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1.
Front Mol Biosci ; 9: 814240, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35187084

RESUMO

Background: microRNAs (miRNAs) from circulating extracellular vesicles (EVs) have been reported as disease biomarkers. This study aimed to identify the diagnostic value of plasma EV-miRNAs in sepsis. Methods: EVs were separated from the plasma of sepsis patients at admission and healthy controls. The expression of EV-miRNAs was evaluated by microarray and qRT-PCR. Results: A preliminary miRNA microarray of plasma EVs from a discovery cohort of 3 sepsis patients at admission and three healthy controls identified 11 miRNAs with over 2-fold upregulation in sepsis group. Based on this finding, EV samples from a validation cohort of 37 sepsis patients at admission and 25 healthy controls were evaluated for the expression of the 6 miRNAs relating injury and inflammation via qRT-PCR. Elevated expression of miR-483-3p and let-7d-3p was validated in sepsis patients and corroborated in a mouse model of sepsis. miR-483-3p and let-7d-3p levels positively correlated with the disease severity. Additionally, a combination of miR-483-3p and let-7d-3p had diagnostic value for sepsis. Furthermore, bioinformatic analysis and experimental validation showed that miR-483-3p and let-7d-3p target pathways regulating immune response and endothelial function. Conclusion: The present study reveals the potential role of plasma EV-miRNAs in the pathogenesis of sepsis and the utility of combining miR-483-3p and let-7d-3p as biomarkers for early sepsis diagnosis.

2.
Nucl Med Commun ; 43(3): 310-322, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34954763

RESUMO

OBJECTIVE: To develop nomograms that combine clinical characteristics, computed tomographic (CT) features and 18F-fluorodeoxyglucose PET (18F-FDG PET) metabolic parameters for individual prediction of epidermal growth factor receptor (EGFR) mutation status and exon 19 deletion mutation and exon 21 point mutation (21 L858R) subtypes in lung adenocarcinoma. METHODS: In total 124 lung adenocarcinoma patients who underwent EGFR mutation testing and whole-body 18F-FDG PET/CT were enrolled. Each patient's clinical characteristics (age, sex, smoking history, etc.), CT features (size, location, margins, etc.) and four metabolic parameters (SUVmax, SUVmean, MTV and TLG) were recorded and analyzed. Logistic regression analyses were performed to screen for significant predictors of EGFR mutation status and subtypes, and these predictors were presented as easy-to-use nomograms. RESULTS: According to the results of multiple regression analysis, three nomograms for individualized prediction of EGFR mutation status and subtypes were constructed. The area under curve values of three nomograms were 0.852 (95% CI, 0.783-0.920), 0.857 (95% CI, 0.778-0.937) and 0.893 (95% CI, 0.819-0.968) of EGFR mutation vs. wild-type, 19 deletion mutation vs. wild-type and 21 L858R vs. wild-type, respectively. Only calcification showed significant differences between the EGFR 19 deletion and 21 L858R mutations. CONCLUSION: EGFR 21 L858R mutation was more likely to be nonsolid texture with air bronchograms and pleural retraction on CT images. And they were more likely to be associated with lower FDG metabolic activity compared with those wild-types. The sex difference was mainly caused by the 19 deletion mutation, and calcification was more frequent in them.


Assuntos
Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada
4.
Yi Chuan ; 43(9): 822-834, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34702696

RESUMO

Transposable elements (TEs) are the most prevalent elements in mammalian genomes. Although potential risks for genome stability, they are a pool of potential regulatory sequences, chromatin control elements, protein-coding genes, and substrates for evolutionary processes. Consequently, a delicate balance is maintained between the potential benefits and deleterious aspects of TEs, and this balance is mediated by the epigenetic regulatory system. In this review, we introduce the role of heterochromatin associated epigentic modifications such as histone 3 lysine 9 trimethylation (H3K9me3) and DNA methylation in the silencing of TEs as well as epigenetic modifications such as histone 3 lysine 4 monomethylation (H3K4me1) and histone 3 lysine 27 acetylation (H3K27ac) in activation of TEs. Further, we elaborate the functions of TEs as binding sites of transcription factors and as anchors of chromosomal conformation in regulation of gene expression. We introduce the impact of TEs on the process of cell fate determination including natural embryonic development in vivo and artificial cell fate transition in vitro. We discuss the main challenges associated with computational TEs analysis and TEs functions exploration, as well as the different experimental and computational strategies in studying these processes. In all, this article provides a comprehensive review of the research advances and existing problems in study of transposable elements in epigenetic regulatory mechanisms, gene transcriptional regulation, and cell fate determination, thereby providing some references for researchers in the fields.


