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Objective: To evaluate the efficacy of 1-year subcutaneous immunotherapy (SCIT) with dust mites in polysensitized allergic rhinitis (AR) patients and to analyze the serological markers associated with clinical response. Methods: A retrospective analysis of data from 69 polysensitized AR patients who completed 1-year SCIT with dust mites from Oct 2020 to Mar 2022 in Shandong Provincial ENT Hospital was conducted. The median patient age was 21 years, including 41 males and 28 females. The changes in symptoms and serum IgE, IgG4 assessed before and after treatment were evaluated. The differences in serological markers between effective and ineffective groups were analyzed. Multivariate regression analysis was used to investigate the predictors of clinical response. SPSS 22.0 software was used for data processing. Results: After immunotherapy, there was a significant reduction in symptom scores and a substantial improvement in the quality of life of polysensitized AR patients (all P<0.001). Dust mite specific IgG4 (sIgG4) significantly increased and dust mite specific IgE (sIgE)/sIgG4 significantly decreased (all P<0.05). sIgE, total IgE (tIgE), sIgE/tIgE and sIgE/sIgG4 were significantly lower in ineffective group than those in effective group (all P<0.05). The clinical response of SCIT related only to dust mite sIgE (r=0.29, P=0.036), and sIgE≥53.86 kU/L had the best sensitivity (77.78%) and specificity (57.89%) to predict effective SCIT in polysensitized AR patients. Conclusions: One-year dust mite SCIT is effective for polysensitized AR patients. Pre-treatment serum dust mite sIgE≥53.86 kU/L may play a role in predicting clinical response of dust mite SCIT in polysensitized AR patients.
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Objective: To investigate the mechanism of S100A7 inducing the migration and invasion in cervical cancers. Methods: Tissue samples of 5 cases of cervical squamous cell carcinoma and 3 cases of adenocarcinoma were collected from May 2007 to December 2007 in the Department of Gynecology of the Affiliated Hospital of Qingdao University. Immunohistochemistry was performed to evaluate the expression of S100A7 in cervical carcinoma tissues. S100A7-overexpressing HeLa and C33A cells were established with lentiviral systems as the experimental group. Immunofluorescence assay was performed to observe the cell morphology. Transwell assay was taken to detect the effect of S100A7-overexpression on the migration and invasion of cervical cancer cells. Reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) was used to examine the mRNA expressions of E-cadherin, N-cadherin, vimentin and fibronectin. The expression of extracellular S100A7 in conditioned medium of cervical cancer cell was detected by western blot. Conditioned medium was added into Transwell lower compartment to detect cell motility. Exosomes were isolated and extracted from the culture supernatant of cervical cancer cell, the expressions of S100A7, CD81 and TSG101 were detected by western blot. Transwell assay was taken to detect the effect of exosomes on the migration and invasion of cervical cancer cells. Results: S100A7 expression was positively expressed in cervical squamous carcinoma and negative expression in adenocarcinoma. Stable S100A7-overexpressing HeLa and C33A cells were successfully constructed. C33A cells in the experimental group were spindle shaped while those in the control group tended to be polygonal epithelioid cells. The number of S100A7-overexpressed HeLa cells passing through the Transwell membrane assay was increased significantly in migration and invasion assay (152.00±39.22 vs 105.13±15.75, P<0.05; 115.38±34.57 vs 79.50±13.68, P<0.05). RT-qPCR indicated that the mRNA expressions of E-cadherin in S100A7-overexpressed HeLa and C33A cells decreased (P<0.05) while the mRNA expressions of N-cadherin and fibronectin in HeLa cells and fibronectin in C33A cells increased (P<0.05). Western blot showed that extracellular S100A7 was detected in culture supernatant of cervical cancer cells. HeLa cells of the experimental group passing through transwell membrane in migration and invasion assays were increased significantly (192.60±24.41 vs 98.80±47.24, P<0.05; 105.40±27.38 vs 84.50±13.51, P<0.05) when the conditional medium was added into the lower compartment of Transwell. Exosomes from C33A cell culture supernatant were extracted successfully, and S100A7 expression was positive. The number of transmembrane C33A cells incubated with exosomes extracted from cells of the experimental group was increased significantly (251.00±49.82 vs 143.00±30.85, P<0.05; 524.60±52.74 vs 389.00±63.23, P<0.05). Conclusion: S100A7 may promote the migration and invasion of cervical cancer cells by epithelial-mesenchymal transition and exosome secretion.
