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1.
Matrix Biol ; 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33068727

RESUMO

Disturbed flow leads to increased inflammatory responses of endothelial cells (ECs) prone to atherogenic state. Currently, little is known about the physiological mechanisms protecting vasculature against disturbed flow-activated ECs leading to atherosclerosis. Understanding the protective mediators involved in EC activation could provide novel therapeutic strategies for atherosclerosis. The extracellular matrix microenvironment profoundly regulates cellular homeostasis. A non-EC resident ECM protein, cartilage oligomeric matrix protein (COMP), has diverse protective roles in the cardiovascular system. To determine whether COMP could protect against disturbed flow-activated EC and atherosclerosis, we compared oscillatory shear stress (OSS) induced EC activation coated with various ECM proteins. Purified COMP inhibited EC activation caused by OSS. EC activation was upregulated in the aortic arch where the flow is disturbed in COMP-/- mice as compared with wild-type mice under physiological conditions or pathologically in partially ligated mouse carotid arteries. Mechanistically, co-immunoprecipitation, mammalian two-hybrid and FRET assay results suggest that COMP bound directly to integrin α5 via its C-terminus. We next synthesized a COMP-derived peptidomimetics (CCPep24) mimicking a specific COMP-integrin α5 interaction and found that CCPep24 protected against EC activation and atherogenesis in vivo. This study extends our current understanding of how ECM and flow coordinately fine-tune EC homeostasis and reveals the potential therapeutic effect of COMP or COMP-derived peptidomimetics on blocking aberrant integrin α5 activation, inflammatory EC activation and atherosclerosis pathogenesis.

2.
Genome Res ; 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060171

RESUMO

The advances of large-scale genomics studies have enabled compilation of cell type-specific, genome-wide DNA functional elements at high resolution. With the growing volume of functional annotation data and sequencing variants, existing variant annotation algorithms lack the efficiency and scalability to process big genomic data, particularly when annotating whole genome sequencing variants against a huge database with billions of genomic features. Here, we develop VarNote to rapidly annotate genome-scale variants in large and complex functional annotation resources. Equipped with a novel index system and a parallel random-sweep searching algorithm, VarNote shows substantial performance improvements (two to three orders of magnitude) over existing algorithms at different scales. It supports both region-based and allele-specific annotations, and introduces advanced functions for the flexible extraction of annotations. By integrating massive base-wise and context-dependent annotations in the VarNote framework, we introduce three efficient and accurate pipelines to prioritize the causal regulatory variants for common diseases, Mendelian disorders and cancers.

3.
Sci Adv ; 6(16): eaaz0356, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32494608

RESUMO

TUDOR domain-containing proteins (TDRDs) are chiefly responsible for recognizing methyl-lysine/arginine residue. However, how TDRD dysregulation contributes to breast tumorigenesis is poorly understood. Here, we report that TUDOR domain-containing PHF20L1 as a H3K27me2 reader exerts transcriptional repression by recruiting polycomb repressive complex 2 (PRC2) and Mi-2/nucleosome remodeling and deacetylase (NuRD) complex, linking PRC2-mediated methylation and NuRD-mediated deacetylation of H3K27. Furthermore, PHF20L1 was found to serve as a potential MYC and hypoxia-driven oncogene, promoting glycolysis, proliferation, and metastasis of breast cancer cells by directly inhibiting tumor suppressors such as HIC1, KISS1, and BRCA1. PHF20L1 expression was also strongly correlated with higher histologic grades of breast cancer and markedly up-regulated in several cancers. Meanwhile, Phf20l1 deletion not only induces growth retardation and mammary ductal outgrowth delay but also inhibits tumorigenesis in vivo. Our data indicate that PHF20L1 promotes tumorigenesis, supporting the pursuit of PHF20L1 as a target for cancer therapy.