Assuntos
Elementos de DNA Transponíveis , Epigênese Genética , Animais , Metilação de DNA , Elementos de DNA Transponíveis/genética , Epigenômica , Histonas/metabolismo
5.
Nucleic Acids Res ; 49(16): 9132-9153, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34390351

RESUMO

Transposable elements (TEs) occupy nearly 40% of mammalian genomes and, whilst most are fragmentary and no longer capable of transposition, they can nevertheless contribute to cell function. TEs within genes transcribed by RNA polymerase II can be copied as parts of primary transcripts; however, their full contribution to mature transcript sequences remains unresolved. Here, using long and short read (LR and SR) RNA sequencing data, we show that 26% of coding and 65% of noncoding transcripts in human pluripotent stem cells (hPSCs) contain TE-derived sequences. Different TE families are incorporated into RNAs in unique patterns, with consequences to transcript structure and function. The presence of TE sequences within a transcript is correlated with TE-type specific changes in its subcellular distribution, alterations in steady-state levels and half-life, and differential association with RNA Binding Proteins (RBPs). We identify hPSC-specific incorporation of endogenous retroviruses (ERVs) and LINE:L1 into protein-coding mRNAs, which generate TE sequence-derived peptides. Finally, single cell RNA-seq reveals that hPSCs express ERV-containing transcripts, whilst differentiating subpopulations lack ERVs and express SINE and LINE-containing transcripts. Overall, our comprehensive analysis demonstrates that the incorporation of TE sequences into the RNAs of hPSCs is more widespread and has a greater impact than previously appreciated.


Assuntos
Retrovirus Endógenos/genética , Elementos Nucleotídeos Longos e Dispersos/genética , Células-Tronco Pluripotentes/metabolismo , Transcriptoma , Linhagem Celular , Humanos , RNA não Traduzido/genética , Proteínas de Ligação a RNA/metabolismo
6.
Cell Mol Life Sci ; 78(15): 5847-5863, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34181046

RESUMO

Human induced pluripotent stem cells (iPSCs) technology has been widely applied to cell regeneration and disease modeling. However, most mechanism of somatic reprogramming is studied on mouse system, which is not always generic in human. Consequently, the generation of human iPSCs remains inefficient. Here, we map the chromatin accessibility dynamics during the induction of human iPSCs from urine cells. Comparing to the mouse system, we found that the closing of somatic loci is much slower in human. Moreover, a conserved AP-1 motif is highly enriched among the closed loci. The introduction of AP-1 repressor, JDP2, enhances human reprogramming and facilitates the reactivation of pluripotent genes. However, ESRRB, KDM2B and SALL4, several known pluripotent factors promoting mouse somatic reprogramming fail to enhance human iPSC generation. Mechanistically, we reveal that JDP2 promotes the closing of somatic loci enriching AP-1 motifs to enhance human reprogramming. Furthermore, JDP2 can rescue reprogramming deficiency without MYC or KLF4. These results indicate AP-1 activity is a major barrier to prevent chromatin remodeling during somatic cell reprogramming.


