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1.
Healthcare (Basel) ; 10(3)2022 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-35326896

RESUMO

BACKGROUND: Total knee arthroplasty (TKA) is the only effective treatment of end-stage knee osteoarthritis (OA). Lower limb neutral alignment has been a criterion to predict prosthesis life; however, there has been recent controversy over this. Some researchers believe that lower limb static alignment does not significantly affect prosthesis life and some researchers have found that dynamic mechanical alignment may affect prosthesis life, which needs to be further studied. METHODS: Eighty-seven patients with knee OA were evaluated by a three-dimensional (3D) gait analysis system before TKA and six months after TKA, dynamic mechanical alignment and basic gait parameters were then calculated. Based on the static alignment of the lower limb on the postoperative X-radiographs, they were divided into a neutral alignment group (58 cases), varus alignment group (20 cases), and valgus alignment group (9 cases). Simple linear regression was used to assess the correlation between static and dynamic alignment. One-way analysis of variance (ANOVA) was used to compare the differences in gait parameters between and within groups. RESULTS: Eighty-seven patients were followed up for an average of six months after the operation. There was no significant difference in all gait parameters among the three groups after TKA. There was no correlation found between static alignment and dynamic alignment/knee adduction moment (KAM) after TKA, although patients showed a significant linear correlation before operation. There was a significant linear correlation between dynamic alignment and KAM before and after the operation. CONCLUSIONS: Static alignment has no significant effect on postoperative gait function. Static alignment is no longer an effective predictor of the dynamic alignment or KAM six months after TKA, although they are correlated before TKA. The dynamic alignment allows for better prediction of KAM, which may be a risk factor for the life of the prosthesis.

2.
Mol Biol Rep ; 2022 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-35262820

RESUMO

BACKGROUND: The emergence of nonresponse or resistance to traditional chemotherapeutic agents is one of the main challenges of colorectal cancer (CRC) therapies. Thus, novel therapeutic drugs that can improve the clinical outcomes of CRC patients are urgently needed. The purpose of this study was to investigate the effects and mechanisms of pyrimethamine in CRC. METHODS AND RESULTS: In this study, we assessed the role of pyrimethamine on CRC cell growth by cell counting kit-8 and colony formation assays. Cell cycle distribution and cellular senescence were determined by flow cytometry and senescence-associated ß-galactosidase staining respectively. RNA-seq analysis and western blotting were used to investigate the potential pathways of pyrimethamine in CRC development. Moreover, animal experiments were performed to evaluate the effect of pyrimethamine in vivo. Our results demonstrated that pyrimethamine could inhibit cell growth by inducing S phase arrest followed by cellular senescence in CRC cells, and the p38MAPK-p53 axis was probably involved in that effect. In addition, pyrimethamine could also boost CD8+ T-cell mediated cytotoxicity and exert antitumor activity in vivo. CONCLUSION: These results indicated that pyrimethamine may be a promising candidate agent for CRC treatment.

3.
J Parasitol ; 108(1): 53-56, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-35100372

RESUMO

Rural children are seriously afflicted with intestinal helminth infections in China. Of note, the term rural children includes rural left-behind children (LBC) and rural non-left-behind children (NLBC); the difference in the prevalence of intestinal helminths between the 2 groups remains unclear. In this study, Gulin and Xuyong counties in southern Sichuan were chosen for investigation in 2019. The Kato Katz thick smear method was used to detect the presence of intestinal helminth eggs in rural children. For children aged 3-6 yr, the adhesive tape perianal swab method was used to detect Enterobius vermicularis and tapeworm eggs. Statistical differences in infection rates between the 2 groups were determined by the chi-square test. In total, 1,608 rural children, 911 LBC and 697 NLBC, participated in the investigation. Six species of intestinal helminths were detected. A total of 358 (39.3%) and 130 (18.7%) intestinal helminth positives were found among LBC and NLBC, respectively; the former had a higher (P < 0.05) infection level. Moreover, an analysis of double worm infection rates among intestinal helminth positive LBC and NLBC showed a difference between the 2 groups that was also statistically significant. These surveys indicated that the risk of intestinal helminth infection was substantially higher and the severity of infection much worse in rural LBC in southern Sichuan. More attention should be paid to the parasitic infection of LBC.


