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Although oncogenicity of the stem cell regulator SOX9 has been implicated in many solid tumors, its role in lymphomagenesis remains largely unknown. In this study, SOX9 was overexpressed preferentially in a subset of diffuse large B-cell lymphomas (DLBCLs) that harbor IGH-BCL2 translocations. SOX9 positivity in DLBCL correlated with an advanced stage of disease. Silencing of SOX9 decreased cell proliferation, induced G1/S arrest, and increased apoptosis of DLBCL cells, both in vitro and in vivo. Whole-transcriptome analysis and chromatin immunoprecipitation-sequencing assays identified DHCR24, a terminal enzyme in cholesterol biosynthesis, as a direct target of SOX9, which promotes cholesterol synthesis by increasing DHCR24 expression. Enforced expression of DHCR24 was capable of rescuing the phenotypes associated with SOX9 knockdown in DLBCL cells. In models of DLBCL cell line xenografts, SOX9 knockdown resulted in a lower DHCR24 level, reduced cholesterol content, and decreased tumor load. Pharmacological inhibition of cholesterol synthesis also inhibited DLBCL xenograft tumorigenesis, the reduction of which is more pronounced in DLBCL cell lines with higher SOX9 expression, suggesting that it may be addicted to cholesterol. In summary, our study demonstrated that SOX9 can drive lymphomagenesis through DHCR24 and the cholesterol biosynthesis pathway. This SOX9-DHCR24-cholesterol biosynthesis axis may serve as a novel treatment target for DLBCLs.
Assuntos
Colesterol/genética , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma Difuso de Grandes Células B/genética , Proteínas do Tecido Nervoso/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Fatores de Transcrição SOX9/genética , Vias Biossintéticas , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Proteínas de Fusão Oncogênica/genética , Oncogenes , TranscriptomaRESUMO
Electrochemical alkalization of (Cu-S)n metal-organic framework (MOF) and graphene oxide ((Cu-S)n MOF/GO) composite yields a new CuO/(Cu-S)n MOF/RGO (reduced GO) composite with porous morphology on screen printed carbon electrode (SPCE) which facilitated the electron transfer properties in electrochemical quercetin (QUE) detection. A selective QUE detection ability has been demonstrated by the constructed electrochemical sensor (CuO/(Cu-S)n MOF/RGO/SPCE), which also has a broad dynamic range of 0.5 to 115 µM in pH 3 by differential pulse voltammetry. The detection limit is 0.083 µM (S/N = 3). In this study, it was observed that the real samples contained 0.34 mg mL-1 and 27.7 µg g-1 QUE in wine and onion, respectively.
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Prior evidence has suggested the alleviatory effect of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) on neuroinflammation in neurodegenerative diseases. This study primarily investigates the underlying mechanism of how the long non-coding RNA MALAT1 affects neuronal apoptosis in the hippocampus of mice with autism spectrum disorder (ASD). The findings demonstrate that CASP3 is highly expressed while MALAT1 is downregulated in the hippocampal neurons of autistic mice. MALAT1 mainly localizes within the cell nucleus and recruits DNA methyltransferases (including DNMT1, DNMT3a, and DNMT3b) to the promoter region of CASP3, promoting its methylation and further inhibiting its expression. In vitro experiments reveal that reducing MALAT1 expression promotes the expression of CASP3 and Bax while suppressing Bcl-2 expression, thereby enhancing cellular apoptosis. Conversely, increasing MALAT1 expression yields the opposite effect. Consequently, these results further confirm the role of MALAT1 in suppressing neuronal apoptosis in the hippocampus of mice with ASD through the regulation of CASP3 promoter methylation. Thus, this research unveils the significant roles of MALAT1 and CASP3 in the pathogenesis of ASD, offering new possibilities for future therapeutic interventions.
