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1.
Cancer Sci ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32020720

RESUMO

The signaling of interleukin (IL) 23 and its receptor (IL-23R) play a crucial role in the development of cancers. However, the clinical significance of human serum soluble IL-23R (sIL-23R) and its relationship with IL-23 are still not explored in non-small cell lung cancer (NSCLC). In our study, sIL-23R was firstly identified in the serum of NSCLC patients but not in healthy controls by proteomics. The IL-23R mRNA and protein were upregulated in NSCLC cell lines and tissues tested by qPCR, Western blotting and IHC. The levels of sIL-23R, IL-23 and IL-17 in 195 NSCLC patients' serum were determined by ELISA, and high level of sIL-23R was significantly associated with advanced N stage (P = 0.039), clinical stage (P = 0.007) and poor 5-year survival rate. In vitro, sIL-23R was shown binding to IL-23 and the balance may affect patients N, T stage, overall survival (OS) and downstream cytokine IL-17 in a potential antagonistic relationship. Although sIL-23R, IL-23 and IL-17 were all associated with poor prognosis, only sIL-23R/IL-23 ratio [Hazard Ratio (HR): 1.945, 95% CI: 1.147-3.299, P = 0.014] can be an independent factor for prognosis. Therefore, we identified fragments of soluble cytokine receptor of IL-23R with affinity-ability to its natural ligand IL-23 in NSCLC patients' serum. The balance between the two antagonists can work as a potential prognostic serum marker.

2.
Mol Med Rep ; 21(3): 1517-1526, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016472

RESUMO

Non­small cell lung cancer (NSCLC) is prevalent worldwide. Lung squamous cell carcinoma (LUSC) is one of the main subtypes of NSCLC yet, currently, few biomarkers are available for the diagnosis of LUSC. The present study aimed to investigate the expression and role of adenosine deaminase RNA specific B1 (ADARB1) in lung squamous cell carcinoma (LUSC). Integrative bioinformatics analysis was used to identify the effects of ADARB1 expression on the occurrence and prognosis of LUSC. The expression of ADARB1 was further examined by immunohistochemistry (IHC). Bioinformatics analysis suggested that ADARB1 was downregulated in LUSC, serving as a potential tumor suppressor, and these results were verified by IHC performed on a lung cancer tissue array. Clinical studies suggested that ADARB1 expression and methylation levels were significantly associated with patient characteristics in LUSC. Moreover, ADARB1 global methylation levels were upregulated in LUSC tissues compared with normal lung tissues. Higher methylation levels of cg24063645 were associated with shorter overall survival time of patients with LUSC. A negative correlation was identified between ADARB1 and epidermal growth factor receptor (EGFR) expression in LUSC. Using the Gene Expression Omnibus database, it was suggested that the expression of ADARB1 in LUSC was significantly different compared with that in lung adenocarcinoma. Furthermore, protein­protein interactions were studied and a biological process annotation analysis was conducted. The present study suggested that ADARB1 was downregulated in LUSC; therefore, ADARB1 may serve as a specific biomarker and a potential therapeutic target for LUSC.

4.
Sci Transl Med ; 12(524)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31894106

RESUMO

Circulating tumor DNA (ctDNA) has emerged as a useful diagnostic and prognostic biomarker in many cancers. Here, we conducted a study to investigate the potential use of ctDNA methylation markers for the diagnosis and prognostication of colorectal cancer (CRC) and used a prospective cohort to validate their effectiveness in screening patients at high risk of CRC. We first identified CRC-specific methylation signatures by comparing CRC tissues to normal blood leukocytes. Then, we applied a machine learning algorithm to develop a predictive diagnostic and a prognostic model using cell-free DNA (cfDNA) samples from a cohort of 801 patients with CRC and 1021 normal controls. The obtained diagnostic prediction model discriminated patients with CRC from normal controls with high accuracy (area under curve = 0.96). The prognostic prediction model also effectively predicted the prognosis and survival of patients with CRC (P < 0.001). In addition, we generated a ctDNA-based molecular classification of CRC using an unsupervised clustering method and obtained two subgroups of patients with CRC with significantly different overall survival (P = 0.011 in validation cohort). Last, we found that a single ctDNA methylation marker, cg10673833, could yield high sensitivity (89.7%) and specificity (86.8%) for detection of CRC and precancerous lesions in a high-risk population of 1493 participants in a prospective cohort study. Together, our findings showed the value of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of CRC.

