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A comprehensive approach for the construction of NIR-I/NIR-II nanofluorophores with exceptional brightness and excellent chemo- and photostability has been developed. This study first confirmed that the amphiphilic molecules with stronger hydrophobic moieties and weaker hydrophilic moieties are superior candidates for constructing brighter nanofluorophores, which are attributed to its higher efficiency in suppressing the intramolecular charge transfer/aggregation-caused fluorescence quenching of donor-acceptor-donor type fluorophores. The prepared nanofluorophore demonstrates a fluorescence quantum yield exceeding 4.5% in aqueous solution and exhibits a strong NIR-II tail emission up to 1300 nm. The superior performance of the nanofluorophore enabled the achievement of high-resolution whole-body vessel imaging and brain vessel imaging, as well as high-contrast fluorescence imaging of the lymphatic system in vivo. Furthermore, their potential for highly sensitive fluorescence detection of tiny tumors in vivo has been successfully confirmed, thus supporting their future applications in precise fluorescence imaging-guided surgery in the early stages of cancer.
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Neoplasias , Humanos , Neoplasias/patología , Colorantes Fluorescentes/química , Imagen Óptica/métodos , Espectroscopía Infrarroja Corta/métodosRESUMEN
BACKGROUND: Given the significant role of immune-related genes in uterine corpus endometrial carcinoma (UCEC) and the long-term outcomes of patients, our objective was to develop a prognostic risk prediction model using immune-related genes to improve the accuracy of UCEC prognosis prediction. METHODS: The Limma, ESTIMATE, and CIBERSORT methods were used for cluster analysis, immune score calculation, and estimation of immune cell proportions. Univariate and multivariate analyses were utilized to develop a prognostic risk model for UCEC. Risk model scores and nomograms were used to evaluate the models. String constructs a protein-protein interaction (PPI) network of genes. The qRT-PCR, immunofluorescence, and immunohistochemistry (IHC) all confirmed the genes. RESULTS: Cluster analysis divided the immune-related genes into four subtypes. 33 immune-related genes were used to independently predict the prognosis of UCEC and construct the prognosis model and risk score. The analysis of the survival nomogram indicated that the model has excellent predictive ability and strong reliability for predicting the survival of patients with UCEC. The protein-protein interaction network analysis of key genes indicates that four genes play a pivotal role in interactions: GZMK, IL7, GIMAP, and UBD. The quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence, and immunohistochemistry (IHC) all confirmed the expression of the aforementioned genes and their correlation with immune cell levels. This further revealed that GZMK, IL7, GIMAP, and UBD could potentially serve as biomarkers associated with immune levels in endometrial cancer. CONCLUSION: The study identified genes related to immune response in UCEC, including GZMK, IL7, GIMAP, and UBD, which may serve as new biomarkers and therapeutic targets for evaluating immune levels in the future.
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Neoplasias Endometriales , Nomogramas , Femenino , Humanos , Neoplasias Endometriales/genética , Neoplasias Endometriales/inmunología , Neoplasias Endometriales/patología , Pronóstico , Medición de Riesgo/métodos , Mapas de Interacción de Proteínas/genética , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Análisis por ConglomeradosRESUMEN
BACKGROUND: Endometrial carcinoma (EC) is a common malignant tumor of the female reproductive system, often accompanied by lymph node metastasis. Artificial vascular implantation is a common surgical treatment for mediastinal tumors and abdominal aortic aneurysms but is rarely used in gynecological surgery. CASE PRESENTATION: A 54-year-old female patient was first admitted to the hospital in January 2018 due to "irregular vaginal bleeding over 3 months". CT showed a mass in the uterine cavity, and several swollen lymph nodes in the retroperitoneum and pelvic cavity. The initial diagnosis was an endometrial malignant tumor. We performed radical endometrial cancer surgery with parallel resection of inferior vena cava, abdominal aorta, bilateral common iliac arteries, bilateral external iliac arteries, and artificial vessel replacement, which was successful, with good postoperative recovery and no lesion progression at 3 years postoperative follow-up. CONCLUSION: This is an early case of gynecological clinical use of prostheses. Through multidisciplinary cooperation, the surgical resection rate of patients with EC in radical surgery was improved without serious fatal complications and achieved a high long-term postoperative survival rate.