Assuntos
Helmintíase/epidemiologia , Enteropatias Parasitárias/epidemiologia , População Rural/estatística & dados numéricos , Adolescente , Canal Anal/parasitologia , Criança , Pré-Escolar , China/epidemiologia , Família , Feminino , Humanos , Masculino
4.
J Org Chem ; 87(1): 892-903, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34958214

RESUMO

Herein we demonstrate the first successful application of cycloalkyl silyl peroxides (CSP) as an electrophilic coupling partner in the cross-electrophile coupling reaction. Diverse CSP are efficiently cross-coupled with an array of α-trifluoromethyl alkenes under the catalysis of nickel with the assistance of zinc as the reducing agent. This method allows the use of unstrained CSP as the carbonyl-containing alkyl source in the allylic defluorinative reaction, to access a variety of gem-difluoroalkenes bearing a pendent ketone moiety with high functionality tolerance.


Assuntos
Níquel , Peróxidos , Alcenos , Catálise , Cetonas
5.
Pharmgenomics Pers Med ; 14: 1591-1599, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34908864

RESUMO

PURPOSE: The association between apolipoprotein E (ApoE) gene polymorphisms and the risk of coronary artery disease (CAD) among different populations has been assessed in numerous previous studies, but the results remain inconclusive. The present study aimed to determine the role of ApoE genotypes in CAD risk and the interrelationships between lipid profiles and ApoE alleles and genotypes among the population of northwest China. PATIENTS AND METHODS: This study was performed on 308 patients with CAD and 308 control participants. ApoE gene polymorphism was analysed using the polymerase chain reaction and hybridization. RESULTS: The findings indicated that the frequencies of ε3/ε4 genotype and ε4 allele frequency were significantly higher in patients with CAD than in the control participants. ε2 carriers had significantly lower total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) levels than did ε3 or ε4 carriers among the control participants. However, our study found no significant differences in plasma lipoprotein levels between ɛ2, ɛ3 and ɛ4 carriers in patients with CAD. Moreover, ε4 carriers had significantly higher ApoB, ApoB/ApoA-I levels and significantly lower ApoE levels in both patients with CAD and control participants. ε4 allele presence was associated with a nearly two-fold higher CAD risk. After adjusting for other established risk factors, ε4 allele was an independent risk factor for CAD. After stratified by age (≤ 60 years and >60 years), ε4 allele was indicated to increase the CAD risk 3.3-fold in elderly patients with CAD, but not in young patients with CAD. After stratified by sex, ε4 allele was not a risk factor in females and males patients with CAD. CONCLUSION: This study provides evidence that the ε4 allele, drinking, smoking, hypertension, and TG and ApoE levels are independent risk factor for CAD among patients in northwest China.

7.
J Transl Int Med ; 9(2): 84-97, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34497748

RESUMO

BACKGROUND AND OBJECTIVES: Obesity is the accumulation of adipose tissue caused by excess energy in the body, accompanied by long-term chronic low-grade inflammation of adipose tissue. More than 50% of interstitial cells in adipose tissue are macrophages, which produce cytokines closely related to insulin resistance. Macrophage biology is driven by two polarization phenotypes, M1 (proinflammatory) and M2 (anti-inflammatory). This study aimed to investigate the effect of gastric hormone des-acyl ghrelin (DAG) on the polarization phenotype of macrophages and elucidate the role of macrophages in adipose tissue inflammation and insulin sensitivity and its molecular mechanism. METHODS: Mice were subcutaneously administrated with DAG in osmotic minipumps. The mice were fed a normal diet or a high-fat diet (HFD). Different macrophage markers were detected by real-time revere transcription polymerase chain reaction. RESULTS: Exogenous administration of DAG significantly inhibited the increase of adipocyte volume caused by HFD and reduced the number of rosette-like structures in adipose tissue. HFD in the control group significantly increased M1 macrophage markers, tumor necrosis factor α (TNFα), and inducible NO synthase (iNOS). However, these increases were reduced or even reversed after DAG administration in vitro. The M2 markers, macrophage galactose type C-type Lectin-1 (MGL1), arginase 1 (Arg1), and macrophage mannose receptor 1 (MRC1) were decreased by HFD, and the downward trend was inhibited or reversed after DAG administration. Although Arg1 was elevated after HFD, the fold increase after DAG administration in vitro was much greater than that in the control group. CONCLUSION: DAG inhibits adipose tissue inflammation caused by HFD, reduces infiltration of macrophages in adipose tissue, and promotes polarization of macrophages to M2, thus alleviating obesity and improving insulin sensitivity.