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Transtorno do Espectro Autista , Transtorno Autístico , Caspase 3 , RNA Longo não Codificante , Animais , Camundongos , Apoptose/genética , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Transtorno Autístico/genética , Transtorno Autístico/metabolismo , Caspase 3/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Metilação de DNA , Hipocampo/metabolismo , Neurônios/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
The toxicity of nitrofuran drugs has attracted great attention, and the reported electroanalytical methods suffered limited sensitivity. In this work, a sensitive electrochemical assay in the cathodic region is developed to determine four nitrofuran derivatives, including nitrofurantoin (NFT), nitrofurazone (NFZ), furaltadone (FTD), and furazolidone (FZD). The screen-printed carbon electrode (SPCE) was used as the electrode substrate, and the sensing surface was composed of multi-walled carbon nanotube (MWCNT) and conducting poly(melamine) (PME). The overoxidation-pretreated MWCNTs affect the surface morphology of the electrodeposited PME and, thus, the interaction with nitrofuran drugs. The characteristics of the nanocomposite-modified electrode surfaces were well characterized by field emission scanning electron microscopy (FE-SEM), X-ray photoelectron spectroscopy (XPS), and surface water contact angle experiments. The nanocomposite-modified electrodes exhibited excellent adsorption and electrochemical reduction of nitrofurans by cyclic voltammetry. The proposed assay exhibited a linear range of sub-micro to micro molar concentrations for the four drugs under the optimized differential pulse voltammetric (DPV) technique. The detection limits were found to be in the nanomolar ranges. The developed assay was applied to detect NFT in two real samples, and the results showed good recoveries that ranged from 99.0 to 104.8% and 98.0 to 103.2% for milk and lake water samples, respectively. Graphical abstract á .
Assuntos
Nanopartículas/química , Nanotubos de Carbono/química , Nitrofuranos/química , Polímeros/química , Triazinas/química , Animais , Técnicas Eletroquímicas , Eletrodos , Água Doce/química , Limite de Detecção , Leite/química , Estrutura Molecular , Fatores de TempoRESUMO
AIM: To examine first-line nurse managers' perceptions of safety culture and explore relationships between their safety attitudes and safety factors in Henan Province, China. BACKGROUND: Health providers' perceptions of patient safety culture have been studied widely, but little is known about first-line nurse managers' safety attitudes. METHODS: A cross-sectional survey was conducted with a convenience sample of 823 first-line nurse managers in 216 hospitals across Henan Province, China. The Safety Attitudes Questionnaire (Chinese version) was distributed to first-line nurse managers during training meetings; responses were returned in a sealed envelope in person or by mail. ANOVAs were used to analyse the differences in Safety Attitudes Questionnaire (Chinese version) scores between first-line nurse managers' attitudes and safety factors. RESULTS: The mean scores across the six domains of Safety Attitudes Questionnaire (Chinese version) ranged from 56.6 to 79.4 on a 100-point scale. First-line nurse managers: ≥45 years of age perceived better safety climate (p < .05); those with higher professional ranks and medical centre positions reported higher mean scores for teamwork climate (p < .01) and stress recognition (p < .01); and those with baccalaureate degrees or higher had significantly higher mean scores for stress recognition (p < .01). CONCLUSION: First-line nurse managers' safety attitudes were not satisfactory and there is great potential to improve patient safety culture. Age, hospital level, educational background and professional rank are positively related to first-line nurse managers' attitudes. IMPLICATIONS FOR NURSING MANAGEMENT: Hospital administrators and nurse directors should focus on the safety factors identified in this study and enact a variety of strategies to create a strong patient safety culture in China.
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Enfermeiros Administradores/psicologia , Percepção , Gestão da Segurança/normas , Adulto , Análise de Variância , Atitude do Pessoal de Saúde , China , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e QuestionáriosRESUMO
BACKGROUND/AIMS: In order to further characterize the biological traits of Dp71, HBE over expressing two most abundantly expressed Dp71 spliced isoforms, Dp71d and Dp71f, were established and their biological traits were explored. METHODS: The proliferation, migration and invasion capabilities of HBE-Dp71d and HBE-Dp71f cells were evaluated by MTT, colony formation, transwell and scratch assay. Cell cycle and apoptosis induced by H2O2 were measured by flow cytometer. Co-IP was performed to prove the interaction between lamin B1, FAK and Dp71. Western blot was performed to detect lamin B1, FAK, ERK and Cyclin D expression in HBE-Dp71d and HBE-Dp71f cells. RESULTS: HBE-Dp71d and HBE-Dp71f cells proliferated faster than their mock and blank controls; shortened their G0/G1 phase; enhanced their invasion and migration capabilities; reduced their apoptosis induced by H2O2. Co-IP proved Dp71 directly interacting with focal adhesion kinase (FAK) and lamin B1 in HBE cells. Increased lamin B1, FAK mRNA and protein expression, over activation of integrin/focal adhesion kinase/extracellular signal-regulated kinase (ERK)/cyclin D pathway were observed in HBE-Dp71d and HBE-Dp71f cells. CONCLUSIONS: Via increasing FAK in the cytoplasmic FAK-Dp71 , lamin B1 of nucleus laminB1-Dp71 complex, HBE-Dp71d and HBE-Dp71f cells alter their proliferation, migration, invasion, cell cycle and apoptosis rate induced by H2O2.
