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1.
Virus Res ; 275: 197791, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31628980

RESUMO

Human parainfluenza virus type 3 (HPIV3) fuses the viral envelope with the host cell membrane through the concerted action of the fusion (F) protein and the hemagglutinin-neuraminidase (HN). Upon HN binding to sialic acid (SA), the F protein in a metastable prefusion form is activated to undergo a series of structural rearrangements into a stable postfusion form to actuate the fusion between membranes. Various domains of F protein of some other paramyxoviruses, including HPIV3, have been reported to be differently functional. However, it is not yet clear what roles HRB linker plays. To clarify the roles that HRB linker might play in the F-mediated membrane fusion process, here we examined the effects of mutations introduced into the HRB linker of HPIV3 F protein. Six Single amino acid mutants, three chimeric mutants, and one deletion mutant were obtained and analyzed for membrane fusion activity and cell surface expression. The results showed that the membrane fusion activity of mutants changed to varying degrees in comparison with wild-type (wt) F, and some mutants even forfeited fusogenicity absolutely. It is indicated that the HRB linker domain plays an important role in the F-mediated membrane fusion process.

2.
J Hazard Mater ; 383: 121063, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31539660

RESUMO

Microalgae photosynthesis is sensitive to coexisted contaminates in aquatic environment, thereby causes adverse effect on algal growth and nutrients uptake. Here, we investigated the photosynthetic toxicity mechanism of cetyltrimethyl ammonium chloride (CTAC)-induced on a green microalga Chlorella vulgaris F1068 (C. vulgaris F1068). Results showed that CTAC reduced the algal growth rate, nutrients removal efficiency and weakened the photosynthetic performance. Meanwhile, the efficiency of oxygen evolution complex (OEC) and oxygen evolvement rates stressed by CTAC were significantly declined to 90.48% and 58.48% of the control (without CTAC), respectively. In addition, atomic force microscopy (AFM) detected the damage of PSII-OEC morphology and structure by CTAC. Furthermore, proteomic analysis showed that 41% of proteins were in the chloroplast thylakoid membranes which function in photosynthesis. The activity of oxygen-evolving enhancer protein 2 (OEE2 or PsbP) involved in electron transfer was significantly inhibited by CTAC, which down-regulated 15.14-fold in the presence of 0.6 mg/L CTAC. These results indicated that photosynthetic inhibition of CTAC mainly occurred in the PSII-OEC. This study provided a new perspective of the photosynthetic response in evaluation of environmental bioimpacts of surfactants on microalgae.

3.
Spectrochim Acta A Mol Biomol Spectrosc ; 224: 117396, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31394391

RESUMO

In this paper, we have proposed a method to detect a mixture of carbamate pesticides using a back propagation network (BP), which is optimized by genetic algorithm (GA) for quantitative analysis. This method aims to combine the advantages of BP and GA to remedy their drawbacks. The training samples were taken as input, some performance indexes such as the predicted values, iteration time, mean squared error, correlation coefficient and recovery rate were compared between BP neural network and the constructed GA-BP model to evaluate the performance of two neural networks. Results show that the optimized GA-BP model can effectively predict the concentrations, the mean squared error and recovery rate are better. In addition, the correlation coefficient has a significant improvement. This study can provide a new way for detection of the pesticides mixture and help to analysis in a reliable way.