Assuntos
Reprogramação Celular/fisiologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Fator de Transcrição AP-1/metabolismo , Animais , Células Cultivadas , Cromatina/metabolismo , Proteínas F-Box/metabolismo , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Receptores de Estrogênio/metabolismo , Fatores de Transcrição/metabolismo
7.
Nature ; 591(7849): 322-326, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658714

RESUMO

The RNA modification N6-methyladenosine (m6A) has critical roles in many biological processes1,2. However, the function of m6A in the early phase of mammalian development remains poorly understood. Here we show that the m6A reader YT521-B homology-domain-containing protein 1 (YTHDC1) is required for the maintenance of mouse embryonic stem (ES) cells in an m6A-dependent manner, and that its deletion initiates cellular reprogramming to a 2C-like state. Mechanistically, YTHDC1 binds to the transcripts of retrotransposons (such as intracisternal A particles, ERVK and LINE1) in mouse ES cells and its depletion results in the reactivation of these silenced retrotransposons, accompanied by a global decrease in SETDB1-mediated trimethylation at lysine 9 of histone H3 (H3K9me3). We further demonstrate that YTHDC1 and its target m6A RNAs act upstream of SETDB1 to repress retrotransposons and Dux, the master inducer of the two-cell stage (2C)-like program. This study reveals an essential role for m6A RNA and YTHDC1 in chromatin modification and retrotransposon repression.


Assuntos
Adenosina/análogos & derivados , Inativação Gênica , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , RNA/genética , Retroelementos/genética , Adenosina/metabolismo , Animais , Cromatina/química , Cromatina/genética , Cromatina/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/química , Histonas/metabolismo , Masculino , Camundongos , RNA/química , RNA/metabolismo , Proteínas Repressoras/metabolismo
8.
Nat Commun ; 12(1): 1456, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674594

RESUMO

Transposable elements (TEs) make up a majority of a typical eukaryote's genome, and contribute to cell heterogeneity in unclear ways. Single-cell sequencing technologies are powerful tools to explore cells, however analysis is typically gene-centric and TE expression has not been addressed. Here, we develop a single-cell TE processing pipeline, scTE, and report the expression of TEs in single cells in a range of biological contexts. Specific TE types are expressed in subpopulations of embryonic stem cells and are dynamically regulated during pluripotency reprogramming, differentiation, and embryogenesis. Unexpectedly, TEs are expressed in somatic cells, including human disease-specific TEs that are undetectable in bulk analyses. Finally, we apply scTE to single-cell ATAC-seq data, and demonstrate that scTE can discriminate cell type using chromatin accessibly of TEs alone. Overall, our results classify the dynamic patterns of TEs in single cells and their contributions to cell heterogeneity.


Assuntos
Elementos de DNA Transponíveis/genética , Heterogeneidade Genética , Análise de Célula Única/métodos , Animais , Cromatina , Células-Tronco Embrionárias , Gastrulação , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Organogênese/genética
9.
Cell ; 184(7): 1895-1913.e19, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33657410

RESUMO

A dysfunctional immune response in coronavirus disease 2019 (COVID-19) patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 196 COVID-19 patients and controls and created a comprehensive immune landscape with 1.46 million cells. The large dataset enabled us to identify that different peripheral immune subtype changes are associated with distinct clinical features, including age, sex, severity, and disease stages of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in diverse epithelial and immune cell types, accompanied by dramatic transcriptomic changes within virus-positive cells. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis of and developing effective therapeutic strategies for COVID-19.


Assuntos
COVID-19/imunologia , Megacariócitos/imunologia , Monócitos/imunologia , RNA Viral , SARS-CoV-2/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , China , Estudos de Coortes , Citocinas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , RNA Viral/isolamento & purificação , Análise de Célula Única , Transcriptoma/imunologia , Adulto Jovem
10.
Clin Lab ; 67(2)2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33616328

RESUMO

BACKGROUND: Classic homocystinuria is caused by cystathionine beta synthase deficiency owing to genetic mutations. The most common symptoms are ectopia lentis, osteoporosis, thrombosis, and mental retardation. This disease is prone to misdiagnosis and delayed diagnosis. METHODS: Here, we report a 19-year-old woman with Marfan's morphotype, high blood homocysteine, and a history of ectopia lentis. Total homocysteine levels became normal following treatment with vitamin therapy. RESULTS: Genetic analysis revealed two heterozygous nucleotide mutations in the parents. The mutation from the patient's father had not been described previously. CONCLUSIONS: Screening for blood homocysteine should be performed early. Early diagnosis and treatment can prevent related symptoms.