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Distrofina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Ciclina D/metabolismo , Distrofina/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Fase G1/genética , Fase G1/fisiologia , Células HeLa , Humanos , Peróxido de Hidrogênio/farmacologia , Células PC12 , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ratos , Fase de Repouso do Ciclo Celular/genética , Fase de Repouso do Ciclo Celular/fisiologiaRESUMO
Innate immunity represents the first line of inducible defence against microbial infection in plants and animals. In both kingdoms, recognition of pathogen- or microbe-associated molecular patterns (PAMPs or MAMPs, respectively), such as flagellin, initiates convergent signalling pathways involving mitogen-activated protein kinase (MAPK) cascades and global transcriptional changes to boost immunity. Although Ca(2+) has long been recognized as an essential and conserved primary mediator in plant defence responses, how Ca(2+) signals are sensed and relayed into early MAMP signalling is unknown. Using a functional genomic screen and genome-wide gene expression profiling, here we show that four calcium-dependent protein kinases (CDPKs) are Ca(2+)-sensor protein kinases critical for transcriptional reprogramming in plant innate immune signalling. Unexpectedly, CDPKs and MAPK cascades act differentially in four MAMP-mediated regulatory programs to control early genes involved in the synthesis of defence peptides and metabolites, cell wall modifications and redox signalling. Transcriptome profile comparison suggests that CDPKs are the convergence point of signalling triggered by most MAMPs. Double, triple and quadruple cpk mutant plants display progressively diminished oxidative burst and gene activation induced by the 22-amino-acid peptide flg22, as well as compromised pathogen defence. In contrast to negative roles of calmodulin and a calmodulin-activated transcription factor in plant defence, the present study reveals Ca(2+) signalling complexity and demonstrates key positive roles of specific CDPKs in initial MAMP signalling.
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Arabidopsis/enzimologia , Arabidopsis/imunologia , Imunidade Inata/imunologia , Proteínas Quinases/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Cálcio/metabolismo , Sinalização do Cálcio , Flagelina/química , Flagelina/imunologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Genoma de Planta/genética , Sistema de Sinalização das MAP Quinases , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Explosão Respiratória , Transcrição GênicaRESUMO
Ibrutinib inhibits Bruton tyrosine kinase (BTK), a key component of early B-cell receptor (BCR) signalling pathways. A multicentre phase 2 trial of ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL) demonstrated a remarkable response rate. However, approximately one-third of patients have primary resistance to the drug while other patients appear to lose response and develop secondary resistance. Understanding the molecular mechanisms underlying ibrutinib sensitivity is of paramount importance. In this study, we investigated cell lines and primary MCL cells that display differential sensitivity to ibrutinib. We found that the primary cells display a higher BTK activity than normal B cells and MCL cells show differential sensitivity to BTK inhibition. Genetic knockdown of BTK inhibits the growth, survival and proliferation of ibrutinib-sensitive but not resistant MCL cell lines, suggesting that ibrutinib acts through BTK to produce its anti-tumour activities. Interestingly, inhibition of ERK1/2 and AKT, but not BTK phosphorylation per se, correlates well with cellular response to BTK inhibition in cell lines as well as in primary tumours. Our study suggests that, to prevent primary resistance or to overcome secondary resistance to BTK inhibition, a combinatory strategy that targets multiple components or multiple pathways may represent the most effective approach.
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Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Linfoma de Célula do Manto/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Linfoma de Célula do Manto/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Piperidinas , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Células Tumorais CultivadasRESUMO
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and the role of SYK in its pathogenesis is not completely understood. Using tissue microarray, we demonstrated for the first time that SYK protein is activated in 27 of 61 (44%) primary human DLBCL tissues. Among DLBCL cell lines, 7 were sensitive and 3 were resistant to a highly specific SYK inhibitor, PRT060318. In sensitive DLBCL cells, SYK inhibition blocked the G(1)-S transition and caused cell-cycle arrest. This effect was reproduced by genetic reduction of SYK using siRNA. A detailed analysis of the BCR signaling pathways revealed that the consequence of SYK inhibition on PLCγ2 and AKT, as opposed to ERK1/2, was responsible for cell-cycle arrest. Genetic knock-down of these key molecules decelerated the proliferation of lymphoma cells. In addition, BCR signaling can be blocked by PRT060318 in primary lymphoma cells. Together, these findings provide insights into cellular pathways required for lymphoma cell growth and support the rationale for considering SYK inhibition as a potentially useful therapy for DLBCL. The results further suggest the possibility of using PLCγ2 and AKT as biomarkers to predict therapeutic response in prospective clinical trials of specific SYK inhibitors.
