RESUMEN
Acute promyelocytic leukemia (APL), a distinctive subtype of acute myeloid leukemia (AML), is characterized by the t(15; 17) translocation forming the PML-RARα fusion protein. Recent studies have revealed a crucial role of retinoid X receptor α (RXRα) in PML-RARα's tumorigenesis. This necessitates the development of dual RARα and RXRα targeting compounds for treating APL. Here, we developed a pair of brominated retinoid isomers, 5a and 5b, exhibiting RARα agonistic selectivity among the RAR subtypes and RXRα partial agonistic activities. In the treatment of APL cells, low doses (RARα activation range) of 5a and 5b degrade PML-RARα and strongly induce differentiation, while higher doses (RXRα activation range) induce G2/M arrest and apoptosis in both all-trans retinoic acid (ATRA)-sensitive and resistant cells. We replaced the bromine in 5a with chlorine or iodine to obtain compounds 7 or 8a. Interestingly, the chlorinated compound 7 tends to activate RXRα and induce G2/M arrest and apoptosis, while the iodinated compound 8a tends to activate RARα and induce differentiation. Together, our work underscores several advantages and characteristics of halogens in the rational design of RARα and RXRα ligands, offering three promising drug candidates for treating both ATRA-sensitive and resistant APL.
RESUMEN
The comprehensive analysis of single or multiple microarray datasets is currently available in Gene Expression Omnibus (GEO) databases, with several studies having identified genes strongly associated with the development of lung adenocarcinoma (LUAD). However, the mechanisms of LUAD development remain largely unknown and has not yet been systematically studied; thus, further studies are required in this field. In the present study, weighted gene co-expression network analysis (WGCNA) was used for the evaluation of key genes with potential high risk of LUAD, and to provide more reliable evidence concerning its pathogenesis. The GSE140797 dataset from the high-throughput GEO database was downloaded and was first analyzed using the Limma package in the R language in order to determine the differentially expressed genes. The dataset was then analyzed using the WGCNA package to analyze the co-expressed genes, and the modular genes with the highest correlation with the clinical phenotype were identified. Subsequently, the pathogenic genes shared in common between the result of the two analyses were imported into the STRING database for protein-protein interaction network analysis. The hub genes were screened out using Cytoscape, and then The Cancer Genome Atlas analysis, receiver operating characteristic analysis and survival analysis were subsequently performed. Finally, the key genes were evaluated using reverse transcription-quantitative PCR and western blot analysis. Bioinformatics analysis of the GSE140797 dataset revealed eight key genes: AURKA, BUB1, CCNB1, CDK1, MELK, NUSAP1, TOP2A and PBK. Finally, the AURKA, TOP2A and MELK genes were evaluated in samples from patients with lung cancer using WGCNA and RT-qPCR, western blot analysis experiments, providing basis for further research on the mechanisms of LUAD development and targeted therapy.
RESUMEN
In order to evaluate the elevated temperature creep performance of the ABOw/Al-12Si composite as a prospective piston crown material, the tensile creep behaviors and creep fracture mechanisms have been investigated in the temperatures range from 250 to 400 °C and the stress range from 50 to 230 MPa using a uniaxial tensile creep test. The creep experimental data can be explained by the creep constitutive equation with stress exponents of 4.03-6.02 and an apparent activation energy of 148.75 kJ/mol. The creep resistance of the ABOw/Al-12Si composite is immensely improved by three orders of magnitude, compared with the unreinforced alloy. The analysis of the ABOw/Al-12Si composite creep data revealed that dislocation climb is the main creep deformation mechanism. The values of the threshold stresses are 37.41, 25.85, and 17.36 at elevated temperatures of 300, 350 and 400 °C, respectively. A load transfer model was introduced to interpret the effect of whiskers on the creep rate of this composite. The creep test data are very close to the predicted values of the model. Finally, the fractographs of the specimens were analyzed by Scanning Electron Microscope (SEM), the fracture mechanisms of the composites at different temperatures were investigated. The results showed that the fracture characteristic of the ABOw/Al-12Si composite exhibited a macroscale brittle feature range from 300 to 400 °C, but a microscopically ductile fracture was observed at 400 °C. Additionally, at a low tensile creep temperature (300 °C), the plastic flow capacity of the matrix was poor, and the whisker was easy to crack and fracture. However, during tensile creep at a higher temperature (400 °C), the matrix was so softened that the whiskers were easily pulled out and interfacial debonding appeared.