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Adenocarcinoma , Carcinoma de Células Escamosas , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/patologia , Células HeLa , Fibronectinas/metabolismo , Meios de Cultivo Condicionados , Carcinoma de Células Escamosas/metabolismo , Caderinas/metabolismo , RNA Mensageiro/metabolismo , Movimento Celular , Transição Epitelial-Mesenquimal/genética , Linhagem Celular Tumoral , Proliferação de Células , Proteína A7 Ligante de Cálcio S100/metabolismoRESUMO
Objective: To evaluate the effect of "Smoking cessation: Doctor first" program on smoking medical staff. Methods: From December 2016 to September 2019, 1 747 smoking medical staff from 54 units of China Tobacco Cessation Alliance were enrolled into"Smoking cessation: Doctor first"program. Demographic characteristics, smoking characteristics, degree of tobacco dependence, willingness to quit smoking and other related factors were collected during the baseline survey. Multivariate logistic regression model was used to analyze the related factors of willingness to quit. The subjects were given intensive smoking cessation intervention from October 2017 to September 2019, including education on the hazards of smoking, methods of smoking cessation and giving smoking cessation drugs. After intervention, the subjects were investigated about their smoking cessation progress and the effect of the project was evaluated. Results: The subjects were (41±11) years old, 91.9% (1 609/1 747) were male and 62.2% (1 086/1 747) were daily smokers. The main reasons for smoking included the influence of friends [697 (39.9%)], the need for social entertainment [629 (36.0%)], the relief of mental stress [589 (33.7%)] and the refreshment [459 (26.3%)]. At baseline, 52.9% (885/1 672) and 43.2% (755/1 747) smokers had intention to quit smoking and had planned to quit within one year, respectively. Multivariate logistic regression model analysis showed that: low education level [OR (95%CI) of high school and junior high school and below were 2.42 (1.61, 3.63) and 1.57 (1.18, 2.11)], daily smoking [OR (95%CI): 1.38 (1.06, 1.78)], thinking quitting smoking is not important [OR (95%CI): 4.15 (3.33, 5.18)] and having no quitting experience [OR (95%CI): 3.21 (2.53, 4.05)] were associated with no intention to quit smoking. After intensive smoking cessation intervention, 81.0% (1 415/1 747) smokers started to quit and 36.6% (518/1 415) quit smoking with drugs, both higher than the baseline level (all P values<0.001). By the end of the program, 60.2% (852/1 415) of the medical staff had quit smoking successfully. Conclusion: "Smoking cessation: Doctor first"program can improve the willingness to quit and the proportion of using smoking cessation drugs of medical staff.
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Objective: Autologous peripheral blood stem cells (PBSC) derived from bone marrow can promote liver regeneration and improve the liver function of patients, but there are few studies on its effect on the long-term outcomes in patients with decompensated cirrhosis. Based on previous work, this study observed the clinical outcomes of PBSC treatment in patients with decompensated cirrhosis for 10 years, in order to provide more data support for the safety and efficacy of stem cells in clinical applications. Methods: Data of patients with decompensated liver cirrhosis who completed PBSC treatment in the Department of Gastroenterology of the First Affiliated Hospital of Air Force Military Medical University from August 2005 to February 2012 were included. The follow-up endpoint was death or liver transplantation, and patients who did not reach the follow-up endpoint were followed-up for at least 10 years. The patients with decompensated liver cirrhosis who met the conditions for PBSC treatment but did not receive PBSC treatment in our hospital during the same period were used as controls. Results: A total of 287 cases with decompensated liver cirrhosis had completed PBSC treatment, and 90 cases were lost to follow-up within 10 years after surgery. A total of 151 cases with complete survival follow-up data were included in the control group. There were no statistically significant differences in baseline information such as gender, age, etiological composition and liver function score between the two groups. The 10-year survival rate was higher in PBSC than control group (37.56% vs. 26.49%, P<0.05). Cholinesterase, albumin, international normalized ratio, Child-Turcotte-Pugh score, model for end-stage liver disease score, and other indicators were gradually recovered within 3 months to 1 year after PBSC treatment, and stabilized at a more desirable level in the long-term after follow-up for up to 10 years. There was no statistically significant difference in the incidence of liver cancer between the two groups (25.22% vs.31.85%, P=0.267). The age of onset of hepatocellular carcinoma was later in PBSC than control group [(56.66±7.21) years vs. (52.69±8.42) years, P<0.05]. Conclusions: This long-term observational follow-up study of more than ten years confirms that PBSC treatment can bring long-term benefits to patients with decompensated cirrhosis, with good long-term safety, thus providing more data support on the safety and efficacy of stem cells for clinical applications.
