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1.
J Pathol ; 259(2): 194-204, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36373784

RESUMO

Excessive genomic instability coupled with abnormalities in DNA repair pathways induces high levels of 'replication stress' when cancer cells propagate. Rather than hampering cancer cell proliferation, novel treatment strategies are turning their attention towards targeting cell cycle checkpoint kinases (such as ATR, CHK1, WEE1, and others) along the DNA damage response and replicative stress response pathways, thereby allowing unrepaired DNA damage to be carried forward towards mitotic catastrophe and apoptosis. The selective ATR kinase inhibitor elimusertib (BAY 1895344) has demonstrated preclinical and clinical monotherapy activity; however, reliable predictive biomarkers of treatment benefit are still lacking. In this study, using gene expression profiling of 24 cell lines from different cancer types and in a panel of ovarian cancer cell lines, we found that nuclear-specific enrichment of checkpoint kinase 1 (CHK1) correlated with increased sensitivity to elimusertib. Using an advanced multispectral imaging system in subsequent cell line-derived xenograft specimens, we showed a trend between nuclear phosphorylated CHK1 (pCHK1) staining and increased sensitivity to the ATR inhibitor elimusertib, indicating the potential value of pCHK1 expression as a predictive biomarker of ATR inhibitor sensitivity. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Dano ao DNA , Inibidores de Proteínas Quinases , Feminino , Humanos , Proliferação de Células , Linhagem Celular , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Biomarcadores , Quinase 1 do Ponto de Checagem/genética , Quinase 1 do Ponto de Checagem/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo
2.
Mol Cancer ; 22(1): 69, 2023 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-37032358

RESUMO

BACKGROUND: Extranodal natural killer/T-cell lymphoma (NKTL) is an aggressive type of non-Hodgkin lymphoma with dismal outcome. A better understanding of disease biology and key oncogenic process is necessary for the development of targeted therapy. Super-enhancers (SEs) have been shown to drive pivotal oncogenes in various malignancies. However, the landscape of SEs and SE-associated oncogenes remain elusive in NKTL. METHODS: We used Nano-ChIP-seq of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs NKTL primary tumor samples. Integrative analysis of RNA-seq and survival data further pinned down high value, novel SE oncogenes. We utilized shRNA knockdown, CRISPR-dCas9, luciferase reporter assay, ChIP-PCR to investigate the regulation of transcription factor (TF) on SE oncogenes. Multi-color immunofluorescence (mIF) staining was performed on an independent cohort of clinical samples. Various function experiments were performed to evaluate the effects of TOX2 on the malignancy of NKTL in vitro and in vivo. RESULTS: SE landscape was substantially different in NKTL samples in comparison with normal tonsils. Several SEs at key transcriptional factor (TF) genes, including TOX2, TBX21(T-bet), EOMES, RUNX2, and ID2, were identified. We confirmed that TOX2 was aberrantly overexpressed in NKTL relative to normal NK cells and high expression of TOX2 was associated with worse survival. Modulation of TOX2 expression by shRNA, CRISPR-dCas9 interference of SE function impacted on cell proliferation, survival and colony formation ability of NKTL cells. Mechanistically, we found that RUNX3 regulates TOX2 transcription by binding to the active elements of its SE. Silencing TOX2 also impaired tumor formation of NKTL cells in vivo. Metastasis-associated phosphatase PRL-3 has been identified and validated as a key downstream effector of TOX2-mediated oncogenesis. CONCLUSIONS: Our integrative SE profiling strategy revealed the landscape of SEs, novel targets and insights into molecular pathogenesis of NKTL. The RUNX3-TOX2-SE-TOX2-PRL-3 regulatory pathway may represent a hallmark of NKTL biology. Targeting TOX2 could be a valuable therapeutic intervene for NKTL patients and warrants further study in clinic.