Assuntos
Homocistinúria , Adulto , Cistationina beta-Sintase/genética , Feminino , Testes Genéticos , Heterozigoto , Homocistinúria/diagnóstico , Homocistinúria/genética , Humanos , Mutação , Adulto Jovem
11.
Protein Cell ; 12(9): 717-733, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33314005

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is spread primary via respiratory droplets and infects the lungs. Currently widely used cell lines and animals are unable to accurately mimic human physiological conditions because of the abnormal status of cell lines (transformed or cancer cells) and species differences between animals and humans. Organoids are stem cell-derived self-organized three-dimensional culture in vitro and model the physiological conditions of natural organs. Here we showed that SARS-CoV-2 infected and extensively replicated in human embryonic stem cells (hESCs)-derived lung organoids, including airway and alveolar organoids which covered the complete infection and spread route for SARS-CoV-2 within lungs. The infected cells were ciliated, club, and alveolar type 2 (AT2) cells, which were sequentially located from the proximal to the distal airway and terminal alveoli, respectively. Additionally, RNA-seq revealed early cell response to virus infection including an unexpected downregulation of the metabolic processes, especially lipid metabolism, in addition to the well-known upregulation of immune response. Further, Remdesivir and a human neutralizing antibody potently inhibited SARS-CoV-2 replication in lung organoids. Therefore, human lung organoids can serve as a pathophysiological model to investigate the underlying mechanism of SARS-CoV-2 infection and to discover and test therapeutic drugs for COVID-19.


Assuntos
Células Epiteliais Alveolares/metabolismo , COVID-19/patologia , Pulmão/metabolismo , SARS-CoV-2/fisiologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/uso terapêutico , Células Epiteliais Alveolares/citologia , Células Epiteliais Alveolares/virologia , Anticorpos Neutralizantes/farmacologia , Anticorpos Neutralizantes/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/virologia , Regulação para Baixo , Descoberta de Drogas , Células-Tronco Embrionárias Humanas/citologia , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Imunidade , Metabolismo dos Lipídeos , Pulmão/citologia , Pulmão/virologia , RNA Viral/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , Replicação Viral/efeitos dos fármacos
12.
Med Phys ; 48(1): 264-272, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33159809

RESUMO

PURPOSE: The accurate segmentation of liver and liver tumors from CT images can assist radiologists in decision-making and treatment planning. The contours of liver and liver tumors are currently obtained by manual labeling, which is time-consuming and subjective. Computer-aided segmentation methods have been widely used in the segmentation of liver and liver tumors. However, due to the diversity of shape, volume, and image intensity, the segmentation is still a difficult task. In this study, we present a Spatial Feature Fusion Convolutional Network (SFF-Net) to automatically segment liver and liver tumors from CT images. METHODS: First, we extract side-outputs at each convolutional block in SFF-Net to make full use of multiscale features. Second, skip-connections are added in the down-sampling phase, therefore, the spatial information can be efficiently transferred to later layers. Third, we present feature fusion blocks (FFBs) to merge spatial features and high-level semantic features from early layers and later layers, respectively. Finally, a fully connected 3D conditional random fields (CRFs) is applied to refine the liver and liver tumor segmentation results. RESULTS: We test our method on the MICCAI 2017 Liver Tumor Segmentation (LiTS) challenge dataset. The Dice Global (DG) score, Dice per case (DC) score, Volume Overlap Error (VOE), Average Symmetric Surface Distance (ASSD), and tumor precision score are calculated to evaluate the liver and liver tumor segmentation accuracies. For the liver segmentation, DG is 0.955; DC is 0.937; VOE is 0.106; and ASSD is 3.678. For the tumor segmentation, DG is 0.746; DC is 0.592; VOE is 0.416; ASSD is 1.585 and the tumor precision score is 0.369. CONCLUSIONS: The SFF-Net learns more spatial information by adding skip-connections and feature fusion blocks. The experiments validate that our method can accurately segment liver and liver tumors from CT images.


