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Super-enhancers are a class of DNA cis-regulatory elements that can regulate cell identity, cell fate, stem cell pluripotency, and even tumorigenesis. Increasing evidence shows that epigenetic modifications play an important role in the pathogenesis of various types of cancer. However, the current research is far from enough to reveal the complex mechanism behind it. This study found a super-enhancer enriched with abnormally active histone modifications in pancreatic ductal adenocarcinoma (PDAC), called DKK1-super-enhancer (DKK1-SE). The major active component of DKK1-SE is component enhancer e1. Mechanistically, AP1 induces chromatin remodeling in component enhancer e1 and activates the transcriptional activity of DKK1. Moreover, DKK1 was closely related to the malignant clinical features of PDAC. Deletion or knockdown of DKK1-SE significantly inhibited the proliferation, colony formation, motility, migration, and invasion of PDAC cells in vitro, and these phenomena were partly mitigated upon rescuing DKK1 expression. In vivo, DKK1-SE deficiency not only inhibited tumor proliferation but also reduced the complexity of the tumor microenvironment. This study identifies that DKK1-SE drives DKK1 expression by recruiting AP1 transcription factors, exerting oncogenic effects in PDAC, and enhancing the complexity of the tumor microenvironment.
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Proliferação de Células , Progressão da Doença , Peptídeos e Proteínas de Sinalização Intercelular , Neoplasias Pancreáticas , Fator de Transcrição AP-1 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Animais , Fator de Transcrição AP-1/metabolismo , Linhagem Celular Tumoral , Camundongos , Regulação Neoplásica da Expressão Gênica , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Movimento Celular/genética , Microambiente Tumoral , Masculino , Camundongos Nus , Elementos Facilitadores Genéticos/genética , FemininoRESUMO
BACKGROUND: Due to the high heterogeneity of lung adenocarcinoma (LUAD), which restricts the effectiveness of therapy, precise molecular subgrouping of LUAD is of great significance. Clinical research has demonstrated the significant potential of DNA methylation as a classification indicator for human malignancies. METHODS: WGML framework (which was developed based on weighted gene correlation network analysis (WGCNA), Gene Ontology (GO), and machine learning) was developed to precisely subgroup molecular subtypes of LUAD. This framework included two parts: the WG algorithm and the machine learning part. The WG algorithm part was an original algorithm used to obtain a crucial module, which was characterized by weighted correlation network analysis, functional annotation, and mathematical algorithms. The machine learning part utilized the Boruta algorithm, random forest algorithm, and Gradient Boosting Regression Tree algorithm to select feature genes. Then, based on the results of the WGML framework, subtypes were computed by the hierarchical clustering algorithm. A series of analyses, including dimensionality reduction methods, survival analysis, clinical stage analysis, immune infiltration analysis, tumor environment analysis, immune checkpoints analysis, TIDE analysis, CYT analysis, somatic mutation analysis, and drug sensitivity analysis, were utilized to demonstrate the effectiveness of subgrouping. GEO datasets were used to externally validate the results. Meanwhile, another subgrouping method of LUAD from another study was employed to compare with the WGML framework. RESULT: By importing DNA methylation data into the WGML framework, nine genes were obtained to further subgroup LUAD. Three subtypes, the Carcinogenesis subtype, Immune-infiltration subtype, and Chemoresistance subtype, were identified. The dimensionality reduction method exhibited great distinctness between subtypes. A series of analyses were employed to exhibit the difference among the three subtypes and to demonstrate the accuracy of the definition of subtypes. Besides, the WGML framework was compared with a LUAD subgrouping method from another research, which demonstrated that WGML had better efficiency for subgrouping LUAD. CONCLUSION: This study provides a novel LUAD subgrouping framework named WGML for the accurate subgrouping of lung adenocarcinoma.