4.
J Nanosci Nanotechnol ; 20(4): 2072-2078, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31492214

RESUMO

Fluorescent organic dots have been widely utilized for various biological imaging. To obtain organic dots with high quantum yield (QY), different molecules with aggregation-induced emission (AIE) property and polymers with amphiphilic are used. By encapsulating AIE molecule 9,10-divinyl anthracene (DSA) with poly(styrene-co-maleic anhydride) and poly(isobutylene-alt-maleic anhydride) (PSMA and PIMA), novel bright AIE organic dots were obtained. The prepared AIE organic dots (PSMA dots and PIMA dots) had uniform particle size distribution, spherical appearance and small particle size (about 23 nm). However, PSMA dots had higher QYs than PIMA dots, and reached about 28.9% when the mass ratio of PSMA:DSA was 1:1. After folic acid (FA) conjugating to the surface of the PSMA dots, FA-dots were obtained. FA-dots possessed uniform particle size, good optical properties, stability and biocompatibility. The FA-dots could mark the cells where folate receptors were over-expressing. In vitro cell experiment indicated that FA-dots could be endocytosed into Hela cells, and marked the cell with specific.

5.
Shanghai Kou Qiang Yi Xue ; 28(4): 426-429, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31792487

RESUMO

PURPOSE: To retrospectively analyze the clinical characteristics of impacted supernumerary teeth in 115 patients. METHODS: One hundred and fifteen patients with im-pacted supernumerary teeth who were admitted to the Department of Oral and Max-illofacial Surgery of Hefei Stomatological Hospital were selected randomly. The age, sex, number of teeth, location, direction, clinical manifestation, anaes-thesia method and operation time were analyzed retrospectively, T test and Chi-square test were used to determine the statistical differences with SPSS 19.0 software package. RESULTS: Among 115 patients, there were 176 impacted supernu-merary, most of them were in mixed dentition period (66.96%), the sex ratio was 2.29:1, and Most patients (59.1%) had one supernumerary tooth, followed by two supernumerary teeth(33.9%). Most supernumerary teeth were located in the middle of the maxilla (68.2%). Inverted ones were the most common (52.8%). The most common symptoms were delayed eruption, displacement, crowding, torsion and space of the adjacent teeth. 92.2% of patients underwent general anesthesia. The dee-per the locations of impacted supernumerary were, the longer the operation time was. CONCLUSIONS: There are regional characteristics of supernumerary teeth in Hefei City, which can provide a reference for clinical diagnosis and treatment.

6.
Environ Pollut ; : 113456, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31784270

RESUMO

Fructose was utilized as an additional co-substrate to systematically investigate the molecular mechanism of its boosting effect for the degradation of refractory dye reactive black 5 (RB5) by a natural bacterial flora DDMZ1. A decolorizing rate of 98% was measured for sample YE + FRU(200) (with 3 g/L fructose additionally to yeast extract medium, 10% (v/v) inoculation size of flora DDMZ1, 200 mg/L RB5) after 48 h. This result was 21% and 77%, respectively, higher than those of samples with only yeast extract or only fructose. Fructose was found to significantly stimulated both intracellular and extracellular azoreductase secretion causing enhanced activity. Metagenomic sequencing technology was used to analyze the functional potential of genes. A label-free quantitative proteomic approach further confirmed the encoding of functional proteins by the candidate genes. Subsequently, the molecular mechanism of RB5 degradation by candidate genes and functional proteins of the dominant species were proposed. This study provides important perspectives to the molecular mechanism of co-metabolic degradation of refractory pollutants by a natural bacterial flora.

7.
Orphanet J Rare Dis ; 14(1): 237, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666091

RESUMO

BACKGROUND: Hirschsprung disease (HSCR) is an inherited congenital disorder characterized by the absence of enteric ganglia in the distal part of the gut. RET is the major causative gene and contains > 80% of all known disease-causing mutations. RESULTS: To determine the incidence of RET pathogenic variants, be they Mendelian inherited, mosaic in parents or true de novo variants (DNVs) in 117 Chinese families, we used high-coverage NGS and droplet digital polymerase chain reaction (ddPCR) to identify 15 (12.8%) unique RET coding variants (7 are novel); one was inherited from a heterozygous unaffected mother, 11 were DNVs (73.3%), and 3 full heterozygotes were inherited from parental mosaicism (2 paternal, 1 maternal): two clinically unaffected parents were identified by NGS and confirmed by ddPCR, with mutant allele frequency (13-27%) that was the highest in hair, lowest in urine and similar in blood and saliva. An extremely low-level paternal mosaicism (0.03%) was detected by ddPCR in blood. Six positive-controls were examined to compare the mosaicism detection limit and sensitivity of NGS, amplicon-based deep sequencing and ddPCR. CONCLUSION: Our findings expand the clinical and molecular spectrum of RET variants in HSCR and reveal a high frequency of RET DNVs in the Chinese population.