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Aorta Abdominal , Neoplasias Endometriales , Humanos , Femenino , Persona de Mediana Edad , Aorta Abdominal/diagnóstico por imagen , Aorta Abdominal/cirugía , Aorta Abdominal/patología , Arteria Ilíaca/cirugía , Arteria Ilíaca/patología , Vena Cava Inferior/cirugía , Vena Cava Inferior/patología , Escisión del Ganglio Linfático , Neoplasias Endometriales/cirugía , Neoplasias Endometriales/patologíaRESUMEN
Viruses such as human cytomegalovirus (HCMV), human papillomavirus (HPV), Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), and coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) represent a great burden to human health worldwide. FDA-approved anti-parasite drug ivermectin is also an antibacterial, antiviral, and anticancer agent, which offers more potentiality to improve global public health, and it can effectively inhibit the replication of SARS-CoV-2 in vitro. This study sought to identify ivermectin-related virus infection pathway alterations in human ovarian cancer cells. Stable isotope labeling by amino acids in cell culture (SILAC) quantitative proteomics was used to analyze human ovarian cancer cells TOV-21G treated with and without ivermectin (20 µmol/L) for 24 h, which identified 4447 ivermectin-related proteins in ovarian cancer cells. Pathway network analysis revealed four statistically significant antiviral pathways, including HCMV, HPV, EBV, and HIV1 infection pathways. Interestingly, compared with the reported 284 SARS-CoV-2/COVID-19-related genes from GencLip3, we identified 52 SARS-CoV-2/COVID-19-related protein alterations when treated with and without ivermectin. Protein-protein network (PPI) was constructed based on the interactions between 284 SARS-CoV-2/COVID-19-related genes and between 52 SARS-CoV-2/COVID-19-related proteins regulated by ivermectin. Molecular complex detection analysis of PPI network identified three hub modules, including cytokines and growth factor family, MAP kinase and G-protein family, and HLA class proteins. Gene Ontology analysis revealed 10 statistically significant cellular components, 13 molecular functions, and 11 biological processes. These findings demonstrate the broad-spectrum antiviral property of ivermectin benefiting for COVID-19 treatment in the context of predictive, preventive, and personalized medicine in virus-related diseases.
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Antivirales/farmacología , Tratamiento Farmacológico de COVID-19 , Ivermectina/farmacología , Línea Celular Tumoral , Humanos , Proteómica/métodos , SARS-CoV-2RESUMEN
T lymphocytes are key cellular components of an acquired immune system and play essential roles in cell-mediated immunity. T cell development occurs in the thymus where 95% of immature thymocytes are eliminated via apoptosis. It is known that mutation of Zeb1, one of the retinoblastoma 1 (Rb1) target genes, results in a decrease in the number of immature T cells in mice. E2F1, an RB1-interacting protein, has been shown to regulate mature T cell development by interfering with thymocyte apoptosis. However, whether Rb1 regulates thymocyte development in vivo still needs to be further investigated. Here, we use a zebrafish model to investigate the role of Rb1 in T cell development. We show that Rb1-deficient fish exhibit a significant reduction in T cell number during early development that it is attributed to the accelerated apoptosis of immature T cells in a caspase-dependent manner. We further show that E2F1 overexpression could mimic the reduced T lymphocytes phenotype of Rb1 mutants, and E2F1 knockdown could rescue the phenotype in Rb1-deficient mutants. Collectively, our data indicate that the Rb1-E2F1-caspase axis is crucial for protecting immature T cells from apoptosis during early T lymphocyte maturation.
