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1.
Sci Total Environ ; 802: 149793, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34454143

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) are epidemiologically associated with cardiovascular diseases characterized by early key events involving in the disruption of endothelial barrier function. Whether PAHs can induce adverse cardiovascular outcome by directly destabilizing endothelial barrier function remains elusive. Herein, we investigated the effect of anthracene (ANT), 9-nitroanthracene (9-NANT), and 9,10-anthraquinone (9,10-AQ) on vascular endothelial barrier functions in human umbilical vein endothelial cells (HUVECs). The integrity of endothelial barrier in HUVECs was disturbed with a 1.15-1.42 fold increase in fluorescein leakage, and 21.8%-58.3% downregulated transendothelial electrical resistance. ANT, 9-NANT and 9,10-AQ promoted paracellular gap formation as revealed by transmission electron microscope. The disrupted cell junctions after 24 h exposure to ANT, 9-NANT and 9,10-AQ at 0.01 µM were indicated by the downregulated mRNA expression of vascular endothelial cadherin (VE-cadherin), zona occludens-1 (ZO-1) and occludin by 33.2%-71.4%, 19.1%-21.0%, and 31.9% respectively, and the downregulated protein expression of ZO-1 and occludin, and by the internalization of VE-cadherin. We demonstrated that ANT and its derivatives at environmentally relevant concentrations induced endothelial barrier dysfunction via the disruption of cell junctions, providing essential in vitro evidence on the association with their adverse cardiovascular outcomes.

2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(8): 783-786, 2021 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-34365625

RESUMO

OBJECTIVE: To carry out prenatal diagnosis for a fetus with absent nasal bone by using cytogenetic and molecular techniques. METHODS: Chromosomal karyotyping, single nucleotide polymorphism array (SNP-array) and fluorescence in situ hybridization (FISH) assays were applied for the diagnoses. Peripheral blood samples were also taken from the parents for chromosomal karyotyping and FISH analysis. RESULTS: The fetus was found to have a 46,XX,add(21)(p11.2) karyotype, and SNP-array has revealed a 11.3 Mb duplication at 21q22.12q22.3 (hg19: 36 762 648-48 093 361), which was confirmed by FISH. Both parents were found to be normal by chromosomal karyotyping and FISH analysis. The fetus was ultimately found to have a karyotype of 46,XX,der(21)t(21;21)(p11.2;q22.1), resulting a de novo partial trisomy of 21q22.1. CONCLUSION: Combined use of various techniques has enabled accurate prenatal diagnosis and genetic counseling for the fetus.


Assuntos
Osso Nasal , Trissomia , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Gravidez , Diagnóstico Pré-Natal , Trissomia/genética
3.
Artigo em Inglês | MEDLINE | ID: mdl-34207332

RESUMO

Cerebrovascular disease (CVD) is the leading cause of death in many countries including China. Early diagnosis and risk assessment represent one of effective approaches to reduce the CVD-related mortality. The purpose of this study was to understand the prevalence and influencing factors of cerebrovascular disease among community residents in Qingyunpu District, Nanchang City, Jiangxi Province, and to construct a model of cerebrovascular disease risk index suitable for local community residents. A stratified cluster sampling method was used to sample 2147 community residents aged 40 and above, and the prevalence of cerebrovascular diseases and possible risk factors were investigated. It was found that the prevalence of cerebrovascular disease among local residents was 4.5%. Poisson regression analysis found that old age, lack of exercise, hypertension, diabetes, smoking, and family history of cerebrovascular disease are the main risk factors for local cerebrovascular disease. The relative risk ORs were 3.284, 2.306, 2.510, 3.194, 1.949, 2.315, respectively. For these six selected risk factors, a cerebrovascular disease risk prediction model was established using the Harvard Cancer Index method. The R value of the risk prediction model was 1.80 (sensitivity 81.8%, specificity 47.0%), which was able to well predict the risk of cerebrovascular disease among local residents. This provides a scientific basis for the further development of local cerebrovascular disease prevention and control work.