8.
Biomed Res Int ; 2019: 5249675, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31687391

RESUMO

The broad spectrum of disabilities caused by white matter injury (WMI) cannot be explained simply by hypomyelination. Synaptic injury in the thalamus may be related to disabilities in WMI survivors. Neuronal injury in the thalamus has been found most commonly in autopsy cases of preterm WMI. We hypothesized that hypoxia/ischemia (HI) in neonatal rats results in synaptic abnormalities in the thalamus that contribute to disabilities in WMI survivors. We examined changes in synapses in a neonatal rat model of HI-induced WMI. Right common carotid artery ligation and hypoxia (8% oxygen for 2.5 hours (h)) were performed in three-day-old Sprague-Dawley rats. We found HI rats performed worse in the Morris water maze test than sham rats, suggesting long-term cognition impairment after HI injury. A loss of synapses in the thalamus accompanied by hypomyelination and oligodendrocytes (OLs) reduction was observed. At the ultrastructural level, reductions in active zone (AZ) length and postsynaptic density (PSD) thickness were detected at 2 weeks after HI exposure. Furthermore, increased expression of synaptophysin and PSD-95 in both groups was observed from 3 days (d) to 21 d after hypoxic/ischemic (HI) injury. PSD-95 expression was significantly lower in HI rats than in sham rats from 14 d to 21 d after HI injury, and synaptophysin expression was significantly lower in HI rats from 7 d to 14 d after HI injury. However, no significant difference in synaptophysin expression was observed between HI rats and sham rats at 21 d after HI injury. The results demonstrated synaptic abnormalities in the thalamus accompanied by hypomyelination in WMI in response to HI exposure, which may contribute to the diverse neurological defects observed in WMI patients. Although synaptic reorganization occurred as a compensatory response to HI injury, the impairments in synaptic transmission were not reversed.

9.
J Gen Virol ; 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31702540

RESUMO

To gain insights into the role of the head-stalk linker region in the fusion triggering, we constructed mutants by deleting or substituting the linker region (115-NGAANNSG-122) of Newcastle disease virus (NDV) haemagglutinin-neuraminidase (HN) with the corresponding sequences of other paramyxoviruses. The results showed that these HN mutants exhibited different levels of fusion-triggering activity, but most of them maintained comparable levels with wide-type HN in both receptor recognition and neuraminidase activity. We tried to figure out reasons for fusion alteration through assessing the expression and the oligomeric state of HN mutants. Moreover, four mutants with significant fusion changes were introduced into the headless HN stem (HN1-123) to intensively investigate the role of the linker region in fusion triggering. Consequently, the stability of HN oligomers and the structural integrity of the 4 helical-bundle of stalk have complicated influences on the alteration of fusion-triggering activities for different mutants. These data suggested that the head-stalk linker could regulate the fusion triggering at both full-length and headless HN levels.

10.
Dermatol Ther ; : e13165, 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31705774

RESUMO

Psoriasis and pemphigus are clinically well-characterized chronic, inflammatory skin diseases. Many case reports have described the coexistence of psoriasis and bullous pemphigoid. However, the present report is about a rare case of pemphigus vulgaris in a patient with psoriasis vulgaris. We had a 68-year-old male psoriatic patient who developed blisters lesions and erosions on the trunk and extremities. The histopathology of a blister lesion showed the intraepidermal blisters that contained serous fluid and inflammatory cells. Both of desmoglein core protein 1 antibody and desmoglein core protein 3 antibody were detected. Diagnoses of pemphigus vulgaris and psoriasis vulgaris were made. The patient was treated with methotrexate (12.5 mg/week) and methylprednisone (16 mg/day) after his admission. Two weeks after admission, the patient's lesions gradually subsided. This case reminds us that the therapeutic effect of pemphigus vulgaris may be related to the incidence of psoriasis.