4.
Cell Death Dis ; 11(5): 320, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32371982

RESUMO

Decreased intercellular adhesion is a key step in the metastasis and recurrence of many cancers, including hepatocellular carcinoma (HCC). SVEP1 is an important cell adhesion molecule that plays a key role in regulating intercellular adhesion and embryonic lymphatic development. However, the expression patterns and roles of SVEP1 in HCC are still largely unknown. We identified SVEP1 expression by analyzing 220 HCC samples from our cancer center. TCGA and GEO online-databases were used for data calibration and validation. SVEP1 was differentially expressed in two groups of HCCs with different risks of recurrence and was deemed as an independent risk factor for the prognosis of HCC. The expression of SVEP1 is negatively related to the proliferation and metastasis of HCC. Downregulation of SVEP1 expression promoted in vitro HCC cell migration, chemotaxis, invasion and proliferation, as well as in vivo tumor growth, local invasion and metastasis in a mouse model. Bioinformatic analysis and RT-PCR results showed that miR-1269b expression is negatively correlated with the SVEP1 expression and the prognosis of HCC patients. Further experiments showed that miR-1269b directly targets and downregulates the expression of SVEP1, which further induces the phosphorylation of Akt at thr308. These regulatory effects ultimately mediate the proliferation and metastasis of HCC cells. SVEP1 could serve as a promising prognostic marker of HCC. MiR-1269b downregulates SVEP1 expression and promotes HCC proliferation and metastasis likely through the PI3k/Akt signaling pathway.

5.
Nucleic Acids Res ; 48(12): 6563-6582, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32459350

RESUMO

Functional crosstalk between histone modifications and chromatin remodeling has emerged as a key regulatory mode of transcriptional control during cell fate decisions, but the underlying mechanisms are not fully understood. Here we discover an HRP2-DPF3a-BAF epigenetic pathway that coordinates methylated histone H3 lysine 36 (H3K36me) and ATP-dependent chromatin remodeling to regulate chromatin dynamics and gene transcription during myogenic differentiation. Using siRNA screening targeting epigenetic modifiers, we identify hepatoma-derived growth factor-related protein 2 (HRP2) as a key regulator of myogenesis. Knockout of HRP2 in mice leads to impaired muscle regeneration. Mechanistically, through its HIV integrase binding domain (IBD), HRP2 associates with the BRG1/BRM-associated factor (BAF) chromatin remodeling complex by interacting directly with the BAF45c (DPF3a) subunit. Through its Pro-Trp-Trp-Pro (PWWP) domain, HRP2 preferentially binds to H3K36me2. Consistent with the biochemical studies, ChIP-seq analyses show that HRP2 colocalizes with DPF3a across the genome and that the recruitment of HRP2/DPF3a to chromatin is dependent on H3K36me2. Integrative transcriptomic and cistromic analyses, coupled with ATAC-seq, reveal that HRP2 and DPF3a activate myogenic genes by increasing chromatin accessibility through recruitment of BRG1, the ATPase subunit of the BAF complex. Taken together, these results illuminate a key role for the HRP2-DPF3a-BAF complex in the epigenetic coordination of gene transcription during myogenic differentiation.


Assuntos
Montagem e Desmontagem da Cromatina , Proteínas de Ligação a DNA/metabolismo , Código das Histonas , Mioblastos/metabolismo , Fatores de Transcrição/metabolismo , Animais , Sítios de Ligação , Diferenciação Celular , Proteínas de Ligação a DNA/genética , Células HEK293 , Humanos , Masculino , Camundongos , Desenvolvimento Muscular , Mioblastos/citologia , Ligação Proteica , Fatores de Transcrição/genética
6.
Mol Ther ; 28(5): 1339-1358, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32209436

RESUMO

The need to distribute therapy evenly systemically throughout the large muscle volume within the body makes Duchenne muscular dystrophy (DMD) therapy a challenge. Cell and exon-skipping therapies are promising but have limited effects, and thus enhancing their therapeutic potency is of paramount importance to increase the accessibility of these therapies to DMD patients. In this study, we demonstrate that co-administered glycine improves phosphorodiamidate morpholino oligomer (PMO) potency in mdx mice with marked functional improvement and an up to 50-fold increase of dystrophin in abdominal muscles compared to PMO in saline. Glycine boosts satellite cell proliferation and muscle regeneration by increasing activation of mammalian target of rapamycin complex 1 (mTORC1) and replenishing the one-carbon unit pool. The expanded regenerating myofiber population then results in increased PMO uptake. Glycine also augments the transplantation efficiency of exogenous satellite cells and primary myoblasts in mdx mice. Our data provide evidence that glycine enhances satellite cell proliferation, cell transplantation, and oligonucleotide efficacy in mdx mice, and thus it has therapeutic utility for cell therapy and drug delivery in muscle-wasting diseases.