5.
J Mol Biol ; 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31821812

RESUMO

Prion diseases, such as Creutzfeldt-Jakob disease and bovine spongiform encephalopathy, are fatal neurodegenerative diseases that affect many mammals including humans and are caused by the misfolding of prion protein (PrP). A naturally occurring protective polymorphism G127V in human PrP has recently been found to significantly attenuate prion diseases, but the mechanism has remained elusive. We herein report that the hydrophobic chain introduced in G127V significantly inhibits amyloid fibril formation by human PrP, highlighting the protective effect of the G127V polymorphism. We further introduce an amino acid with a different hydrophobic chain (Ile) at the same position and find that G127I has similar protective effects as G127V. Moreover, we show that these two neutralizing mutations, G127V and G127I, significantly decrease the human PrP cytotoxicity resulting from PrP fibril formation, mitochondrial damage, and elevated reactive oxygen species production enhanced by a strong prion-prone peptide PrP 106-126. These findings elucidate the molecular basis for a natural protective polymorphism in PrP and will enable the development of novel therapeutic strategies against prion diseases.

6.
Infect Drug Resist ; 12: 2683-2691, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695444

RESUMO

Purpose: To describe trends and correlation between antibacterial exposure and bacterial resistance from hospitalized patients in a hospital in southern China. Patients and methods: This study used hospital-wide data regarding antimicrobial resistance and consumption between January 1, 2014 and December 31, 2018. Antibacterial consumption was expressed as antimicrobial use density (AUD). The changes in trends and associations between antibacterial utilization and resistance were analyzed using linear regression and time series analysis. Results: The total AUD of all antimicrobials decreased year by year (50.66 in 2014 vs 44.28 in 2018, P=0.03). The annual use of antimicrobials, such as penicillins, monobactams, aminoglycosides, macrolides, and lincosamides, significantly decreased (P<0.05), while the annual use of quinolones and tetracyclines significantly increased (P<0.05). Among the top ten isolated bacteria, antimicrobial resistance trends of Escherichia coli, Pseudomonas aeruginosa, Candida albicans, Staphylococcus aureus, and Staphylococcus epidermidis significantly decreased (P<0.05). Significant positive correlation was found between AUD of carbapenems and resistance rate of Acinetobacter baumannii to imipenem (ß=32.87, P<0.01), as well as the correlation between AUD of quinolones and resistance rate of Enterococcus faecium to levofloxacin (ß=104.40, P<0.01). Conclusion: The consumption of antibiotics and antibiotic resistance has been significantly improved in this tertiary hospital. Additionally, the efforts of China's antibiotic management may be suggested by the relationship between indicated antibiotic resistance and consumption. However, overall AUD levels and poor control of the use of antibiotics, such as quinolones and tetracyclines, still require strengthened management.

7.
Adv Immunol ; 144: 23-63, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31699219

RESUMO

B cells are essential to the adaptive immune system for providing the humoral immunity against cohorts of pathogens. The presentation of antigen to the B cell receptor (BCR) leads to the initiation of B cell activation, which is a process sensitive to the stiffness features of the substrates presenting the antigens. Mechanosensing of the B cells, potentiated through BCR signaling and the adhesion molecules, efficiently regulates B cell activation, proliferation and subsequent antibody responses. Defects in sensing of the antigen-presenting substrates can lead to the activation of autoreactive B cells in autoimmune diseases. The use of high-resolution, high-speed live-cell imaging along with the sophisticated biophysical materials, has uncovered the mechanisms underlying the initiation of B cell activation within seconds of its engagement with the antigen presenting substrates. In this chapter, we reviewed studies that have contributed to uncover the molecular mechanisms of B cell mechanosensing during the initiation of B cell activation.

9.
Front Oncol ; 9: 852, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31552177

RESUMO

Nafamostat mesylate (NM), a synthetic serine protease inhibitor first placed on the market by Japan Tobacco in 1986, has been approved to treat inflammatory-related diseases, such as pancreatitis. Recently, an increasing number of studies have highlighted the promising effects of NM in inhibiting cancer progression. Alone or in combination treatments, studies have shown that NM attenuates various malignant tumors, including pancreatic, colorectal, gastric, gallbladder, and hepatocellular cancers. In this review, based on several activating pathways, including the canonical Nuclear factor-κB (NF-κB) signaling pathway, tumor necrosis factor receptor-1 (TNFR1) signaling pathway, and tumorigenesis-related tryptase secreted by mast cells, we summarize the anticancer properties of NM in existing studies both in vitro and in vivo. In addition, the efficacy and side effects of NM in cancer patients are summarized in detail. To further clarify NM's antitumor activities, clinical trials devoted to validating the clinical applications and underlying mechanisms are needed in the future.