11.
Viruses ; 11(11)2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31731691

RESUMO

Ebola virus (EBOV) disease outbreaks have resulted in many fatalities, yet no licensed vaccines are available to prevent infection. Recombinant glycoprotein (GP) production may contribute to finding a cure for Ebola virus disease, which is the key candidate protein for vaccine preparation. To explore GP1,2 expression in BmN cells, EBOV-GP1,2 with its native signal peptide or the GP64 signal peptide was cloned and transferred into a normal or gp64 null Bombyx mori nucleopolyhedrovirus (BmNPV) bacmid via transposition. The infectivity of the recombinant bacmids was investigated after transfection, expression and localization of EBOV-GP were investigated, and cell morphological changes were analyzed by TEM. The GP64 signal peptide, but not the GP1,2 native signal peptide, caused GP1,2 localization to the cell membrane, and the differentially localized GP1,2 proteins were cleaved into GP1 and GP2 fragments in BmN cells. GP1,2 expression resulted in dramatic morphological changes in BmN cells in the early stage of infection. However, GP1,2 expression did not rescue GP64 deficiency in BmNPV infection. This study provides a better understanding of GP expression and processing in BmN cells, which may lay a foundation for EBOV-GP expression using the BmNPV baculovirus expression system.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31732995

RESUMO

Rationale Erianin, a bioactive component isolated from Dctidrobium chrysotoxum Lindl, was demonstrated to have many biological properties relevant to cancer prevention and therapy. However, the metabolic profiles of erianin remain unknown. This study was carried out to investigate the metabolic profiles of erianin in rats and humans. Methods Erianin was orally administered to rats at a single dose of 50 mg/kg. The urine and bile samples were collected. For in vitro metabolism, erianin was co-incubated with rat or human hepatocytes at 37 o C for 2 h. The samples from incubations and rat were analyzed by liquid chromatography combined with electrospray ionization high resolution mass spectrometry. The data were processed by MetWorks software. The structures of the metabolites were proposed by comparing the mass spectra with that of the parent compound. Results A total of twenty-four metabolites were detected in vitro and in vivo, including seven phase I and eighteen phase II metabolites. The phase I metabolic pathways of erianin were hydroxylation, demethylation and dehydrogenation. Erianin undergoes metabolic activation to form reactive metabolites quinoids intermediates, which were further trapped by glutathione or N-acetyl-cysteine. The phase II metabolic pathways were glucuronidation, glutathione and N-acetyl-cysteine conjugation. Conclusions The present study provides an overview pertaining to the in vitro and in vivo metabolic profiles of erianin, which is indispensable for us to understand the efficacy and safety of erianin, as well as the herb medicine D. chrysotoxum.

13.
Geriatr Nurs ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31668460

RESUMO

The objective was to examine the feasibility, reliability and validity of the Groningen Frailty Indicator (GFI) among Chinese community-dwelling older adults. Of the 1230 participants, 1202 (97.7%) completed all items on the GFI. The internal consistency was acceptable (Cronbach's α = 0.64), and the test-retest reliability within a 7-15-day interval was good (ICC = 0.87). The GFI showed good diagnostic accuracy in the identification of frailty with reference to the frailty index (AUC = 0.84), and the optimal frailty cut-point was 3. Convergent validity was supported by significant correlations between each domain of the GFI and the corresponding alternative measurement(s). Higher proportions of frailty (GFI ≥ 3) were found in those who were older, female, less-educated, lived alone, and had 2 or more chronic diseases than in their counterparts, supporting its known-group discriminant validity. The Chinese GFI has good feasibility, acceptable reliability and satisfactory validity among community-dwelling older adults.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31682978