7.
Commun Biol ; 3(1): 6, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31925297

RESUMO

Mutation-specific effects of cancer driver genes influence drug responses and the success of clinical trials. We reasoned that these effects could unbalance the distribution of each mutation across different cancer types, as a result, the cancer preference can be used to distinguish the effects of the causal mutation. Here, we developed a network-based framework to systematically measure cancer diversity for each driver mutation. We found that half of the driver genes harbor cancer type-specific and pancancer mutations simultaneously, suggesting that the pervasive functional heterogeneity of the mutations from even the same driver gene. We further demonstrated that the specificity of the mutations could influence patient drug responses. Moreover, we observed that diversity was generally increased in advanced tumors. Finally, we scanned potentially novel cancer driver genes based on the diversity spectrum. Diversity spectrum analysis provides a new approach to define driver mutations and optimize off-label clinical trials.

8.
Nucleic Acids Res ; 48(D1): D807-D816, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31691819

RESUMO

Genome-wide association studies (GWASs) have revolutionized the field of complex trait genetics over the past decade, yet for most of the significant genotype-phenotype associations the true causal variants remain unknown. Identifying and interpreting how causal genetic variants confer disease susceptibility is still a big challenge. Herein we introduce a new database, CAUSALdb, to integrate the most comprehensive GWAS summary statistics to date and identify credible sets of potential causal variants using uniformly processed fine-mapping. The database has six major features: it (i) curates 3052 high-quality, fine-mappable GWAS summary statistics across five human super-populations and 2629 unique traits; (ii) estimates causal probabilities of all genetic variants in GWAS significant loci using three state-of-the-art fine-mapping tools; (iii) maps the reported traits to a powerful ontology MeSH, making it simple for users to browse studies on the trait tree; (iv) incorporates highly interactive Manhattan and LocusZoom-like plots to allow visualization of credible sets in a single web page more efficiently; (v) enables online comparison of causal relations on variant-, gene- and trait-levels among studies with different sample sizes or populations and (vi) offers comprehensive variant annotations by integrating massive base-wise and allele-specific functional annotations. CAUSALdb is freely available at http://mulinlab.org/causaldb.

9.
Nucleic Acids Res ; 48(D1): D983-D991, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31598699

RESUMO

Recent advances in genome sequencing and functional genomic profiling have promoted many large-scale quantitative trait locus (QTL) studies, which connect genotypes with tissue/cell type-specific cellular functions from transcriptional to post-translational level. However, no comprehensive resource can perform QTL lookup across multiple molecular phenotypes and investigate the potential cascade effect of functional variants. We developed a versatile resource, named QTLbase, for interpreting the possible molecular functions of genetic variants, as well as their tissue/cell-type specificity. Overall, QTLbase has five key functions: (i) curating and compiling genome-wide QTL summary statistics for 13 human molecular traits from 233 independent studies; (ii) mapping QTL-relevant tissue/cell types to 78 unified terms according to a standard anatomogram; (iii) normalizing variant and trait information uniformly, yielding >170 million significant QTLs; (iv) providing a rich web client that enables phenome- and tissue-wise visualization; and (v) integrating the most comprehensive genomic features and functional predictions to annotate the potential QTL mechanisms. QTLbase provides a one-stop shop for QTL retrieval and comparison across multiple tissues and multiple layers of molecular complexity, and will greatly help researchers interrogate the biological mechanism of causal variants and guide the direction of functional validation. QTLbase is freely available at http://mulinlab.org/qtlbase.


Assuntos
Bases de Dados Genéticas , Estudo de Associação Genômica Ampla , Genômica , Genótipo , Fenótipo , Locos de Características Quantitativas , Característica Quantitativa Herdável , Biologia Computacional/métodos , Genômica/métodos , Humanos , Software , Navegador
10.
Nucleic Acids Res ; 47(21): e134, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31511901

RESUMO

Predicting the functional or pathogenic regulatory variants in the human non-coding genome facilitates the interpretation of disease causation. While numerous prediction methods are available, their performance is inconsistent or restricted to specific tasks, which raises the demand of developing comprehensive integration for those methods. Here, we compile whole genome base-wise aggregations, regBase, that incorporate largest prediction scores. Building on different assumptions of causality, we train three composite models to score functional, pathogenic and cancer driver non-coding regulatory variants respectively. We demonstrate the superior and stable performance of our models using independent benchmarks and show great success to fine-map causal regulatory variants on specific locus or at base-wise resolution. We believe that regBase database together with three composite models will be useful in different areas of human genetic studies, such as annotation-based casual variant fine-mapping, pathogenic variant discovery as well as cancer driver mutation identification. regBase is freely available at https://github.com/mulinlab/regBase.