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Apoptosis/fisiología , Factor de Transcripción E2F1/metabolismo , Proteína de Retinoblastoma/metabolismo , Linfocitos T/metabolismo , Pez Cebra/metabolismo , Animales , Factor de Transcripción E2F1/genética , Proteína de Retinoblastoma/genética , Linfocitos T/citología , Pez Cebra/genética , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismoRESUMEN
Glioblastoma (GBM) is the most malignant primary brain tumor in adults. Due to its invasive nature, it cannot be thoroughly eliminated. WD repeat domain 12 (WDR12) processes the 32S precursor rRNA but cannot affect the synthesis of the 45S/47S primary transcript. In this study, we found that WDR12 is highly expressed in GBM according to the analysis results of mRNA expression by The Cancer Genome Atlas database. The high expression level of WDR12 is dramatically related to shorter overall survival and reduced disease-free survival. Next, we knocked down WDR12 and found that knockdown of WDR12 promoted the apoptosis and inhibited the proliferation by cell biology experiments. Differential expression genes in gene-chip revealed that WDR12 knockdown mainly inhibited cell cycle. Finally, we also found that WDR12 is associated with PLK1 and EZH2 in cell proliferation of GBM. Resumptively, this report showed a possible evidence that WDR12 drove malignant behavior of GBM, whose expression may present a neoteric independent prognostic biomarker in GBM.
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Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Glioblastoma/genética , Oncogenes/genética , Proteínas de Unión al ARN/genética , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular/genética , Genómica/métodos , Glioblastoma/patología , Humanos , Pronóstico , ARN Mensajero/genéticaRESUMEN
SUMMARY: We present a web server, GenCLiP 3, which is an updated version of GenCLiP 2.0 to enhance analysis of human gene functions and regulatory networks, with the following improvements: i) accurate recognition of molecular interactions with polarity and directionality from the entire PubMed database; ii) support for Boolean search to customize multiple-term search and to quickly retrieve function related genes; iii) strengthened association between gene and keyword by a new scoring method; and iv) daily updates following literature release at PubMed FTP. AVAILABILITY: The server is freely available for academic use at: http://ci.smu.edu.cn/genclip3/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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PURPOSE: The aim of this study was to investigate the role of miR-33-5p in abdominal aortic aneurysm progression, which regulated adenosine triphosphate-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux and lipid accumulation in THP-1 macrophage-derived foam cells through the PI3K/Akt pathway. METHODS: Quantitative reverse transcription polymerase chain reaction was used to evaluate the expression level of miR-33-5p and ABCA1 mRNA in abdominal aortic aneurysm patient and normal person tissues. The relationship between miR-33-5p and ABCA1 was examined by dual luciferase report assay. High-performance liquid chromatography was used to evaluate the levels of cholesterol contents. Cholesterol efflux detection was performed by liquid scintillator. The expression of inflammatory cytokines was detected by quantitative reverse transcription polymerase chain reaction. Western blot was applied to determine the expression levels of ABCA1, PI3K (p-PI3K), and Akt (p-Akt). RESULTS: The quantitative reverse transcription polymerase chain reaction analysis results revealed miR-33-5p overexpression in abdominal aortic aneurysm tissues, but the expression level of ABCA1 was lower in abdominal aortic aneurysm tissues than non-abdominal aortic aneurysm tissues. Subsequently, the dual luciferase report gene assay confirmed that ABCA1 was a target of miR-33-5p, and miR-33-5p-negative regulated ABCA1 expression. Moreover, the expression levels of p-PI3K, p-Akt, and ABCA1 were decreased in THP-1 cell transferred with ABCA1 siRNA, but knockdown of miR-33-5p had an opposite effect. Furthermore, knockdown of miR-33-5p decreased the expression of MMP-2, MMP-9, TNF-α, total cellular cholesterol, and promoted cholesterol efflux in THP-1-derived foam cells. Importantly, LY294002 (PI3K inhibitor) or si-ABCA1 completely inhibited the stimulatory effects of miR-33-5p inhibitor. CONCLUSION: This study has found that knockdown of miR-33-5p induced ABCA1 expression and promoted inflammatory cytokines and cholesterol efflux likely via activating the PI3K/Akt signaling pathway.