Assuntos
Transtornos Cerebrovasculares , Hipertensão , Transtornos Cerebrovasculares/epidemiologia , China/epidemiologia , Cidades , Humanos , Prevalência , Fatores de Risco
4.
Aging (Albany NY) ; 13(12): 16696-16712, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34158412

RESUMO

In this study, we performed a bioinformatics analysis to identify immune checkpoint genes (ICGs) associated with prognosis and the immunotherapeutic response in endometrial carcinoma (EC) patients. We classified 47 ICGs into high, medium, and low expression groups by performing RNA-sequencing data analysis of EC patient samples from The Cancer Genome Atlas (n = 521) and GSE77688 (n = 88) datasets. Univariate Cox regression analysis showed that seven ICGs (VTCN1, TNFRSF18, TNFRSF14, TNFRSF4, CD40LG, TMIGD2, and BTLA) were associated with prognosis in EC patients. Spearman correlation analysis showed that prognosis-related ICGs correlated positively with immunotherapy response factors, including tumor mutation burden (TMB), mismatch repair gene mutations, neoantigens, clinical stages, and adaptive immune resistance pathway genes. We identified a prognostic gene signature of four ICGs (IDO1, CD274, CTLA4, and TNFRSF14) that accurately predicted survival outcomes of EC patients. TIMER database and Kaplan-Meier survival analysis showed that OS among EC patients with low TNFRSF14 expression was significantly shorter than among those with high TNFRSF14 expression. In vitro experiments showed that TNFRSF14 silencing increased the migration and invasiveness of EC cells by promoting epithelial-mesenchymal transition (EMT). Collectively, these findings reveal an immune checkpoint gene signature that accurately predicts survival outcomes and immunotherapeutic responses in EC patients.


Assuntos
Neoplasias do Endométrio/genética , Neoplasias do Endométrio/terapia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Checkpoint Imunológico/genética , Imunoterapia , Imunidade Adaptativa/genética , Antígenos de Neoplasias , Reparo do DNA/genética , Bases de Dados Genéticas , Resistência à Doença/genética , Neoplasias do Endométrio/imunologia , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Proteínas de Checkpoint Imunológico/metabolismo , Mutação/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Prognóstico , Análise de Sobrevida
5.
Nanoscale ; 13(19): 9018-9030, 2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-33978034

RESUMO

Black phosphorus (BP) nanomaterials have shown great potential in versatile applications including biomedicine and potentially interact with vessel walls following intravenous injection in biomedical usage or environmental exposure. However, it remains unknown whether the exposure to BP nanomaterials induces alterations of the endothelium and further vascular injury. Herein, the endothelial function of human umbilical vein endothelial cells (HUVECs) and the structure and transcriptome of C57BL/6 mouse aortas are evaluated after the exposure to BP quantum dots (BPQDs) and nanosheets (BPNSs). BPNSs with irregular shapes and larger lateral size are more prone to inhibit in vitro angiogenesis at non-cytotoxic concentrations and markedly trigger platelet adhesion to HUVECs compared to BPQDs. Decreased nitric oxide (NO) production resulting from endothelial NO synthase (eNOS) dysregulation is involved in the BP-induced endothelial dysfunction. Both BPQDs and BPNSs at 0.8 and 6.4 µg mL-1 inhibit eNOS enzymatic activity through dephosphorylation of eNOS-Ser1177 and phosphorylation of eNOS-Thr495, but unlike BPQDs, BPNSs also downregulate eNOS expression. Despite no pathological damage in the structure of mouse aortas, BPQDs and BPNSs trigger aberration of aortic transcriptome involved in vasoconstriction abnormality, metabolic disturbance, and immune perturbation. This study demonstrates the adverse effect of BP nanomaterials on vasculature, and suggests that the morphological attribute of BP plays a crucial role in the vascular risks.


