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1.
Medicine (Baltimore) ; 100(14): e24969, 2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33832071

RESUMEN

ABSTRACT: Pancreatic cancer has a very high mortality with a 5-year survival of <5%. The purpose of this study was to classify specific molecular subtypes associated with prognosis of pancreatic cancer using The Cancer Genome Atlas (TCGA) multiplatform genomic data.Multiplatform genomic data (N = 178), including gene expression, copy number alteration, and somatic mutation data, were obtained from cancer browser (https://genome-cancer.ucsc.edu, cohort: TCGA Pancreatic Cancer). Clinical data including survival results were analyzed. We also used validation cohort (GSE50827) to confirm the robustness of these molecular subtypes in pancreatic cancer.When we performed unsupervised clustering using TCGA gene expression data, we found three distinct molecular subtypes associated with different survival results. Copy number alteration and somatic mutation data showed different genomic patterns for these three subtypes. Ingenuity pathway analysis revealed that each subtype showed differentially altered pathways. Using each subtype-specific genes (200 were selected), we could predict molecular subtype in another cohort, confirming the robustness of these molecular subtypes of pancreatic cancer. Cox regression analysis revealed that molecular subtype is the only significant prognostic factor for pancreatic cancer (P = .042, 95% confidence interval 0.523-0.98).Genomic analysis of pancreatic cancer revealed 3 distinct molecular subtypes associated with different survival results. Using these subtype-specific genes and prediction model, we could predict molecular subtype associated with prognosis of pancreatic cancer.


Asunto(s)
Genómica/métodos , Neoplasias Pancreáticas/genética , Anciano , Biomarcadores de Tumor/genética , Variaciones en el Número de Copia de ADN , Bases de Datos Factuales , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/clasificación , Neoplasias Pancreáticas/mortalidad , Estudios Retrospectivos , Transducción de Señal
2.
Nat Commun ; 12(1): 2032, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33795670

RESUMEN

Adherent-invasive Escherichia coli (AIEC) are pathogenic bacteria frequently isolated from patients who have Crohn's disease (CD). Despite the phenotypic differences between AIEC and commensal E. coli, comparative genomic approaches have been unable to differentiate these two groups, making the identification of key virulence factors a challenge. Here, we conduct a high-resolution, in vivo genetic screen to map AIEC genes required for intestinal colonization of mice. In addition, we use in vivo RNA-sequencing to define the host-associated AIEC transcriptome. We identify diverse metabolic pathways required for efficient gut colonization by AIEC and show that a type IV secretion system (T4SS) is required to form biofilms on the surface of epithelial cells, thereby promoting AIEC persistence in the gut. E. coli isolated from CD patients are enriched for a T4SS, suggesting a possible connection to disease activity. Our findings establish the T4SS as a principal AIEC colonization factor and highlight the use of genome-wide screens in decoding the infection biology of CD-associated bacteria that otherwise lack a defined genetic signature.


Asunto(s)
Enfermedad de Crohn/patología , Escherichia coli/genética , Perfilación de la Expresión Génica/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Sistemas de Secreción Tipo IV/genética , Animales , Adhesión Bacteriana/genética , Biopelículas , Células CACO-2 , Enfermedad de Crohn/microbiología , Células Epiteliales/metabolismo , Células Epiteliales/microbiología , Escherichia coli/clasificación , Escherichia coli/fisiología , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/patología , Femenino , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Ratones Endogámicos C57BL , Factores de Virulencia/genética
3.
Nat Commun ; 12(1): 2038, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33795683