8.
J Exp Clin Cancer Res ; 40(1): 300, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556175

RESUMO

BACKGROUND: The global epidemiological studies reported lower cancer risk after long-term use of contraceptives. Our systematic studies demonstrated that abortifacients are effective in preventing cancer metastases induced by circulating tumor cells (CTCs). However, the molecular and cellular mechanisms by which abortifacients prevent CTC-based cancer metastases are almost unknown. The present studies were designed to interdisciplinarily explore similarities and differences between embryo implantation and cancer cell adhesion/invasion. METHODS: Biomarker expressions on the seeding embryo JEG-3 and cancer MCF-7 cells, as well as embedding uterine endometrial RL95-2 and vascular endothelial HUVECs cells were examined and compared before and after treatments with 17ß-estradiol plus progesterone and abortifacients. Effects of oral metapristone and mifepristone on embryo implantation in normal female mice and adhesion/invasion of circulating tumor cells (CTCs) in BALB/C female mice were examined. RESULTS: Both embryo JEG-3 and cancer MCF-7 cells expressed high sLex, CD47, CAMs, while both endometrial RL95-2 and endothelial HUVECs exhibited high integrins and ICAM-1. Near physiological concentrations of 17ß-estradiol plus progesterone promoted migration and invasion of JEG-3 and MCF-7 cells via upregulating integrins and MMPs. Whereas, mifepristone and metapristone significantly inhibited migration and invasion of JEG-3 and MCF-7 cells, and inhibited JEG-3 and MCF-7 adhesion to matrigel, RL95-2 cells and HUVECs, respectively. The inhibitions were realized by downregulating sLex, MMPs in JEG-3 and MCF-7 cells, and downregulating integrins in RL95-2 cells and HUVECs, respectively. Mifepristone and metapristone significantly inhibited both embryo implantation and cancer cell metastasis in mice. CONCLUSIONS: The similarities between the two systems provide fundamentals for abortifacients to intervene CTC adhesion/invasion to the distant metastatic organs. The present studies offer the rationale to repurpose abortifacients for safe and effective cancer metastasis chemoprevention.


Assuntos
Abortivos/farmacologia , Quimioprevenção , Metástase Neoplásica/prevenção & controle , Células Neoplásicas Circulantes/efeitos dos fármacos , Animais , Biomarcadores , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Hormônios Esteroides Gonadais/metabolismo , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Células Neoplásicas Circulantes/metabolismo , Células Tumorais Cultivadas
9.
Cell Biosci ; 11(1): 150, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34344450

RESUMO

INSTRUCTION: Lead (Pb) exposure is a risk factor for male infertility, but the epigenetic changes in sperm DNAattributable to lead exposure is poorly defined. METHODS: In this study, we investigated whether low Pb exposure (< 10 µg/dL) affects the sperm quality. Blood, urine, and semen samples of 297 men of childbearing age were analyzed for all relevant parameters. Based on the blood Pb level (BLL), participants were allocated to RL (0-2.5 µg/dL), RM (2.5-5 µg/dL), and RH (5-10 µg/dL) groups. The 5-methylcytosine and 5-hydroxymethylcytosine patterns in the sperm DNA were identified using methylated DNA immunoprecipitation and hydroxymethylated DNA immunoprecipitation sequencing. RESULTS: The non-progressive motility (NP) was significantly increased and associated with global hypomethylation of sperm DNA in the RH group compared with the RL group, indicating that aberrant sperm methylation due to low Pb exposure is possibly associated with reduced sperm motility. The hypomethylated promoter regions were primarily enriched in the calcium (Ca) homeostasis pathway. Further, the interaction between Ca and Pb was associated with sperm rapid progressive motility and asthenospermia risk, although no significant methylation abnormality was observed in those with BLL < 5 µg/dL. When BLL was > 5 µg/dL or when predicting NP, no significant Pb-Ca interaction was observed. DISCUSSION: Overall, our results indicate that aberrant DNA methylation of the Ca homeostasis pathway, induced by low Pb exposure, is the potential cause for reduced sperm velocity.