Assuntos
Fósforo , Pontos Quânticos , Animais , Aorta/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação , Pontos Quânticos/toxicidade , Transcriptoma
6.
BMC Med Genomics ; 14(1): 106, 2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33853619

RESUMO

BACKGROUND: Noninvasive prenatal testing (NIPT) has been wildly used to screen for common aneuplodies. In recent years, the test has been expanded to detect rare autosomal aneuploidies (RATs) and copy number variations (CNVs). This study was performed to investigate the performance of expanded noninvasive prenatal testing (expanded NIPT) in screening for common trisomies, sex chromosomal aneuploidies (SCAs), rare autosomal aneuploidies (RATs), and copy number variations (CNVs) and parental willingness for invasive prenatal diagnosis in a Chinese prenatal diagnosis center. METHODS: A total of 24,702 pregnant women were retrospectively analyzed at the Women and Children's Hospital from January 2013 to April 2019, among which expanded NIPT had been successfully conducted in 24,702 pregnant women. The high-risk expanded NIPT results were validated by karyotype analysis and chromosomal microarray analysis. All the tested pregnant women were followed up for pregnancy outcomes. RESULTS: Of the 24,702 cases, successful follow-up was conducted in 98.77% (401/446) of cases with common trisomies and SCAs, 91.95% (80/87) of RAT and CNV cases, and 76.25% (18,429/24,169) of cases with low-risk screening results. The sensitivity of expanded NIPT was 100% (95% confidence interval[CI], 97.38-100%), 96.67%(95%CI, 82.78-99.92%), and 100%(95%CI, 66.37-100.00%), and the specificity was 99.92%(95%CI, 99.87-99.96%), 99.96%(95%CI, 99.91-99.98%), and 99.88% (95%CI, 99.82-99.93%) for the detection of trisomies 21, 18, and 13, respectively. Expanded NIPT detected 45,X, 47,XXX, 47,XXY, XYY syndrome, RATs, and CNVs with positive predictive values of 25.49%, 75%, 94.12%, 76.19%, 6.45%, and 50%, respectively. The women carrying fetuses with Trisomy 21/Trisomy 18/Trisomy 13 underwent invasive prenatal diagnosis and terminated their pregnancies at higher rates than those at high risk for SCAs, RATs, and CNVs. CONCLUSIONS: Our study demonstrates that the expanded NIPT detects fetal trisomies 21, 18, and 13 with high sensitivity and specificity. The accuracy of detecting SCAs, RATs, and CNVs is still relatively poor and needs to be improved. With a high-risk expanded NIPT result, the women at high risk for common trisomies are more likely to undergo invasive prenatal diagnosis procedures and terminate their pregnancies than those with unusual chromosome abnormalities.

7.
Eur J Surg Oncol ; 47(7): 1710-1717, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33549377

RESUMO

PURPOSE: To determine the optimal threshold of examined lymph node (ELN) number from cervical lymph node dissection for head and neck squamous cell carcinoma (HNSCC). Further to compare the prognostic value of multiple lymph node classification systems and to determine the most suitable scheme to predict survival. METHODS: A total of 20991 HNSCC patients were included. Odds ratios (ORs) for negative-to-positive node stage migration and hazard ratios (HRs) for survival were fitted using the LOWESS smoother. Structural breakpoints were determined by the Chow test. The R square, C-index, likelihood ratio, and Akaike information criterion (AIC) were used to compare the prognostic abilities among AJCC N stage, number of positive lymph nodes (pN), positive lymph node ratio (LNR) and log odds of positive lymph nodes (LODDS) stages. RESULTS: A minimal threshold ELN number of fifteen had the discriminatory capacities for both stage migration and survival. LODDS stages had the highest R square value (0.208), C-index (0.736) and likelihood ratio (2467) and the smallest AIC value (65874). LODDS stages also showed prognostic value in estimating patients with AJCC N0 stage. A novel staging system was proposed and showed good prognostic performance when stratified by different primary sites. CONCLUSION: Fifteen lymph nodes should be examined for HNSCC patients. LODDS stage allows better prognostic stratification, especially in N0 stage. The proposed staging system may serve as precise evaluation tools to estimate postoperative prognoses.