RESUMEN

Wild-type KRAS (KRASWT) amplification has been shown to be a secondary means of KRAS activation in cancer and associated with poor survival. Nevertheless, the precise role of KRASWT overexpression in lung cancer progression is largely unexplored. Here, we identify and characterize a KRAS-responsive lncRNA, KIMAT1 (ENSG00000228709) and show that it correlates with KRAS levels both in cell lines and in lung cancer specimens. Mechanistically, KIMAT1 is a MYC target and drives lung tumorigenesis by promoting the processing of oncogenic microRNAs (miRNAs) through DHX9 and NPM1 stabilization while halting the biogenesis of miRNAs with tumor suppressor function via MYC-dependent silencing of p21, a component of the Microprocessor Complex. KIMAT1 knockdown suppresses not only KRAS expression but also KRAS downstream signaling, thereby arresting lung cancer growth in vitro and in vivo. Taken together, this study uncovers a role for KIMAT1 in maintaining a positive feedback loop that sustains KRAS signaling during lung cancer progression and provides a proof of principle that interfering with KIMAT1 could be a strategy to hamper KRAS-induced tumorigenesis.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , MicroARNs/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , ARN Largo no Codificante/genética , Células A549 , Animales , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/terapia , Línea Celular Tumoral , Femenino , Perfilación de la Expresión Génica/métodos , Ontología de Genes , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
4.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809330

RESUMEN

Clematis plants play an important role in botanical gardens. Heat stress can destroy the activity, state and conformation of plant proteins, and its regulatory pathway has been well characterized in Arabidopsis and some crop plants. However, the heat resistance response mechanism in horticultural plants including Clematis has rarely been reported. Here, we identified a heat-tolerant clematis species, Clematis vitalba. The relative water loss and electrolytic leakage were significantly lower under heat treatment in Clematis vitalba compared to Stolwijk Gold. Differential expression heat-tolerant genes (HTGs) were identified based on nonparametric transcriptome analysis. For validation, one heat shock transcription factor, CvHSF30-2, extremely induced by heat stimuli in Clematis vitalba, was identified to confer tolerance to heat stress in Escherichia coli and Saccharomyces cerevisiae. Furthermore, silencing of HSF30-2 by virus-induced gene silencing (VIGS) led to heat sensitivity in tobacco and Clematis, suggesting that the candidate heat-resistant genes identified in this RNA-seq analysis are credible and offer significant utility. We also found that CvHSF30-2 improved heat tolerance of Clematis vitalba by elevating heat shock protein (HSP) expression, which was negatively regulated by CvHSFB2a. Taken together, this study provides insights into the mechanism of Clematis heat tolerance and the findings can be potentially applied in horticultural plants to improve economic efficiency through genetic approaches.


Asunto(s)
Clematis/genética , Factores de Transcripción del Choque Térmico/genética , Proteínas de Choque Térmico/genética , Proteínas de Plantas/genética , Arabidopsis/genética , Clematis/crecimiento & desarrollo , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica de las Plantas/genética , Respuesta al Choque Térmico/genética , Plantas Modificadas Genéticamente , Termotolerancia/genética , Tabaco/genética
5.
Medicine (Baltimore) ; 100(15): e25553, 2021 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-33847684

RESUMEN

BACKGROUND: Acute myocardial infarction (AMI) is a common disease leading threat to human health around the world. Here we aimed to explore new biomarkers and potential therapeutic targets in AMI through adopting integrated bioinformatics tools. METHODS: The gene expression Omnibus (GEO) database was used to obtain genes data of AMI and no-AMI whole blood. Furthermore, differentially expressed genes (DEGs) were screened using the "Limma" package in R 3.6.1 software. Functional and pathway enrichment analyses of DEGs were performed via "Bioconductor" and "GOplot" package in R 3.6.1 software. In order to screen hub DEGs, the STRING version 11.0 database, Cytoscape and molecular complex detection (MCODE) were applied. Correlation among the hub DEGs was evaluated using Pearson's correlation analysis. RESULTS: By performing DEGs analysis, 289 upregulated and 62 downregulated DEGs were successfully identified from GSE66360, respectively. And they were mainly enriched in the terms of neutrophil activation, immune response, cytokine, nuclear factor kappa-B (NF-κB) signaling pathway, IL-17 signaling pathway, and tumor necrosis factor (TNF) signaling pathway. Based on the data of protein-protein interaction (PPI), the top 10 hub genes were ranked, including interleukin-8 (CXCL8), TNF, N-formyl peptide receptor 2 (FPR2), growth-regulated alpha protein (CXCL1), transcription factor AP-1 (JUN), interleukin-1 beta (IL1B), platelet basic protein (PPBP), matrix metalloproteinase-9 (MMP9), toll-like receptor 2 (TLR2), and high affinity immunoglobulin epsilon receptor subunit gamma (FCER1G). What's more, the results of correlation analysis demonstrated that there was positive correlation between the 10 hub DEGs. CONCLUSION: Ten DEGs were identified as potential candidate diagnostic biomarkers for patients with AMI in present study. However, further experiments are needed to confirm the functional pathways and hub genes associated with AMI.