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Macrophages are crucial cells in the human body's innate immunity and are engaged in a variety of non-inflammatory reactions. Macrophages can develop into two kinds when stimulated by distinct internal environments: pro-inflammatory M1-like macrophages and anti-inflammatory M2-type macrophages. During inflammation, the two kinds of macrophages are activated alternatively, and maintaining a reasonably steady ratio is critical for maintaining homeostasis in vivo. M1 macrophages can induce inflammation, but M2 macrophages suppress it. The imbalance between the two kinds of macrophages will have a significant impact on the illness process. As a result, there are an increasing number of research being conducted on relieving or curing illnesses by altering the amount of macrophages. This review summarizes the role of macrophage polarization in various inflammatory diseases, including autoimmune diseases (RA, EAE, MS, AIH, IBD, CD), allergic diseases (allergic rhinitis, allergic dermatitis, allergic asthma), atherosclerosis, obesity and type 2 diabetes, metabolic homeostasis, and the compounds or drugs that have been discovered or applied to the treatment of these diseases by targeting macrophage polarization.
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Inflamação , Ativação de Macrófagos , Macrófagos , Humanos , Macrófagos/imunologia , Inflamação/imunologia , Animais , Ativação de Macrófagos/imunologia , Hipersensibilidade/imunologia , Doenças Autoimunes/imunologiaRESUMO
Esophageal squamous cell carcinoma (ESCC) remains an important health concern in developing countries. Patients with advanced ESCC have a poor prognosis and survival rate, and achieving early diagnosis remains a challenge. Metabolic biomarkers are gradually gaining attention as early diagnostic biomarkers. Hence, this multicenter study comprehensively evaluated metabolism dysregulation in ESCC through an integrated research strategy to identify key metabolite biomarkers of ESCC. First, the metabolic profiles were examined in tissue and serum samples from the discovery cohort (n = 162; ESCC patients, n = 81; healthy volunteers, n = 81), and ESCC tissue-induced metabolite alterations were observed in the serum. Afterward, RNA sequencing of tissue samples (n = 46) was performed, followed by an integrated analysis of metabolomics and transcriptomics. The potential biomarkers for ESCC were further identified by censoring gene-metabolite regulatory networks. The diagnostic value of the identified biomarkers was validated in a validation cohort (n = 220), and the biological function was verified. A total of 457 dysregulated metabolites were identified in the serum, of which 36 were induced by tumor tissues. The integrated analyses revealed significant alterations in the purine salvage pathway, wherein the abundance of hypoxanthine/xanthine exhibited a positive correlation with HPRT1 expression and tumor size. A diagnostic model was developed using two purine salvage-associated metabolites. This model could accurately discriminate patients with ESCC from normal individuals, with an area under the curve (AUC) (95% confidence interval (CI): 0.680-0.843) of 0.765 in the external cohort. Hypoxanthine and HPRT1 exerted a synergistic effect in terms of promoting ESCC progression. These findings are anticipated to provide valuable support in developing novel diagnostic approaches for early ESCC and enhance our comprehension of the metabolic mechanisms underlying this disease.
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Heterochromatin plays essential roles in eukaryotic genomes, such as regulating genes, maintaining genome integrity and silencing repetitive DNA elements. Identifying genome-wide heterochromatin regions is crucial for studying transcriptional regulation. We propose the Human Heterochromatin Chromatin Database (HHCDB) for archiving heterochromatin regions defined by specific or combined histone modifications (H3K27me3, H3K9me2, H3K9me3) according to a unified pipeline. 42 839 743 heterochromatin regions were identified from 578 samples derived from 241 cell-types/cell lines and 92 tissue types. Genomic information is provided in HHCDB, including chromatin location, gene structure, transcripts, distance from transcription start site, neighboring genes, CpG islands, transposable elements, 3D genomic structure and functional annotations. Furthermore, transcriptome data from 73 single cells were analyzed and integrated to explore cell type-specific heterochromatin-related genes. HHCDB affords rich visualization through the UCSC Genome Browser and our self-developed tools. We have also developed a specialized online analysis platform to mine differential heterochromatin regions in cancers. We performed several analyses to explore the function of cancer-specific heterochromatin-related genes, including clinical feature analysis, immune cell infiltration analysis and the construction of drug-target networks. HHCDB is a valuable resource for studying epigenetic regulation, 3D genomics and heterochromatin regulation in development and disease. HHCDB is freely accessible at http://hhcdb.edbc.org/.