8.
World J Urol ; 39(6): 1815-1823, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32691147

RESUMO

PURPOSE: We identified the risk predictors related to prostate cancer (PCa) metastasis using contemporary data in a community setting. Then, we assessed the performance of indications for bone imaging recommended from the NCCN, AUA and EAU guidelines. METHODS: Using the Surveillance, Epidemiology, and End Results database (2010-2015), we collected clinicopathological information from PCa patients. The associated risk factors found by multivariate analyses were used to establish forest plots and nomograms for distant metastasis (DM) and bone(s)-only metastasis (BM). We next evaluated the NCCN, AUA and EAU guidelines indications for the discovery of certain subgroups of patients who should receive bone imaging. RESULTS: A total of 120,136 patients were eligible for analysis, of which 96.7% had no metastasis. The odds ratios of positive DM and BM results were 13.90 times and 15.87 times higher in patients with a histologic grade group (GG) 5 than in the reference group. The concordance index of the nomograms based on race, age, T/N stage, PSA, GG, percentage of positive scores for predicting DM and BM was 0.942 and 0.928, respectively. Performance of the NCCN, AUA and EAU guidelines was high and relatively similar in terms of sensitivity (93.2-96.9%) and negative predictive value (99.8-99.9%). NCCN guidelines had the highest accuracy, specificity and positive likelihood ratio, while negative likelihood ratio was lowest in AUA guideline. CONCLUSION: Histologic GG 5 was the foremost factor for DM and BM. NCCN-based recommendations may be more rational in clinical practice. Nomograms predicting metastasis demonstrate high accuracy.

9.
Colloids Surf B Biointerfaces ; 197: 111388, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33096417

RESUMO

Vascular stiffening occurs with advanced age and under pathological conditions such as vascular calcification, during which the osteogenesis of smooth muscle cells (SMCs) plays a key role. However, whether the stiffness of cellular microenvironment influences osteogenic responses in vascular SMCs is not well understood. Here, we cultured SMCs on the poly(dimethylsiloxane) (PDMS) substrates with varying stiffness from 0.363 to 2.327 MPa. The cell osteogenic transdifferentiation was induced by ß-glycerophosphate. Our findings demonstrated that the extent of osteogenesis in SMCs varied with the substrate stiffness. On three substrate stiffness, cells on the intermediate one (0.909 MPa) showed the highest extent of the osteogenesis based on the expression of osteogenic markers and calcium deposition. Transforming growth factor-ß1 and autophagy were involved in this stiffness-dependent process. This work highlights the importance of substrate stiffness to the osteogenesis of vascular SMCs, giving new scientific information for understanding of SMCs-mediated vascular calcification and designing of vascular implants.


Assuntos
Osteogênese , Calcificação Vascular , Células Cultivadas , Humanos , Músculo Liso Vascular , Miócitos de Músculo Liso
10.
Opt Lett ; 45(24): 6679-6682, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33325869

RESUMO

In this Letter, a method for orbital angular momentum (OAM) mode generation is proposed and experimentally demonstrated using a fiber Bragg grating (FBG) and off-axis incidence. The FBG fabricated by a femtosecond laser was used to couple the incidence beam into backward high-order modes. The generated modes were then reformed into ring-shaped OAM modes by adjusting the off-axis displacement of the input beam. The intensity distribution, phase vortex, and mode purity of the output light were experimentally investigated. Results indicates that the order of the generated OAM modes is dependent on the resonant wavelength of the FBG, and the sign of the OAM topological charge is determined by the displacement value of the off-axis incident light. In the experiment, ±1- and ±2-order OAM modes were achieved and confirmed, with purities as high as 90%, 91%, 89%, and 88%, respectively.

11.
Artigo em Inglês | MEDLINE | ID: mdl-32825300

RESUMO

The high turnover rate of new generation employees is becoming an increasingly important issue for business and academia. Based on self-determination theory and conservation of resource theory, our study explores the impact of the inclusive talent development model on the turnover intention of new generation employees and the mediating role of work passion. Based on the questionnaire of 290 new generation employees' data from China, after common method biases and reliability and validity tests, we used SPSS, Mplus and bootstrapping for empirical analysis. The result showed that the inclusive talent development model includes the diversified talent team construction, rational tolerance of employee's opinions and failures, emphasis on employee's training, emphasis on fairness and win-win and emphasis on employee's advantages. The work passion has been divided into harmonious passion and obsessive passion. Among them, rational tolerance of employee's opinions and failures, emphasis on employee's training and emphasis on fairness and win-win have a significant positive impact on harmonious passion. Emphasis on fairness and win-win and emphasis on employee's advantages have negative correlation with obsessive passion. The employee's harmonious passion is significantly negatively correlated with the turnover intention and the obsessive passion is significantly positively correlated with the turnover intention. In addition, the harmonious passion plays a mediating role between rational tolerance of employee's opinions and failures, emphasis on employee's training, emphasis on fairness and win-win and employee's turnover intention, while the obsessive passion plays a mediating role between emphasis on fairness and win-win and emphasis on employee's advantages and employee's turnover intention.