Assuntos
Transformação Celular Neoplásica , Linfoma Extranodal de Células T-NK , Humanos , Transformação Celular Neoplásica/metabolismo , Oncogenes , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , RNA Interferente Pequeno/metabolismo , Células Matadoras Naturais/patologia , Linhagem Celular Tumoral , Proteínas HMGB/genética , Proteínas HMGB/metabolismo
3.
Bioorg Med Chem Lett ; 72: 128880, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35809817

RESUMO

A series of novel pentanediamide derivatives were designed, synthesized and evaluated as S-adenosyl-l-homocysteine hydrolase (SAHase) inhibitors in this study. Some compounds showed good inhibitory activity against SAHase. The optimal compound 7i showed good inhibitory activity against SAHase with IC50 value of 3.58 ± 0.19 µM, cytotoxicity with IC50 values ranging from 13.16 ± 1.44 to 21.23 ± 0.73 µM against four tumor cell lines (MCF-7, A549, MGC-803, Hela) and very weak cytotoxicity (IC50 = 84.22 ± 1.89 µM) on normal LO2 cells. In addition, compound 7i showed potency against respiratory syncytial virus with EC50 value of 27.4 µM and selectivity index of 6.84. Further molecular simulation study suggested that compound 7i had good ADMET properties, and strongly binds to the active site of SAHase. In summary, compound 7i could serve as a new lead compound for further screening novel non-adenosine SAHase inhibitors.


Assuntos
Antineoplásicos , Homocisteína , Adenosil-Homocisteinase , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 30(11): 127146, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32249118

RESUMO

Antibiotic resistance in bacteria has been an emerging public health problem, thus discovery of novel and effective antibiotics is urgent. A series of novel hybrids of N-aryl pyrrothine-base α-pyrone hybrids was designed, synthesized and evaluated as bacterial RNA polymerase (RNAP) inhibitors. Among them, compound 13c exhibited potent antibacterial activity against antibiotic-resistant S. aureus with the minimum inhibitory concentration (MIC) in the range of 1-4 µg/mL. Moreover, compound 13c exhibited strong inhibitory activity against E.coli RNAP with IC50 value of 16.06 µM, and cytotoxicity in HepG2 cells with IC50 value of 7.04 µM. The molecular docking study further suggested that compound 13c binds to the switch region of bacterial RNAP. In summary, compound 13c is a novel bacterial RNAP inhibitor, and a promising lead compound for further optimization.


Assuntos
Antibacterianos/síntese química , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/química , Escherichia coli/enzimologia , Pironas/química , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Sítios de Ligação , Candida albicans/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , RNA Polimerases Dirigidas por DNA/metabolismo , Inibidores Enzimáticos/metabolismo , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Pironas/metabolismo , Pironas/farmacologia , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 264: 115992, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38043493

RESUMO

Farnesoid X receptor (FXR) plays a key role in bile acid homeostasis, inflammation, fibrosis, lipid and glucose metabolism and is emerging as a promising therapeutic target for nonalcoholic steatohepatitis (NASH). Emerging evidence suggested that intestine-specific FXR antagonists exhibited remarkable metabolic improvements and slowed NASH progression. In this study, we discovered several potent FXR antagonists using a multistage ligand- and structure-based virtual screening approach. Notably, compound V023-9340, which possesses a 4-aminophenylacetamide scaffold, emerged as the most potent FXR antagonist with an IC50 value of 4.27 µM. In vivo, V023-9340 demonstrated selective accumulation in the intestine, substantially ameliorating high-fat diet (HFD)-induced NASH in mice by mitigating hepatic steatosis and inflammation. Mechanistic studies revealed that V023-9340 strongly inhibited intestinal FXR while concurrently feedback-activated hepatic FXR. Further structure-activity relationship optimization employing V023-9340 has resulted in the synthesis of a more efficacious compound V02-8 with an IC50 value of 0.89 µM, which exhibited a 4.8-fold increase in FXR antagonistic activity compared to V023-9340. In summary, 4-aminophenylacetamide derivative V023-9340 represented a novel intestine-specific FXR antagonist and showed improved effects against HFD-induced NASH in mice, which may serve as a promising lead in discovering potential therapeutic drugs for NASH treatment.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares , Inflamação , Intestinos
6.
Nat Commun ; 15(1): 2113, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38459052

