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2.
Protein Cell ; 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31814083

RESUMO

The author would like to add the below information in this correction. A similar study from Chao Lu group was published online on 5 September 2019 in Nature, entitled "The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape" (Weinberg et al., 2019). Although both the studies reported the preferential recognition of H3K36me2 by DNMT3A PWWP, ours in addition uncovered a stimulation function by such interaction on the activity of DNMT3A. On the disease connections, we used a NSD2 gain-of-function model which led to the discovery of potential therapeutic implication of DNA inhibitors in the related cancers, while the other study only used NSD1 and DNMT3A loss-of-function models.

3.
Leuk Lymphoma ; : 1-8, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842651

RESUMO

Genetic variants have been identified in the majority of myelodysplastic syndromes (MDS) patients and have considerably influenced the diagnosis, classification, risk stratification and treatment of MDS. To explore the prognostic significance of genomic variants and build a new prognostic scoring model, we performed next-generation sequencing of 51 known genes in 499 Chinese patients with MDS. Ultimately, the TP53, GATA2, DNMT3A, age and the revised International Prognostic Scoring System (IPSS-R) risk stratification were included in a new Cox model and divided into three prognostic categories, and had a better prediction of overall survival. The C-index of the new prognostic scoring model (0.772) was clearly better than IPSS-R risk stratification (0.717), which was validated in 163 cases. Moreover, the new model was also suitable for the prediction of OS for patients undergoing allogeneic hematopoietic stem cell transplantation. The inclusion of genomic variants and age into the IPSS-R could improve prognostic algorithms for MDS patients.

6.
Mar Drugs ; 17(8)2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430922

RESUMO

Two new cembrane-type diterpenoids, lobophytins A (1) and B (3), and four new prostaglandins, (5E)-PGB2 (10), (5E)-13,14-dihydro-PGB2 (11), 13,14-dihydro-PGB2 (12) and 13,14-dihydro-PGB2-Me (13), together with ten known compounds were isolated from the soft coral Lobophytum sarcophytoides. The structures of these new secondary metabolites were identified by high resolution mass spectrometry (HR-ESIMS), nuclear magnetic resonance (NMR) and electron circular dichroism (ECD) analyses, as well as the modified Mosher's method. Compounds 6, 7, 9, 10, 12, 13, 15 and 16 showed potential anti-inflammatory activity by inhibiting the production of nitric oxide (NO) in RAW264.7 cells that were activated by lipopolysaccharide, with IC50 values ranging from 7.1 to 32.1 µM and were better than the positive control indomethacin, IC50 = 39.8 µM.


Assuntos
Antozoários/química , Anti-Inflamatórios/farmacologia , Diterpenos/farmacologia , Prostaglandinas/farmacologia , Animais , Linhagem Celular , Lipopolissacarídeos/farmacologia , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas/métodos , Camundongos , Óxido Nítrico/metabolismo , Células RAW 264.7
8.
Sci Adv ; 5(3): eaat9820, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30854423

RESUMO

Human endogenous retroviruses (HERVs) play pivotal roles in the development of breast cancer. However, the detailed mechanisms of noncoding HERVs remain elusive. Here, our genome-wide transcriptome analysis of HERVs revealed that a primate long noncoding RNA, which we dubbed TROJAN, was highly expressed in human triple-negative breast cancer (TNBC). TROJAN promoted TNBC proliferation and invasion and indicated poor patient outcomes. We further confirmed that TROJAN could bind to ZMYND8, a metastasis-repressing factor, and increase its degradation through the ubiquitin-proteasome pathway by repelling ZNF592. TROJAN also epigenetically up-regulated metastasis-related genes in multiple cell lines. Correlations between TROJAN and ZMYND8 were subsequently confirmed in clinical samples. Furthermore, our study verified that antisense oligonucleotide therapy targeting TROJAN substantially suppressed TNBC progression in vivo. In conclusion, the long noncoding RNA TROJAN promotes TNBC progression and serves as a potential therapeutic target.

9.
Chem Commun (Camb) ; 55(10): 1438-1441, 2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30644459

RESUMO

Trichobamide A (1), a novel pyrrocidine alkaloid with an unprecedented tetrahydro-5H-furo[2,3-b]pyrrol-5-one moiety, was isolated from the ascidian-derived fungus Trichobotrys effuse 4729. Trichobamide A (1) showed significant inhibition of the proliferation of two glioma cell lines, U251 and SNB19. It induced the up-regulation of P53 expression, which in turn induces the up-regulation of downstream pro-apoptotic gene expression and the down-regulation of anti-apoptotic gene expression.