Assuntos
Intenção , Reorganização de Recursos Humanos , Trabalho , Adolescente , Adulto , Fatores Etários , China , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Adulto Jovem
12.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(9): 1036-1038, 2020 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-32820525

RESUMO

OBJECTIVE: To carry out prenatal diagnosis for a fetus with increased nuchal translucency (NT) and another fetus with non-invasive prenatal testing (NIPT) suggested reduced sex chromosomes by cytogenetic and molecular techniques. METHODS: Chromosomal karyotyping, single nucleotide polymorphism array (SNP-array) and fluorescence in situ hybridization (FISH) were applied for the diagnoses. Peripheral blood samples were also taken from their parents for chromosomal karyotyping and SNP-array analysis. RESULTS: Both fetuses showed a 46,X,+mar/45,X karyotype. SNP-array has detected a 22.0 Mb duplication at Yp11.31q11.223 and a 3.9 Mb microdeletion at Yq11.223q11.23 in fetus 1, and a 16.9 Mb duplication at Yp11.31q11.221 and a 8.1 Mb deletion at Yq11.222q11.23 in fetus 2. The results were confirmed by FISH. The parents of both fetuses were normal by chromosomal karyotyping and SNP-array. CONCLUSION: Combined use of various techniques can enable accurate prenatal diagnosis and genetic counseling.


Assuntos
Mosaicismo , Diagnóstico Pré-Natal , Cromossomos Humanos Y , Feminino , Feto , Humanos , Hibridização in Situ Fluorescente , Polimorfismo de Nucleotídeo Único , Gravidez
13.
Lung Cancer ; 148: 86-93, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32846318

RESUMO

OBJECTIVES: To evaluate the prognostic significance of patterns of distant metastatic organs in metastatic pulmonary neuroendocrine tumors (PNETs). METHODS: 891 metastatic PNETs patients (G1-typical carcinoid, 200; G2-atypical carcinoid, 68; G3-large-cell neuroendocrine carcinoma, 623) diagnosed between 2010 and 2016 were identified. Multivariate analysis was performed using a Cox regression model to identify prognostic factors associated with cancer-specific survival (CSS). The novel M component was established based on the hazard ratio of different metastatic organs. A disease-specific staging system was then proposed by using k-means cluster analysis. RESULTS: For metastatic PNETs, involvement of bone, liver or brain and multiple metastatic organs were identified as independent prognostic factors in multivariate analysis. M categories was subdivided into three subcategories: M1a, lung involvement only or distant lymph node involvement only; M1b, bone involvement only or liver involvement only; M1c, brain involvement regardless of number of metastatic organs or multiple organs involvement except brain. Primary site surgery, chemotherapy and histologic subtypes were independently associated with CSS, but T component and N component were not. After regrouping histologic subtypes and novel M component, we proposed the following modified staging system: stage IVA (G1M1any, G2M1a-b), stage IVB (G2M1c, G3M1a-b) and stage IVC (G3M1c). The 2-year CSS were 77.9 %, 16.4 % and 5.3 %. CONCLUSIONS: Subdivision of M component according to patterns of distant metastatic organs facilitates prognostic significance for PNETs. Brain metastases and multiple metastatic organs were associated with significantly inferior prognosis. Incorporating histologic subtypes and novel M categories create a disease-specific staging system showed good discriminatory capacity.


Assuntos
Tumor Carcinoide , Carcinoma Neuroendócrino , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Proteínas do Mieloma , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos
14.
Chem Commun (Camb) ; 56(59): 8222-8225, 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32555793

RESUMO

A transition-metal-free double addition/double rearrangement domino reaction affording CF3-substituted pyrimidines was developed, which enables the one-pot construction of five new bonds, namely three C-C bonds and two C-N bonds. The keys to achieve this highly efficient reaction include the delicate design of the bis-nucleophiles in situ generated from the dimerization of alkyl nitriles and the use of trifluoroacetimidoyl nitriles containing C[double bond, length as m-dash]N, C[triple bond, length as m-dash]N, and CF3 groups as the reactant. The mechanistic studies by the experiments and DFT calculations reveal that the transformation involves two addition and two unprecedented rearrangement processes.