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Transportador 1 de Casete de Unión a ATP/metabolismo , Aorta Abdominal/enzimología , Aneurisma de la Aorta Abdominal/prevención & control , Células Espumosas/enzimología , Técnicas de Silenciamiento del Gen , MicroARNs/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Anciano , Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/enzimología , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/patología , Estudios de Casos y Controles , Colesterol/metabolismo , Citocinas/metabolismo , Progresión de la Enfermedad , Femenino , Células Espumosas/patología , Humanos , Mediadores de Inflamación/metabolismo , Masculino , MicroARNs/genética , Persona de Mediana Edad , Transducción de Señal , Células THP-1 , Regulación hacia ArribaRESUMEN
Neutrophils are the key effectors for generating innate immunity in response to pathogenic infection and tissue injury in vertebrates. Dysregulation of neutrophil development and function is known to associate with various human disorders. Yet, the genetic network that orchestrates lineage commitment, differentiation, and maturation of neutrophils remains incompletely defined. Here, we present an in vivo study to delineate the genetic program underlying neutrophil development during zebrafish embryonic myelopoiesis. We show that loss of c-Myb function has no effect on macrophages but severely impairs neutrophil terminal differentiation, resulting in the accumulation of neutrophils with unsegmented nuclei and scant granule. This neutrophilic defect, which resembles the neutrophil-specific granule deficiency (SGD) caused by the mutations in CCAAT/enhancer-binding protein ε (C/EBPε) in humans, is attributed, at least in part, to the downregulation of the granule protein transcription. Likewise, genetic inactivation of Cebp1, the zebrafish functional homolog of mammalian C/EBPε, also leads to a similar SGD-like phenotype in zebrafish. Genetic epistasis and biochemical analysis further reveals that c-Myb and Cebp1 act in parallel and cooperatively to control neutrophil differentiation by directly regulating granule protein gene transcription. Our study indicates that c-MYB is an intrinsic master regulator for neutrophil terminal differentiation and a potential target in SGD patients.
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Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Diferenciación Celular/fisiología , Neutrófilos/metabolismo , Proteínas Proto-Oncogénicas c-myb/metabolismo , Proteínas de Pez Cebra/metabolismo , Pez Cebra/metabolismo , Animales , Animales Modificados Genéticamente , Proteínas Potenciadoras de Unión a CCAAT/genética , Neutrófilos/citología , Proteínas Proto-Oncogénicas c-myb/genética , Pez Cebra/genética , Proteínas de Pez Cebra/genéticaRESUMEN
Neutrophils play essential roles in innate immunity and are the first responders to kill foreign micro-organisms, a function that partially depends on their granule content. The complicated regulatory network of neutrophil development and maturation remains largely unknown. Here we utilized neutrophil-deficient zebrafish to identify a novel role of Alas1, a heme biosynthesis pathway enzyme, in neutrophil development. We showed that Alas1-deficient zebrafish exhibited proper neutrophil initiation, but further neutrophil maturation was blocked due to heme deficiency, with lipid storage and granule formation deficiencies, and loss of heme-dependent granule protein activities. Consequently, Alas1-deficient zebrafish showed impaired bactericidal ability and augmented inflammatory responses when challenged with Escherichia coli These findings demonstrate the important role of Alas1 in regulating neutrophil maturation and physiological function through the heme. Our study provides an in vivo model of Alas1 deficiency and may be useful to evaluate the progression of heme-related disorders in order to facilitate the development of drugs and treatment strategies for these diseases.
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5-Aminolevulinato Sintetasa , Neutrófilos/inmunología , Proteínas de Pez Cebra , Pez Cebra , 5-Aminolevulinato Sintetasa/genética , 5-Aminolevulinato Sintetasa/inmunología , Animales , Escherichia coli/genética , Escherichia coli/inmunología , Infecciones por Escherichia coli/genética , Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/patología , Enfermedades de los Peces/genética , Enfermedades de los Peces/inmunología , Enfermedades de los Peces/microbiología , Enfermedades de los Peces/patología , Hemo/genética , Hemo/inmunología , Neutrófilos/patología , Pez Cebra/inmunología , Pez Cebra/microbiología , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/inmunologíaRESUMEN
Dentin dysplasia type I (DDI) is an autosomal-dominant genetic disorder resulting from dentin defects. The molecular basis of DDI remains unclear. DDI exhibits unique characteristics with phenotypes featuring obliteration of pulp chambers and diminutive root, thus providing a useful model for understanding the genetics of tooth formation. Using a large Chinese family with 14 DDI patients, we mapped the gene locus responsible for DDI to 3p26.1-3p24.3 and further identified a missense mutation, c.353C>A (p.P118Q) in the SSUH2 gene on 3p26.1, which co-segregated with DDI. We showed that SSUH2 (p.P118Q) perturbed the structure and significantly reduced levels of mutant (MT) protein and mRNA compared with wild-type SSUH2. Furthermore, MT P141Q knock-in mice (+/- and -/-) had a unique partial obliteration of the pulp cavity and upregulation or downregulation of six major genes involved in odontogenesis: Dspp, Dmp1, Runx2, Pax9, Bmp2, and Dlx2. The phenotype of missing teeth was determined in zebrafish with morpholino gene knockdowns and rescued by injection of normal human mRNA. Taken together, our observations demonstrate that SSUH2 disrupts dental formation and that this novel gene, together with other odontogenesis genes, is involved in tooth development.