RESUMO

Although thymus-independent donor-derived T cell expansion may determine the occurrence of graft-versus-host disease (GVHD) and relapse after transplantation, the characteristics and dynamics of the expansion process remain unclear. To address this issue, we monitored T cell receptor ß repertoire at day 0, day 28, and day 61 after transplantation in 30 patients with hematologic malignancies by next-generation sequencing. The clonality index showed an increasing clonality over time (P = .001). The top 200 clonotypes accounted for more than half of the total clonotypes (median frequency, 63.55%) at day 61, and there was a remarkable overlapping between the top 200 clonotypes of each repertoire and its former repertoire (>50%). A normalized index, called the T Cell Response Index (TCRI), was designed on the basis of rank-shift analysis to quantify antigen-driven expansion. The TCRI during the first month was not related to relapse or GVHD (P> .05), whereas the TCRI during the second month was related to relapse (P = .006). Recipients with a TCRI below 1.0 during the second month had a higher cumulative relapse rate (31.25% versus 0%, P = .0323) and had a lower 1-year survival rate (56.25% versus 78.57%, P = .281). The clonotypes with strong competitiveness in the second month in the nonrelapse group preferentially used TRBV2, TRBV12-3, TRBJ1-1 and TRBJ1-5 segments (P< .01). In conclusion, homeostatic expansion predominates in the first month due to nonspecific T cell proliferation, whereas antigen-driven expansion predominates in the second month and results in a graft-versus-tumor (GvT) effect. Moreover, TCRI could serve as a quantitative indicator of GvT against relapse within the first year. The difference in V and J segment usage reveals that T cells responsible for potent GvT effect are similar among patients.

15.
Cell Stress Chaperones ; 24(6): 1211-1217, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31741235

RESUMO

Heme homeostasis is of vital importance to many biological processes associated with cell redox activity. However, the role of heme in the doxorubicin (DOX)-induced cardiotoxicity is still not clear. The aim of the present study was to test the hypothesis that heme is related to the DOX-induced oxidative stress and inhibition of heme expression may protect H9c2 cardiomyocytes against DOX-induced cardiotoxicity. For the evaluation of heme changing under doxorubicin treatment, H9c2 cells were treated with 0.5, 1, 2, and 4 mg/mL doxorubicin respectively. H9c2 cells were divided into 5 groups: Control group (cells were cultured without intervention), DOX group (cells were treated with 2 mg/mL doxorubicin for 6 h), Heme depletion+DOX group (cells were cultured with heme-depleted serum media, 0.5 mM succinylacetone and 2 mg/mL doxorubicin), Heme group (cells were treated with 30 µM heme), and Heme depletion+DOX+Heme group. Apoptotic cells were detected by flow cytometry with Annexin V-FITC/PI. The intracellular oxidant levels were measured by DCFH-DA fluorescence. The levels of heme were detected by ELISA. Doxorubicin significantly increased intracellular heme level from 5013 ± 187 ng/mL to the highest level of 11,720 ± 107 ng/mL, as well as the intracellular oxidants and cell apoptosis rate elevated by the increase of doxorubicin concentration. Heme depletion can significantly suppress the DOX-induced apoptosis from 39.8 ± 0.5% to 20.8 ± 0.5% (p < 0.001). Re-supplemented with exogenous heme partially but significantly restored the DOX-induced apoptosis. Heme plays an important role in doxorubicin toxicity-induced cardiomyocyte injury. By appropriate reduction in the accumulation of free heme in cardiomyocytes, doxorubicin-induced cardiotoxicity may be alleviated.