Asunto(s)
Biología Computacional/métodos , Perfilación de la Expresión Génica/métodos , Infarto del Miocardio/genética , Biomarcadores/análisis , Correlación de Datos , Citocinas/metabolismo , Bases de Datos Genéticas , Humanos , Inmunidad/genética , Activación Neutrófila/genética , Mapas de Interacción de Proteínas/genética , Transducción de Señal/genética
6.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-33806437

RESUMEN

Tiger nut (Cyperus esculentus), a perennial C4 plant of the Cyperaceae family, is an unconventional crop that is distinguished by its oil-rich tubers, which also possesses the advantages of strong resistance, wide adaptability, short life periods, and large biomass. To facilitate studies on gene expression in this species, we identified and validated a series of reference genes (RGs) based on transcriptome data, which can be employed as internal controls for qRT-PCR analysis in tiger nut. Fourteen putative candidate RGs were identified and evaluated across nine different tissues of two cultivars, and the RGs were analyzed using three different algorithms (geNorm, NormFinder, and BestKeeper). The stability rankings of the candidate RGs were merged into consensus lists with RankAggreg. For the below-ground storage organ of tiger nut, the optimal RGs were TUB4 and UCE2 in different developmental stages of tubers. UCE2 and UBL5 were the most stably expressed RGs among all tissues, while Rubisco and PGK exhibited the lowest expression stability. UCE2, UBL5 and Rubisco were compared to normalize the expression levels of the caleosin (CLO) and diacylglycerol acyltransferase 2-2 (DGAT2-2) genes across the same tissues. Our results showed that the RGs identified in this study, which exhibit more uniform expression patterns, may be utilized for the normalization of qRT-PCR results, promoting further research on gene expression in various tissues of tiger nut.


Asunto(s)
Cyperus/genética , Transcriptoma/genética , Proteínas de Unión al Calcio/genética , Cyperus/metabolismo , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica de las Plantas/genética , Aceites Vegetales/metabolismo , Proteínas de Plantas/genética , Tubérculos de la Planta/genética , Estándares de Referencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos
7.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33807564

RESUMEN

Ginkgo (Ginkgo biloba L.) is a deciduous tree species with high timber, medicinal, ecological, ornamental, and scientific values, and is widely cultivated worldwide. However, for such an important tree species, the regulatory mechanisms involved in the photosynthesis of developing leaves remain largely unknown. Here, we observed variations in light response curves (LRCs) and photosynthetic parameters (photosynthetic capacity (Pnmax) and dark respiration rate (Rd)) of leaves across different developmental stages. We found the divergence in the abundance of compounds (such as 3-phospho-d-glyceroyl phosphate, sedoheptulose-1,7-bisphosphate, and malate) involved in photosynthetic carbon metabolism. Additionally, a co-expression network was constructed to reveal 242 correlations between transcription factors (TFs) and photosynthesis-related genes (p < 0.05, |r| > 0.8). We found that the genes involved in the photosynthetic light reaction pathway were regulated by multiple TFs, such as bHLH, WRKY, ARF, IDD, and TFIIIA. Our analysis allowed the identification of candidate genes that most likely regulate photosynthesis, primary carbon metabolism, and plant development and as such, provide a theoretical basis for improving the photosynthetic capacity and yield of ginkgo trees.