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Displasia de la Dentina/diagnóstico , Displasia de la Dentina/genética , Genes Dominantes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Chaperonas Moleculares/genética , Mutación , Adolescente , Adulto , Animales , Niño , Preescolar , Mapeo Cromosómico , Análisis Mutacional de ADN , Femenino , Técnicas de Silenciamiento del Gen , Ligamiento Genético , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Ratones , Ratones Transgénicos , Repeticiones de Microsatélite , Chaperonas Moleculares/química , Chaperonas Moleculares/metabolismo , Linaje , Fenotipo , Radiografía , Adulto Joven , Pez CebraRESUMEN
BACKGROUND: Dentin dysplasia I (DDI) is a genetically heterogeneous autosomal-dominant disorder characterised by rootless teeth with abnormal pulpal morphology, the aetiology of which presents as genetically heterogeneous. METHODS AND RESULTS: Using a cohort of a large Chinese family with 10 patients with DDI, we mapped to a 9.63â Mb candidate region for DDI on chromosome 18q21.2-q21.33. We then identified a mutation IVS7+46C>G which resulted in a novel donor splice site in intron 7 of the VPS4B gene with co-segregation of all 10 affected individuals in this family. The aberrant transcripts encompassing a new insert of 45â bp in size were detected in gingival cells from affected individuals. Protein structure prediction showed that a 15-amino acid insertion altered the ATP-binding cassette of VPS4B. The mutation resulted in significantly reduced expression of mRNA and protein and altered subcellular localisation of VPS4B, indicating a loss of function of VPS4B. Using human gingival fibroblasts, the VPS4B gene was found to act as an upstream transducer linked to Wnt/ß-catenin signalling and regulating odontogenesis. Furthermore, knockdown of vps4b in zebrafish recapitulated the reduction of tooth size and absence of teeth similar to the tooth phenotype exhibited in DDI index cases, and the zebrafish mutant phenotype could be partially rescued by wild-type human VPS4B mRNA. We also observed that vps4b depletion in the zebrafish negatively regulates the expression of some major genes involved in odontogenesis. CONCLUSIONS: This study identifies VPS4B as a disease-causing gene for DDI, which is one of the important contributors to tooth formation, through the Wnt/ß-catenin signalling pathway.
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Adenosina Trifosfatasas/genética , Displasia de la Dentina/genética , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Mutación/genética , Empalme del ARN/genética , ATPasas Asociadas con Actividades Celulares Diversas , Animales , Pueblo Asiatico/genética , Secuencia de Bases , Femenino , Fibroblastos/metabolismo , Humanos , Masculino , Odontogénesis/genética , Linaje , Sitios de Empalme de ARN/genética , ARN Mensajero/genética , Vía de Señalización Wnt/genética , Pez Cebra/genética , beta Catenina/genéticaRESUMEN
BACKGROUND: As the most common type of aneurysm, abdominal aortic aneurysm (AAA) has an unfavorable prognosis due to the high frequency of rupture. Studies have indicated a close relationship between the pathogenesis and progression of AAA and abnormal serum lipid levels. ATP-binding cassette transport protein A1 (ABCA1) is a cell-surface protein facilitating cellular efflux of cholesterol. The single-nucleotide polymorphism (SNP) of ABCA1 gene has been suggested to be correlated with abnormal metabolism of lipids. Therefore, this study aimed to investigate the relationship between ABCA1 polymorphism and apoA-I and HDL-C in an attempt to elucidate its correlation with AAA occurrence. MATERIAL/METHODS: We included 126 AAA patients and 119 healthy controls in this study. PCR and restriction fragment length polymorphism (RFLP) were used to detect the SNP pattern of ABCA1 gene at locus rs2230806 from both AAA patients and healthy controls. The distribution pattern and correlation with apoA-I and HDL-C was analyzed. RESULTS: The distribution of KK/RR genotype of ABCA1 gene had significant difference between disease and control group, with lower rates of RR genotype and R allele in the disease group (p<0.05). Levels of apoA-I and HDL-C, but not triglyceride and LDL-C levels, in AAA patients who carried R allele in ABCA1 gene (including RR and RK genotypes) were higher than in non-carriers (p<0.05). The R allele of ABCA1 gene was shown to be related with the occurrence of AAA (p<0.05). CONCLUSIONS: Polymorphism of ABCA1 gene is correlated with AAA occurrence, possibly via the regulation of serum lipid metabolism by R allele.