Assuntos
Bases de Dados Genéticas , Genoma Humano , Estudo de Associação Genômica Ampla/métodos , Software , Conjuntos de Dados como Assunto , Humanos , Neoplasias/genética , Polimorfismo de Nucleotídeo Único/genética
11.
Emerg Microbes Infect ; 8(1): 734-748, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31130074

RESUMO

Many pathogens infect hosts through various immune evasion strategies. However, the molecular mechanisms by which pathogen proteins modulate and evade the host immune response remain unclear. Enterohemorrhagic Escherichia coli (EHEC) is a pathological strain that can induce mitogen-activated protein (MAP) kinase (Erk, Jnk and p38 MAPK) and NF-κB pathway activation and proinflammatory cytokine production, which then causes diarrheal diseases such as hemorrhagic colitis and hemolytic uremic syndrome. Transforming growth factor ß-activated kinase-1 (TAK1) is a key regulator involved in distinct innate immune signalling pathways. Here we report that EHEC translocated intimin receptor (Tir) protein inhibits the expression of EHEC-induced proinflammatory cytokines by interacting with the host tyrosine phosphatase SHP-1, which is dependent on the phosphorylation of immunoreceptor tyrosine-based inhibition motifs (ITIMs). Mechanistically, the association of EHEC Tir with SHP-1 facilitated the recruitment of SHP-1 to TAK1 and inhibited TAK1 phosphorylation, which then negatively regulated K63-linked polyubiquitination of TAK1 and downstream signal transduction. Taken together, these results suggest that EHEC Tir negatively regulates proinflammatory responses by inhibiting the activation of TAK1, which is essential for immune evasion and could be a potential target for the treatment of bacterial infection.


Assuntos
Escherichia coli Êntero-Hemorrágica/patogenicidade , Infecções por Escherichia coli/fisiopatologia , Proteínas de Escherichia coli/metabolismo , Interações Hospedeiro-Patógeno , Evasão da Resposta Imune , MAP Quinase Quinase Quinases/antagonistas & inibidores , Receptores de Superfície Celular/metabolismo , Fatores de Virulência/metabolismo , Animais , Infecções por Escherichia coli/microbiologia , Células HEK293 , Humanos , Macrófagos Peritoneais , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Células RAW 264.7
12.
Thyroid ; 29(6): 809-823, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30924726

RESUMO

Background: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, with no effective treatment currently available. The molecular mechanisms of ATC carcinogenesis remain poorly understood. The objective of this study was to investigate the mechanisms and functions of super-enhancer (SE)-driven oncogenic transcriptional addiction in the progression of ATC and identify new drug targets for ATC treatments. Methods: High-throughput chemical screening was performed to identify new drugs inhibiting ATC cell growth. Cell viability assay, colony formation analysis, cell-cycle analysis, and animal study were used to examine the effects of drug treatments on ATC progression. Chromatin immunoprecipitation sequencing was conducted to establish a SE landscape of ATC. Integrative analysis of RNA sequencing, chromatin immunoprecipitation sequencing, and CRISPR/Cas9-mediated gene editing was used to identify THZ1 target genes. Drug combination analysis was performed to assess drug synergy. Patient samples were analyzed to evaluate candidate biomarkers of prognosis in ATC. Results: THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), was identified as a potent anti-ATC compound by high-throughput chemical screening. ATC cells, but not papillary thyroid carcinoma cells, are exceptionally sensitive to CDK7 inhibition. An integrative analysis of both gene expression profiles and SE features revealed that the SE-mediated oncogenic transcriptional amplification mediates the vulnerability of ATC cells to THZ1 treatment. Combining this integrative analysis with functional assays led to the discovery of a number of novel cancer genes of ATC, including PPP1R15A, SMG9, and KLF2. Inhibition of PPP1R15A with Guanabenz or Sephin1 greatly suppresses ATC growth. Significantly, the expression level of PPP1R15A is correlated with CDK7 expression in ATC tissue samples. Elevated expression of PPP1R15A and CDK7 are both associated with poor clinical prognosis in ATC patients. Importantly, CDK7 or PPP1R15A inhibition sensitizes ATC cells to conventional chemotherapy. Conclusions: Taken together, these findings demonstrate transcriptional addiction in ATC pathobiology and identify CDK7 and PPP1R15A as potential biomarkers and therapeutic targets for ATC.