Assuntos
Neoplasias Hepáticas , Redes Neurais de Computação , Humanos , Processamento de Imagem Assistida por Computador , Neoplasias Hepáticas/diagnóstico por imagem , Tomografia Computadorizada por Raios X
13.
Cell ; 182(3): 734-743.e5, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32643603

RESUMO

COVID-19, caused by SARS-CoV-2, is a virulent pneumonia, with >4,000,000 confirmed cases worldwide and >290,000 deaths as of May 15, 2020. It is critical that vaccines and therapeutics be developed very rapidly. Mice, the ideal animal for assessing such interventions, are resistant to SARS-CoV-2. Here, we overcome this difficulty by exogenous delivery of human ACE2 with a replication-deficient adenovirus (Ad5-hACE2). Ad5-hACE2-sensitized mice developed pneumonia characterized by weight loss, severe pulmonary pathology, and high-titer virus replication in lungs. Type I interferon, T cells, and, most importantly, signal transducer and activator of transcription 1 (STAT1) are critical for virus clearance and disease resolution in these mice. Ad5-hACE2-transduced mice enabled rapid assessments of a vaccine candidate, of human convalescent plasma, and of two antiviral therapies (poly I:C and remdesivir). In summary, we describe a murine model of broad and immediate utility to investigate COVID-19 pathogenesis and to evaluate new therapies and vaccines.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/prevenção & controle , Modelos Animais de Doenças , Pandemias/prevenção & controle , Pneumonia Viral/patologia , Pneumonia Viral/prevenção & controle , Vacinação , Enzima de Conversão de Angiotensina 2 , Animais , COVID-19 , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Pulmão/patologia , Pulmão/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , SARS-CoV-2 , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Organismos Livres de Patógenos Específicos , Transdução Genética , Células Vero , Carga Viral , Replicação Viral
15.
Nat Cell Biol ; 22(6): 651-662, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32393886

RESUMO

BMP4 regulates a plethora of developmental processes, including the dorsal-ventral axis and neural patterning. Here, we report that BMP4 reconfigures the nuclear architecture during the primed-to-naive transition (PNT). We first established a BMP4-driven PNT and show that BMP4 orchestrates the chromatin accessibility dynamics during PNT. Among the loci opened early by BMP4, we identified Zbtb7a and Zbtb7b (Zbtb7a/b) as targets that drive PNT. ZBTB7A/B in turn facilitate the opening of naive pluripotent chromatin loci and the activation of nearby genes. Mechanistically, ZBTB7A not only binds to chromatin loci near to the genes that are activated, but also strategically occupies those that are silenced, consistent with a role of BMP4 in both activating and suppressing gene expression during PNT at the chromatin level. Our results reveal a previously unknown function of BMP4 in regulating nuclear architecture and link its targets ZBTB7A/B to chromatin remodelling and pluripotent fate control.


Assuntos
Proteína Morfogenética Óssea 4/metabolismo , Cromatina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células-Tronco Embrionárias/citologia , Camadas Germinativas/citologia , Células-Tronco Pluripotentes/citologia , Fatores de Transcrição/metabolismo , Animais , Blastocisto/citologia , Blastocisto/metabolismo , Proteína Morfogenética Óssea 4/genética , Diferenciação Celular , Células Cultivadas , Cromatina/genética , Proteínas de Ligação a DNA/genética , Células-Tronco Embrionárias/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Camadas Germinativas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Células-Tronco Pluripotentes/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética
16.
Med Care ; 58(5): 461-467, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31985586