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Doença Hepática Terminal , Células-Tronco de Sangue Periférico , Seguimentos , Humanos , Cirrose Hepática/tratamento farmacológico , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Mechanical force-induced external root resorption is a major clinical side effect of orthodontic treatment. Recent work has revealed that M1 macrophages play a vital role in promoting orthodontic root resorption (ORR), but the mechanism of how mechanical force stimulation increases the M1/M2 macrophage ratio in periodontal tissue is poorly understood. In the current study, we showed that C-X-C motif chemokine 12 (CXCL12)+ periodontal ligament cells (PDLCs) and C-X-C chemokine receptor type 4 (CXCR4)+ monocytes in the periodontal ligament (PDL) were significantly increased after force application with ongoing root resorption, and these effects were partially rescued after force removal in mice. The expression of CXCL12 in PDLCs was increased by force stimulation in a time- and intensity-dependent manner in vitro. Blockage of the CXCL12/CXCR4 axis using CXCR4 antagonist AMD3100 was sufficient to alleviate ORR and reverse the force-enhanced M1/M2 macrophage ratio. Further mechanism exploration showed that Ly6Chi inflammatory monocytes homed in a CXCL12/CXCR4 axis-dependent manner. The number and proportion of CD11b+ Ly6Chi inflammatory monocytes in cervical lymph nodes were significantly increased by force loading, accompanied by decreased CD11b+ Ly6Chi monocytes in the blood. These changes were blunted by intraperitoneal injection of AMD3100. In addition, blockage of the CXCL12/CXCR4 axis effectively reversed M2 suppression and promoted M1 polarization. Collectively, results indicate that force-induced CXCL12/CXCR4 axis mediates ORR by increasing the M1/M2 ratio in periodontal tissues through attracting Ly6Chi inflammatory monocytes and modulating macrophage polarization. The results also imply that AMD3100 is potentially inhibitory to root resorption.
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Quimiocina CXCL12/metabolismo , Receptores CXCR4/metabolismo , Reabsorção da Raiz , Animais , Ativação de Macrófagos , Macrófagos , Camundongos , Monócitos , Ligamento Periodontal/metabolismo , Reabsorção da Raiz/metabolismoRESUMO
This study aims to observe the efficacy of supplemented Er-xian decoction combined with acupoint application in treating poor ovarian response (POR). This study was a randomized controlled trial. A total of 80 patients, who were treated in the Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine from January 2016 to December 2017, were divided into two groups by tables of random numbers: experimental group (n = 40), and control group (n = 40). In the experimental group, patients orally received supplemented Er-xian decoction with acupoint application. In the control group, a Kuntai capsule was administered according to the course of treatment. The therapeutic effects in the two groups were observed and compared. In the experimental group, the total effective rate was 90%, the cure rate was 15% (six patients), the markedly effective rate was 35% (14 patients), the effective rate was 40% (16 patients), and the ineffective rate was 10% (four patients). In the control group, the total effective rate was 50%, the cure rate was 5% (two patients), the markedly effective rate was 15% (six patients), the effective rate was 30% (12 patients), and the ineffective rate was 50% (20 patients). The differences were statistically significant (P > 0.05). Definite efficacy was observed when a poor ovarian response was treated by supplemented Er-xian decoction combined with acupoint application. Improvements in perimenopausal symptoms, menstruation conditions, hormone levels, inhibin B (INHB), and antral follicle count (AFC) were markedly better in the experimental group than in the control group. In addition, the treatment was safe and had few side effects.