16.
Virus Genes ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31768710

RESUMO

Human parainfluenza virus type 3 (HPIV3) causes the majority of childhood viral pneumonia around the world. Fusing the viral and target cell membranes is crucial for its entry into target cells, and the fusion process requires the concerted actions of two viral glycoproteins: hemagglutinin-neuraminidase (HN) and fusion (F) protein. After binding to the cell surface receptor, sialic acids, HN triggers F to undergo large conformational rearrangements to execute the fusion process. Although it has been reported that several domains of F had important impacts on regulating the membrane fusion activity, what role the DI-DII linker (residues 369-374, namely L1 linker) of the HPIV3 F protein plays in the fusion process still remains confused. We have obtained three chimeric mutant proteins (Ch-NDV-L1, Ch-MV-L1, Ch-HPIV1-L1) containing the full length of HPIV3 F protein but their corresponding DI-DII linker derived from the F protein of Newcastle disease virus (NDV), Measles virus (MV), and Human parainfluenza virus type 1 (HPIV1), respectively. One deletion mutant protein (De-L1), whose DI-DII linker was deleted, has been established simultaneously. Then vaccinia virus-T7 RNA polymerase transient expression system and standard plasmid system were utilized to express the mutant F proteins in BHK-21 cells. These four mutants were determined for membrane fusogenic activity, cell surface expression level, and total mutant F protein expression. All of them resulted in a significant reduction in fusogenic activity in all steps of cell-cell membrane fusion process. There was no significant difference in cell surface protein expression level for the mutants compared with wild-type F. The mutant proteins with inability in fusogenic activity were all at the form of precursor protein, F0, which were not hydrolyzed by intracellular protease furin. The results above suggest that the involvement of the DI-DII linker region is necessary for the complete fusion of the membranes.

17.
Nat Commun ; 10(1): 5190, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729389

RESUMO

As one of next-generation semiconductors, hybrid halide perovskites with tailorable optoelectronic properties are promising for photovoltaics, lighting, and displaying. This tunability lies on variable crystal structures, wherein the spatial arrangement of halide octahedra is essential to determine the assembly behavior and materials properties. Herein, we report to manipulate their assembling behavior and crystal dimensionality by locally collective hydrogen bonding effects. Specifically, a unique urea-amide cation is employed to form corrugated 1D crystals by interacting with bromide atoms in lead octahedra via multiple hydrogen bonds. Further tuning the stoichiometry, cations are bonded with water molecules to create a larger spacer that isolates individual lead bromide octahedra. It leads to zero-dimension (0D) single crystals, which exhibit broadband 'warm' white emission with photoluminescence quantum efficiency 5 times higher than 1D counterpart. This work suggests a feasible strategy to modulate the connectivity of octahedra and consequent crystal dimensionality for the enhancement of their optoelectronic properties.

18.
Adv Exp Med Biol ; 1163: 313-334, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707709

RESUMO

Protein-protein interactions (PPIs) represent promising drug targets of broad-spectrum therapeutic interests due to their critical implications in both health and disease circumstances. Hence, they are widely accepted as the Holy Grail of drug development. Historically, PPIs were rendered "undruggable" for their large, flat, and pocket-less structures. Current attempts to drug these "intractable" targets include orthosteric and allosteric methodologies. Previous efforts employing orthosteric approaches like protein therapeutics and orthosteric small molecules frequently suffered from poor performance caused by the difficulties in directly targeting PPI interfaces. As structural biology progresses rapidly, allosteric modulators, which direct to the allosteric regulatory sites remote to the PPI surfaces, have gradually established as a potential solution. Allosteric pockets are topologically distal from the PPI orthosteric sites, and their ligands do not need to compete with the PPI partners, which helps to improve the physiochemical and pharmacological properties of allosteric PPI modulators. Thus, exploiting allostery to tailor PPIs is regarded as a tempting strategy in future PPI drug discovery. Here, we provide a comprehensive review of our representative achievements along the way we utilize allosteric effects to tame the difficult PPI systems into druggable targets. Importantly, we provide an in-depth mechanistic analysis of this success, which will be instructive to future related lead optimizations and drug design. Finally, we discuss the current challenges in allosteric PPI drug discovery. Their solutions as well as future perspectives are also presented.