RESUMO

Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL. We reveal transcriptomic differences between macrophages within RLTs (light zone /dark zone, germinal center/ interfollicular), and between disease states (RLTs/ DLBCL), which we then use to generate six spatially-derived macrophage signatures (MacroSigs). We proceed to interrogate these MacroSigs in macrophage and DLBCL single-cell RNA-sequencing datasets, and in gene-expression data from multiple DLBCL cohorts. We show that specific MacroSigs are associated with cell-of-origin subtypes and overall survival in DLBCL. This study provides a spatially-resolved whole-transcriptome atlas of macrophages in reactive and malignant lymphoid tissues, showing biological and clinical significance.


Assuntos
Linfoma Difuso de Grandes Células B , Humanos , Prognóstico , Linfoma Difuso de Grandes Células B/patologia , Perfilação da Expressão Gênica , Transcriptoma , Centro Germinativo/patologia , Microambiente Tumoral/genética
7.
Cancer Discov ; 13(5): 1144-1163, 2023 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-37071673

RESUMO

Cancers often overexpress multiple clinically relevant oncogenes, but it is not known if combinations of oncogenes in cellular subpopulations within a cancer influence clinical outcomes. Using quantitative multispectral imaging of the prognostically relevant oncogenes MYC, BCL2, and BCL6 in diffuse large B-cell lymphoma (DLBCL), we show that the percentage of cells with a unique combination MYC+BCL2+BCL6- (M+2+6-) consistently predicts survival across four independent cohorts (n = 449), an effect not observed with other combinations including M+2+6+. We show that the M+2+6- percentage can be mathematically derived from quantitative measurements of the individual oncogenes and correlates with survival in IHC (n = 316) and gene expression (n = 2,521) datasets. Comparative bulk/single-cell transcriptomic analyses of DLBCL samples and MYC/BCL2/BCL6-transformed primary B cells identify molecular features, including cyclin D2 and PI3K/AKT as candidate regulators of M+2+6- unfavorable biology. Similar analyses evaluating oncogenic combinations at single-cell resolution in other cancers may facilitate an understanding of cancer evolution and therapy resistance. SIGNIFICANCE: Using single-cell-resolved multiplexed imaging, we show that selected subpopulations of cells expressing specific combinations of oncogenes influence clinical outcomes in lymphoma. We describe a probabilistic metric for the estimation of cellular oncogenic coexpression from IHC or bulk transcriptomes, with possible implications for prognostication and therapeutic target discovery in cancer. This article is highlighted in the In This Issue feature, p. 1027.


Assuntos
Linfoma Difuso de Grandes Células B , Fosfatidilinositol 3-Quinases , Humanos , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Oncogenes , Linfoma Difuso de Grandes Células B/patologia
8.
Chemistry ; 18(29): 8906-11, 2012 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-22733717

RESUMO

Ru sitting comfortably: Ruthenium oxide nanoparticles show bienzyme-like activities, and are capable of catalyzing H(2)O(2) disproportionation at pH 7.0 and peroxidation at pH 4.0 in aqueous solutions (see scheme). Their specific activities are better than many natural catalases and peroxidases and far better than bifunctional catalase/peroxidases.