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Pontos de Acupuntura , Medicamentos de Ervas Chinesas/uso terapêutico , Fertilização in vitro/métodos , Neoplasias Ovarianas/terapia , Ovulação/efeitos dos fármacos , Adulto , Feminino , Hormônio Foliculoestimulante/metabolismo , Humanos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Saúde Reprodutiva , Resultado do TratamentoRESUMO
Objective: To explore the feasibility of using faster regional convolutional neural network (Faster R-CNN) to evaluate the status of circumferential resection margin (CRM) of rectal cancer in the magnetic resonance imaging (MRI). Methods: This study was registered in the Chinese Clinical Trial Registry (ChiCTR-1800017410). Case inclusion criteria: (1) the positive area of CRM was located between the plane of the levator ani, anal canal and peritoneal reflection; (2) rectal malignancy was confirmed by electronic colonoscopy and histopathological examination; (3) positive CRM was confirmed by postoperative pathology or preoperative high-resolution MRI. Exclusion criteria: patients after neoadjuvant therapy, recurrent cancer after surgery, poor quality images, giant tumor with extensive necrosis and tissue degeneration, and rectal tissue construction changes in previous pelvic surgery. According to the above criteria, MRI plain scan images of 350 patients with rectal cancer and positive CRM in The Affiliated Hospital of Qingdao University from July 2016 to June 2019 were collected. The patients were classified by gender and tumor position, and randomly assigned to the training group (300 cases) and the validation group (50 cases) at a ratio of 6:1 by computer random number method. The CRM positive region was identified on the T2WI image using the LabelImg software. The identified training group images were used to iteratively train and optimize parameters of the Faster R-CNN model until the network converged to obtain the best deep learning model. The test set data were used to evaluate the recognition performance of the artificial intelligence platform. The selected indicators included accuracy, sensitivity, positive predictive value, receiver operating characteristic (ROC) curves, areas under the ROC curves (AUC), and the time taken to identify a single image. Results: The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the CRM status determined by the trained Faster R-CNN artificial intelligence approach were 0.884, 0.857, 0.898, 0.807, and 0.926, respectively; the AUC was 0.934 (95% CI: 91.3% to 95.4%). The Faster R-CNN model's automatic recognition time for a single image was 0.2 s. Conclusion: The artificial intelligence model based on Faster R-CNN for the identification and segmentation of CRM-positive MRI images of rectal cancer is established, which can complete the risk assessment of CRM-positive areas caused by in-situ tumor invasion and has the application value of preliminary screening.
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Imageamento por Ressonância Magnética/métodos , Margens de Excisão , Redes Neurais de Computação , Neoplasias Retais/diagnóstico por imagem , Simulação por Computador , Estudos de Viabilidade , Humanos , Modelos Biológicos , Terapia Neoadjuvante , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia , Neoplasias Retais/terapia , Medição de RiscoRESUMO
Ovarian cancer (OC) is one of the most common tumors in females. Growing evidence shows that microRNA-506-3p (miR-506-3p) is downregulated in OC tissues. The purpose of this study was to investigate the mechanism of miR-506-3p in modulating OC. Quantitative reverse transcriptase PCR (qRT-PCR) was employed to investigate the expression of miR-506-3p and its target in OC tissues or cell lines. CCK-8 or colony formation assay was used to examine cell viability or proliferation, respectively. Flow cytometry was demonstrated to detect cell apoptosis. Western blot was then applied to analyze underlying mechanisms. The potential target of miR-506-3p was examined via luciferase reporter assay. MiR-506-3p was significantly downregulated in both human OC tissues and cell lines. Overexpression of miR-506-3p not only decreased cell viability of OC cell lines but also promoted cell apoptosis, thus inhibiting OC progression. Moreover, SIRT1 (Sirtuin 1) was found to be a direct target of miR-506-3p, and SIRT1 expression was negatively regulated by miR-506-3p in OC cell lines. Further investigation revealed that overexpression of SIRT1 could promote cell viability as well as inhibit cell apoptosis, showing the reversed effect on OC progression compared to miR-506-3p. Lastly, AKT (Protein kinase B) /FOXO3a (Forkhead box O3) signaling pathway was inactivated by miR-506-3p while activated by SIRT1, relating to regulation of miR-506-3p on OC progression. Our results revealed a novel mechanism by which miR-506-3p inhibited proliferation while promoted apoptosis of OC via inactivation of SIRT1/AKT/FOXO3a signaling pathway, suggesting that miR-506-3p might be a potential target for OC.