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Bases de Dados Genéticas , Heterocromatina , Humanos , Epigênese Genética , Heterocromatina/genética , Heterocromatina/metabolismo , Histonas/metabolismo , Análise de Célula ÚnicaRESUMO
BACKGROUND: The pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) of breast cancer is closely related to a better prognosis. However, there are no reliable indicators to accurately identify which patients will achieve pCR before surgery, and a model for predicting pCR to NAC is required. METHODS: A total of 269 breast cancer patients in Shandong Cancer Hospital and Liaocheng People's Hospital receiving anthracycline and taxane-based NAC were prospectively enrolled. Expression profiling using a 457 cancer-related gene sequencing panel (DNA sequencing) covering genes recurrently mutated in breast cancer was carried out on 243 formalin-fixed paraffin-embedded tumor biopsies samples before NAC from 243 patients. The unique personalized panel of nine individual somatic mutation genes from the constructed model was used to detect and analyze ctDNA on 216 blood samples. Blood samples were collected at indicated time points including before chemotherapy initiation, after the 1st NAC and before the 2nd NAC cycle, during intermediate evaluation, and prior to surgery. In this study, we characterized the value of gene profile mutation and circulating tumor DNA (ctDNA) in combination with clinical characteristics in the prediction of pCR before surgery and investigated the prognostic prediction. The median follow-up time for survival analysis was 898 days. RESULTS: Firstly, we constructed a predictive NAC response model including five single nucleotide variant (SNV) mutations (TP53, SETBP1, PIK3CA, NOTCH4 and MSH2) and four copy number variation (CNV) mutations (FOXP1-gain, EGFR-gain, IL7R-gain, and NFKB1A-gain) in the breast tumor, combined with three clinical factors (luminal A, Her2 and Ki67 status). The tumor prediction model showed good discrimination of chemotherapy sensitivity for pCR and non-pCR with an AUC of 0.871 (95% CI, 0.797-0.927) in the training set, 0.771 (95% CI, 0.649-0.883) in the test set, and 0.726 (95% CI, 0.556-0.865) in an extra test set. This tumor prediction model can also effectively predict the prognosis of disease-free survival (DFS) with an AUC of 0.749 at 1 year and 0.830 at 3 years. We further screened the genes from the tumor prediction model to establish a unique personalized panel consisting of 9 individual somatic mutation genes to detect and analyze ctDNA. It was found that ctDNA positivity decreased with the passage of time during NAC, and ctDNA status can predict NAC response and metastasis recurrence. Finally, we constructed the chemotherapy prediction model combined with the tumor prediction model and pretreatment ctDNA levels, which has a better prediction effect of pCR with the AUC value of 0.961. CONCLUSIONS: In this study, we established a chemotherapy predictive model with a non-invasive tool that is built based on genomic features, ctDNA status, as well as clinical characteristics for predicting pCR to recognize the responders and non-responders to NAC, and also predicting prognosis for DFS in breast cancer. Adding pretreatment ctDNA levels to a model containing gene profile mutation and clinical characteristics significantly improves stratification over the clinical variables alone.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Terapia Neoadjuvante , Variações do Número de Cópias de DNA , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prognóstico , Medição de Risco , Proteínas Repressoras/genética , Proteínas Repressoras/uso terapêutico , Fatores de Transcrição ForkheadRESUMO