10.
Int J Biol Sci ; 15(9): 1977-1992, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31523198

RESUMO

Background: Currently, there are no molecular biomarkers for the early detection of non-small-cell lung cancer (NSCLC). This study focused on identifying RNAs found on tumor-educated blood platelets (TEPs) for detecting stage I NSCLC. Methods: Platelet RNAs, isolated from the blood of 9 patients with NSCLC (stages I and II) and 8 healthy controls, were analyzed using RNA-seq. ITGA2B was selected as a candidate marker. Two different Polymerase Chain Reactions (PCR) were used to measure ITGA2B in platelet samples from healthy controls (n = 150), patients with NSCLC (n = 243), and patients with benign pulmonary nodules (n = 141) in two cohorts. Results: Platelet ITGA2B levels were significantly higher (p < 0.001) in patients with NSCLC than in all controls. The diagnostic accuracy of ITGA2B was area under the curve (AUC) of 0.922 [95% confidence interval (CI), 0.892-0.952], sensitivity of 92.8%, and specificity of 78.6% in the test cohort and 0.888, 91.2%, and 56.5% in the validation cohort for NSCLC by quantitative real time PCR (q-PCR). Furthermore, ITGA2B maintained diagnostic accuracy for patients with NSCLC using Droplet Digital PCR (ddPCR) and the other type of internal control, Ribosomal Protein L32 (RPL32) [ddPCR: 0.967 (0.929-1.000) and RPL32: 0.847(0.773-0.920)]. A nomogram incorporating ITGA2B, carcinoembryonic antigen (CEA) and stage could predict the overall survival (C-index = 0.756). Conclusions: TEP ITGA2B is a promising marker to improve identification of patients with stage I NSCLC and differentiate malignant from benign lung nodules.

11.
Immunol Rev ; 291(1): 75-90, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31402506

RESUMO

To efficiently initiate activation responses against rare ligands in the microenvironment, lymphocytes employ sophisticated mechanisms involving signaling amplification. Recently, a signaling amplification mechanism initiated from phosphatidylinositol (PI) 4, 5-biphosphate [PI(4,5)P2] hydrolysis and synthesis for sustained B cell activation has been reported. Antigen and B cell receptor (BCR) recognition triggered the prompt reduction of PI(4,5)P2 density within the BCR microclusters, which led to the positive feedback for the synthesis of PI(4,5)P2 outside of the BCR microclusters. At single molecule level, the diffusion of PI(4,5)P2 was slow, allowing for the maintenance of a PI(4,5)P2 density gradient between the inside and outside of the BCR microclusters and the persistent supply of PI(4,5)P2 from outside to inside of the BCR microclusters. Here, we review studies that have contributed to uncovering the molecular mechanisms of PI(4,5)P2-derived signaling amplification model. Based on these studies, we proposed a "gasoline engine model" in which the activation of B cell signaling inside the microclusters is similar to the working principle of burning gasoline within the engine chamber of a gasoline engine. We also discuss the evidences showing the potential universality of this model and future prospects.

12.
J Allergy Clin Immunol ; 144(5): 1377-1390.e4, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31405607

RESUMO

BACKGROUND: B-cell receptor (BCR) signaling, combined with CD19 and CD21 signals, imparts specific control of B-cell responses. Dedicator of cytokinesis protein 2 (DOCK2) is critical for the migration and motility of lymphocytes. Although absence of DOCK2 leads to lymphopenia, little is known about the signaling mechanisms and physiologic functions of DOCK2 in B cells. OBJECTIVE: We sought to determine the underlying molecular mechanism of how DOCK2 regulates BCR signaling and peripheral B-cell differentiation. METHODS: In this study we used genetic models for DOCK2, Wiskott-Aldrich syndrome protein (WASP), and lymphoid enhancer-binding factor 1 deficiency to study their interplay in BCR signaling and B-cell differentiation. RESULTS: We found that the absence of DOCK2 led to downregulation of proximal and distal BCR signaling molecules, including CD19, but upregulation of SH2-containing inositol 5 phosphatase 1, a negative signaling molecule. Interestingly, DOCK2 deficiency reduced CD19 and CD21 expression at the mRNA and/or protein levels and was associated with reduced numbers of marginal zone B cells. Additionally, loss of DOCK2 reduced activation of WASP and accelerated degradation of WASP, resulting into reduced actin accumulation and early activation of B cells. Mechanistically, the absence of DOCK2 upregulates the expression of lymphoid enhancer-binding factor 1. These differences were associated with altered humoral responses in the absence of DOCK2. CONCLUSIONS: Overall, our study has provided a novel underlying molecular mechanism of how DOCK2 deficiency regulates surface expression of CD21, which leads to downregulation of CD19-mediated BCR signaling and marginal zone B-cell differentiation.