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Apoptose , MicroRNAs/genética , Neoplasias Ovarianas/patologia , Transdução de Sinais , Proteínas de Caenorhabditis elegans/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sirtuína 1/metabolismoRESUMO
The maturation of dendritic cells is critical for chronic rhinosinusitis with nasal polyps (CRSwNPs), especially eosinophilic chronic rhinosinusitis with nasal polyps (EosCRSwNPs), but the regulation mechanism of dendritic cells (DCs) maturation is still unclear. We identified nasal mucosa of 20 patients with EosCRSwNP, 16 non-EosCRSwNP patients, and inferior turbinate of 14 patients with nasal septum deviation after surgery. The expression of cyclin-dependent kinase 5 (CDK5) and programmed cell death 1 ligand 1 (PD-L1) were detected by immunofluorescent, real-time quantitative PCR, and Western blot in EosCRSwNP. The level of dendritic cell maturation was detected by flow cytometry and immunofluorescence staining after CDK5 expression interference with small interfering RNA (siRNA). The expression of CDK5 and PD-L1 in EosCRSwNP nasal mucosal tissue was significantly higher than that of non-EosCRSwNP and inferior turbinate nasal mucosa tissue, and there was a positive correlation between them. Immunofluorescence staining showed that CDK5 and PD-L1 were co-localized in dendritic cells. Synergistic stimulation of dendritic cells with LPS and TNF-α promotes the maturation of dendritic cells and increases the expression of CDK5 and PD-L1. However, blocking the expression of CDK5 in dendritic cells with siRNAs leads to a blockage of cell maturation. CDK5 can regulate the expression of PD-L1, and its presence is critical for the maturation of dendritic cells. CDK5 may play an important role in the pathogenesis of CRSwNP disease.
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Antígeno B7-H1/análise , Quinase 5 Dependente de Ciclina/análise , Células Dendríticas/metabolismo , Pólipos Nasais/patologia , Rinite/patologia , Sinusite/patologia , Antígeno B7-H1/efeitos dos fármacos , Diferenciação Celular , Doença Crônica , Quinase 5 Dependente de Ciclina/efeitos dos fármacos , Humanos , Lipopolissacarídeos/farmacologia , Mucosa Nasal , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
MicroRNAs represent a component of the innate immune responses that can restrain inflammatory signaling, miR124 is an important member of inflammation-associated miRNAs, and abnormal miR124 expression is observed in many inflammatory diseases and immune disorders. However, the role and signaling pathways of miR124 in chronic rhinosinusitis with nasal polyps (CRSwNPs) have not been studied in detail. The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor that is highly conserved in evolution and plays important roles in the inflammatory response process. In our study, we describe the role of miR124 in the inflammatory response of CRS with nasal polyps. We found that the expression of miR124 was decreased in nasal polyps, and negatively correlated with the expression of AHR. MiR124 can inhibit AHR expression by directly target 3' untranslated region (3'-UTR) of AHR. To further investigate the relationship between miR124, AHR and CRS inflammatory response, we transfect HNEpC cells with miR124 mimic, miR124 inhibitors or siRNA of AHR, then all the results showed that miR124 could regulates cellular inflammatory response through negatively regulating AHR expression. This study demonstrated that the regulation of AHR expression by miR124 is critical to the development of inflammatory response in CRSwNPs.