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Transportador 1 de Casete de Unión a ATP/genética , Aneurisma de la Aorta Abdominal/sangre , Aneurisma de la Aorta Abdominal/genética , Apolipoproteína A-I/genética , HDL-Colesterol/sangre , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Niño , Femenino , Frecuencia de los Genes/genética , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
RNAi technology is taking strong position among the key therapeutic modalities, with dozens of siRNA-based programs entering and successfully progressing through clinical stages of drug development. To further explore potentials of RNAi technology as therapeutics, we engineered and tested VEGFR2 siRNA molecules specifically targeted to tumors through covalently conjugated cyclo(Arg-Gly-Asp-d-Phe-Lys[PEG-MAL]) (cRGD) peptide, known to bind αvß3 integrin receptors. cRGD-siRNAs were demonstrated to specifically enter and silence targeted genes in cultured αvß3 positive human cells (HUVEC). Microinjection of zebrafish blastocysts with VEGFR2 cRGD-siRNA resulted in specific inhibition of blood vessel growth. In tumor-bearing mice, intravenously injected cRGD-siRNA molecules generated no innate immune response and bio-distributed to tumor tissues. Continuous systemic delivery of two different VEGFR2 cRGD-siRNAs resulted in down-regulation of corresponding mRNA (55 and 45%) and protein (65 and 45%) in tumors, as well as in overall reduction of tumor volume (90 and 70%). These findings demonstrate strong potential of cRGD-siRNA molecules as anti-tumor therapy.
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Neoplasias/terapia , Péptidos Cíclicos/administración & dosificación , Interferencia de ARN , ARN Interferente Pequeño/administración & dosificación , Animales , Línea Celular Tumoral , Células Cultivadas , Femenino , Técnicas de Silenciamiento del Gen , Células HeLa , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias/irrigación sanguínea , Neovascularización Fisiológica , Péptidos Cíclicos/análisis , Péptidos Cíclicos/química , ARN Interferente Pequeño/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Pez Cebra/embriologíaRESUMEN
UNLABELLED: Identifying biological functions and molecular networks in a gene list and how the genes may relate to various topics is of considerable value to biomedical researchers. Here, we present a web-based text-mining server, GenCLiP 2.0, which can analyze human genes with enriched keywords and molecular interactions. Compared with other similar tools, GenCLiP 2.0 offers two unique features: (i) analysis of gene functions with free terms (i.e. any terms in the literature) generated by literature mining or provided by the user and (ii) accurate identification and integration of comprehensive molecular interactions from Medline abstracts, to construct molecular networks and subnetworks related to the free terms. AVAILABILITY AND IMPLEMENTATION: http://ci.smu.edu.cn. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Minería de Datos/métodos , Redes Reguladoras de Genes , Genes , Programas Informáticos , Análisis por Conglomerados , Humanos , Internet , MEDLINERESUMEN