10.
Aging (Albany NY) ; 13(10): 14170-14184, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33988129

RESUMO

Premature all-cause mortality is high in patients receiving peritoneal dialysis (PD). The accurate and early prediction of mortality is critical and difficult. Three prediction models, the logistic regression (LR) model, artificial neural network (ANN) classic model and a new structured ANN model (ANN mixed model), were constructed and evaluated using a receiver operating characteristic (ROC) curve analysis. The permutation feature importance was used to interpret the important features in the ANN models. Eight hundred fifty-nine patients were enrolled in the study. The LR model performed slightly better than the other two ANN models on the test dataset; however, in the total dataset, the ANN models fit much better. The ANN mixed model showed the best prediction performance, with area under the ROC curves (AUROCs) of 0.8 and 0.79 for the 6-month and 12-month datasets. Our study showed that age, diastolic blood pressure (DBP), and low-density lipoprotein cholesterol (LDL-c) levels were common risk factors for premature mortality in patients receiving PD. Our ANN mixed model had incomparable advantages in fitting the overall data characteristics, and age is a steady risk factor for premature mortality in patients undergoing PD. Otherwise, DBP and LDL-c levels should receive more attention for all-cause mortality during follow-up.


Assuntos
Redes Neurais de Computação , Diálise Peritoneal/mortalidade , Adulto , Idoso , Feminino , Seguimentos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Mortalidade Prematura , Análise Multivariada , Curva ROC , Resultado do Tratamento
11.
Appl Microbiol Biotechnol ; 105(4): 1477-1487, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33521848

RESUMO

Chlamydia trachomatis (C. trachomatis) is the leading cause of preventable blindness worldwide and the most prevalent cause of bacterial sexually transmitted diseases. At present, there is no available vaccine, and recurrences after antibiotics treatment are substantial problems. Major outer membrane protein (MOMP) accounts for 60% of the outer mass of C. trachomatis, functioning as trimeric porin, and it is highly antigenic. Therefore, MOMP is the most promising candidate for vaccine developing and target therapy of Chlamydia. Affibody, a new class of affinity ligands derived from the Z-domain in the binding region of Staphylococcus aureus protein A, has been the focus of researchers as a viable alternative to antibodies. In this study, the MOMP-targeted affibody molecule (ZMOMP:461) was screened by phage-displayed peptide library. Further, the affinity and specificity were characterized by surface plasmon resonance (SPR) and Western blot. Immunofluorescence assay (IFA) indicated that the MOMP-binding affibody could recognize native MOMP in HeLa229 cells infected C. trachomatis. Immunoprecipitation assay confirmed further that ZMOMP:461 molecule specifically recognizes the epitope on relaxed trimer MOMP. Our findings provide strong evidence that affibody molecule (ZMOMP:461) serves as substitute for MOMP antibody for biological applications and has a great potential for delivering drugs for target therapy. KEY POINTS : • We screened a novel affibody molecule ZMOMP:461 targeting Chlamydia trachomatis MOMP. • ZMOMP:461 recognizes the recombinant and native MOMP with high affinity and specificity. • ZMOMP:461 could be internalized into live target cells.


Assuntos
Infecções por Chlamydia , Chlamydia trachomatis , Anticorpos Antibacterianos , Proteínas da Membrana Bacteriana Externa , Epitopos , Humanos , Porinas
12.
Drug Discov Today ; 26(3): 631-636, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33385574

RESUMO

The Coronavirus 2019 (COVID-19) pandemic represents the greatest worldwide public health crisis of recent times. The lack of proven effective therapies means that COVID-19 rages relatively unchecked. Current anti-COVID-19 pharmacotherapies are drugs originally designed for other diseases, and administered orally or intravascularly. Thus, they can have various adverse effects. A specific anti-Coronavirus drug should not only target the virus per se, but also treat the related respiratory and cardiovascular symptoms. Here, we examine the advantages and disadvantages of current anti-COVID-19 pharmacotherapies, and analyze the reasons why in the era of big data we have not yet established specific coronavirus therapies and related technical bottlenecks. Finally, we present our design of a novel nebulized S-nitrosocaptopril that is under development for targeting both coronaviruses and their related symptoms.