Assuntos
Antineoplásicos/química , Fungos/química , Pirróis/química , Animais , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Regulação para Baixo/efeitos dos fármacos , Fungos/isolamento & purificação , Fungos/metabolismo , Glioma/metabolismo , Glioma/patologia , Humanos , Espectroscopia de Ressonância Magnética , Conformação Molecular , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pirróis/isolamento & purificação , Pirróis/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos dos fármacos , Urocordados/microbiologia
10.
Nat Prod Res ; 33(9): 1262-1268, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-29726718

RESUMO

Seven polyketides, including two new isochromanes, penisochromanes A and B (1 and 2), as well as five known compounds were obtained from an ascidian-derived fungus Penicillium sp. 4829. Their structures were identified by extensive spectroscopic analyses. The structures of compounds 1 and 3 were further determined by the X-ray crystallography. Compounds 1 and 2 were the first example of isochromane with three adjacent oxy substituents in natural source. Compound 4 exhibited selective activities against two Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis, with MIC values 6.25 and 12.5 µM, respectively.


Assuntos
Penicillium/química , Policetídeos/isolamento & purificação , Urocordados/microbiologia , Animais , Antibacterianos/isolamento & purificação , Testes de Sensibilidade Microbiana , Policetídeos/química , Policetídeos/farmacologia
11.
Clin Lymphoma Myeloma Leuk ; 19(2): e107-e115, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30555035

RESUMO

BACKGROUND: FLT3 mutations have been well-studied in acute myeloid leukemia (AML), and the detection of the FLT3 gene has become a clinical routine. However, it has not been fully analyzed in other hematologic malignancies, such as myelodysplastic syndromes (MDS). MATERIALS AND METHODS: Between 2010 and 2016, 304 adult patients with de novo MDS had the FLT3 sequence tested on their bone marrow sample. With 279 patients who had follow-up information, we also analyzed the impact of clinical and laboratory characteristics as well as FLT3 mutation status and treatment on prognosis. RESULTS: We found that the transformation rate was 3 (42.9%) of 7 patients in the FLT3-ITD-positive group, compared with 31 (10.4%) of 297 among FLT3-ITD-negative patients (P = .033). The median progression-free survival of the FLT3-ITD mutated and wild-type groups were 43 days and 363.5 days, respectively (P < .0001). The median overall survival (OS) of the 2 groups were 218 days and 410.5 days, respectively (P < .0001). We also found that 5 factors had independent prognostic impact on OS: white blood cell counts, bone marrow blast percentage, cytogenetics, transplantation status, and FLT3-ITD mutation. Furthermore, compared with the transformation group, the non-progression group was younger (P = .034), with a lower platelet count (P = .022), a lower bone marrow blast percentage (P = .001), a lower FLT3-ITD incidence (P = .007), and a longer OS (P < .0001). CONCLUSIONS: When observed at the MDS stage, patients harboring FLT3-ITD mutations had higher AML transformation rate, quicker disease progression, and shorter survival than wild-type patients. Nevertheless, once the disease progressed to leukemia, the impact of FLT3-ITD mutations on prognosis was slight. In addition, the prognosis of secondary AML was very poor whether there was an FLT3-ITD mutation or not.

12.
Bone Marrow Transplant ; 54(2): 236-243, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29942002

RESUMO

To investigate the prognosis of patients with adult B-cell acute lymphoblastic leukemia (B-ALL) with Ikaros family zinc-finger 1 (IKZF1) mutation and determine the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in improving the clinical outcome, we detected the IKZF1 mutation and BCR-ABL fusion gene at diagnosis in the bone marrow of 164 adult patients with B-ALL, and analyzed the clinical data of these patients retrospectively. Our analysis showed that grade III-IV acute graft-versus-host disease and IKZF1 mutation in the transplantation group and age and IKZF1 mutation in the non-transplantation group were independent factors for poor prognosis by univariate and multivariate analyses.The 3-year overall survival (OS) and leukemia-free survival (LFS) rates were much lower in the IKZF1+/BCR-ABL+ subgroup than in the IKZF1+/BCR-ABL- and IKZF1-/BCR-ABL- subgroups in both the transplantation and non-transplantation groups. The 3-year OS and LFS rates were significantly higher in the transplantation group than in the non-transplantation group with IKZF1 mutation.The study demonstrated that IKZF1 mutation was an independent factor indicating the poor prognosis of adult B-ALL and much worse prognosis in the BCR-ABL+ subgroup in both non-transplantation and transplantation groups. However, allo-HSCT significantly improved the OS and LFS of patients and also their clinical outcomes.