15.
J Diabetes Res ; 2020: 7463082, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32405505

RESUMO

The New Chinese Diabetes Risk Score (NCDRS) is one of the recommended tools for screening undiagnosed type 2 diabetes in China. However, its performance in detecting undiagnosed diabetes needs to be verified in different community populations. Also, it is unknown whether NCDRS can be used in detecting prediabetes. In the present study, we aimed to evaluate the performance of NCDRS in detecting undiagnosed diabetes and prediabetes among the community residents in eastern China. We applied NCDRS in 7675 community residents aged 18-65 years old in Jiangsu Province. The results showed that the participants with undiagnosed diabetes reported the highest NCDRS value, followed by those with prediabetes (P < 0.001). The best cut-off points of NCDRS for detecting undiagnosed diabetes and prediabetes were 27 (with a sensitivity of 78.0% and a specificity of 57.7%) and 27 (with a sensitivity of 66.0% and a specificity of 62.9%). The AUCs of NCDRS for identifying undiagnosed diabetes and prediabetes were 0.749 (95% CI: 0.739~0.759) and 0.694 (95% CI: 0.683~0.705). These results demonstrate the excellent performance of NCDRS in screening undiagnosed diabetes in the community population in eastern China and further provide evidence for using NCDRS in detecting prediabetes.


Assuntos
Glicemia , Diabetes Mellitus Tipo 2/diagnóstico , Estado Pré-Diabético/diagnóstico , Adolescente , Adulto , Idoso , China , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Humanos , Programas de Rastreamento , Pessoa de Meia-Idade , Estado Pré-Diabético/sangue , Medição de Risco , Fatores de Risco , Adulto Jovem
16.
Environ Sci Technol ; 54(5): 2922-2930, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32022550

RESUMO

Nitrated and oxygenated polycyclic aromatic hydrocarbons (NPAHs and OPAHs) from the direct atmospheric emission or the degradation of parent PAHs are increasingly recognized because of their potential health risks. Herein, we investigated the effects of four NPAHs/OPAHs (1-NNAP, 9-NANT, 9,10-AQ, and 9-FLU) and their parent PAHs (NAP, ANT, and FLU) on endothelium function with regard to endothelial nitric oxide synthase (eNOS) and endothelium-derived nitric oxide (NO) production in human umbilical vein endothelial cells. The eNOS enzymatic activity and NO production were promoted by NAP, ANT, and FLU; however, eNOS activity was dropped by 52.8, 52.1, 52.5, and 44.5%, and NO production was decreased by 31.1, 50.3, 65.0, and 35.0% after 24 h exposure to 0.01 µM 1-NNAP, 9-NANT, 9,10-AQ, and 9-FLU, respectively. The mRNA expression of eNOS and protein expression of phosphorylated eNOS (Ser1177) were increased by three PAHs but decreased by four NPAHs/OPAHs. The 100 ns molecular dynamics simulations reveal the conformational alteration in the key propionate of heme upon the binding of NPAHs/OPAHs. Our findings provide the first in silico and in vitro evidence for the potential endothelial dysfunction of nitrated and oxygenated PAHs. The health risk implications of NPAHs/OPAHs and corresponding parent PAHs warrant further research.


Assuntos
Poluentes Atmosféricos , Hidrocarbonetos Policíclicos Aromáticos , Células Endoteliais , Monitoramento Ambiental , Humanos , Nitratos , Óxido Nítrico , Óxido Nítrico Sintase Tipo III
17.
Radiother Oncol ; 144: 189-200, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31911366