Assuntos
Antivirais , COVID-19 , Captopril/análogos & derivados , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antivirais/classificação , Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , COVID-19/fisiopatologia , COVID-19/virologia , Captopril/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/metabolismo , Desenvolvimento de Medicamentos/métodos , Reposicionamento de Medicamentos/métodos , Humanos , Nebulizadores e Vaporizadores , Preparações Farmacêuticas , Sistema Respiratório/diagnóstico por imagem , Sistema Respiratório/metabolismo , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Resultado do Tratamento
13.
Int J Infect Dis ; 96: 105-111, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32251797

RESUMO

BACKGROUND: Significant alterations in the pharmacokinetic characteristics of linezolid are often seen in sepsis patients. The study aimed to identify a target pharmacokinetics/pharmacodynamics (PK/PD) index of the efficacy of linezolid treatment, and to estimate the optimum dosage regimen of linezolid in sepsis patients. METHODS: The PK data were modeled using the one-compartment model, which determined the target PK/PD index for successful treatment by logistic regression. The probability of thrombocytopenia was identified by establishing a logistic model. Different dosing regimens were evaluated using Monte Carlo simulation. RESULTS: Reaching 80% bacterial eradication required an AUC24/MIC of 100, which defined the therapeutic target. The proposed regimen to attain a cumulative fraction of response ≥80% was 800 mg/12 h (safety probability 66.8%) for sepsis patients with normal renal function or mild kidney damage. By contrast, the target cumulative fraction of response was attained with a standard dosing regimen in sepsis patients on continuous renal replacement therapy [600 mg/12 h (safety probability 49.7%)]. CONCLUSIONS: This study identified different dosing strategies to achieve target linezolid PK/PD values according to whether sepsis patients were treated with continuous renal replacement therapy. Due to the high incidence of thrombocytopenia in sepsis patients on continuous renal replacement therapy, therapeutic drug monitoring should be encouraged for optimizing linezolid exposure in sepsis patients.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Linezolida/administração & dosagem , Linezolida/efeitos adversos , Sepse/tratamento farmacológico , Adulto , Idoso , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Feminino , Humanos , Linezolida/farmacocinética , Linezolida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Método de Monte Carlo , Medição de Risco , Sepse/complicações , Sepse/metabolismo , Trombocitopenia/epidemiologia , Trombocitopenia/etiologia
14.
iScience ; 23(4): 101017, 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32289735

RESUMO

Herein we demonstrate the successful application of reductive strategy in the asymmetric domino ring opening/cross-coupling reaction of prochiral cyclobutanones. Under the catalysis of a chiral nickel complex, various aryl iodide-tethered cyclobutanones were reacted with alkyl bromides as the electrophilic coupling partner, providing a variety of chiral indanones bearing a quaternary stereogenic center in highly enantioselective manner, which can be further converted to diverse benzene-fused cyclic compounds including indane, indene, dihydrocoumarin, and dihydroquinolinone. The preliminary mechanistic investigations support a mechanism involving Ni(I)-mediated enantiotopic C-C σ-bond activation of cyclobutanones as key elementary step in the catalytic cycle.

15.
Pak J Pharm Sci ; 33(1): 161-168, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32122844

RESUMO

Tigecycline (TGC) and cefoperazone/sulbactam (CPS) both have been shown good in vitro activity against carbapenem-resistant Acinetobacter baumannii (CRAB) isolates. We aim to compare the efficacy of TGC versus CPS for CRAB infections. We conducted a retrospective cohort study of patients with CRAB at a single center in China from 2013 to 2015. Outcomes comprised in-hospital mortality, clinical and microbiological response. The method of inverse probability of treatment weighting and multivariable logistic regression analysis incorporated with propensity score were employed to estimate the effect of treatment groups. There were 130 subjects included in our study. The patients in TGC, CPS and TGC plus CPS combination group were 42, 66, and 22, respectively. After adjustment, in-hospital mortality was lower in CPS group than TGC group (weighted OR 0.173; 95% CI 0.06-0.497; P=0.001) but without differences in clinical success and microbiological eradication (P>0.05). TGC monotherapy had a similar outcome with TGC plus CPS combination group. This is the first study comparing the efficacy of tigecycline and cefoperazone/sulbactam for CRAB infections. Cefoperazone/sulbactam appears to be more efficacious than tigecycline during treatment.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Cefoperazona/uso terapêutico , Sulbactam/uso terapêutico , Tigeciclina/uso terapêutico , Infecções por Acinetobacter/mortalidade , Acinetobacter baumannii/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/farmacologia , Cefoperazona/farmacologia , Farmacorresistência Bacteriana , Quimioterapia Combinada/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pentostatina/análogos & derivados , Estudos Retrospectivos , Sulbactam/farmacologia , Tigeciclina/farmacologia
16.
Occup Environ Med ; 77(3): 201-206, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32024660