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Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Fase G1/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Linfonodos/patologia , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Terapia de Alvo Molecular , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Fosfolipase C gama/antagonistas & inibidores , Fosfolipase C gama/genética , Fosfolipase C gama/metabolismo , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , RNA Mensageiro/metabolismo , RNA Interferente Pequeno , Transdução de Sinais/efeitos dos fármacos , Quinase Syk , Células Tumorais CultivadasAssuntos
Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Linfocítica Crônica de Células B/genética , Mutação Puntual , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pessoa de Meia-Idade , Fosforilação , Piperidinas , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/metabolismo , Pirazóis/metabolismo , Pirimidinas/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Recidiva , Análise de Sequência de DNARESUMO
OBJECTIVE: Hippocampal neuron apoptosis contributes to autism, while METTL3 has been documented to possess great potentials in neuron apoptosis. Our study probed into the role of METTL3 in neuron apoptosis in autism and to determine the underlying mechanism. METHODS: Bioinformatics analysis was used to analyze expressed genes in autism samples. Institute of Cancer Research mice were treated with valproic acid to develop autism models. The function of METTL3 in autism-like symptoms in mice was analyzed with behavioral tests and histological examination of their hippocampal tissues. Primary mouse hippocampal neurons were extracted for in vitro studies. Downstream factors of METTL3 were explored and validated. RESULTS: METTL3, MALAT1, and Wnt/ß-catenin signaling were downregulated, while SFRP2 was upregulated in the hippocampal tissues of a mouse model of autism. METTL3 stabilized MALAT1 expression by promoting m6A modification of MALAT1. MALAT1 promoted SFRP2 methylation and led to reduced SFRP2 expression by recruiting DNMT1, DNMT3A, and DNMT3B to the promoter region of SFRP2. Furthermore, SFRP2 facilitated activation of the Wnt/ß-catenin signaling. By this mechanism, METTL3 suppressed autism-like symptoms and hippocampal neuron apoptosis. CONCLUSION: This research suggests that METTL3 can reduce autism-like symptoms and hippocampal neuron apoptosis by regulating the MALAT1/SFRP2/Wnt/ß-catenin axis.
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Objective: To analyze the interictal discharge (IID) patterns on pre-operative scalp electroencephalogram (EEG) and compare the changes in IID patterns after removal of epileptogenic tubers in preschool children with tuberous sclerosis complex (TSC)-related epilepsy. Methods: Thirty-five preschool children who underwent resective surgery for TSC-related epilepsy were enrolled retrospectively, and their EEG data collected before surgery to 3 years after surgery were analyzed. Results: Twenty-three (65.7%) patients were seizure-free post-operatively at 1-year follow-up, and 37-40% of post-operative patients rendered non-IID on scalp EEGs, and patients with focal IIDs or generalized IID patterns on pre-operative EEG presented a high percentage of normal post-operative scalp EEGs. IID patterns on pre-operative scalp EEGs did not influence the outcomes of post-operative seizure controls, while patients with non-IID and focal IID on post-operative EEGs were likely to achieve post-operative seizure freedom. Patients with new focal IIDs presented a significantly lower percentage of seizure freedom than those without new focal IIDs on post-operative EEGs at 3-year follow-up. Conclusion: Over 1/3 children with TSC presented normal scalp EEGs after resective epileptsy surgery. Patients with post-operative seizure freedom were more likely to have non-IIDs on post-operative EEGs. New focal IIDs were negative factors for seizure freedom at the 3-year follow-up.