Assuntos
Catalase/química , Peróxido de Hidrogênio/química , Nanopartículas/química , Peroxidases/química , Compostos de Rutênio/química , Biomimética , Catálise , Concentração de Íons de Hidrogênio
9.
J Mol Model ; 28(10): 336, 2022 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-36180796

RESUMO

S-adenosyl-L-homocysteine hydrolase (SAHase) is an important regulator in the methylation reactions in many organisms and thus is crucial for numerous cellular functions. In recent years, SAHase has become one of the popular targets for drug design, and SAHase inhibitors have exhibited potent antiviral activity. In this study, we established the complex-based pharmacophore models based on the known crystal complex of SAHase (PDB ID: 1A7A) to screen the drug-likeness compounds of ChEMBL database. Then, three molecular docking programs were used to validate the reliability of compounds, involving Libdock, CDOCKER, and AutoDock Vina programs. The four promising hit compounds (CHEMBL420751, CHEMBL346387, CHEMBL1569958, and CHEMBL4206648) were performed molecular dynamics simulations and MM-PBSA calculations to evaluate their stability and binding-free energy in the binding site of SAHase. After screening and analyzing, the hit compounds CHEMBL420751 and CHEMBL346387 were suggested to further research to obtain novel potential SAHase inhibitors. A series of computer-aided drug design methods, including pharmacophore, molecular docking, molecular dynamics simulation and MM-PBSA calculations, were employed in this study to identity novel inhibitors of S-adenosyl-L-homocysteine hydrolase (SAHase). Some compounds from virtual screening could form various interactions with key residues of SAHase. Among them, compounds CHEMBL346387 and CHEMBL420751 exhibited potent binding affinity from molecular docking and MM-PBSA, and maintained good stability at the binding site during molecular dynamics simulations as well. All these results indicated that the selected compounds might have the potential to be novel SAHase inhibitors.


Assuntos
Hidrolases , Simulação de Dinâmica Molecular , Antivirais , Homocisteína , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica , Reprodutibilidade dos Testes
10.
Oncogene ; 41(13): 1986-2002, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35236967

RESUMO

Inhibitors of the mitotic kinase PLK1 yield objective responses in a subset of refractory cancers. However, PLK1 overexpression in cancer does not correlate with drug sensitivity, and the clinical development of PLK1 inhibitors has been hampered by the lack of patient selection marker. Using a high-throughput chemical screen, we discovered that cells deficient for the tumor suppressor ARID1A are highly sensitive to PLK1 inhibition. Interestingly this sensitivity was unrelated to canonical functions of PLK1 in mediating G2/M cell cycle transition. Instead, a whole-genome CRISPR screen revealed PLK1 inhibitor sensitivity in ARID1A deficient cells to be dependent on the mitochondrial translation machinery. We find that ARID1A knock-out (KO) cells have an unusual mitochondrial phenotype with aberrant biogenesis, increased oxygen consumption/expression of oxidative phosphorylation genes, but without increased ATP production. Using expansion microscopy and biochemical fractionation, we see that a subset of PLK1 localizes to the mitochondria in interphase cells. Inhibition of PLK1 in ARID1A KO cells further uncouples oxygen consumption from ATP production, with subsequent membrane depolarization and apoptosis. Knockdown of specific subunits of the mitochondrial ribosome reverses PLK1-inhibitor induced apoptosis in ARID1A deficient cells, confirming specificity of the phenotype. Together, these findings highlight a novel interphase role for PLK1 in maintaining mitochondrial fitness under metabolic stress, and a strategy for therapeutic use of PLK1 inhibitors. To translate these findings, we describe a quantitative microscopy assay for assessment of ARID1A protein loss, which could offer a novel patient selection strategy for the clinical development of PLK1 inhibitors in cancer.