Background: Limited data are available on applying circulating tumor DNA (ctDNA) in metastatic triple-negative breast cancer (mTNBC) patients. Here, we investigated the value of ctDNA for predicting the prognosis and monitoring the treatment response in mTNBC patients. Methods: We prospectively enrolled 70 Chinese patients with mTNBC who had progressed after ≤2 lines of chemotherapy and collected blood samples to extract ctDNA for 457-gene targeted panel sequencing. Results: Patients with ctDNA+, defined by 12 prognosis-relevant mutated genes, had a shorter progression-free survival (PFS) than ctDNA- patients (5.16 months vs. 9.05 months, p=0.001), and ctDNA +was independently associated with a shorter PFS (HR, 95% CI: 2.67, 1.2-5.96; p=0.016) by multivariable analyses. Patients with a higher mutant-allele tumor heterogeneity (MATH) score (≥6.316) or a higher ctDNA fraction (ctDNA%≥0.05) had a significantly shorter PFS than patients with a lower MATH score (5.67 months vs.11.27 months, p=0.007) and patients with a lower ctDNA% (5.45 months vs. 12.17 months, p<0.001), respectively. Positive correlations with treatment response were observed for MATH score (R=0.24, p=0.014) and ctDNA% (R=0.3, p=0.002), but not the CEA, CA125, or CA153. Moreover, patients who remained ctDNA +during dynamic monitoring tended to have a shorter PFS than those who did not (3.90 months vs. 6.10 months, p=0.135). Conclusions: ctDNA profiling provides insight into the mutational landscape of mTNBC and may reliably predict the prognosis and treatment response of mTNBC patients. Funding: This work was supported by the National Natural Science Foundation of China (Grant No. 81902713), Natural Science Foundation of Shandong Province (Grant No. ZR2019LZL018), Breast Disease Research Fund of Shandong Provincial Medical Association (Grant No. YXH2020ZX066), the Start-up Fund of Shandong Cancer Hospital (Grant No. 2020-PYB10), Beijing Science and Technology Innovation Fund (Grant No. KC2021-ZZ-0010-1).
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DNA Tumoral Circulante , Neoplasias de Mama Triplo Negativas , Humanos , Estudos Prospectivos , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Biomarcadores Tumorais/genética , Estimativa de Kaplan-Meier , MutaçãoRESUMO
Background: In recent years, tumor immunotherapy has become a viable treatment option for triple negative breast cancer (TNBC). Among these, immune checkpoint inhibitors (ICIs) have demonstrated good efficacy in advanced TNBC patients with programmed death-ligand 1 (PD-L1) positive expression. However, only 63% of PD-L1-positive individuals showed any benefit from ICIs. Therefore, finding new predictive biomarkers will aid in identifying patients who are likely to benefit from ICIs. In this study, we used liquid biopsies and next-generation sequencing (NGS) to dynamically detect changes in circulating tumor DNA (ctDNA) in the blood of patients with advanced TNBC treated with ICIs and focused on its potential predictive value. Methods: From May 2018 to October 2020, patients with advanced TNBC treated with ICIs at Shandong Cancer Hospital were included prospectively. Patient blood samples were obtained at the pretreatment baseline, first response evaluation, and disease progression timepoints. Furthermore, 457 cancer-related genes were evaluated by NGS, and patients' ctDNA mutations, gene mutation rates, and other indicators were determined and coupled with clinical data for statistical analysis. Results: A total of 11 TNBC patients were included in this study. The overall objective response rate (ORR) was 27.3%, with a 6.1-month median progression-free survival (PFS) (95% confidence interval: 3.877-8.323 months). Of the 11 baseline blood samples, 48 mutations were found, with the most common mutation types being frame shift indels, synonymous single-nucleotide variations (SNVs), frame indel missenses, splicing, and stop gains. Additionally, univariate Cox regression analysis revealed that advanced TNBC patients with one of 12 mutant genes (CYP2D6 deletion and GNAS, BCL2L1, H3F3C, LAG3, FGF23, CCND2, SESN1, SNHG16, MYC, HLA-E, and MCL1 gain) had a shorter PFS with ICI treatment (p < 0.05). To some extent, dynamic changes of ctDNA might indicate the efficacy of ICIs. Conclusion: Our data indicate that ICI efficacy in patients with advanced TNBC may be predicted by 12 mutant ctDNA genes. Additionally, dynamic alterations in peripheral blood ctDNA might be used to track the effectiveness of ICI therapy in those with advanced TNBC.