Asunto(s)
Ginkgo biloba/genética , Metaboloma/genética , Fotosíntesis/genética , Transcriptoma/genética , Perfilación de la Expresión Génica/métodos , Hojas de la Planta/genética , Proteínas de Plantas/genética , Factores de Transcripción/genética
8.
Nat Commun ; 12(1): 1980, 2021 03 31.
Artículo en Inglés | MEDLINE | ID: mdl-33790300

RESUMEN

The majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these 'SLE-like' conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Perfilación de la Expresión Génica/métodos , Interferón Tipo I/inmunología , Lupus Eritematoso Sistémico/inmunología , Adulto , Anciano , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Femenino , Humanos , Interferón Tipo I/metabolismo , Interferón Tipo I/farmacología , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/metabolismo , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Redes y Vías Metabólicas/genética , Persona de Mediana Edad , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Mitocondrias/metabolismo , Adulto Joven
9.
Gene ; 786: 145626, 2021 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-33798682

RESUMEN

Viruses are abundant entities that infect almost every living organism. In recent years, Next Generation Sequencing coupled with bioinformatic analyses is widely adopted for identification of known and unknown viruses in a plant sample. In the present study, nine putative novel viruses were discovered from public domain transcriptome datasets of five endangered plant species by de novo assembly of reads using CLC and SPAdes followed by BLAST analysis. Of the identified viruses, ten coding-complete and five partial genomic segments were recovered. Based on phylogeny and BLAST analysis, the identified viruses were putatively assigned to various plant viral genera except dactylorhiza hatagirea benylike virus that probably represents a new group of plant virus. The methodology followed can be adopted for the discovery of novel viruses in plant species with little genomic information. Viral genome sequences recovered in the study will serve as a valuable resource for further characterization of identified viruses.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Virus de Plantas/clasificación , Virus de Plantas/aislamiento & purificación , Plantas/genética , China , Biología Computacional , Especies en Peligro de Extinción , Secuenciación de Nucleótidos de Alto Rendimiento , India , Filogenia , Virus de Plantas/genética , Plantas/virología , Análisis de Secuencia de ARN
10.
Gene ; 786: 145625, 2021 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-33798683

RESUMEN

BACKGROUND: Mounting evidences suggested that anlotinib exhibits effective anti-tumor activity in various cancer types, such as lung cancer, glioblastoma and medullary thyroid cancer. However, its function in colon cancer remains to be further revealed. METHODS: Colon cancer cells (HCT-116) were treated with or without anlotinib. Transcript and metabolite data were generated through RNA sequencing and liquid chromatography-tandem mass spectrometry, respectively. The integrated analysis transcriptomics and metabolomics was conducted using R programs and online tools, including ClusterProfiler R program, GSEA, Prognoscan and Cytoscape. RESULTS: We found that differentially expressed genes (DEGs) were mainly involved in metabolic pathways and ribosome pathway. Structural maintenance of chromosome 3 (SMC3), Topoisomerase II alpha (TOP2A) and Glycogen phosphorylase B (PYGB) are the most significant DEGs which bring poor clinical prognosis in colon cancer. The analysis of metabolomics presented that most of the differentially accumulated metabolites (DAMs) were amino acids, such as L-glutamine, DL-serine and aspartic acid. The joint analysis of DEGs and DAMs showed that they were mainly involved in protein digestion and absorption, ABC transporters, central carbon metabolism, choline metabolism and Gap junction. Anlotinib affected protein synthesis and energy supporting of colon cancer cells by regulating amino acid metabolism. CONCLUSIONS: Anlotinib has a significant effect on colon cancer in both transcriptome and metabolome. Our research will provide possible targets for colon cancer treatment using anlotinib.


Asunto(s)
Neoplasias del Colon/genética , Perfilación de la Expresión Génica/métodos , Indoles/farmacología , Metabolómica/métodos , Quinolinas/farmacología , Ácido Aspártico/metabolismo , Proteínas de Ciclo Celular/genética , Proteoglicanos Tipo Condroitín Sulfato/genética , Cromatografía Liquida , Proteínas Cromosómicas no Histona/genética , Neoplasias del Colon/química , Neoplasias del Colon/tratamiento farmacológico , ADN-Topoisomerasas de Tipo II/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Redes Reguladoras de Genes , Glutamina/metabolismo , Glucógeno Fosforilasa/genética , Células HCT116 , Humanos , Proteínas de Unión a Poli-ADP-Ribosa/genética , Análisis de Secuencia de ARN , Espectrometría de Masas en Tándem
11.
Mol Cell ; 81(8): 1631-1639, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33826920