14.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 26(6): 1663-1667, 2018 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-30501701

RESUMO

OBJECTIVE: To investigate the feasibility of sensitive and quantitative detection of MYD88 gene L265P mutation in lymphoma patients by using ARMS-PCR combined with capillary electrophoresis. METHODS: ARMS-PCR amplified MYD88 gene was analyzed by capillary electrophoresis in ABI 3730 sequencer; Exon 5 of the same gene was sequenced bi-directionally as reported. RESULTS: The sensitivity of detection L265P mutations by the ARMS-PCR combined with capillary electrophoresis and direct sequencing was 0.2% and 5%, respectively, according to the detection of the gradient-diluted plasmid standards. The detection rate of 184 patients was 13.59% and 8.28%, respectively (p<0.001). Moreover, the former method can successfully detect the mutation ratio(R2=0.979), and the repeatabilities (CV=2.86%, 1.94%, 5.49%) are acceptable. CONCLUSION: ARMS-PCR combined with capillary electrophoresis can quantitatively detect the MYD88 gene L265P mutation, and the detection sensitivity is significantly higher than sanger sequencing. As a supplement to the latter, it can effectively lead to the earlier diagnose and monitoring of minimal residual disease.


Assuntos
Análise Mutacional de DNA , Linfoma , Fator 88 de Diferenciação Mieloide/genética , Eletroforese Capilar , Humanos , Mutação , Reação em Cadeia da Polimerase
15.
Clin Appl Thromb Hemost ; : 1076029618790696, 2018 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-30103613

RESUMO

Inherited thrombocytopenia is a group of hereditary diseases with a reduction in platelet count as the main clinical manifestation. Clinically, there is an urgent need for a convenient and rapid diagnosis method. We introduced a high-throughput, next-generation sequencing (NGS) platform into the routine diagnosis of patients with unexplained thrombocytopenia and analyzed the gene sequencing results to evaluate the value of NGS technology in the screening and diagnosis of inherited thrombocytopenia. From a cohort of 112 patients with thrombocytopenia, we screened 43 patients with hereditary features. For the blood samples of these 43 patients, a gene sequencing platform for hemorrhagic and thrombotic diseases comprising 89 genes was used to perform gene detection using NGS technology. When we combined the screening results with clinical features and other findings, 15 (34.9%) of 43patients were diagnosed with inherited thrombocytopenia. In addition, 19 pathogenic variants, including 8 previously unreported variants, were identified in these patients. Through the use of this detection platform, we expect to establish a more effective diagnostic approach to such disorders.

16.
Proc Natl Acad Sci U S A ; 115(29): 7611-7616, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-29967166

RESUMO

Brain "inflammaging," a low-grade and chronic inflammation, is a major hallmark for aging-related neurodegenerative diseases. Here, by profiling H3K27ac and gene expression patterns in human and mouse brains, we found that age-related up-regulated (Age-Up) and down-regulated (Age-Down) genes have distinct H3K27ac patterns. Although both groups show promoter H3K27ac, the Age-Up genes, enriched for inflammation-related functions, are additionally marked by broad H3K27ac distribution over their gene bodies, which is progressively reduced during aging. Age-related gene expression changes can be predicted by gene-body H3K27ac level. Contrary to the presumed transcription activation function of promoter H3K27ac, we found that broad gene-body hyper H3K27ac suppresses overexpression of inflammaging genes. Altogether, our findings revealed opposite regulations by H3K27ac of Age-Up and Age-Down genes and a mode of broad gene-body H3K27ac in repressing transcription.


Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Histonas/metabolismo , Regiões Promotoras Genéticas , Transcrição Genética , Transcriptoma , Acetilação , Envelhecimento/genética , Animais , Perfilação da Expressão Gênica , Histonas/genética , Humanos , Inflamação/genética , Inflamação/metabolismo , Camundongos
18.
Cancer Res ; 78(12): 3190-3206, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29700004

RESUMO

Alternative splicing (AS) and its regulation play critical roles in cancer, yet the dysregulation of AS and its molecular bases in breast cancer development have not yet been elucidated. Using an in vivo CRISPR screen targeting RNA-binding proteins, we identified PHD finger protein 5A (PHF5A) as a key splicing factor involved in tumor progression. PHF5A expression was frequently upregulated in breast cancer and correlated with poor survival, and knockdown of PHF5A significantly suppressed cell proliferation, migration, and tumor formation. PHF5A was required for SF3b spliceosome stability and linked the complex to histones, and the PHF5A-SF3b complex modulated AS changes in apoptotic signaling. In addition, expression of a short truncated FAS-activated serine/threonine kinase (FASTK) protein was increased after PHF5A ablation and facilitated Fas-mediated apoptosis. This PHF5A-modulated FASTK-AS axis was widely present in breast cancer specimens, particularly those of the triple-negative subtype. Taken together, our findings reveal that PHF5A serves as an epigenetic suppressor of apoptosis and thus provides a mechanistic basis for breast cancer progression and may be a valuable therapeutic target.Significance: This study provides an epigenetic mechanistic basis for the aggressive biology of breast cancer and identifies a translatable therapeutic target. Cancer Res; 78(12); 3190-206. ©2018 AACR.