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Luminal breast cancer (BC) accounts for a large proportion of patients in BC, with high heterogeneity. Determining the precise subtype and optimal selection of treatment options for luminal BC is a challenge. In this study, we proposed an MSBR framework that integrate DNA methylation profiles and transcriptomes to identify immune subgroups of luminal BC. MSBR was implemented both on a key module scoring algorithm and "Boruta" feature selection method by DNA methylation. Luminal A was divided into two subgroups and luminal B was divided into three subgroups using the MSBR. Furthermore, these subgroups were defined as different immune subgroups in luminal A and B respectively. The subgroups showed significant differences in DNA methylation levels, immune microenvironment (immune cell infiltration, immune checkpoint PD1/PD-L1 expression, immune cell cracking activity (CYT)) and pathology features (texture, eccentricity, intensity and tumor-infiltrating lymphocytes (TILs)). The results also showed that there is a subgroup in both luminal A and B that has the benefit from immunotherapy. This study proposed a classification of luminal BC from the perspective of epigenetics and immune characteristics, which provided individualized treatment decisions.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/metabolismo , Metilação de DNA , Linfócitos do Interstício Tumoral , Transcriptoma , Imunoterapia , Microambiente Tumoral/genéticaRESUMO
Background: The immune system plays a crucial role in rectal adenocarcinoma (READ). Immune-related genes may help predict READ prognoses. Methods: The Cancer Genome Atlas dataset and GSE56699 were used as the training and validation datasets, respectively, and differentially expressed genes (DEGs) were identified. The optimal DEG combination was determined, and the prognostic risk model was constructed. The correlation between optimal DEGs and immune infiltrating cells was evaluated. Results: Nine DEGs were selected for analysis. Moreover, ADAMDEC1 showed a positive correlation with six immune infiltrates, most notably with B cells and dendritic cells. F13A1 was also positively correlated with six immune infiltrates, particularly macrophage and dendritic cells, whereas LGALS9C was negatively correlated with all immune infiltrates except B cells. Additionally, the prognostic risk model was strongly correlated with the actual situation. We retained only three prognosis risk factors: age, pathologic stage, and prognostic risk model. The stratified analysis revealed that lower ages and pathologic stages have a better prognosis with READ. Age and mRNA prognostic factors were the most important factors in determining the possibility of 3- and 5-year survival. Conclusion: In summary, we identified a nine-gene prognosis risk model that is applicable to the treatment of READ. Altogether, characteristics such as the gene signature and age have a strong predictive value for prognosis risk.
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PURPOSE: Long noncoding RNAs (lncRNAs) and glycolysis regulate multiple types of cancer. However, the prognostic roles and biological functions of glycolysis-related lncRNAs in lung adenocarcinoma (LUAD) remain unclear. In this study, we investigated the role of glycolysis-related lncRNAs in LUAD. PATIENTS AND METHODS: We retrieved glycolysis-related genes from the Molecular Signatures Database and screened for prognostic glycolysis-related lncRNAs from The Cancer Genome Atlas. RESULTS: We identified three LUAD subtypes (clusters 1-3) by univariate Cox regression analysis and consensus clustering. Patients in cluster 1 had the best overall survival rates. Immune, stromal, and cytolytic-activity scores were the highest in cluster 1. The expression of immune checkpoint molecules (programmed cell death protein 1 and cytotoxic T-lymphocyte-associated protein 4) and other immune-related indicators was the highest in cluster 1, whereas that of epithelial cell biomarkers (Cadherin 1, Cadherin 2, and MET) was the lowest. Therefore, patients in cluster 1 may benefit from immunotherapy. Lasso-Cox regression and multivariate Cox regression analyses were used to select nine lncRNAs to build a robust prognostic model of LUAD. The area under the curve classifier values and a nomogram performed well in predicting survival times for patients with LUAD. The expression levels of nine lncRNAs were validated by quantitative reverse transcriptase-polymerase chain reaction analysis, and most of these lncRNAs were significantly related to immune-related mRNAs. Gene set enrichment analysis revealed that the high-risk group was enriched for cell cycle-related pathways and the low-risk group was enriched for pathways associated with immunity or immune-related diseases. CONCLUSION: The LUAD subtypes and prognostic model developed here may help in clinical risk stratification, prognosis management, and treatment decisions for patients with LUAD.