Assuntos
Proteínas de Ciclo Celular , Proteínas de Ligação a DNA , Neoplasias , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas , Fatores de Transcrição , Trifosfato de Adenosina/metabolismo , Apoptose , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Consumo de Oxigênio , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Quinase 1 Polo-Like
11.
Anal Chem ; 83(3): 820-7, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-21207998

RESUMO

A highly sensitive microRNA (miRNA) biosensor that employs ruthenium oxide nanoparticle (RuO(2) NP)-initiated polymerization of 3,3'-dimethoxybenzidine (DB) and miRNA-templated deposition of an insulating poly(3,3'-dimethoxybenzidine) (PDB) film is described in this work. The biosensor was made of a mixed monolayer of oligonucleotide capture probes (CPs) and 4-mercaptoaniline on a gold electrode. Following hybridization with a RuO(2) NP-tagged target miRNA, a mixture of DB/H(2)O(2) in pH 5.0 0.10 M acetate buffer was applied to the biosensor. The RuO(2) NPs serve as polymerization initiator/catalyst for the polymerization of DB. And the hybridized anionic miRNA strands and free CPs serve as templates, guiding the deposition of PDB. The amount of the deposited PDB and its insulating power directly correlated to the concentration of the target miRNA in solution. Electrochemical impedance spectroscopic tests showed that a linear charge-transfer resistance-concentration relationship from 6.0 fM to 2.0 pM was attained after 60 min of incubation in the DB/H(2)O(2) mixture. There was no cross-hybridization between pre-miRNA and mature miRNA and very little cross-hybridization among closely related miRNA family members even at single-base-mismatched levels. This impedance-based biosensor offers an attractive alternative for miRNA expression profiling and may enable the development of a portable multiplexing miRNA profiling system.


Assuntos
Técnicas Biossensoriais/métodos , Nanopartículas Metálicas/química , MicroRNAs/análise , Técnicas de Amplificação de Ácido Nucleico/métodos , Hibridização de Ácido Nucleico/métodos , Compostos de Rutênio/química , Calibragem , Linhagem Celular , Dianisidina/química , Humanos , Reprodutibilidade dos Testes
12.
J Pediatr Surg ; 56(9): 1479-1484, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33838898

RESUMO

PURPOSE: the aim of this clinical trial was to evaluate the safety and efficacy of early enteral feeding (EEN) following intestinal anastomosis in neonates with congenital gastrointestinal malformation. METHODS: a multicenter, prospective, randomized controlled trial (registered under chictr.org.cn Identifier no.ChiCTR-INR-17014179) was conducted between 2018 and 2019. Four centers in China analyzed 156 newborns of congenital gastrointestinal malformation undergoing intestinal anastomosis to EEN group (n = 78) or control (C) group (n = 78). The primary outcomes of this study were length of postoperative stay (LOPS) and time to full feeds. Secondary outcomes included morbidity of complications, parenteral nutrition (PN) duration, feeding intolerance, 30 day mortality rate and 30 day readmission rate. RESULTS: the mean time to full feeds and LOPS in the EEN group were 15.0 (9.8-22.8) days and 17.6 (12.0-29.8) days, while that were 18.0 (12.0-24.0) days and 20.0 (15.0-30.3) days in C groups respectively. There was no significant difference between two groups(P >0.05). No significant intergroup difference was found with respect to postoperative morbidity, PN duration or feeding intolerance(P >0.05). CONCLUSIONS: early enteral feeding following intestinal anastomosis in neonates with congenital gastrointestinal malformation is safe. Post-operative outcomes demonstrated a trend toward improvement. LEVEL OF EVIDENCE: Level Ⅰ.


Assuntos
Recuperação Pós-Cirúrgica Melhorada , Nutrição Enteral , Anastomose Cirúrgica , Humanos , Recém-Nascido , Tempo de Internação , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos
13.
Anal Chem ; 82(14): 5958-64, 2010 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-20578701