Assuntos
Apoptose/genética , Neoplasias da Mama/genética , Proteínas de Transporte/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Adulto , Idoso , Idoso de 80 Anos ou mais , Processamento Alternativo/genética , Animais , Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Progressão da Doença , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Histonas/genética , Histonas/metabolismo , Humanos , Camundongos , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Processamento de RNA/metabolismo , Transdução de Sinais/genética , Spliceossomos/metabolismo , Análise de Sobrevida , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Mol Cell ; 69(6): 1028-1038.e6, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29547716

RESUMO

N6-methyladenosine (m6A) is an abundant modification in eukaryotic mRNA, regulating mRNA dynamics by influencing mRNA stability, splicing, export, and translation. However, the precise m6A regulating machinery still remains incompletely understood. Here we demonstrate that ZC3H13, a zinc-finger protein, plays an important role in modulating RNA m6A methylation in the nucleus. We show that knockdown of Zc3h13 in mouse embryonic stem cell significantly decreases global m6A level on mRNA. Upon Zc3h13 knockdown, a great majority of WTAP, Virilizer, and Hakai translocate to the cytoplasm, suggesting that Zc3h13 is required for nuclear localization of the Zc3h13-WTAP-Virilizer-Hakai complex, which is important for RNA m6A methylation. Finally, Zc3h13 depletion, as does WTAP, Virilizer, or Hakai, impairs self-renewal and triggers mESC differentiation. Taken together, our findings demonstrate that Zc3h13 plays a critical role in anchoring WTAP, Virilizer, and Hakai in the nucleus to facilitate m6A methylation and to regulate mESC self-renewal.


Assuntos
Adenosina/análogos & derivados , Núcleo Celular/metabolismo , Proliferação de Células , Autorrenovação Celular , Células-Tronco Embrionárias Murinas/metabolismo , Proteínas Nucleares/metabolismo , Processamento Pós-Transcricional do RNA , RNA Mensageiro/metabolismo , Regiões 3' não Traduzidas , Transporte Ativo do Núcleo Celular , Adenosina/metabolismo , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular , Diferenciação Celular , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Humanos , Metilação , Camundongos , Proteínas Nucleares/genética , Estabilidade de RNA , RNA Mensageiro/genética , Transdução de Sinais , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
20.
Hematology ; 23(3): 131-138, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28876197

RESUMO

OBJECTIVE: Two distinct forms of FMS-like tyrosine kinase 3 (FLT3) mutations, internal tandem duplication (ITD) in the juxtamembrane domain and point mutation within the activation loop of the tyrosine kinase domain (TKD), have been identified in considerable number of patients with AML. This study was aimed to analyze the impacts of these mutations on clinical outcomes, and assess the efficacy of different therapeutic regimens (allo-HSCT, sorafenib, or conventional chemotherapy) for AML patients with FLT3 mutations after the standard induction therapy. MATERIALS AND METHODS: We analyzed DNA samples from 158 consecutive de novo AML patients (18-60 years, excluding APL) with FLT3 mutations between July 2010 and October 2015. RESULTS: We found that AML patients with FLT3-TKD mutations have more favorable clinical outcomes than those with FLT3-ITD mutations. We also found that allo-HSCT therapy subgroup achieved longer OS and RFS than non-allo-HSCT therapy subgroup for FLT3-ITD positive patients (p < 0.001, p = 0.071). However, compared with the clinical outcomes in non-primary refractory patients, sorafenib did not show an obvious beneficial effect for the primary refractory patients. Further study on a large scale is still recommended. CONCLUSIONS: FLT3-TKD-mutated AML patients have more favorable clinical outcomes than those with FLT3-ITD mutations. Allo-HSCT therapy subgroup achieved longer OS and RFS than non-allo-HSCT therapy subgroup for FLT3-ITD positive patients. Compared with the clinical outcomes in non-primary refractory patients, sorafenib did not show an obvious beneficial effect for the primary refractory patients.


Assuntos
Leucemia Mieloide/genética , Leucemia Mieloide/terapia , Mutação , Tirosina Quinase 3 Semelhante a fms/genética , Doença Aguda , Adulto , Grupo com Ancestrais do Continente Asiático/genética , China , Tratamento Farmacológico/métodos , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide/etnologia , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/genética , Sorafenibe , Sequências de Repetição em Tandem/genética , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
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