RESUMO

BACKGROUND AND PURPOSE: Access to healthcare data is indispensable for scientific progress and innovation. Sharing healthcare data is time-consuming and notoriously difficult due to privacy and regulatory concerns. The Personal Health Train (PHT) provides a privacy-by-design infrastructure connecting FAIR (Findable, Accessible, Interoperable, Reusable) data sources and allows distributed data analysis and machine learning. Patient data never leaves a healthcare institute. MATERIALS AND METHODS: Lung cancer patient-specific databases (tumor staging and post-treatment survival information) of oncology departments were translated according to a FAIR data model and stored locally in a graph database. Software was installed locally to enable deployment of distributed machine learning algorithms via a central server. Algorithms (MATLAB, code and documentation publicly available) are patient privacy-preserving as only summary statistics and regression coefficients are exchanged with the central server. A logistic regression model to predict post-treatment two-year survival was trained and evaluated by receiver operating characteristic curves (ROC), root mean square prediction error (RMSE) and calibration plots. RESULTS: In 4 months, we connected databases with 23 203 patient cases across 8 healthcare institutes in 5 countries (Amsterdam, Cardiff, Maastricht, Manchester, Nijmegen, Rome, Rotterdam, Shanghai) using the PHT. Summary statistics were computed across databases. A distributed logistic regression model predicting post-treatment two-year survival was trained on 14 810 patients treated between 1978 and 2011 and validated on 8 393 patients treated between 2012 and 2015. CONCLUSION: The PHT infrastructure demonstrably overcomes patient privacy barriers to healthcare data sharing and enables fast data analyses across multiple institutes from different countries with different regulatory regimens. This infrastructure promotes global evidence-based medicine while prioritizing patient privacy.


Assuntos
Neoplasias Pulmonares , Aprendizado de Máquina , Algoritmos , China , Humanos , Privacidade
18.
Neuroendocrinology ; 110(5): 364-376, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31357196

RESUMO

BACKGROUND: Significant modifications have been made to the 8th edition of the American Joint Committee on Cancer (AJCC) distant metastases (M) stage classification for metastatic pancreatic neuroendocrine tumors (PanNETs). We aimed to validate this revised classification among metastatic PanNET patients using the Surveillance, Epidemiology, and End Results database. We further sought to evaluate the feasibility of applying this classification to metastatic pancreatic neuroendocrine carcinoma (PanNEC) and pancreatic ductal adenocarcinoma (PDAC) patients. METHODS: Stage IV pancreatic neuroendocrine neoplasm (PanNEN, including G1/G2 PanNET and G3 PanNEC classified according to the World Health Organization [WHO] 2010 grading scheme) and PDAC patients with metastatic disease diagnosed between 2010 and 2015 were identified and restaged according to the revised M stage classification for PanNET. Overall survival (OS) was compared using Kaplan-Meier analysis and log-rank test. Uni- and multivariate Cox regression models were utilized to identify prognostic factors. RESULTS: A total of 1,371 stage IV PanNEN and 634 PDAC patients were included. Among PanNEN patients, liver (75.0%) was the most common metastatic site, followed by distant lymph nodes (8.5%), lung (8.4%), bone (7.3%), and brain (1.0%). The 5-year OS for PanNET patients with M1a, M1b, and M1c stage was 44.15, 53.32, and 19.70%, respectively. However, survival comparison showed no significant difference between M1a and M1b stages among PanNET patients. Similar findings were noted after applying this classification to PanNEC patients. Multivariate analysis showed that the age at diagnosis and the number of distant metastatic sites were independent prognostic factors for metastatic PanNEN patients. Interestingly, excellent survival discrimination by M stage among stage IV PDAC patients was noted (M1a vs. M1b vs. M1c, 5-year OS: 5.42, 2.46, and 0%, respectively). CONCLUSION: Our study is the first large sample-based validation of the AJCC 8th M stage classification for PanNET. The revised classification did not effectively stratify metastatic PanNEN patients. However, further study is warranted to validate this classification for PanNET patients according to the WHO 2017 classification. Interestingly, the revised M stage classification might be feasible for PDAC patients with metastatic disease.