13.
Nucleic Acids Res ; 46(W1): W114-W120, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29771388

RESUMO

Genome-wide association studies have generated over thousands of susceptibility loci for many human complex traits, and yet for most of these associations the true causal variants remain unknown. Tissue/cell type-specific prediction and prioritization of non-coding regulatory variants will facilitate the identification of causal variants and underlying pathogenic mechanisms for particular complex diseases and traits. By leveraging recent large-scale functional genomics/epigenomics data, we develop an intuitive web server, GWAS4D (http://mulinlab.tmu.edu.cn/gwas4d or http://mulinlab.org/gwas4d), that systematically evaluates GWAS signals and identifies context-specific regulatory variants. The updated web server includes six major features: (i) updates the regulatory variant prioritization method with our new algorithm; (ii) incorporates 127 tissue/cell type-specific epigenomes data; (iii) integrates motifs of 1480 transcriptional regulators from 13 public resources; (iv) uniformly processes Hi-C data and generates significant interactions at 5 kb resolution across 60 tissues/cell types; (v) adds comprehensive non-coding variant functional annotations; (vi) equips a highly interactive visualization function for SNP-target interaction. Using a GWAS fine-mapped set for 161 coronary artery disease risk loci, we demonstrate that GWAS4D is able to efficiently prioritize disease-causal regulatory variants.


Assuntos
Doenças Genéticas Inatas , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Software , Biologia Computacional/tendências , Genômica/métodos , Humanos , Polimorfismo de Nucleotídeo Único/genética
14.
Free Radic Biol Med ; 120: 1-12, 2018 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-29524606

RESUMO

Metabolic reprogramming is a hallmark of cancer. Glycine decarboxylase (GLDC), an oxidoreductase, plays an important role in amino acid metabolism. While GLDC promotes tumor initiation and proliferation in non-small cell lung cancer and glioma and it was reported as a putative tumor suppressor gene in gastric cancer, the role of GLDC in hepatocellular carcinoma (HCC) is unknown. In the current study, microarray-based analysis suggested that GLDC expression was low in highly malignant HCC cell lines, and clinicopathological analysis revealed a decrease in GLDC in HCC tumor samples. While the knockdown of GLDC enhanced cancer cell migration and invasion, GLDC overexpression inhibited them. Mechanistic studies revealed that GLDC knockdown increased the levels of reactive oxygen species (ROS) and decreased the ratio of glutathione/oxidized glutathione (GSH/GSSG), which in turn dampened the ubiquitination of cofilin, a key regulator of actin polymerization. Consequently, the protein level of cofilin was elevated, which accounted for the increase in cell migration. The overexpression of GLDC reversed the phenotype. Treatment with N-acetyl-L-cysteine decreased the protein level of cofilin while treatment with H2O2 increased it, further confirming the role of ROS in regulating cofilin degradation. In a tumor xenographic transplant nude mouse model, the knockdown of GLDC promoted intrahepatic metastasis of HCC while GLDC overexpression inhibited it. Our data indicate that GLDC downregulation decreases ROS-mediated ubiquitination of cofilin to enhance HCC progression and intrahepatic metastasis.