RESUMEN

Spatial transcriptional profiling provides gene expression information within the important anatomical context of tissue architecture. This approach is well suited to characterizing solid tumors, which develop within a complex landscape of malignant cells, immune cells, and stroma. In a single assay, spatial transcriptional profiling can interrogate the role of spatial relationships among these cell populations as well as reveal spatial patterns of relevant oncogenic genetic events. The broad utility of this approach is reflected in the array of strategies that have been developed for its implementation as well as in the recent commercial development of several profiling platforms. The flexibility to apply these technologies to both hypothesis-driven and discovery-driven studies allows widespread applicability in research settings. This review discusses available technologies for spatial transcriptional profiling and several applications for their use in cancer research.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Neoplasias/genética , Transcripción Genética/genética , Animales , Expresión Génica/genética , Humanos
12.
Mol Cell ; 81(8): 1586-1587, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33861944

RESUMEN

Troy McEachron, corresponding author of the technology review article "Applicability of spatial transcriptional profiling to cancer research," discusses his motivation for becoming a scientist and pursing pediatric cancer research, the challenges he faces as a Black scientist, and strategies for writing a review article.


Asunto(s)
Neoplasias/genética , Transcripción Genética/genética , Perfilación de la Expresión Génica/métodos , Humanos , Personal de Laboratorio Clínico , Investigación
13.
World J Surg Oncol ; 19(1): 123, 2021 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-33865399

RESUMEN

BACKGROUND: Pancreatic cancer (PAC) is one of the most devastating cancer types with an extremely poor prognosis, characterized by a hypoxic microenvironment and resistance to most therapeutic drugs. Hypoxia has been found to be one of the factors contributing to chemoresistance in PAC, but also a major driver of the formation of the tumor immunosuppressive microenvironment. However, the method to identify the degree of hypoxia in the tumor microenvironment (TME) is incompletely understood. METHODS: The mRNA expression profiles and corresponding clinicopathological information of PAC patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, respectively. To further explore the effect of hypoxia on the prognosis of patients with PAC as well as the tumor immune microenvironment, we established a hypoxia risk model and divided it into high- and low-risk groups in line with the hypoxia risk score. RESULTS: We established a hypoxia risk model according to four hypoxia-related genes, which could be used to demonstrate the immune microenvironment in PAC and predict prognosis. Moreover, the hypoxia risk score can act as an independent prognostic factor in PAC, and a higher hypoxia risk score was correlated with poorer prognosis in patients as well as the immunosuppressive microenvironment of the tumor. CONCLUSIONS: In summary, we established and validated a hypoxia risk model that can be considered as an independent prognostic indicator and reflected the immune microenvironment of PAC, suggesting the feasibility of hypoxia-targeted therapy for PAC patients.


Asunto(s)
Hipoxia/genética , Neoplasias Pancreáticas/genética , Microambiente Tumoral , Biomarcadores de Tumor/genética , Bases de Datos Genéticas , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Pancreáticas/patología , Pronóstico
14.
Sci Rep ; 11(1): 8570, 2021 04 21.
Artículo en Inglés | MEDLINE | ID: mdl-33883570

RESUMEN

Although a defective vitamin D endocrine system has been widely suspected to be associated in SARS-CoV-2 pathobiology, the status of the vitamin D endocrine system and vitamin D-modulated genes in lung cells of patients infected with SARS-CoV-2 remains unknown. To understand the significance of the vitamin D endocrine system in SARS-CoV-2 pathobiology, computational approaches were applied to transcriptomic datasets from bronchoalveolar lavage fluid (BALF) cells of such patients or healthy individuals. Levels of vitamin D receptor, retinoid X receptor, and CYP27A1 in BALF cells of patients infected with SARS-CoV-2 were found to be reduced. Additionally, 107 differentially expressed, predominantly downregulated genes, as potentially modulated by vitamin D endocrine system, were identified in transcriptomic datasets from patient's cells. Further analysis of differentially expressed genes provided eight novel genes with a conserved motif with vitamin D-responsive elements, implying the role of both direct and indirect mechanisms of gene expression by the dysregulated vitamin D endocrine system in SARS-CoV-2-infected cells. Protein-protein interaction network of differentially expressed vitamin D-modulated genes were enriched in the immune system, NF-κB/cytokine signaling, and cell cycle regulation as top predicted pathways that might be affected in the cells of such patients. In brief, the results presented here povide computational evidence to implicate a dysregulated vitamin D endocrine system in the pathobiology of SARS-CoV-2 infection.