RESUMO

OBJECTIVES: Trichloroethylene (TCE) -induced hypersensitivity syndrome (TIHS) is a potentially life-threatening disease. Several genetic susceptibility biomarkers have been found to be associated with TIHS, and this systematic prospective study has been conducted to evaluate the utility of these genetic susceptibility biomarkers in preventing the disease. METHODS: The newly hired TCE-exposed workers were recruited from March 2009 to October 2010. HLA-B*13:01 genotyping and 3-month follow-up procedure were conducted. All workers were monitored for adverse reaction by telephone interview every week. The workers with early symptoms of TIHS were asked to go to the hospital immediately for further examination, diagnosis and treatment. The medical expense record data of patients with TIHS were collected for cost-effectiveness analysis in 2018. RESULTS: Among 1651 workers, 158 (9.57%) were found to carry the HLA-B*13:01 allele and 16 (0.97%) were diagnosed with TIHS. HLA-B*13:01 allele was significantly associated with an increased TIHS risk (relative risk=28.4, 95% CI 9.2 to 86.8). As a risk predictor of TIHS, HLA-B*13:01 testing had a sensitivity of 75%, a specificity of 91.1% and an area under curve of 0.83 (95% CI 0.705 to 0.955), the positive and negative predictive values were 7.6% and 99.7%, respectively. The incidence of TIHS was significantly decreased in HLA-B*13:01 non-carriers (0.27%) compared with all workers (0.97%, p=0.014). Cost-effectiveness analysis showed that HLA-B*13:01 screening could produce an economic saving of $4604 per TIHS avoided. CONCLUSIONS: Prospective HLA-B*13:01 screening may significantly reduce the incidence of TIHS and could be a cost effective option for preventing the disease in TCE-exposed workers.


Assuntos
Dermatite/genética , Hipersensibilidade a Drogas/genética , Antígenos HLA-B/genética , Exposição Ocupacional , Tricloroetileno/efeitos adversos , Adulto , Biomarcadores , China , Análise Custo-Benefício , Dermatite/prevenção & controle , Hipersensibilidade a Drogas/prevenção & controle , Feminino , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Masculino , Programas de Rastreamento/economia , Polimorfismo Genético , Valor Preditivo dos Testes , Estudos Prospectivos , Adulto Jovem
17.
Nat Commun ; 11(1): 243, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31913267

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

18.
PLoS Pathog ; 16(1): e1008223, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31905218

RESUMO

Epstein-Barr virus (EBV) infection is closely linked to several human malignancies including endemic Burkitt's lymphoma, Hodgkin's lymphoma and nasopharyngeal carcinomas (NPC). Latent membrane protein 2 (LMP-2) of EBV plays a pivotal role in pathogenesis of EBV-related tumors and thus, is a potential target for diagnosis and targeted therapy of EBV LMP-2+ malignant cancers. Affibody molecules are developing as imaging probes and tumor-targeted delivery of small molecules. In this study, four EBV LMP-2-binding affibodies (ZEBV LMP-212, ZEBV LMP-2132, ZEBV LMP-2137, and ZEBV LMP-2142) were identified by screening a phage-displayed LMP-2 peptide library for molecular imaging and targeted therapy in EBV xenograft mice model. ZEBV LMP-2 affibody has high binding affinity for EBV LMP-2 and accumulates in mouse tumor derived from EBV LMP-2+ xenografts for 24 h after intravenous (IV) injection. Subsequent fusion of Pseudomonas exotoxin PE38KDEL to the ZEBV LMP-2 142 affibody led to production of Z142X affitoxin. This fused Z142X affitoxin exhibits high cytotoxicity specific for EBV+ cells in vitro and significant antitumor effect in mice bearing EBV+ tumor xenografts by IV injection. The data provide the proof of principle that EBV LMP-2-speicifc affibody molecules are useful for molecular imaging diagnosis and have potentials for targeted therapy of LMP-2-expressing EBV malignancies.