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Background: Although advance has been made in understanding the pathogenesis of mature T-cell neoplasms, the initiation and progression of angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), remain poorly understood. A subset of AITL/PTCL-NOS patients develop concomitant hematologic neoplasms (CHN), and a biomarker to predict this risk is lacking. Methods: We generated and analyzed the mutation profiles through 537-gene targeted sequencing of the primary tumors and matched bone marrow/peripheral blood samples in 25 patients with AITL and two with PTCL-NOS. Results: Clonal hematopoiesis (CH)-associated genomic alterations, found in 70.4% of the AITL/PTCL-NOS patients, were shared among CH and T-cell lymphoma, as well as concomitant myeloid neoplasms or diffuse large B-cell lymphoma (DLBCL) that developed before or after AITL. Aberrant AID/APOBEC activity-associated and tobacco smoking-associated mutational signatures were respectively enriched in the early CH-associated mutations and late non-CH-associated mutations during AITL/PTCL-NOS development. Moreover, analysis showed that the presence of CH harboring ≥2 pathogenic TET2 variants with ≥15% of allele burden conferred higher risk for CHN (p=0.0006, hazard ratio = 14.01, positive predictive value = 88.9%, negative predictive value = 92.1%). Conclusions: We provided genetic evidence that AITL/PTCL-NOS, CH, and CHN can frequently arise from common mutated hematopoietic precursor clones. Our data also suggests smoking exposure as a potential risk factor for AITL/PTCL-NOS progression. These findings provide insights into the cell origin and etiology of AITL and PTCL-NOS and provide a novel stratification biomarker for CHN risk in AITL patients. Funding: R01 grant (CA194547) from the National Cancer Institute to WT.
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Hematopoiese Clonal , Linfadenopatia Imunoblástica/patologia , Linfoma de Células T/patologia , Mutação , Fumar Tabaco , Análise Mutacional de DNA , Feminino , Perfilação da Expressão Gênica , Humanos , Linfadenopatia Imunoblástica/genética , Linfoma de Células T/genética , MasculinoRESUMO
BACKGROUND: Unresolved inflammation and tissue destruction are considered to underlie the failure of dental pulp repair. As key mediators of the injury response, dental pulp stem cells (DPSCs) play a critical role in pulp tissue repair and regeneration. Resolvin E1 (RvE1), a major dietary omega-3 polyunsaturated fatty-acid metabolite, is effective in resolving inflammation and activating wound healing. However, whether RvE1 facilitates injured pulp-tissue repair and regeneration through timely resolution of inflammation and rapid mobilization of DPSCs is unknown. Therefore, we established a pulp injury model and investigated the effects of RvE1 on DPSC-mediated inflammation resolution and injured pulp repair. METHODS: A pulp injury model was established using 8-week-old Sprague-Dawley rats. Animals were sacrificed on days 1, 3, 7, 14, 21, and 28 after pulp capping with a collagen sponge immersed in PBS with RvE1 or PBS. Hematoxylin-eosin and Masson's trichrome staining, immunohistochemistry, and immunohistofluorescence were used to evaluate the prohealing properties of RvE1. hDPSCs were incubated with lipopolysaccharide (LPS) to induce an inflammatory response, and the expression of inflammatory factors after RvE1 application was measured. Effects of RvE1 on hDPSC proliferation, chemotaxis, and odontogenic differentiation were evaluated by CCK-8 assay, transwell assay, alkaline phosphatase (ALP) staining, alizarin red staining, and quantitative PCR, and possible signaling pathways were explored using western blotting. RESULTS: In vivo, RvE1 reduced the necrosis rate of damaged pulp and preserved more vital pulps, and promoted injured pulp repair and reparative dentin formation. Further, it enhanced dentin matrix protein 1 and dentin sialoprotein expression and accelerated pulp inflammation resolution by suppressing TNF-α and IL-1ß expression. RvE1 enhanced the recruitment of CD146+ and CD105+ DPSCs to the damaged molar pulp mesenchyme. Isolated primary cells exhibited the mesenchymal stem cell immunophenotype and differentiation. RvE1 promoted hDPSC proliferation and chemotaxis. RvE1 significantly attenuated pro-inflammatory cytokine (TNF-α, IL-1ß, and IL-6) release and enhanced ALP activity, nodule mineralization, and especially, expression of the odontogenesis-related genes DMP1, DSPP, and BSP in LPS-stimulated DPSCs. RvE1 regulated AKT, ERK, and rS6 phosphorylation in LPS-stimulated DPSCs. CONCLUSIONS: RvE1 promotes pulp inflammation resolution and dentin regeneration and positively influences the proliferation, chemotaxis, and differentiation of LPS-stimulated hDPSCs. This response is, at least partially, dependent on AKT, ERK, and rS6-associated signaling in the inflammatory microenvironment. RvE1 has promising application potential in regenerative endodontics.