Assuntos
Sítio Alostérico , Descoberta de Drogas , Regulação Alostérica , Sítio Alostérico/fisiologia , Ligantes , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia
19.
J Immunother Cancer ; 7(1): 298, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31722750

RESUMO

BACKGROUND: Immunotherapy, especially immune checkpoint inhibition, has provided powerful tools against cancer. We aimed to detect the expression of common immune checkpoints and evaluate their prognostic values in nasopharyngeal carcinoma (NPC). METHODS: The expression of 9 immune checkpoints consistent with 13 features was detected in the training cohort (n = 208) by immunohistochemistry and quantified by computational pathology. Then, the LASSO cox regression model was used to construct an immune checkpoint-based signature (ICS), which was validated in a validation cohort containing 125 patients. RESULTS: High positive expression of PD-L1 and B7-H4 was observed in tumour cells (TCs), whereas PD-L1, B7-H3, B7-H4, IDO-1, VISTA, ICOS and OX40 were highly expressed in tumour-associated immune cells (TAICs). Eight of the 13 immune features were associated with patient overall survival, and an ICS classifier consisting of 5 features (B7-H3TAIC, IDO-1TAIC, VISTATAIC, ICOSTAIC, and LAG3TAIC) was established. Patients with high-risk scores in the training cohort had shorter overall (P < 0.001), disease-free (P = 0.002), and distant metastasis-free survival (P = 0.004), which were confirmed in the validation cohort. Multivariate analysis revealed that the ICS classifier was an independent prognostic factor. A combination of the ICS classifier and TNM stage had better prognostic value than the TNM stage alone. In addition, the ICS classifier was significantly associated with survivals in patients with high EBV-DNA load. CONCLUSIONS: We determined the expression status of nine immune checkpoints consistent with 13 features in NPC and further constructed an ICS prognostic model, which might add prognostic value to the TNM staging system.

20.
BMC Nephrol ; 20(1): 411, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727005

RESUMO

BACKGROUND: Peritoneal fibrosis is the most common complication of peritoneal dialysis, but there is currently no effective treatment. We previously reported that suramin pretreatment prevents the development of peritoneal fibrosis in a rat model of peritoneal fibrosis induced by chlorhexidine gluconate (CG). Here, we further examined the effectiveness of delayed administration of suramin on peritoneal fibrosis and the mechanism (s) involved in this process. METHODS: In the rat model of peritoneal fibrosis induced by CG, suramin or saline was administered at day 21 and 28. All rats were then sacrificed to collect peritoneal tissues for Western blot analysis and histological staining at day 35. RESULTS: Our results demonstrated that delayed administration of suramin starting at 21 days following CG injection can ameliorate peritoneal damage, with greater efficacy after two injections. Suramin also reduced the expression of α-smooth muscle actin, Collagen 1, and Fibronectin and suppressed phosphorylation of Smad-3, epidermal growth factor receptor (EGFR), signal transducers, activator of transcription 3 (STAT3) as well as extracellular signal-regulated kinases 1/2 (ERK 1/2) in the peritoneum injured with CG. Moreover, delayed administration of suramin inhibited overproduction of transforming growth factor-ß1(TGF-ß1) and expression of several pro-inflammatory cytokines, including monocyte chemoattractant protein-1, tumor necrosis factor-α, interleukin-1, and interleukin-6. CONCLUSIONS: Our results indicated that suramin can attenuate progression of peritoneal fibrosis by a mechanism involving inhibition of the TGF-ß1/Smad3 and EGFR signaling pathways as well as suppression of multiple proinflammatory cytokines. Thus, suramin may have the potential to offer an effective treatment for peritoneal fibrosis.

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