Assuntos
Carcinoma Ductal Pancreático/classificação , Estadiamento de Neoplasias/normas , Tumores Neuroendócrinos/classificação , Neoplasias Pancreáticas/classificação , Adulto , Idoso , Bases de Dados Factuais , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Reprodutibilidade dos Testes
19.
J Ethnopharmacol ; 246: 112231, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31520671

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Liangxue Tongyu Prescription (LTP) is a traditional Chinese medicine formula composed of 8 crude drugs that is widely used to treat acute intracerebral hemorrhage (AICH). AIM OF THE STUDY: To verify the efficacy of LTP on the survival time in the treatment of acute intracerebral hemorrhagic rats (AICHs), and to elucidate its network pharmacodynamic mechanism of multi-component, multi-target, and multi-signaling pathways. MATERIALS AND METHODS: Survival analysis was used to evaluate the survival time of AICH rats induced by different doses of collagenase and the efficacy of three doses of LTP in the treatment of AICH rats. The Kaplan-Meier curves for survival time were produced and compared with the Log-rank test and Wilcoxon (Gehan) χ2. Differential mRNA-seq combined with network pharmacology was used to disclose the network effect mechanism of LTP on AICH, and the obtained differential genes were mapped into the predictive empirical compound-target network model (ECT network model) and the empirical compound-target-pathogenesis (disease) network model (ECTP network model). RESULTS: The median survival time of four different doses of LTP-treated groups (0.00 g/kg, 5.78 g/kg, 11.55 g/kg, 23.10 g/kg) for adult AICH rats by 0.18 U collagenase was 14 h, 37 h, 150 h, and 51 h respectively, and the 7-day survival rates were 33.3%, 41.7%, 50.0%, and 38.5%, of which the medium-dose group (MD) had a longer survival time and higher survival rate. Through further validation experiments, the MD group had a better efficacy trend with a median survival time of 168 h vs 23 h in the model control group (MC) (Wilcoxon Gehan Test, χ2 = 3.478, P = 0.062). The transcriptomic analysis of mRNA showed that 583 significant differential genes were found between the MC and MD group and 7 key therapeutic targets regulated by 29 compounds in LTP on AICH were screened out by VCT and VCTP network model. These targets were involved in 5 regulatory models or pathways. CONCLUSION: Our study confirmed the exact efficacy of the LTP in the treatment of AICH and revealed the potential pharmacodynamic components and mode of action of the LTP on AICH. Using differential transcriptome of mRNA combined with network pharmacology, we screened out 29 chemical compounds as the potential effective ingredients of LTP which acted on 7 targets of AICH involving 5 pathological pathways, mainly including repairing the brain function defect, improving neural function, protecting blood-brain barrier from damage, reducing inflammatory factors, and inhibiting apoptosis. The present study not only provides a new explanation for the 'multi-component, multi-target, multi-pathway' effects of the LTP on AICH but also screened out some major compounds of LTP and their potential targets which will facilitate the development of new drugs for AICH.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Masculino , RNA Mensageiro , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
20.
Radiat Oncol ; 14(1): 232, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31856866

RESUMO

OBJECTIVE: This study aims to investigate a hybrid automated treatment planning (HAP) solution that combines knowledge-based planning (KBP) and script-based planning for esophageal cancer. METHODS: In order to fully investigate the advantages of HAP, three planning strategies were implemented in the present study: HAP, KBP, and full manual planning. Each method was applied to 20 patients. For HAP and KBP, the objective functions for plan optimization were generated from a dose-volume histogram (DVH) estimation model, which was based on 70 esophageal patients. Script-based automated planning was used for HAP, while the regular IMRT inverse planning method was used for KBP. For full manual planning, clinical standards were applied to create the plans. Paired t-tests were performed to compare the differences in dose-volume indices among the three planning methods. RESULTS: Among the three planning strategies, HAP exhibited the best performance in all dose-volume indices, except for PTV dose homogeneity and lung V5. PTV conformity and spinal cord sparing were significantly improved in HAP (P < 0.001). Compared to KBP, HAP improved all indices, except for lung V5. Furthermore, the OAR sparing and target coverage between HAP and full manual planning were similar. Moreover, HAP had the shortest average planning time (57 min), when compared to KBP (63 min) and full manual planning (118 min). CONCLUSION: HAP is an effective planning strategy for obtaining a high quality treatment plan for esophageal cancer.


Assuntos
Neoplasias Esofágicas/radioterapia , Bases de Conhecimento , Órgãos em Risco/efeitos da radiação , Planejamento da Radioterapia Assistida por Computador/métodos , Adulto , Automação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada/métodos
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