RESUMO

A simple and sensitive electrical sensor array for polymerase chain reaction-free (PCR-free) messenger RNA (mRNA) expression profiling is described in this work. The sensor array, consisting of vertically aligned gold microband electrode/SiO(2)/gold microband electrode sandwich structures (nanogap sensors) in orthogonal configurations, was fabricated on a 1 cm x 1 cm silicon chip. A target mRNA was first hybridized with its specific capture probes (CP) on the bottom side of the nanogap, followed by a second hybridization (annealing) of its poly(A) tail with poly(T) annealing probes (AP) on the top side of the nanogap, holding the hybridized mRNA strands vertically across the nanogap. A subsequent metallization of the hybridized mRNA strands bridged the nanogap and consequently produced a substantial change in conductance, allowing ultrasensitive detection of mRNA without any amplification. Noticeable conductance changes were observed in the presence of as little as 0.10 fM mRNA. A linear relationship between the conductance and mRNA concentration was obtained from 0.50 fM to 1.0 pM with exceptional signal intensity. As little as a 50% difference in mRNA expression was successfully detected. The sensor array also exhibited excellent mismatch discrimination due to its unique vertically aligned nanostructure and the two-step hybridization.


Assuntos
Técnicas Eletroquímicas/métodos , Perfilação da Expressão Gênica , RNA Mensageiro/metabolismo , Linhagem Celular Tumoral , Eletrodos , Ouro/química , Humanos , Nanoestruturas/química , Hibridização de Ácido Nucleico , Reação em Cadeia da Polimerase , Sondas RNA/química , Dióxido de Silício/química
14.
Zhongguo Dang Dai Er Ke Za Zhi ; 12(12): 943-6, 2010 Dec.
Artigo em Zh | MEDLINE | ID: mdl-21172128

RESUMO

OBJECTIVE: To evaluate the reliability and validity of parent proxyreport scales of Pediatric Quality of Life Inventory Version 3.0 (PedsQLTM) Asthma Module (Chinese version). METHODS: Two hundred and thirty-three asthmatic children and their parents from the Children's Hospital of Chongqing Medical University were enrolled. Health related quality of life was assessed using the above mentioned PedsQLTM Asthma Module. The internal consistency was assessed using Cronbach's α coefficient, while its validity was tested through correlation analysis and exploratory factor analysis. RESULTS: The internal consistency reliability for Total Scale Summary Score (Cronbach's α=0.86), Asthma Score (Cronbach's α=0.80), Treatment Score (Cronbach's α=0.78), Worry Score (Cronbach's α=0.89) and Communication Score (Cronbach's α=0.93) were excellent. Seven major factors were extracted by factor analysis which basically matched the designed structure of the original version accounting for nearly 66% of the variance. Moderate to high correlations between items and the subscales were found, and the correlation coefficients ranged from 0.41 to 0.92(P<0.01). CONCLUSIONS: The reliability and validity of the parent proxy-report scales of PedsQLTM 3.0 Asthma Module of the Chinese version are as good as the original version.


Assuntos
Psicometria , Qualidade de Vida , Asma , Criança , Análise Fatorial , Humanos , Reprodutibilidade dos Testes , Inquéritos e Questionários
15.
Chem Biol Drug Des ; 96(5): 1262-1271, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32491252

RESUMO

Bacterial RNA polymerase (RNAP) is a validated drug target for broad-spectrum antibiotics, and its "switch region" is considered as the promising binding site for novel antibiotics. Based on the core scaffold of dithiolopyrrolone, a series of N-aryl pyrrothine derivatives was designed, synthesized, and evaluated for their antibacterial activity. Compounds generally displayed more active against Gram-positive bacteria, but less against Gram-negative bacteria. Among them, compound 6e exhibited moderate antibacterial activity against clinical isolates of rifampin-resistant Staphylococcus aureus with minimum inhibition concentration value of 1-2 µg/ml and inhibited Escherichia coli RNAP with IC50 value of 12.0 ± 0.9 µM. In addition, compound 6e showed certain degree of cytotoxicity against HepG2 and LO2 cells. Furthermore, molecular docking studies suggested that compound 6e might interact with the switch region of bacterial RNAP in a similar conformation to myxopyronin A. Together, the N-aryl pyrrothine scaffold is a promising lead for discovery of antibacterial drugs acting against bacterial RNAP.