Assuntos
Fatores de Despolimerização de Actina/metabolismo , Carcinoma Hepatocelular/enzimologia , Glicina Desidrogenase (Descarboxilante)/metabolismo , Neoplasias Hepáticas/enzimologia , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular , Regulação para Baixo , Xenoenxertos , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/patologia
15.
Mol Cell Proteomics ; 17(4): 607-618, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29371291

RESUMO

The systematic investigation of gene mutation and expression is important to discover novel biomarkers and therapeutic targets in cancers. Here, we integrated genomics, transcriptomics, proteomics, and metabolomics to analyze three hepatocellular carcinoma (HCC) cell lines with differential metastatic potentials. The results revealed the profile of the prometastasis metabolism potentially associated with HCC metastasis. The multiomic analysis identified 12 genes with variations at multiple levels from three metabolic pathways, including glycolysis, starch, and sucrose metabolism, and glutathione metabolism. Furthermore, uridine diphosphate (UDP)-glucose pyrophosphorylase 2 (UGP2), was observed to be persistently up-regulated with increased metastatic potential. UGP2 overexpression promoted cell migration and invasion and enhanced glycogenesis in vitro The role of UGP2 in metastasis was further confirmed using a tumor xenograft mouse model. Taken together, the compendium of multiomic data provides valuable insights in understanding the roles of shifted cellular metabolism in HCC metastasis.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Genômica , Glucose/metabolismo , Glicólise , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Metabolômica , Invasividade Neoplásica/genética , Nucleotidiltransferases/fisiologia , Proteômica , Amido/metabolismo
16.
Biomed Rep ; 4(4): 493-497, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27073640

RESUMO

The aim of the present study was to assess the anti-hepatitis B virus (HBV) effect of Cimicifuga foetida L. (C. foetida) in the patients with chronic hepatitis B (CHB). A total of 60 randomly selected patients with CHB were recruited and divided into groups I and II. The patients in group I received a monotherapy of adefovir (ADV), and the patients in group II received a combination therapy of ADV and C. foetida for >48 weeks. Intrahepatic (IH) HBV covalently closed circular DNA (cccDNA), serum HBV DNA, hepatitis B surface antigen (HBsAg), alanine aminotransferase levels and serum interferon-γ (IFN-γ) and transforming growth factor-ß (TGF-ß) levels were quantified during the test. Following the treatment, a significant reduction of the median IH cccDNA level was identified in group II (P=0.017), but not in group I (P=0.05, and P=0.01 between the 2 groups), and a significant reduction of log10 HBsAg was identified in groups I (P=0.012) and II (P<0.0001, and P=0.20 between the 2 groups). A significant increase of the median serum IFN-γ level was found in group II (P=0.0005), but not in group I (P=0.06, and P=0.004 between the 2 groups), and a significant reduction of the median TGF-ß level was identified in groups I (P<0.0001) and II (P<0.0001, and P=0.002 between the 2 groups). A total of 24 patients in group I, and 27 patients in group II achieved a sustained virological response (P=0.0386), and 20 patients in group I and 24 in group II achieved hepatitis B e antigen seroclearance (P=0.0442). In conclusion, C. foetida can effectively inhibit HBV transcription and replication in the patients by stimulating the release of the inflammatory cytokines, such as IFN-γ.

17.
Nucleic Acids Res ; 44(10): 4934-46, 2016 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-27016738

RESUMO

Mitotic chromosomes are one of the most commonly recognized sub-cellular structures in eukaryotic cells. Yet basic information necessary to understand their structure and assembly, such as their composition, is still lacking. Recent proteomic studies have begun to fill this void, identifying hundreds of RNA-binding proteins bound to mitotic chromosomes. However, by contrast, there are only two RNA species (U3 snRNA and rRNA) that are known to be associated with the mitotic chromosome, suggesting that there are many mitotic chromosome-associated RNAs (mCARs) not yet identified. Here, using a targeted protocol based on 5'-tag sequencing to profile the mammalian mCAR population, we report the identification of 1279 mCARs, the majority of which are ncRNAs, including lncRNAs that exhibit greater conservation across 60 vertebrate species than the entire population of lncRNAs. There is also a significant enrichment of snoRNAs and specific SINE RNAs. Finally, ∼40% of the mCARs are presently unannotated, many of which are as abundant as the annotated mCARs, suggesting that there are also many novel ncRNAs in the mCARs. Overall, the mCARs identified here, together with the previous proteomic and genomic data, constitute the first comprehensive catalogue of the molecular composition of the eukaryotic mitotic chromosomes.