Asunto(s)
Líquido del Lavado Bronquioalveolar/química , Biología Computacional/métodos , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes , Vitamina D/metabolismo , Células A549 , Estudios de Casos y Controles , Línea Celular , Colestanotriol 26-Monooxigenasa/genética , Bases de Datos Genéticas , Regulación hacia Abajo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mapas de Interacción de Proteínas , Receptores de Calcitriol/genética , Receptores X Retinoide/genética
15.
Nat Commun ; 12(1): 1464, 2021 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-33674610

RESUMEN

The interpretation of high throughput sequencing data is limited by our incomplete functional understanding of coding and non-coding transcripts. Reliably predicting the function of such transcripts can overcome this limitation. Here we report the use of a consensus independent component analysis and guilt-by-association approach to predict over 23,000 functional groups comprised of over 55,000 coding and non-coding transcripts using publicly available transcriptomic profiles. We show that, compared to using Principal Component Analysis, Independent Component Analysis-derived transcriptional components enable more confident functionality predictions, improve predictions when new members are added to the gene sets, and are less affected by gene multi-functionality. Predictions generated using human or mouse transcriptomic data are made available for exploration in a publicly available web portal.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Transcriptoma , Animales , Biología Computacional , Técnicas de Inactivación de Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Ratones , ARN Mensajero/metabolismo
16.
Nat Commun ; 12(1): 1426, 2021 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-33658518

RESUMEN

Metastatic prostate cancer (mPC) comprises a spectrum of diverse phenotypes. However, the extent of inter- and intra-tumor heterogeneity is not established. Here we use digital spatial profiling (DSP) technology to quantitate transcript and protein abundance in spatially-distinct regions of mPCs. By assessing multiple discrete areas across multiple metastases, we find a high level of intra-patient homogeneity with respect to tumor phenotype. However, there are notable exceptions including tumors comprised of regions with high and low androgen receptor (AR) and neuroendocrine activity. While the vast majority of metastases examined are devoid of significant inflammatory infiltrates and lack PD1, PD-L1 and CTLA4, the B7-H3/CD276 immune checkpoint protein is highly expressed, particularly in mPCs with high AR activity. Our results demonstrate the utility of DSP for accurately classifying tumor phenotype, assessing tumor heterogeneity, and identifying aspects of tumor biology involving the immunological composition of metastases.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Antígenos B7/genética , Antígeno B7-H1/genética , Antígeno CTLA-4/genética , Regulación Neoplásica de la Expresión Génica , Receptor 2 Celular del Virus de la Hepatitis A/genética , Humanos , Masculino , Adhesión en Parafina , Fenotipo , Receptor de Muerte Celular Programada 1/genética , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Análisis de Matrices Tisulares , Transcriptoma
17.
Medicine (Baltimore) ; 100(9): e24953, 2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33655961

RESUMEN

ABSTRACT: Colon cancer is one of the most common cancers in the world. To identify the candidate genes in the carcinogenesis and progression of colon cancer, the microarray datasets GSE10950, GSE44861 and GSE74602 were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified, and functional enrichment analyses were performed. A total of 176 DEGs were identified, consisting of 55 genes upregulated and 121 genes downregulated in colon cancer tissues compared to non-cancerous tissues. The DEGs were mainly enriched in mineral absorption, nitrogen metabolism and complement and coagulation cascades. By using STRING database analysis, we constructed a coexpression network composed of 140 nodes and 280 edges for the DEGs with a combined score >0.4 and a significant interaction relation. Thirteen hub genes were identified, and poor OS of patients was only associated with high expression of Matrix Metallopeptidase 7 (MMP7), which may be involved in the carcinogenesis, invasion or recurrence of colon cancer. In conclusion, we propose that the DEGs and hub genes identified in the present study may be regarded as diagnostic biomarkers for colon cancer. Moreover, the overexpression of MMP7 may correlate with poor prognosis.