13.
Int J Clin Pharm ; 41(5): 1133-1137, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31468253

RESUMO

This article reviews the current status of the overuse of intravenous (IV) infusions in China and implications to patient safety, and analyzes factors associated with the overuse. Although many factors contribute to the overuse of IV infusions in China, we focus on the construction of an IV infusion management system and tackling cultural problems as the first step to address issues of IV therapy in this commentary.

14.
Sci Adv ; 5(7): eaaw0315, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31328160

RESUMO

B cell activation is regulated by the stimulatory or inhibitory co-receptors of B cell receptors (BCRs). Here, we investigated the signaling mechanism of Fc receptor-like 1 (FcRL1), a newly identified BCR co-receptor. FcRL1 was passively recruited into B cell immunological synapses upon BCR engagement in the absence of FcRL1 cross-linking, suggesting that FcRL1 may intrinsically regulate B cell activation and function. BCR cross-linking alone led to the phosphorylation of the intracellular Y281ENV motif of FcRL1 to provide a docking site for c-Abl, an SH2 domain-containing kinase. The FcRL1 and c-Abl signaling module, in turn, potently augmented B cell activation and proliferation. FcRL1-deficient mice exhibited markedly impaired formation of extrafollicular plasmablasts and germinal centers, along with decreased antibody production upon antigen stimulation. These findings reveal a critical BCR signal-enhancing function of FcRL1 through its intrinsic recruitment to B cell immunological synapses and subsequent recruitment of c-Abl upon BCR cross-linking.

15.
Elife ; 82019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31343409

RESUMO

FcγRIIB binding to its ligand suppresses immune cell activation. A single-nucleotide polymorphic (SNP) change, I232T, in the transmembrane (TM) domain of FcγRIIB loses its suppressive function, which is clinically associated with systemic lupus erythematosus (SLE). Previously, we reported that I232T tilts FcγRIIB's TM domain. In this study, combining with molecular dynamics simulations and single-cell FRET assay, we further reveal that such tilting by I232T unexpectedly bends the FcγRIIB's ectodomain toward plasma membrane to allosterically impede FcγRIIB's ligand association. I232T substitution reduces in situ two-dimensional binding affinities and association rates of FcγRIIB to interact with its ligands, IgG1, IgG2 and IgG3 by three to four folds. This allosteric regulation by an SNP provides an intrinsic molecular mechanism for the functional loss of FcγRIIB-I232T in SLE patients.

16.
Elife ; 82019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31290744

RESUMO

B lymphocytes use B cell receptors (BCRs) to recognize antigens. It is still not clear how BCR transduces antigen-specific physical signals upon binding across cell membrane for the conversion to chemical signals, triggering downstream signaling cascades. It is hypothesized that through a series of conformational changes within BCR, antigen engagement in the extracellular domain of BCR is transduced to its intracellular domain. By combining site-specific labeling methodology and FRET-based assay, we monitored conformational changes in the extracellular domains within BCR upon antigen engagement. Conformational changes within heavy chain of membrane-bound immunoglobulin (mIg), as well as conformational changes in the spatial relationship between mIg and Igß were observed. These conformational changes were correlated with the strength of BCR activation and were distinct in IgM- and IgG-BCR. These findings provide molecular mechanisms to explain the fundamental aspects of BCR activation and a framework to investigate ligand-induced molecular events in immune receptors.