Assuntos
Antibacterianos/farmacologia , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Antibacterianos/química , Inibidores Enzimáticos/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana
16.
Adv Healthc Mater ; 9(3): e1901257, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31854130

RESUMO

Biomedical implant failure due to the host's response remains a challenging problem. In particular, the formation of the fibrous capsule is a common barrier for the normal function of implants. Currently, there is mounting evidence indicating that the polarization state of macrophages plays an important role in effecting the foreign body reaction (FBR). This opens up a potential avenue for improving host-implant integration. Here, electrospun poly(caprolactone-co-ethyl ethylene phosphate) nanofiber scaffolds are utilized to deliver microRNAs (miRs) to induce macrophage polarization and modulate FBR. Specifically, C57BL/6 mice that are treated with M2-inducing miRs, Let-7c and miR-124, display relatively thinner fibrous capsule formation around the scaffolds at both Week 2 and 4, as compared to treatment with M1-inducing miR, Anti-Let-7c. Histological analysis shows that the density of blood vessels in the scaffolds are the highest in miR-124 treatment group, followed by Anti-Let-7c and Let-7c treatment groups. Based on immunohistochemical quantifications, these miR-encapsulated nanofiber scaffolds are useful for localized and sustained delivery of functional miRs and are able to modulate macrophage polarization during the first 2 weeks of implantation to result in significant alteration in host-implant integration at longer time points.


Assuntos
Macrófagos/fisiologia , MicroRNAs/administração & dosagem , Nanofibras/química , Próteses e Implantes/efeitos adversos , Animais , Vasos Sanguíneos/crescimento & desenvolvimento , Feminino , Reação a Corpo Estranho/prevenção & controle , Técnicas de Transferência de Genes , Macrófagos/patologia , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Organofosfatos/química , Poliésteres/química
17.
Nat Commun ; 11(1): 3520, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32665551

RESUMO

PRDM (PRDI-BF1 and RIZ homology domain containing) family members are sequence-specific transcriptional regulators involved in cell identity and fate determination, often dysregulated in cancer. The PRDM15 gene is of particular interest, given its low expression in adult tissues and its overexpression in B-cell lymphomas. Despite its well characterized role in stem cell biology and during early development, the role of PRDM15 in cancer remains obscure. Herein, we demonstrate that while PRDM15 is largely dispensable for mouse adult somatic cell homeostasis in vivo, it plays a critical role in B-cell lymphomagenesis. Mechanistically, PRDM15 regulates a transcriptional program that sustains the activity of the PI3K/AKT/mTOR pathway and glycolysis in B-cell lymphomas. Abrogation of PRDM15 induces a metabolic crisis and selective death of lymphoma cells. Collectively, our data demonstrate that PRDM15 fuels the metabolic requirement of B-cell lymphomas and validate it as an attractive and previously unrecognized target in oncology.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Western Blotting , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Imunoprecipitação da Cromatina , Biologia Computacional , Proteínas de Ligação a DNA/genética , Feminino , Citometria de Fluxo , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Humanos , Linfoma/genética , Linfoma/metabolismo , Camundongos , Camundongos SCID , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Distribuição Aleatória , Fatores de Transcrição/genética , Transcriptoma/genética
18.
J Am Chem Soc ; 131(34): 12211-7, 2009 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-19655794

RESUMO

In this report, an electrical detection scheme for the quantification of DNA using a nanogap sensor array is detailed. The prime objective is to develop a novel sensing procedure, based on the electronic transduction mechanism, which would mitigate the problems intrinsic to nanostructure-based biosensing devices. Design considerations of the sensor array take into account the feasibility of mass production in a cost-effective way by using standard silicon microfabrication technologies. The sensing mechanism relies on bridging the nanogap upon hybridization of the two termini of a target DNA with two different surface-bound capture probes, followed by a simple metallization step. About 2 orders of magnitude enhancement in conductance, as referred to a clean background (<1.0 pS) observed at a control sensor, was obtained in the presence of as little as 1.0 fM target DNA. This sensitivity is comparable to the best of electrochemical/electrical biosensors. A linear relationship between the conductance and the DNA concentration was obtained from 1.0 fM to 1.0 pM with an exceptional signal intensity of 2.1 x 10(4)% change per unit concentration. This change in conductivity is so large that it can unambiguously detect the concentration of DNA quantitatively and may obviate the need for target amplification used in current DNA tests. Moreover, the sensor array exhibited excellent single-base mismatch discrimination due to its unique vertically aligned nanostructure and the two-probe configuration.