Asunto(s)
Neoplasias del Colon/genética , Biología Computacional/métodos , Regulación Neoplásica de la Expresión Génica , Metaloproteinasa 7 de la Matriz/genética , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Neoplasias del Colon/diagnóstico , Neoplasias del Colon/metabolismo , ADN de Neoplasias/genética , Bases de Datos Genéticas , Progresión de la Enfermedad , Perfilación de la Expresión Génica/métodos , Humanos , Metaloproteinasa 7 de la Matriz/biosíntesis , Análisis por Micromatrices , Pronóstico
18.
Anticancer Res ; 41(3): 1341-1348, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788725

RESUMEN

BACKGROUND/AIM: Cancer profiling tests using formalin-fixed paraffin-embedded (FFPE) specimens with various conditions have become an essential tool for cancer treatment. The robustness of these tests needs to be addressed. MATERIALS AND METHODS: A cancer profiling test, NCC oncopanel, was tested with FFPE specimens from various tissues with different storage conditions and fixation lengths. Next generation sequencing was performed with Miseq and the data were assembled using the human reference genome hg19. RESULTS: Duration of storage and fixation affected the mapping statistics. Prolonged storage increased outward read paring and longer fixation rates caused increased singletons and unmapped reads. CONCLUSION: Our results indicate that a cancer profiling test with target capturing method, NCC oncopanel, shows robustness for FFPE cancer specimens with various storage conditions.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias/genética , Adhesión en Parafina/métodos , Manejo de Especímenes/métodos , Fijación del Tejido/métodos , Fijadores/química , Formaldehído/química , Genómica/métodos , Humanos , Mutación , Neoplasias/patología
19.
Nat Commun ; 12(1): 1873, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33767149

RESUMEN

Clustering is a critical step in single cell-based studies. Most existing methods support unsupervised clustering without the a priori exploitation of any domain knowledge. When confronted by the high dimensionality and pervasive dropout events of scRNA-Seq data, purely unsupervised clustering methods may not produce biologically interpretable clusters, which complicates cell type assignment. In such cases, the only recourse is for the user to manually and repeatedly tweak clustering parameters until acceptable clusters are found. Consequently, the path to obtaining biologically meaningful clusters can be ad hoc and laborious. Here we report a principled clustering method named scDCC, that integrates domain knowledge into the clustering step. Experiments on various scRNA-seq datasets from thousands to tens of thousands of cells show that scDCC can significantly improve clustering performance, facilitating the interpretability of clusters and downstream analyses, such as cell type assignment.


Asunto(s)
Perfilación de la Expresión Génica/métodos , RNA-Seq/métodos , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual/métodos , Animales , Caenorhabditis elegans/genética , Análisis por Conglomerados , Bases de Datos Genéticas , Humanos , Hígado/citología , Ratones , Transcriptoma/genética
20.
Nat Commun ; 12(1): 1912, 2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33771989

RESUMEN

Glioblastoma (GB) is a highly invasive type of brain cancer exhibiting poor prognosis. As such, its microenvironment plays a crucial role in its progression. Among the brain stromal cells, the microglia were shown to facilitate GB invasion and immunosuppression. However, the reciprocal mechanisms by which GB cells alter microglia/macrophages behavior are not fully understood. We propose that these mechanisms involve adhesion molecules such as the Selectins family. These proteins are involved in immune modulation and cancer immunity. We show that P-selectin mediates microglia-enhanced GB proliferation and invasion by altering microglia/macrophages activation state. We demonstrate these findings by pharmacological and molecular inhibition of P-selectin which leads to reduced tumor growth and increased survival in GB mouse models. Our work sheds light on tumor-associated microglia/macrophage function and the mechanisms by which GB cells suppress the immune system and invade the brain, paving the way to exploit P-selectin as a target for GB therapy.


Asunto(s)
Neoplasias Encefálicas/genética , Glioblastoma/genética , Macrófagos/metabolismo , Microglía/metabolismo , Selectina-P/genética , Animales , Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Células Cultivadas , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Células HEK293 , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones SCID , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Selectina-P/antagonistas & inhibidores , Selectina-P/metabolismo , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética
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