RESUMO

BACKGROUND: Prognostic modeling in health care has been predominantly statistical, despite a rapid growth of literature on machine-learning approaches in biological data analysis. We aim to assess the relative importance of variables in predicting overall survival among patients with non-small cell lung cancer using a Variable Importance (VIMP) approach in a machine-learning Random Survival Forest (RSF) model for posttreatment planning and follow-up. METHODS: A total of 935 non-small cell lung cancer patients were randomly and equally divided into 2 training and testing cohorts in an RFS model. The prognostic variables included age, sex, race, the TNM Classification of Malignant Tumors (TNM) stage, smoking history, Eastern Cooperative Oncology Group performance status, histologic type, treatment category, maximum standard uptake value of whole-body tumor (SUVmaxWB), whole-body metabolic tumor volume (MTVwb), and Charlson Comorbidity Index. The VIMP was calculated using a permutation method in the RSF model. We further compared the VIMP of the RSF model to that of the standard Cox survival model. We examined the order of VIMP with the differential functional forms of the variables. RESULTS: In both the RSF and the standard Cox models, the most important variables are treatment category, TNM stage, and MTVwb. The order of VIMP is more robust in RSF model than in Cox model regarding the differential functional forms of the variables. CONCLUSIONS: The RSF VIMP approach can be applied alongside with the Cox model to further advance the understanding of the roles of prognostic factors, and improve prognostic precision and care efficiency.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/mortalidade , Aprendizado de Máquina , Modelos Estatísticos , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Comorbidade , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prognóstico , Compostos Radiofarmacêuticos , Distribuição Aleatória , Estudos Retrospectivos , Carga Tumoral , Imagem Corporal Total
17.
Cell Rep ; 30(1): 25-36.e6, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31914391

RESUMO

Known as a histone H3K9 methyltransferase, SETDB1 is essential for embryonic development and pluripotent inner cell mass (ICM) establishment. However, its function in pluripotency regulation remains elusive. In this study, we find that under the "ground state" of pluripotency with two inhibitors (2i) of the MEK and GSK3 pathways, Setdb1-knockout fails to induce trophectoderm (TE) differentiation as in serum/LIF (SL), indicating that TE fate restriction is not the direct target of SETDB1. In both conditions, Setdb1-knockout activates a group of genes targeted by SETDB1-mediated H3K9 methylation, including Dux. Notably, Dux is indispensable for the reactivation of 2C-like state genes upon Setdb1 deficiency, delineating the mechanistic role of SETDB1 in totipotency restriction. Furthermore, Setdb1-null ESCs maintain pluripotent marker (e.g., Nanog) expression in the 2i condition. This "ground state" Setdb1-null population undergoes rapid cell death by activating Ripk3 and, subsequently, RIPK1/RIPK3-dependent necroptosis. These results reveal the essential role of Setdb1 between totipotency and pluripotency transition.


Assuntos
Linhagem da Célula , Histona-Lisina N-Metiltransferase/metabolismo , Células-Tronco Pluripotentes/metabolismo , Trofoblastos/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Ectoderma/metabolismo , Técnicas de Inativação de Genes , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Proteína Homeobox Nanog/metabolismo , Necroptose , Células-Tronco Pluripotentes/citologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Células-Tronco Totipotentes/metabolismo
18.
Medicine (Baltimore) ; 98(41): e17455, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593102

RESUMO

INTRODUCTION: Behçet disease (BD) is an autoimmune disorder characterized by oral aphthosis, genital aphthosis, ocular lesions, and arthritis. However, other fatal complications are often misdiagnosed, which implies that the early diagnosis of the disease is important for a good prognosis. PATIENT CONCERNS: A 51-year-old man complained of hematemesis for 5 hours and syncope once. DIAGNOSIS: BD as demonstrated by esophageal ulcer and aortic aneurysm rupture. INTERVENTIONS: Surgeries were conducted to repair the thoracic aortic aneurysm, proton-pump inhibitor was used to reduce acid secretion, antibiotics were applied for anti-infective therapy, and immunosuppressor was administered to control the injuries of BD. OUTCOMES: The patient was discharged and his medication dosage was reduced gradually until the minimum maintenance dose. In the follow-ups, the gastric ulcer and vascular aneurysm were not found. CONCLUSION: We presented a rare case of BD with the concurrence of huge esophageal ulcer and thoracic aortic aneurysms rupture, which helped us to diagnose BD at the early stage, while confronting atypical manifestations.