Assuntos
Cromossomos de Mamíferos/química , Mitose/genética , RNA não Traduzido/análise , Células 3T3 , Animais , Sequenciamento de Nucleotídeos em Larga Escala , Metáfase/genética , Camundongos , RNA não Traduzido/química , RNA não Traduzido/isolamento & purificação , Análise de Sequência de RNA , Sitios de Sequências Rotuladas
18.
Sci Rep ; 5: 16938, 2015 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-26582414

RESUMO

Questions remain about the significance of the dose-response relationship between body mass index (BMI) and lung cancer (LC) risk. Pertinent studies were identified through a search in EMBASE and PUBMED from July 2014 until March 2015. The summary relative risk (SRR) and confidence interval (CI) were estimated. The dose-response relationship was assessed using a restricted cubic spline. The overall meta-analysis showed evidence of a nonlinear association between BMI and LC risk (Pnonlinearity < 0.001). The SRR were 0.98 (95%CI: 0.95-1.01) for 25 kg/m(2), 0.91 (95%CI: 0.85-0.98) for 30 kg/m(2) and 0.81 (95% CI: 0.72-0.91) for 35 kg/m(2), with mild between-study heterogeneity (I(2) = 5%). The results of the stratified analysis by gender were comparable to those of the overall meta-analysis. When stratified by smoking status, linear dose-response associations were observed for current smokers, ex-smokers and non-smokers (Pnonlinearity > 0.05), whereas the effects were attenuated when restricting analysis to non-smokers, and at the point of 30 kg/m(2), the SRR was 0.96 (95%CI: 0.86-1.07) for males and 0.95 (95%CI: 0.89-1.02) for females. This meta-analysis provides quantitative evidence that increasing BMI is a protective factor against LC. Keeping normal-to-moderate BMI should be prescribed as an evidence-based lifestyle tip for LC prevention in smokers.


Assuntos
Índice de Massa Corporal , Neoplasias Pulmonares/epidemiologia , Estudos de Coortes , Intervalos de Confiança , Feminino , Heterogeneidade Genética , Humanos , Masculino , Sobrepeso/complicações , Viés de Publicação , Fatores de Risco , Magreza/complicações
19.
Biomed Res Int ; 2014: 469103, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25093167

RESUMO

BACKGROUND: Lung cancer is the most important cause of cancer mortality worldwide, but the underlying mechanisms of this disease are not fully understood. Copy number variations (CNVs) are promising genetic variations to study because of their potential effects on cancer. METHODOLOGY/PRINCIPAL FINDINGS: Here we conducted a pilot study in which we systematically analyzed the association of CNVs in two lung cancer datasets: the Environment And Genetics in Lung cancer Etiology (EAGLE) and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial datasets. We used a preestablished association method to test the datasets separately and conducted a combined analysis to test the association accordance between the two datasets. Finally, we identified 167 risk SNP loci and 22 CNVs associated with lung cancer and linked them with recombination hotspots. Functional annotation and biological relevance analyses implied that some of our predicted risk loci were supported by other studies and might be potential candidate loci for lung cancer studies. CONCLUSIONS/SIGNIFICANCE: Our results further emphasized the importance of copy number variations in cancer and might be a valuable complement to current genome-wide association studies on cancer.


Assuntos
Variações do Número de Cópias de DNA/genética , Estudo de Associação Genômica Ampla , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único/genética , Humanos , Neoplasias Pulmonares/patologia , Risco
20.
Sci Rep ; 4: 6036, 2014 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-25112956

RESUMO

Lung cancer is the most common cause of cancer mortality worldwide, with an estimated 1.4 million deaths each year. Here we report whole-exome sequencing of nine tumor/normal tissue pairs from Chinese patients with non-small cell lung carcinoma (NSCLC). This allows us to identify a number of significantly mutated genes in NSCLC, which were highly enriched in DNA damage repair, NF-κB pathway, JAK/STAT signaling and chromatin modification. Notably, we identify a histone-lysine methyltransferase gene, namely, MLL2, as one of the most significantly mutated genes in our screen. In a following validation study, we identify deleterious mutations of MLL2 in 12 out of 105 (11.4%) NSCLC patients. Additionally, reduced or lost expression of MLL2 was commonly observed in tumor tissues as compared with paired adjacent non-tumor tissues regardless of mutation status. Together, our study defines the landscape of somatic mutations in Chinese NSCLC and supports the role of MLL2 mutation in the pathogenesis of the disease.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas de Ligação a DNA/genética , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , China , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Taxa de Mutação , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Análise de Sobrevida
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