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Various factors affect the prognosis of patients with colon cancer. Complicated factors are found to be conducive to accurate assessment of prognosis. In this study, we developed a series of prognostic prediction models for survival time of colon cancer patients after surgery. Analysis of nine clinical characteristics showed that the most important factor was the positive lymph node ratio (LNR). High LNR was the most important clinical factor affecting 1- and 3-year survival; M0&age < 70 was the most important feature for 5 years. The performance of the model was improved through the integration of clinical characteristics and four types of molecule features (mRNA, lncRNA, miRNA, DNA methylation). The model provides guidance for clinical practice. According to the high-risk molecular features combined with age ≥ 70&T3, poorly differentiated or undifferentiated, M0&well differentiated, M0&T2, LNR high, T4&poorly differentiated, or undifferentiated, the survival time may be less than 1 year; for patients with high risk of molecular features combined with M0&T2, M0&T4, LNR 0& M0, LNR median &T3, and LNR high, the survival is predicted less than 3 years; and the survival of patients with M1&T3, M0 and high risk molecular features is less than 5 years. Using multidimensional and complex patient information, this study establishes potential criteria for clinicians to evaluate the survival of patients for colon cancer.
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Super-enhancers or stretch enhancers (SEs) consist of large clusters of active transcription enhancers which promote the expression of critical genes that define cell identity during development and disease. However, the role of many super-enhancers in tumor cells remains unclear. This study aims to explore the function and mechanism of a new super-enhancer in various tumor cells. A new super-enhancer that exists in a variety of tumors named EphA2-Super-enhancer (EphA2-SE) was found using multiple databases and further identified. CRISPR/Cas9-mediated deletion of EphA2-SE results in the significant downregulation of its target gene EphA2. Mechanistically, we revealed that the core active region of EphA2-SE comprises E1 component enhancer, which recruits TCF7L2 and FOSL2 transcription factors to drive the expression of EphA2, induce cell proliferation and metastasis. Bioinformatics analysis of RNA-seq data and functional experiments in vitro illustrated that EphA2-SE deletion inhibited cell growth and metastasis by blocking PI3K/AKT and Wnt/ß-catenin pathway in HeLa, HCT-116 and MCF-7 cells. Overexpression of EphA2 in EphA2-SE-/- clones rescued the effect of EphA2-SE deletion on proliferation and metastasis. Subsequent xenograft animal model revealed that EphA2-SE deletion suppressed tumor proliferation and survival in vivo. Taken together, these findings demonstrate that EphA2-SE plays an oncogenic role and promotes tumor progression in various tumors by recruiting FOSL2 and TCF7L2 to drive the expression of oncogene EphA2.
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Elementos Facilitadores Genéticos , Antígeno 2 Relacionado a Fos/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Receptor EphA2/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Células A549 , Animais , Movimento Celular , Proliferação de Células , Antígeno 2 Relacionado a Fos/metabolismo , Células HCT116 , Células HeLa , Humanos , Células MCF-7 , Camundongos Nus , Metástase Neoplásica , Neoplasias/metabolismo , Neoplasias/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor EphA2/metabolismo , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Via de Sinalização WntRESUMO
Aim: We aim to predict transcription factor (TF) binding events from knowledge of gene expression and epigenetic modifications. Materials & methods: TF-binding events based on the Encode project and The Cancer Genome Atlas data were analyzed by the random forest method. Results: We showed the high performance of TF-binding predictive models in GM12878, HeLa, HepG2 and K562 cell lines and applied them to other cell lines and tissues. The genes bound by the top TFs (MAX and MAZ) were significantly associated with cancer-related processes such as cell proliferation and DNA repair. Conclusion: We successfully constructed TF-binding predictive models in cell lines and applied them in tissues.