OBJECTIVE: To explore the mechanisms of large-conductance calcium-activated potassium channel (BKCa) involved in inflammatory response in sepsis. METHODS: The serum levels of BKCa were measured by enzyme-linked immunosorbent assay (ELISA) in patients with sepsis (28 cases), patients with common infection (25 cases) and healthy people (25 cases). The relationship between levels of BKCa and acute physiology and chronic health evaluation II (APACHE II) were analyzed. Cultured RAW 264.7 cells were stimulated by lipopolysaccharide (LPS). In some experiments, a cell model of sepsis was constructed using Nigericin as the second stimulus signal. The mRNA and protein expressions of BKCa in RAW 264.7 cells stimulated with LPS (0, 50, 100, 1 000 µg/L) were measured by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and Western blotting. RAW 264.7 cells were transfected with small interfering RNA of BKCa (siRNA-BKCa), and the levels of caspase-1 precursor (pro-caspase-1), interleukin-1ß precursor (pro-IL-1ß) in cell, and the levels of caspase-1 p20, IL-1ß p17 of cell culture medium, and NOD-like receptor protein 3 (NLRP3), nuclear factor-κB (NF-κB) were measured by Western blotting. The apoptosis were detected by staining with propidium iodide (PI), the release rate of lactate dehydrogenase (LDH) were measured, and the expression of apoptotic protein Gasdermin D (GSDMD) was measured by Western blotting to evaluate the effect of silencing BKCa on cell pyrosis. RESULTS: The level of serum BKCa in patients with sepsis was significantly higher than that in patients with common infection and health peoples (ng/L: 165.2±25.9 vs. 102.5±25.9, 98.8±20.0, both P < 0.05). In addition, the level of serum BKCa in patients with sepsis was significantly positively correlated with APACHE II score (r = 0.453, P = 0.013). LPS could construct a sepsis cell model by which LPS could promote BKCa expression in mRNA and protein with a concentration-dependent manner. The mRNA and protein expressions of BKCa in the cells stimulated by 1 000 µg/L LPS were significantly higher than that in the blank group (0 µg/L) [BKCa mRNA (2-ΔΔCt): 3.00±0.36 vs. 1.00±0.16, BKCa/ß-actin: 1.30±0.16 vs. 0.37±0.09, both P < 0.05]. Compared with the control group, the ratios of caspase-1 p20/pro-caspase-1 and IL-1ß p17/pro-IL-1ß in the model group were significantly increased (caspase-1 p20/pro-caspase-1: 0.83±0.12 vs. 0.27±0.05, IL-1ß p17/pro-IL-1ß: 0.77±0.12 vs. 0.23±0.12, both P < 0.05), however, transfection of siRNA-BKCa induced the decrease both of them (caspase-1 p20/pro-capase-1: 0.23±0.12 vs. 0.83±0.12, IL-1ß p17/pro-IL-1ß: 0.13±0.05 vs. 0.77±0.12, both P < 0.05). Compared with the control group, the number of apoptotic cells, LDH release rate and GSDMD expression in the model group were significantly increased [LDH release rate: (30.60±8.40)% vs. (15.20±7.10)%, GSDMD-N/GSDMD-FL: 2.10±0.16 vs. 1.00±0.16, both P < 0.05], however, transfection of siRNA-BKCa induced the decrease both of them [LDH release rate: (15.60±7.30)% vs. (30.60±8.40)%, GSDMD-N/GSDMD-FL: 1.13±0.17 vs. 2.10±0.16, both P < 0.05]. The mRNA and protein expressions of NLRP3 in sepsis cells were significantly higher than those in the control group [NLRP3 mRNA (2-ΔΔCt): 2.06±0.17 vs. 1.00±0.24, NLRP3/GAPDH: 0.46±0.05 vs. 0.15±0.04, both P < 0.05]. However, the expression of NLRP3 after siRNA-BKCa transfection was significantly lower than that in model group [NLRP3 mRNA (2-ΔΔCt): 1.57±0.09 vs. 2.06±0.17, NLRP3/GAPDH: 0.19±0.02 vs. 0.46±0.05, both P < 0.05]. Compared with the control group, the NF-κB p65 nuclear transfer of sepsis cell were significantly increased (NF-κB p65/Histone: 0.73±0.12 vs. 0.23±0.09, P < 0.05). However, the NF-κB p65 expression in the nucleus were decreased after siRNA-BKCa transfection (NF-κB p65/Histone: 0.20±0.03 vs. 0.73±0.12, P < 0.05). CONCLUSIONS: BKCa is involved in the pathogenesis of sepsis, and its possible mechanism is to activate NF-κB/NLRP3/caspase-1 signaling pathway to induce inflammatory factor production and cell death.