RESUMEN
BACKGROUND: This study aimed to investigate the influence of CYP2D6 polymorphisms on risperidone plasma concentrations in patients with schizophrenia. Based on pharmacogenomics, we examined whether plasma concentration of risperidone is associated with clinical response and adverse side-effects. METHODS: We recruited patients with chronic schizophrenia who were then treated with risperidone. The CYP2D6 genotypes were determined using targeted sequencing. All high-frequency mutation sites of the nine exons of the gene were assayed in the present study. Plasma concentrations of risperidone and 9-hydroxyrisperidone (9-OH-RIS) were measured using high-performance liquid chromatography (HPLC). Psychiatric symptoms were monitored using The Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression (CGI). Adverse effects were evaluated using the Barnes Akathisia Scale (BAS) and Extrapyramidal Symptom Rating Scale (ESRS). Follow-up visits were scheduled at weeks 2,4, and 8 after treatment initiation. RESULTS: Among the 76 patients, 100 C > T (rs1065852), 1038 C > T (rs1081003), 1662 G > C (rs1058164), 2851 C > T (rs16947), and 4181G > C (rs1135840) variants were detected. The most common allele was CYP2D6*10 (81.6%), whereas CYP2D6*2 (9.2%) and CYP2D6*5 (17.1%) were relatively rare. Plasma levels of risperidone and the risperidone/9-OH risperidone ratio (R/9-OH) were significantly increased in individuals with CYP2D6*10 (P < 0.05). The change in PANSS score, weight, high-density lipoprotein (HDL) level, prolactin (PRL) level, and ESRS were significantly different from baseline, between the different genotypes (P < 0.01). Moreover, individuals with CYP2D6*10 homozygous (TT) mutations were associated with higher risperidone concentration and R/9-OH ratio than those with heterozygous mutations (CT) (P < 0.01). A change from baseline in BPRS scores was observed only during week 8 and was different between heterozygous and homozygous mutations. As for the C2851T polymorphism, the incidence of adverse metabolic effects was significantly different between the C/C and C/T genotypes (P < 0.01). Regarding the G4181C polymorphisms, the changes from baseline in GLU and TG, were different between the C/C and C/G genotypes (P < 0.01). CONCLUSIONS: The genotype of CYP2D6 significantly influences the plasma concentration of risperidone and may subsequently influence the adverse side-effects following risperidone treatment, while also exerting a slight influence on clinical outcomes.
Asunto(s)
Antipsicóticos , Risperidona , Antipsicóticos/uso terapéutico , Citocromo P-450 CYP2D6/genética , Humanos , Isoxazoles , Palmitato de Paliperidona , Plasma , Pirimidinas , Risperidona/uso terapéuticoRESUMEN
Tuberculosis (TB) remains a major worldwide health problem and has caused millions of deaths in the past few years. Current diagnostic methods, such as sputum smear microscopy and sputum culture, are time-consuming and cannot prevent the rapid spreading of TB during the diagnostic period. In this connection, detecting biomarkers specific to TB at molecular level in plasma of patients will provide a rapid means for diagnosis. In this study, we first evaluated the differential expression of the long non-coding RNAs (lncRNAs) in the plasma from patients with TB (TB positive), community acquired pneumonia (CAP) and healthy individuals (CG) using lncRNA microarray scanning. It was found that there were 2116 specific lncRNAs differentially expressed in the TB positive samples (1102 up-regulated and 1014 down-regulated), which accounted for 6.96% of total lncRNAs. Twelve differentially expressed lncRNAs discovered in microarray were subsequently validated by using real-time quantitative PCR (RT-qPCR). Two lncRNAs (ENST00000354432 and ENST00000427151) were further validated with more Tuberculosis samples. These results suggested the expression level of lncRNAs and the two validated lncRNAs in plasma could be the potential molecular biomarkers for the rapid diagnosis of Tuberculosis.