Assuntos
Herpesvirus Humano 4 , Imunotoxinas/uso terapêutico , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/terapia , Proteínas da Matriz Viral/metabolismo , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Imunotoxinas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Imagem Molecular , Carcinoma Nasofaríngeo/diagnóstico por imagem , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/diagnóstico por imagem , Neoplasias Nasofaríngeas/virologia , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/terapia , Biblioteca de Peptídeos , Ligação Proteica , Proteínas da Matriz Viral/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Onco Targets Ther ; 13: 13465-13477, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33447051

RESUMO

BACKGROUND/OBJECTIVE: Circulating tumor cells (CTCs) are known as the root of cancer metastasis. Capture and inhibition of CTCs may prevent metastasis. Due to the rarity of CTCs in vivo, the current technology about CTCs capture is still challenging. The aim of our study was to conjugate the enhanced biostable double-strand (ds) circular aptamer (dApR) with dendrimers for capturing and restraining CTCs in vitro and in vivo. METHODS: CEM-targeting aptamer (Ap) was looped by ligation after phosphorylation to form circular ds aptamer dApR, which was then conjugated to dendrimers by biotin-streptavidin affinity reaction and named as G-dApR. The physicochemical properties of G-dApR were characterized by using PAGE gel electrophoresis, UV, DLS, AFM, fluorophotometer and laser confocal microscope. Biostability of G-dApR was also analyzed by gel electrophoresis. Confocal microscopy and flow cytometry were then performed to determine the binding specificity of G-dApR to CEM cells and the captured CTCs in mice and in human blood. Apoptosis of the captured cells was finally evaluated by using MTT assay, DAPI staining, AO/EB staining, cell cycle analysis and Annexin V-FITC/PI staining. RESULTS: Physicochemical characterization demonstrated the entity of dApR and G-dApR, and the nano-size of G-dApR (about 180 nm in aqueous phase). G-dApR exhibited the excellent biostability that confers their resistance to nuclease-mediated biodegradation in serum for at least 6 days. In our established CTCs model, we found that G-dApR could specifically and sensitively capture CTCs not non-target cells even in the presence of millions of interfering cells (108), in mice and in human blood. Finally, the activity of captured CTCs was significantly down-regulated by G-dApR, resulting in apoptosis. CONCLUSION: We created the enhanced biostable dApR-coated dendrimers (G-dApR) that could specifically capture and restrain CTCs in vitro and in vivo for preventing CTC-mediated cancer metastasis.

20.
Nat Commun ; 10(1): 5476, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792209

RESUMO

There are disease-causing biohazards in the blood that cannot be treated with modern medicines. Here we show that an intelligently designed safe biomaterial can precisely identify, tow and dump a targeted biohazard from the blood into the small intestine. Positively charged mesoporous silica nanoparticles (MSNs) functionalized with EGFR-targeting aptamers (MSN-AP) specifically recognize and bind blood-borne negatively charged oncogenic exosomes (A-Exo), and tow A-Exo across hepatobiliary layers and Oddi's sphincter into the small intestine. MSN-AP specifically distinguish and bind A-Exo from interfering exosomes in cell culture and rat and patient blood to form MSN-AP and A-Exo conjugates (MSN-Exo) that transverse hepatocytes, cholangiocytes, and endothelial monolayers via endocytosis and exocytosis mechanisms, although Kupffer cells have been shown to engulf some MSN-Exo. Blood MSN-AP significantly decreased circulating A-Exo levels, sequentially increased intestinal A-Exo and attenuated A-Exo-induced lung metastasis in mice. This study opens an innovative avenue to relocate blood-borne life-threatening biohazards to the intestine.


Assuntos
Sangue/metabolismo , Exossomos/metabolismo , Intestino Delgado/metabolismo , Nanopartículas/metabolismo , Células A549 , Animais , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/metabolismo , Análise Química do Sangue , Endocitose , Receptores ErbB/genética , Receptores ErbB/metabolismo , Exossomos/química , Hepatócitos/metabolismo , Humanos , Cinética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Ratos , Dióxido de Silício/química , Dióxido de Silício/metabolismo
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