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Regulação da Expressão Gênica , Inflamação/genética , MicroRNAs/metabolismo , Pólipos Nasais/genética , Receptores de Hidrocarboneto Arílico/genética , Rinite/genética , Sinusite/genética , Adulto , Sequência de Bases , Doença Crônica , Feminino , Humanos , Inflamação/complicações , Inflamação/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Pólipos Nasais/complicações , Pólipos Nasais/patologia , Receptores de Hidrocarboneto Arílico/metabolismo , Rinite/complicações , Rinite/patologia , Sinusite/complicações , Sinusite/patologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
To investigate physicians' knowledge about chronic obstructive pulmonary disease (COPD) in tertiary hospitals in northeast China. Physicians from 77 tertiary hospitals in northeast China were surveyed with a questionnaire, which included questions such as risk factors, symptoms, exacerbations, comorbidities and diagnostic criteria of COPD. Besides cigarette smoking, air pollution and pulmonary infections, only 22.5%(40/178) physicians recognized that the biomass fuels may induce COPD. Totally 59.0%(105/178) physicians recognized the importance of spirometry to the diagnosis of COPD. Besides dyspnea, cough, sputum production, wheezing and chest tightness, only 23.7%(42/177) of physicians considered that limitation of activity was an important symptom of COPD. 65.5%(116/177) physicians believed that recurrent lung infections was one of the most important comorbidities of COPD. However, less than 30%[20.9%(37/177)-28.8%(51/177)] physicians were aware of the other important comorbidities. The physicians of tertiary hospitals in northeast China need to be systematically educated on COPD to meet the new guideline.
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Atitude do Pessoal de Saúde , Conhecimentos, Atitudes e Prática em Saúde , Médicos , Doença Pulmonar Obstrutiva Crônica , China , Comorbidade , Tosse , Estudos Transversais , Dispneia , Feminino , Humanos , Masculino , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Fatores de Risco , Fumar , Espirometria , Inquéritos e Questionários , Centros de Atenção TerciáriaRESUMO
Deformation twinning in pure aluminum has been considered to be a unique property of nanostructured aluminum. A lingering mystery is whether deformation twinning occurs in coarse-grained or single-crystal aluminum at scales beyond nanotwins. Here, we present the first experimental demonstration of macrodeformation twins in single-crystal aluminum formed under an ultrahigh strain rate (â¼10^{6} s^{-1}) and large shear strain (200%) via dynamic equal channel angular pressing. Large-scale molecular dynamics simulations suggest that the frustration of subsonic dislocation motion leads to transonic deformation twinning. Deformation twinning is rooted in the rate dependences of dislocation motion and twinning, which are coupled, complementary processes during severe plastic deformation under ultrahigh strain rates.
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N-acetyltransferase 2 (NAT2) is an essential phase II enzyme in the metabolism of aromatic and heterocyclic amines and of hydrazines. NAT2 activity can be divided into three phenotypes: rapid, intermediate, and slow. Studies identifying an association between NAT2 polymorphism and the risk of pancreatic cancer have shown conflicting results. In order to assess this relationship comprehensively, we performed a meta-analysis that involved 1607 patients with pancreatic cancer and 1682 controls from six studies, which were selected from a group of ten, identified by a search of PubMed and Embase databases up to July 2014. Relative risks (RRs) with 95% confidence intervals (CIs) were used to evaluate the relationships. In the overall analysis, no significant associations between NAT2 rapid acetylation genotypes and pancreatic cancer risk (RR = 0.93, 95%CI = 0.73-1.19) were found; however, the results showed significant heterogeneity (I2 = 55.0%). The results from subgroup analysis suggested that the rapid genotypes might decrease the risk of pancreatic cancer (RR = 0.56, 95%CI = 0.38-0.84) in Turkey, although the association was not significant in the United States population (RR = 0.97, 95%CI = 0.71-1.34) or in the multi-center studies (RR = 1.10, 95%CI = 0.90-1.34). Analysis of the slow acetylation genotypes demonstrated the converse outcomes. In conclusion, the results of our study suggested that the NAT2 slow acetylation genotypes might increase the susceptibility to pancreatic cancer in Europe but that these have no significant effects in the United States and multi-center populations.