Assuntos
DNA/análise , Nanotecnologia/instrumentação , Nanotecnologia/métodos , Técnicas Biossensoriais/instrumentação , Técnicas Biossensoriais/métodos , DNA/química , Sondas de DNA/química , Eletroquímica , Nanofios , Hibridização de Ácido Nucleico , Reprodutibilidade dos Testes , Prata/química
19.
ACS Appl Bio Mater ; 2(10): 4142-4153, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-35021429

RESUMO

Theranostic agents that integrate far-red/near-infrared fluorescence and anticancer drugs are useful for biomedical applications such as imaging-guided therapy of cancers. However, the clinical translation of previously reported theranostic agents is still limited by factors such as weak fluorescence of the imaging probe, premature and off-target release of fluorophores and drugs during blood circulation, the long-term retention in the reticuloendothelial system, and side effects of toxicity. Here, we report a new type of ultrasmall theranostic unimolecular micelles with an average diameter below 10 nm, and dual functionalities of bright fluorescence in the spectral window of 600-800 nm toward noninvasive in vivo bioimaging and covalently bound anticancer drugs for specific cancer treatment. Each unimolecular micelle is formed by an amphiphilic bottlebrush copolymer containing a fluorescent conjugated backbone of poly(fluorene-alt-(4,7-bis(hexylthien)-2,1,3-benzothiadiazole)), from which hydrophobic disulfide-linked camptothecin as an anticancer drug and hydrophilic oligo(ethylene glycol) are grafted. These ultrasmall unimolecular micelles exhibit remarkably high efficiency of accumulation and retention in tumor tissues with a tumor inhibitory rate of 50%, but little distribution in other healthy organs and tissues. Such a feature of enhanced tumor targeting and reduced toxic side effects against healthy cells and tissues is promising for future clinical translation of imaging-guided cancer therapy.

20.
ACS Appl Mater Interfaces ; 11(5): 4833-4841, 2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30624894

RESUMO

We report multiscale structured fibers and patterned films based on a semiconducting polymer, poly(3-hexylthiophene) (P3HT), as photoconductive biointerfaces to promote neuronal stimulation upon light irradiation. The micro/nanoscale structures of P3HT used for neuronal interfacing and stimulation include nanofibers with an average diameter of 100 nm, microfibers with an average diameter of about 1 µm, and lithographically patterned stripes with width of 3, 25, and 50 µm, respectively. The photoconductive effect of P3HT upon light irradiation provides electrical stimulation for neuronal differentiation and directed growth. Our results demonstrate that neurons on P3HT nanofibers showed a significantly higher total number of branches, while neurons grown on P3HT microfibers had longer and thinner neurites. Such a combination strategy of topographical and photoconductive stimulation can be applied to further enhance neuronal differentiation and directed growth. These photoconductive polymeric micro/nanostructures demonstrated their great potential for neural engineering and development of novel neural regenerative devices.


Assuntos
Técnicas de Cultura de Células/métodos , Nanofibras/química , Neurônios , Semicondutores , Tiofenos/química , Animais , Técnicas de Cultura de Células/instrumentação , Estimulação Elétrica/instrumentação , Desenho de Equipamento , Neurônios/citologia , Neurônios/efeitos da radiação , Células PC12 , Processos Fotoquímicos , Ratos , Engenharia Tecidual/instrumentação
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