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Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Neoplasias do Colo do Útero/genética , Linhagem Celular , Metilação de DNA , Epigênese Genética , Feminino , Expressão Gênica , Histonas/metabolismo , Humanos , Modelos Biológicos , Ligação ProteicaRESUMO
IMPACT STATEMENT: Gene mutations are closely related to cancers and drug sensitivity and noninvasive liquid biopsy was used to detect mutations of ctDNA in plasma. In this study, we performed exon sequencing of 416 cancer-related genes for cancer primary tissue and plasma samples of 20 patients in 11 cancers and obtained the comprehensive mutation landscape. We found that liquid biopsy is reliable in place of tissue biopsy. And 31 potential unique mutation prognostic markers were screened in 7 cancer types. Moreover, the drug-mutation network (DMN) was constructed and 9 gene mutations (B-Mut-9) were confirmed that can be served as drug biomarkers in blood. Our study showed that the variation in ctDNA can be used as the biomarkers for cancer prognosis and drug efficacy prediction. This can provide a reference for clinical noninvasive testing.
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Biomarcadores Tumorais/genética , Carcinoma/genética , DNA Tumoral Circulante/genética , Mutação , Proteína da Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Carcinoma/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Exoma , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
This study investigated the application of fungus Aspergillus niger and geological fluorapatite (FAp) to cadmium (Cd) immobilization in aqueous solution. The initial Cd concentrations were set at 100, 50, 25, and 10 mg L-1. The mineralogy of the products was investigated by using scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), and attenuated total reflection-infrared spectroscopy (ATR-IR). In both A. niger + FAp + Cd and A. niger + Cd treatments, A. niger secreted abundant oxalic acid, then dissolved the FAp, and reacted with Cd2+ cations to produce relatively insoluble Cd oxalate. Meanwhile, FAp can provide P source to improve microbial growth. The fungal tolerance to Cd2+ was identified at around 100 mg L-1. The final Cd concentrations of 13.7, 3.2, and 0.2 mg L-1 were recorded for A. niger + FAp + Cd treatments with initial Cd concentrations of 50, 25, and 10 mg L-1 respectively. Meanwhile, it was observed that the Cd concentration at 25 mg L-1 stimulated higher bioactivities of A. niger, which further enhanced Cd bioremediation. The immobilization efficiency (%) of the treatments at low to medium Cd concentrations was in the order: Asp + FAp > Asp > FAp, while FAp alone was most efficient at the high Cd concentration of 100 mg L-1. This research provides insights into the mechanisms of combining fungus and FAp as a composite to Cd contamination at various Cd levels.
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Apatitas/química , Aspergillus niger/metabolismo , Biodegradação Ambiental , Cádmio/química , Concentração de Íons de HidrogênioRESUMO
Aim: To comprehensively identify allele-specific DNA methylation (ASM) at the genome-wide level. Methods: Here, we propose a new method, called GeneASM, to identify ASM using high-throughput bisulfite sequencing data in the absence of haplotype information. Results: A total of 2194 allele-specific DNA methylated genes were identified in the GM12878 lymphocyte lineage using GeneASM. These genes are mainly enriched in cell cytoplasm function, subcellular component movement or cellular linkages. GM12878 methylated DNA immunoprecipitation sequencing, and methylation sensitive restriction enzyme sequencing data were used to evaluate ASM. The relationship between ASM and disease was further analyzed using the The Cancer Genome Atlas (TCGA) data of lung adenocarcinoma (LUAD), and whole genome bisulfite sequencing data. Conclusion: GeneASM, which recognizes ASM by high-throughput bisulfite sequencing and heterozygous single-nucleotide polymorphisms, provides new perspective for studying genomic imprinting.