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Arilamina N-Acetiltransferase/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Neoplasias Pancreáticas/genética , Polimorfismo Genético , Acetilação , Estudos de Casos e Controles , Genótipo , Humanos , Razão de Chances , Neoplasias Pancreáticas/epidemiologia , RiscoRESUMO
The purpose of this study was to identify the clinical features and mutations in the fibrillin-1 gene (FBN1) in a large Chinese family with autosomal dominant Marfan syndrome (MFS). Seventeen members from a Chinese family of 4 generations were included in the study. All members underwent complete ophthalmic examination. Molecular genetic analysis was performed on all subjects. All exons of FBN1 were amplified by polymerase chain reaction, sequenced, and the sequences were compared with a reference database. Variations were evaluated in family members as well as 100 normal controls. Changes in structure and function of the protein induced by amino acid variation were predicted by bioinformatic analysis. Ectopia lentis, dolichostenomelia, arachnodactyly, and tall stature were present in all patients diagnosed with MFS. The novel heterozygous missense mutation c.2243 T>G (p.C781W) in exon 19 of FBN1 was identified in all 5 patients, but not in other family members or 100 normal controls. This mutation caused an amino acid substitution of cysteine to tryptophan at position 781 (p.C781W) of the FBN1 protein. This mutation occurred in a highly conserved region and may cause structural and functional changes in the protein according to our bioinformatic analysis. Our results suggest that the novel mutation C781W of FBN1 is responsible for the pathogenesis of MFS in this pedigree.
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Povo Asiático/genética , Ectopia do Cristalino/genética , Fibrilina-1/genética , Síndrome de Marfan/genética , Adolescente , Adulto , Idoso , Substituição de Aminoácidos , Sequência de Bases , Criança , Análise Mutacional de DNA , Éxons/genética , Feminino , Fibrilinas , Genótipo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Análise de Sequência de DNARESUMO
BACKGROUND: Previous studies have shown that human cathelicidin and defensins have effective antimicrobial activity against Mycobacterium spp. OBJECTIVE: To investigate the antimycobacterial effect of mature bovine neutrophil ß-defensin (mBNBD) 4 against Mycobacterium spp. infection for the first time. DESIGN: mBNBD4 protein was expressed in Pichia pastoris GS115. We used immunofluorescent assay to detect whether the recombinant mBNBD4 had entered the macrophages. The antimycobacterial activity of mBNBD4 was tested through colony-forming unit (cfu) assay. Morphological changes in the cell wall of M. bovis treated with mBNBD4 were observed by scanning electron microscope. RESULTS: mBNBD4 was expressed and successfully purified from P. pastoris with intact antimicrobial activity. The recombinant protein was able to enter Raw 264.7 macrophages and exhibited potent in vitro bactericidal activity against M. smegmatis and M. bovis. The cell wall of M. bovis was disrupted after interaction with mBNBD4. Exogenous addition of mBNBD4 to both Raw 264.7 and THP-1 derived macrophages reduced the intracellular survival of M. bovis and M. tuberculosis relative to control cells. CONCLUSION: Our data show that mBNBD4 plays an important role in inhibiting mycobacterial growth and in controlling intracellular survival of mycobacteria. mBNBD4 could therefore an effective antimycobacterial molecule in combination with other measures.
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Antibacterianos/farmacologia , Mycobacterium bovis/efeitos dos fármacos , Mycobacterium smegmatis/efeitos dos fármacos , beta-Defensinas/farmacologia , Animais , Bovinos , Parede Celular/efeitos dos fármacos , Parede Celular/ultraestrutura , Contagem de Colônia Microbiana , Relação Dose-Resposta a Droga , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Camundongos , Viabilidade Microbiana/efeitos dos fármacos , Microscopia Eletrônica de Varredura , Mycobacterium bovis/crescimento & desenvolvimento , Mycobacterium bovis/ultraestrutura , Mycobacterium smegmatis/crescimento & desenvolvimento , Mycobacterium smegmatis/ultraestrutura , Células RAW 264.7 , Proteínas Recombinantes/farmacologia , Fatores de TempoRESUMO
This study aimed to characterize the clinical features of a Chinese pedigree with neurofibromatosis type 1 (NF1) and to identify mutations in the NF1 gene. In this three-generation family containing 8 members, 5 had been diagnosed with NF1 and the others were asymptomatic. All members of the family underwent complete medical examinations. Molecular genetic analyses were performed on all subjects included in the study. All exons of NF1 were amplified by polymerase chain reaction, sequenced, and compared with a reference database. Possible changes in function of the protein induced by amino acid variants were predicted by bioinformatic analysis. In this family, the 5 patients presented different clinical phenotypes, but all manifested typical café-au-lait macules. One novel frame-shift mutation, c.702_703delGT, in exon 7 of NF1 was identified in all affected family members, but not in the unaffected family members or in 102 normal controls. This mutation generates a premature stop codon at amino acid position 720. Additionally, a synonymous mutation c.702 G>A was found in 3 family members, including 2 affected and 1 normal individuals. In conclusion, our study suggests that a novel c.702_703delGT frame-shift mutation in NF1 is likely to be responsible for the pathogenesis of NF1 in this family. To the best of our knowledge, it is the first time that a c.702_703delGT mutation has been identified in a family with neurofibromatosis type 1.
