. To address this problem, we describe a fiber bundle endomicroscopy system that utilizes the HiLo technique to enhance the optical sectioning while still maintaining high image acquisition rates. Confocal HiLo endomicroscopy is achieved by synchronizing the scanning hybrid-illumination laser line with the rolling shutter of a CMOS camera. An evident improvement of axial sectioning is achieved as compared to the line-scanning confocal endomicroscopy without the HiLo technique. Comparisons are also made with epifluorescence endomicroscopy with and without HiLo. The optical sectioning enhancement is demonstrated on lens tissue as well as porcine kidney tissue.

19.
J Neural Eng ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31726440

RESUMO

OBJECTIVE: Brain Computer Interfaces (BCI) are becoming important tools for assistive technology, particularly through the use of Motor Imagery (MI) for aiding task completion. However, most existing methods of MI classification have been applied in a trial-wise fashion, with window sizes of approximately 2 seconds or more. Application of this type of classifier could cause a delay when switching between MI events. APPROACH: In this study, state-of-the-art classification methods for motor imagery are assessed with considerations for real-time and self-paced control, and a Convolutional Long-Short Term Memory (C-LSTM) network based on Filter Bank Common Spatial Patterns (FBCSP) is proposed. In addition, the effects of several methods of data augmentation on different classifiers are explored. MAIN RESULTS: The results of this study show that the proposed network achieves adequate results in distinguishing between different control classes, but both considered deep learning models are still less reliable than a Riemannian Minimum Distance to the Mean (MDM) classifier. In addition, controlled skewing of the data and the explored data augmentation methods improved the average overall accuracy of the classifiers by 14.0% and 5.3%, respectively. SIGNIFICANCE: This manuscript is among the first to attempt combining convolutional and recurrent neural network layers for the purpose of MI classification, and is also one of the first to provide an in-depth comparison of various data augmentation methods for MI classification. In addition, all of these methods are applied on smaller windows of data and with consideration to ambient data, which provides a more realistic test bed for real-time and self-paced control.

20.
Artigo em Inglês | MEDLINE | ID: mdl-31738990

RESUMO

BACKGROUND: Eosinophilic gastritis (EG) is a clinicopathologic disorder with marked gastric eosinophilia and clinical symptoms. There is an unmet need in EG for more precise diagnostic tools. OBJECTIVE: We aimed to develop tissue- and blood-based diagnostic platforms for EG. METHODS: Patients with EG and non-EG controls were enrolled across 9 Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR)-associated sites. An EG Diagnostic Panel (EGDP; gastric transcript subset) and EG blood biomarker panel (protein multiplex array) were analyzed. The EGDP18 scores were derived from the expression of 18 highly dysregulated genes and Blood EG scores from dysregulated cytokines/chemokine levels. RESULTS: Gastric biopsies and blood samples from 185 subjects (EG 74, non-EG 111) were analyzed. The EGDP a) identified patients with active EG (P < .0001, AUC ≥0.95); b) effectively monitored disease activity in longitudinal samples (P = .0078); c) highly correlated in same-patient samples (antrum vs. body, r = 0.85, P < .0001); and d) inversely correlated with gastric peak eosinophil levels (r = -0.83, P < .0001), periglandular circumferential collars (r = -0.73, P < .0001), and endoscopic nodularity (r = -0.45, P < .0001). For blood-based platforms, eotaxin-3, TARC, IL-5, and TSLP levels were significantly increased. Blood EG scores a) distinguished patients with EG from non-EG controls (P < .0001, AUC ≥0.91); b) correlated with gastric eosinophil levels (plasma r = 0.72, P = .0002; serum r = 0.54, P = .0015); and c) inversely correlated with EGDP18 scores (plasma r = -0.64, P = .0015; serum r = -0.46, P = .0084). Plasma eotaxin-3 strongly associated with gastric CCL26 expression (r = 0.81, P < .0001). CONCLUSION: We developed tissue- and blood-based platforms for assessment of EG and uncovered robust associations between specific gastric molecular profiles and histologic and endoscopic features, providing insight and tools for this emerging rare disease.

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