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Histonas , Sepsis , Humanos , Caspasa 1 , Canales de Potasio de Gran Conductancia Activados por el Calcio , Lipopolisacáridos , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , L-Lactato Deshidrogenasa , ARN Interferente Pequeño , CaspasasRESUMEN
Objective: This study aims to establish a radiomics-based machine learning model that predicts the risk of transient ischemic attack in patients with mild carotid stenosis (30-50% North American Symptomatic Carotid Endarterectomy Trial) using extracted computed tomography radiomics features and clinical information. Methods: A total of 179 patients underwent carotid computed tomography angiography (CTA), and 219 carotid arteries with a plaque at the carotid bifurcation or proximal to the internal carotid artery were selected. The patients were divided into two groups; patients with symptoms of transient ischemic attack after CTA and patients without symptoms of transient ischemic attack after CTA. Then we performed random sampling methods stratified by the predictive outcome to obtain the training set (N = 165) and testing set (N = 66). 3D Slicer was employed to select the site of plaque on the computed tomography image as the volume of interest. An open-source package PyRadiomics in Python was used to extract radiomics features from the volume of interests. The random forest and logistic regression models were used to screen feature variables, and five classification algorithms were used, including random forest, eXtreme Gradient Boosting, logistic regression, support vector machine, and k-nearest neighbors. Data on radiomic feature information, clinical information, and the combination of these pieces of information were used to generate the model that predicts the risk of transient ischemic attack in patients with mild carotid artery stenosis (30-50% North American Symptomatic Carotid Endarterectomy Trial). Results: The random forest model that was built based on the radiomics and clinical feature information had the highest accuracy (area under curve = 0.879; 95% confidence interval, 0.787-0.979). The combined model outperformed the clinical model, whereas the combined model showed no significant difference from the radiomics model. Conclusion: The random forest model constructed with both radiomics and clinical information can accurately predict and improve discriminative power of computed tomography angiography in identifying ischemic symptoms in patients with carotid atherosclerosis. This model can aid in guiding the follow-up treatment of patients at high risk.
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A polymeric engineering design principle is proposed for the construction of small-sized (â¼20 nm) NIR-II AIEgen-doped nanodots (AIEdots) with high brightness and prolonged circulation time in blood vessels. With the utilization of the as-designed NIR-II AIEdots, the successful achievement of high-resolution NIR-II fluorescence imaging of tumor vessels and precise detection of abdominal metastases of ovarian cancer has been attained.
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Colorantes Fluorescentes , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/diagnóstico por imagen , Neoplasias Ováricas/patología , Imagen Óptica , PolímerosRESUMEN
Thermochromic fluorescent materials (TFMs) exhibit great potential in information encryption applications but are limited by low thermosensitivity, poor color tunability, and a wide temperature-responsive range. Herein, a novel strategy for constructing highly sensitive TFMs with tunable emission (450-650 nm) toward multilevel information encryption is proposed, which employs polarity-sensitive fluorophores with donor-acceptor-donor (D-A-D) type structures as emitters and long-chain alkanes as thermosensitive loading matrixes. The structure-function relationships between the performance of TFMs and the structures of both fluorescent emitters and phase-change molecules are systematically studied. Benefiting from the above design, the obtained TFMs exhibit over 9500-fold fluorescence enhancement toward the temperature change, as well as ultrahigh relative temperature sensitivity up to 80% K-1 , which are first confirmed. Thanks to the superior transducing performance, the above-prepared TFMs can be further developed as information-storage platforms within a relatively narrow interval of temperature variation, including temperature-dominated multicolored information display and multilevel information encryption. This work will not only provide a novel perspective for designing superior TFMs for information encryption but also bring inspiration to the design and preparation of other response-switching-type fluorescent probes with ultrahigh conversion efficiency.
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Correction for 'Conjugated polymer-based luminescent probes for ratiometric detection of biomolecules' by Lingfeng Zhao et al., J. Mater. Chem. B, 2022, https://doi.org/10.1039/d2tb00937d.