Asunto(s)
Perfilación de la Expresión Génica/métodos , Mycobacterium tuberculosis/patogenicidad , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Largo no Codificante/genética , Tuberculosis Pulmonar/diagnóstico , Estudios de Casos y Controles , Diagnóstico Diferencial , Marcadores Genéticos , Interacciones Huésped-Patógeno , Humanos , Mycobacterium tuberculosis/aislamiento & purificación , Valor Predictivo de las Pruebas , ARN Largo no Codificante/sangre , Reacción en Cadena en Tiempo Real de la Polimerasa , Reproducibilidad de los Resultados , Esputo/microbiología , Transcriptoma , Tuberculosis Pulmonar/sangre , Tuberculosis Pulmonar/microbiología , Flujo de TrabajoRESUMEN
Four enterovirus D68 (EV-D68) strains from four children with influenza-like illness were identified in Shenzhen, southern China, in late 2015. Here, we announce the availability of these viral genomes in GenBank. The genomic sequences of these EV-D68 strains showed the closest phylogenetic relationship to strains from northern China.
RESUMEN
Several studies have reported a positive association between caesarean section for expeditious pregnancy termination and perinatal outcomes in acute fatty liver of pregnancy (AFLP); however, the risks remain unclear and independent studies have reported conflicting findings. In this meta-analysis, we aimed to confirm the relationship between caesarean section and perinatal outcomes in AFLP. The PubMed, Embase, and China National Knowledge Infrastructure databases were searched (until July 17, 2015) for observational clinical studies focusing on the association between caesarean section and perinatal outcomes in AFLP. Data were extracted and processed independently by 2 authors. We also compared caesarean section with vaginal delivery to further investigate this relationship. We observed that 2 of the 3 primary outcomes in caesarean section exhibited positive effects-the maternal mortality rate was 44% lower (relative risk [RR], 0.56 [0.41-0.76]) and perinatal mortality rate was also reduced (RR, 0.52 [0.38-0.71]), compared to those for vaginal delivery. We did not find any associations between caesarean section and perinatal outcomes in AFLP in terms of neonatal mortality type and maternal multiple organ complications. These findings emphasise the significant prognostic value and clinical implications of caesarean section in AFLP, and suggest that the adverse outcomes should be reduced.
Asunto(s)
Cesárea/efectos adversos , Hígado Graso/complicaciones , Hígado Graso/diagnóstico , Complicaciones del Embarazo/diagnóstico , Resultado del Embarazo , Adolescente , Adulto , China , Femenino , Humanos , Recién Nacido , Mortalidad Perinatal , Embarazo , Pronóstico , Resultado del Tratamiento , Adulto JovenRESUMEN
In this paper, we report the development of a protein microarray-based biosensor for the detection of the hepatitis B virus (HBV) serological markers using surface plasmon resonance (SPR Printing buffer, protein immobilization time and concentration of the capture protein were optimized systematically to determine the best performance of the biosensor. Under optimal conditions, five hepatitis B markers in 20 µL human serum can be simultaneously detected within 30 minutes, whereas other methods such as ELISA and PCR can detect only one marker within four hours. This platform has been validated by analysis of 35 patients known to have hepatitis B, with 85% agreement between the test platform and analysis by commercial enzyme-linked immunosorbent assay (ELISA) kits. The results demonstrate that the protein microarray with SPR displayed a sensitivity of 0.1 ng mL(-1) for HBsAg. In addition to high sensitivity, it also shows excellent specificity, reproducibility and stability. This integrated protein microarray technique combined with SPR is a promising candidate for hepatitis B diagnosis with high-throughput.