Assuntos
Éxons , Mutação da Fase de Leitura , Neurofibromatose 1/genética , Neurofibromina 1/genética , Adulto , Sequência de Aminoácidos , Povo Asiático , Sequência de Bases , Estudos de Casos e Controles , Criança , Pré-Escolar , Códon sem Sentido , Feminino , Expressão Gênica , Genótipo , Humanos , Masculino , Dados de Sequência Molecular , Neurofibromatose 1/etnologia , Neurofibromatose 1/patologia , Linhagem , FenótipoRESUMO
BACKGROUND: Pharmacogenetics-based algorithms would be especially desirable for patients undergoing heart valve replacement (HVR), who are particularly sensitive to warfarin during the initial treatment phase following surgery. We aimed to derive a warfarin dosing algorithm from data of Chinese patients undergoing HVR, and to compare it with previously published dosing algorithms as applied to our HVR patients. METHODS: 641 Chinese HVR patients on stable maintenance dose of warfarin were enrolled from a single clinic site. Data of 321 patients were used to derive a warfarin dosing algorithm using stepwise multiple linear regression analysis. Previously published algorithms were selected from Pubmed database for comparison. The performance of all the algorithms was characterized according to mean absolute error (MAE) and percentage of predicted doses falling within +/- 20% of clinically observed doses (percentage of ideal prediction) in the other 320 patients. RESULTS: The newly developed algorithm included eight factors: VKORC1-1639G > A, CYP2C9*3, BSA, age, number of increasing INR drugs, smoking habit, preoperative stroke history and hypertension. Our algorithm accounted for 56.4% of variations in the inter-patient warfarin stable doses. All the algorithms showed better performance in a medium-dose (1.88-4.38 mg/day) and high-dose (> or = 4.38 mg/day) groupings than in a low-dose (< or = 1.88 mg/day) grouping. Compared with the 14 previously published algorithms, our algorithm had the lowest MAE (-0.07 mg/day) and the highest percentage of ideal prediction (62.8%) in the total validation cohort. CONCLUSIONS: Our warfarin dosing algorithm is potentially useful for patients whose population profiles are similar to those of our patients.
Assuntos
Anticoagulantes/administração & dosagem , Hidrocarboneto de Aril Hidroxilases/genética , Implante de Prótese de Valva Cardíaca/métodos , Varfarina/administração & dosagem , Adolescente , Adulto , Idoso , Algoritmos , Povo Asiático , Citocromo P-450 CYP2C9 , DNA/biossíntese , DNA/genética , Feminino , Genótipo , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Medicina de Precisão , Análise de Regressão , Reprodutibilidade dos Testes , Adulto JovemRESUMO
Interleukin (IL)-24, a promising therapeutic gene, has been widely used for Cancer Targeting Gene-Viro-Therapy (CTGVT). In this study, IL-24 was inserted into an oncolytic adenovirus in which the E1A gene is driven by an enhanced, short α-fetoprotein (AFP) promoter and the E1B gene is completely deleted to form Ad.enAFP-E1A-ΔE1B-IL-24. This construct has a potent antitumor effect on liver cancer cell lines in vitro, but little or no effect on normal cell lines, such as L-02 and QSG-7701. In vivo, the complete elimination of Huh-7 liver cancer in nude mice with Ad.enAFP-E1A-ΔE1B-IL-24 intratumor injection was observed. The design of Ad.enAFP-E1A-ΔE1B-IL-24 and its potent antitumor effect on liver cancer have not been published previously. The mechanism of the potent antitumor effect of Ad.enAFP-E1A-ΔE1B-IL-24 is due to the upregulation of GADD34 and intrinsic and extrinsic apoptotic signaling.