Assuntos
Aneurisma da Aorta Torácica/etiologia , Ruptura Aórtica/etiologia , Síndrome de Behçet/complicações , Doenças do Esôfago/etiologia , Hemorragia Gastrointestinal/etiologia , Humanos , Masculino , Pessoa de Meia-Idade
19.
Cell Death Dis ; 10(4): 255, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30874538

RESUMO

Hepatocellular carcinoma (HCC), a common liver malignancy worldwide, has high morbidity and mortality. ß-Thujaplicin, a tropolone derivative, has been used in some health-care products and clinical adjuvant drugs, but its use for HCC is unknown. In this study, we found that ß-Thujaplicin inhibits the growth of HCC cells, but not normal liver cells, with nanomolar potency. Mechanistically, we found that ß-Thujaplicin could induce autophagy, as judged by western blot, confocal microscopy, and transmission electron microscopy. Further using ß-Thujaplicin combined with an autophagy blocker or agonist treatment HepG2 cells, we found that ß-Thujaplicin induced autophagic cell death (ACD) mediated by ROS caused inhibition of the Akt-mTOR signaling pathway. Moreover, ß-Thujaplicin triggered HepG2 apoptosis and increased cleaved PARP1, cleaved caspase-3, and Bax/Bcl-2 ratio, which indicated that ß-Thujaplicin induced apoptosis mediated by the mitochondrial-dependent pathway. We also found that increased expression of p21 and decreased expression of CDK7, Cyclin D1, and Cyclin A2 participating in ß-Thujaplicin caused the S-phase arrest. It seems that ß-Thujaplicin exerts these functions by ROS-mediated p38/ERK MAPK but not by JNK signaling pathway activation. Consistent with in vitro findings, our in vivo study verified that ß-Thujaplicin treatment significantly reduced HepG2 tumor xenograft growth. Taken together these findings suggest that ß-Thujaplicin have an ability of anti-HCC cells and may conducively promote the development of novel anti-cancer agents.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Morte Celular Autofágica/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Monoterpenos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Tropolona/análogos & derivados , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Idoso , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/genética , Morte Celular Autofágica/genética , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Autofagossomos/ultraestrutura , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/ultraestrutura , Células Cultivadas , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/ultraestrutura , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Monoterpenos/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/genética , Espécies Reativas de Oxigênio/metabolismo , Pontos de Checagem da Fase S do Ciclo Celular/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Transplante Heterólogo , Tropolona/farmacologia , Tropolona/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno/genética
20.
Nat Commun ; 10(1): 34, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30604769

RESUMO

The majority of mammalian genomes are devoted to transposable elements (TEs). Whilst TEs are increasingly recognized for their important biological functions, they are a potential danger to genomic stability and are carefully regulated by the epigenetic system. However, the full complexity of this regulatory system is not understood. Here, using mouse embryonic stem cells, we show that TEs are suppressed by heterochromatic marks like H3K9me3, and are also labelled by all major types of chromatin modification in complex patterns, including bivalent activatory and repressive marks. We identified 29 epigenetic modifiers that significantly deregulated at least one type of TE. The loss of Setdb1, Ncor2, Rnf2, Kat5, Prmt5, Uhrf1, and Rrp8 caused widespread changes in TE expression and chromatin accessibility. These effects were context-specific, with different chromatin modifiers regulating the expression and chromatin accessibility of specific subsets of TEs. Our work reveals the complex patterns of epigenetic regulation of TEs.


Assuntos
Cromatina/metabolismo , Elementos de DNA Transponíveis/genética , Epigênese Genética , Histonas/metabolismo , Animais , Linhagem Celular , Cromatina/genética , Metilação de DNA/genética , Técnicas de Silenciamento de Genes , Código das Histonas , Histonas/genética , Camundongos , Células-Tronco Embrionárias Murinas
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