Assuntos
Antígenos/metabolismo , Linfócitos B/fisiologia , Ativação Linfocitária , Receptores de Antígenos de Linfócitos B/química , Receptores de Antígenos de Linfócitos B/metabolismo , Linhagem Celular , Transferência Ressonante de Energia de Fluorescência , Humanos , Ligação Proteica , Conformação Proteica
17.
Biomed Res Int ; 2019: 1528278, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31355248

RESUMO

Oxidative stress and cardiomyocytes apoptosis were closely involved in the pathological process of doxorubicin- (Dox-) induced cardiac injury. MicroRNA-451 (miR-451) was mainly expressed in cardiomyocytes. However, the role of miR-451 in Dox-induced cardiac injury remained unclear. Our study aimed to investigate the effect of miR-451 on Dox-induced cardiotoxicity in mice. We established a Dox-induced cardiotoxicity model in the mice and manipulated miR-451 expression in the heart using a miR-451 inhibitor, which was injected every other day beginning at one day before Dox injection. Oxidative stress and apoptosis in the hearts were evaluated. miR-451 levels were significantly increased in Dox-treated mice or cardiomyocytes. miR-451 inhibition attenuated Dox-induced whole-body wasting and heart atrophy, reduced cardiac injury, restored cardiac function, and improved cardiomyocyte contractile function. Moreover, miR-451 inhibition reduced oxidative stress and cardiomyocytes apoptosis in vivo and in vitro. miR-451 inhibition increased the expression of calcium binding protein 39 (Cab39) and activated adenosine monophosphate activated protein kinase (AMPK) signaling pathway. A specific inhibitor of AMPK abolished the protection provided by miR-451 inhibition against cell injury in vitro. In conclusion, miR-451 inhibition protected against Dox-induced cardiotoxicity via activation of AMPK signaling pathway.


Assuntos
Cardiotoxicidade/genética , Traumatismos Cardíacos/genética , MicroRNAs/genética , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade/patologia , Modelos Animais de Doenças , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Traumatismos Cardíacos/induzido quimicamente , Traumatismos Cardíacos/patologia , Humanos , Camundongos , MicroRNAs/antagonistas & inibidores , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Quinases/genética , Transdução de Sinais/efeitos dos fármacos
18.
Cell Immunol ; : 103926, 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31151736

RESUMO

Immune cells including B and T lymphocytes have a remarkable ability to sense the physical perturbations through their surface expressed receptors. At the advent of modern imaging technologies paired with biophysical methods, we have gained the understanding of mechanical forces exerted by immune cells to perform their functions. This review will go over the imaging techniques already being used to study mechanical forces in immune cells. We will also discuss the dire need for new modern technologies for future work.

19.
Int Immunol ; 31(12): 759-770, 2019 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-31169885

RESUMO

Antibody production results from B-cell activation and proliferation upon antigen binding. Discs large homolog 1 (Dlg1), a scaffold protein from the membrane-associated guanylate kinase family, has been shown to regulate the antigen receptor signaling and cell polarity in lymphocytes; however, the physiological function of Dlg1 in humoral responses is not completely clear. Here, we addressed this question using a conditional knockout (KO) mouse model with Dlg1 deficiency in different B-cell subsets by crossing dlg1fl/fl mice with either mb1cre/+ or aicdacre/+ mice, respectively. In both mouse models, we observed that Dlg1 deficiency in B cells (Dlg1-KO B cells) led to obvious hyper-antibody responses upon immunization, the effect of which was more obvious in antigen-recall responses. Mechanistically, we found that Dlg1-KO B cells exhibited hyper-proliferation compared with wild-type B cells upon antigen stimulation, suggesting that the hyper-antibody responses are likely induced by the hyper-proliferation of Dlg1-KO B cells. Indeed, further studies demonstrated that Dlg1 deficiency in B cells led to the down-regulation of a tumor suppressor, FoxO1. Thus, all these results reveal an unexpected function of Dlg1 in restraining hyper-antibody responses through the inhibition of FoxO1 and thus antigen-binding-induced proliferation in B cells.

20.
Clin Ther ; 41(8): 1631-1637.e4, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31174860

RESUMO

This study categorizes the types of inappropriate intravenous prescriptions in hospitalized patients in China. Prescription data from 2016 were retrospectively analyzed based on predefined categories of inappropriateness. Of the 123,521 patients included, 89.2% received intravenous medications, contributing to 80% of the patients' hospital medication costs. Of significant concern, antibiotics and traditional Chinese medicines were administered to 44.3% and 14.5% of hospitalized patients, respectively. Overall, 11.4% of all intravenous prescriptions were classified as inappropriate, with improper diluent and diluent volumes being the primary cause. A team-based collaborative approach is necessary to address this widespread issue in China.

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