Asunto(s)
Virus de la Hepatitis B/aislamiento & purificación , Hepatitis B/sangre , Hepatitis B/diagnóstico , Resonancia por Plasmón de Superficie/métodos , Anticuerpos Inmovilizados/química , Biomarcadores/sangre , Ensayo de Inmunoadsorción Enzimática , Antígenos de Superficie de la Hepatitis B/sangre , Humanos , Inmunoensayo/métodos , Límite de Detección , Análisis por Matrices de Proteínas , Reproducibilidad de los ResultadosRESUMEN
A surface plasmon resonance (SPR)-based biosensor was developed for specific detection of nine common respiratory virus, including influenza A and influenza B, H1N1, respiratory syncytial virus (RSV), parainfluenza virus 1-3 (PIV1, 2, 3), adenovirus, and severe acute respiratory syndrome coronavirus (SARS). The SPR biosensor was developed by immobilizing nine respiratory virus-specific oligonucleotides in an SPR chip. To increase the biosensor sensitivity, biotin was used to label the PCR primer and further amplify the signal by introducing streptavidin after hybridization. Throat swab specimens representing nine common respiratory viruses were tested by the innovative SPR-based biosensor to evaluate the sensitivity, specificity and reproducibility of this method. Results suggest that this biosensor has the potential to simultaneously identify common respiratory viruses.
Asunto(s)
Adenoviridae/aislamiento & purificación , Betainfluenzavirus/aislamiento & purificación , Virus de la Influenza A/aislamiento & purificación , Virus Sincitiales Respiratorios/aislamiento & purificación , Respirovirus/aislamiento & purificación , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/aislamiento & purificación , Resonancia por Plasmón de Superficie/métodos , Adenoviridae/genética , Infecciones por Adenoviridae/diagnóstico , Infecciones por Adenoviridae/virología , Humanos , Subtipo H1N1 del Virus de la Influenza A/genética , Subtipo H1N1 del Virus de la Influenza A/aislamiento & purificación , Virus de la Influenza A/genética , Gripe Humana/diagnóstico , Gripe Humana/virología , Betainfluenzavirus/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Infecciones por Virus Sincitial Respiratorio/diagnóstico , Infecciones por Virus Sincitial Respiratorio/virología , Virus Sincitiales Respiratorios/genética , Respirovirus/genética , Infecciones por Respirovirus/diagnóstico , Infecciones por Respirovirus/virología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/genética , Sensibilidad y Especificidad , Síndrome Respiratorio Agudo Grave/diagnóstico , Síndrome Respiratorio Agudo Grave/virologíaRESUMEN
We report the design of a polyrotaxane surface for biosensor applications. The results show that a three-fold improvement in immobilization and hybridization efficiency has been achieved compared to PEG SAM. The results confirm that polyrotaxane is a very promising platform candidate for biosensor applications.
RESUMEN
The aim of this study was to build a gene chip system with surface plasmon resonance (SPR) technique, for which Gamma-peptide nucleic acid (Gamma-PNA) functioned as a probe, in order to improve sensitivity and its specificity. With the use of self-assembled monolayer (SAM) technology, surface chemistry of two-dimensional structure was used. Gamma-PNA was designed according to the bioinformatics, and was plated on the SPR chip modified by SAM. Subsequently, relevant parameters of the experiment were ensured and optimized. The results showed that the performances of Gamma-PNA probe was little affected by the ion concentration of buffer, and it had a strong light signal in a stable state. As the ion concentration was 0, there were still good hybrid reactions; pH value had less influence upon Gamma-PNA probe, and acid environment of buffer could be better. Gamma-PNA probe combined with sensor technologies achieved made the probe with dispensable labels and real-time detection. It also improved the efficiency of the hybridization and the stability, providing the foundation for clinical application.