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Metilação de DNA/genética , Genoma Humano/genética , Alelos , Epigênese Genética/genética , Impressão Genômica/genética , Haplótipos/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Linfócitos/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA/métodos , Sequenciamento Completo do Genoma/métodosRESUMO
BACKGROUND: Gallbladder cancer (GBC) is the main pathological type of biliary tract cancers. Due to its aggressive nature, GBC is usually diagnosed at advanced stages with limited therapeutic options and poor outcome, especially after failure of chemotherapy. CASE PRESENTATION: Herein, we report a recurrent metastatic GBC patient with strong programmed death-ligand 1 (PD-L1) expression (≥50%) who obtained a significant response to radiotherapy combining nivolumab treatment. CONCLUSIONS: To our knowledge this is the first case presenting significant nivolumab response in a Chinese GBC patient. This remarkable response was most likely associated with the strong PD-L1 expression, and indicated that PD-L1 expression could be considered as a biomarker for nivolumab treatment in metastatic gallbladder cancer. However, more studies are needed for validation.
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Magnetic resonance imaging (MRI) offers the most detailed brain structure image available today; it can identify tiny lesions or cerebral cortical abnormalities. The primary purpose of the procedure is to confirm whether there is structural variation that causes epilepsy, such as hippocampal sclerotherapy, local cerebral cortical dysplasia, and cavernous hemangioma. Cerebrovascular disease, the second most common factor of death in the world, is also the fourth leading cause of death in Taiwan, with cerebrovascular disease having the highest rate of stroke. Among the most common are large vascular atherosclerotic lesions, small vascular lesions, and cardiac emboli. The purpose of this thesis is to establish a computer-aided diagnosis system based on small blood vessel lesions in MRI images, using the method of Convolutional Neural Network and deep learning to analyze brain vascular occlusion by analyzing brain MRI images. Blocks can help clinicians more quickly determine the probability and severity of stroke in patients. We analyzed MRI data from 50 patients, including 30 patients with stroke, 17 patients with occlusion but no stroke, and 3 patients with dementia. This system mainly helps doctors find out whether there are cerebral small vessel lesions in the brain MRI images, and to output the found results into labeled images. The marked contents include the position coordinates of the small blood vessel blockage, the block range, the area size, and if it may cause a stroke. Finally, all the MRI images of the patient are synthesized, showing a 3D display of the small blood vessels in the brain to assist the doctor in making a diagnosis or to provide accurate lesion location for the patient.
Assuntos
Biomarcadores/química , Técnicas Biossensoriais , Doenças de Pequenos Vasos Cerebrais/diagnóstico , Processamento de Imagem Assistida por Computador/métodos , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Aprendizado Profundo , Humanos , Imageamento por Ressonância Magnética/métodos , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/fisiopatologiaRESUMO
BACKGROUND: It is generally believed that DNA methylation, as one of the most important epigenetic modifications, participates in the regulation of gene expression and plays an important role in the development of cancer, and there exits epigenetic heterogeneity among cancers. Therefore, this study tried to screen for reliable prognostic markers for different cancers, providing further explanation for the heterogeneity of cancers, and more targets for clinical transformation studies of cancer from epigenetic perspective. METHODS: This article discusses the epigenetic heterogeneity of cancer in detail. Firstly, DNA methylation data of seven cancer types were obtained from Illumina Infinium HumanMethylation 450 K platform of TCGA database. Then, differential methylation analysis was performed in the promotor region. Secondly, pivotal gene markers were obtained by constructing the DNA methylation correlation network and the gene interaction network in the KEGG pathway, and 317 marker genes obtained from two networks were integrated as candidate markers for the prognosis model. Finally, we used the univariate and multivariate COX regression models to select specific independent prognostic markers for each cancer, and studied the risk factor of these genes by doing survival analysis. RESULTS: First, the cancer type-specific gene markers were obtained by differential methylation analysis and they were found to be involved in different biological functions by enrichment analysis. Moreover, specific and common diagnostic markers for each type of cancer was sorted out and Kaplan-Meier survival analysis showed that there was significant difference in survival between the two risk groups. CONCLUSIONS: This study screened out reliable prognostic markers for different cancers, providing a further explanation for the heterogeneity of cancer at the DNA methylation level and more targets for clinical conversion studies of cancer.