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Polpa Dentária , Células-Tronco , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Dentina , Ácido Eicosapentaenoico/análogos & derivados , Inflamação , Ratos , Ratos Sprague-DawleyRESUMO
The epichaperome is a new cancer target composed of hyperconnected networks of chaperome members that facilitate cell survival. Cancers with an altered chaperone configuration may be susceptible to epichaperome inhibitors. We developed a flow cytometry-based assay for evaluation and monitoring of epichaperome abundance at the single cell level, with the goal of prospectively identifying patients likely to respond to epichaperome inhibitors, to measure target engagement, and dependency during treatment. As proof of principle, we describe a patient with an unclassified myeloproliferative neoplasm harboring a novel PML-SYK fusion, who progressed to acute myeloid leukemia despite chemotherapy and allogeneic stem cell transplant. The leukemia was identified as having high epichaperome abundance. We obtained compassionate access to an investigational epichaperome inhibitor, PU-H71. After 16 doses, the patient achieved durable complete remission. These encouraging results suggest that further investigation of epichaperome inhibitors in patients with abundant baseline epichaperome levels is warranted.
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The triclosan contamination in daily life has attracted great attention, and there is rare electroanalytical assay based on π-system dyes. In this work, a facile preparation and electroanalytical application of an organic dispersion containing bacteriochlorin dyes (LS11) and gold nanoparticles (AuNPs) was proposed. The organic-inorganic hybrid nanocomposites were characterized by transmission electron microscope (TEM) showing a core-shell structure with a uniform layer of dye molecules. The as-prepared nanocomposites were successfully coated onto glassy carbon electrodes, and the surface characteristics of the top most layer of the modified electrodes were examined by atomic force microscopy (AFM), field emission scanning electron microscopy (FE-SEM) and water contact angle experiments. The nanocomposite film-modified electrodes exhibited good electrochemical activity towards oxidation of triclosan. The oxidation of adsorbed triclosan occurred at a reduced overpotential, and the anodic current responses under a pre-concentration step prior to the potential scan were used for quantitative analysis. A good linear relationship from 0.01 µM to 0.5 µM was obtained using differential pulse voltammetry. The sensitivity and detection limit (S/N = 3) were 23.69 µA µM-1 and 0.03 µM, respectively. The proposed assay was applied to detect triclosan in two personal hygiene products using standard addition method, and the results showed good recoveries that ranged from 96.6% to 101.5% and from 99.3% to 103.8% for a toothpaste sample and a hand wash sample, respectively. A reference HPLC-UV method was used to evaluate the proposed electroanalytical method, and a good agreement was achieved.
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Técnicas Biossensoriais , Técnicas Eletroquímicas , Ouro/química , Nanopartículas Metálicas/química , Porfirinas/química , Triclosan/análise , Carbono/química , Eletrodos , Desinfecção das Mãos , Estrutura Molecular , Cremes Dentais/químicaRESUMO
Breast implant-associated lymphoma (BIA-ALCL) has recently been recognized as an independent peripheral T-cell lymphoma (PTCL) entity. In this study, we generated the first BIA-ALCL patient-derived tumor xenograft (PDTX) model (IL89) and a matching continuous cell line (IL89_CL#3488) to discover potential vulnerabilities and druggable targets. We characterized IL89 and IL89_CL#3488, both phenotypically and genotypically, and demonstrated that they closely resemble the matching human primary lymphoma. The tumor content underwent significant enrichment along passages, as confirmed by the increased variant allele frequency (VAF) of mutations. Known aberrations (JAK1 and KMT2C) were identified, together with novel hits, including PDGFB, PDGFRA, and SETBP1. A deep sequencing approach allowed the detection of mutations below the Whole Exome Sequencing (WES) sensitivity threshold, including JAK1G1097D, in the primary sample. RNA sequencing confirmed the expression of a signature of differentially expressed genes in BIA-ALCL. Next, we tested IL89's sensitivity to the JAK inhibitor ruxolitinib and observed a potent anti-tumor effect, both in vitro and in vivo. We also implemented a high-throughput drug screening approach to identify compounds associated with increased responses in the presence of ruxolitinib. In conclusion, these new IL89 BIA-ALCL models closely recapitulate the primary correspondent lymphoma and represent an informative platform for dissecting the molecular features of BIA-ALCL and performing pre-clinical drug discovery studies, fostering the development of new precision medicine approaches.
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To reduce fresh water load on ships, seawater can be used for toilet flushing on-board. And saline black water was treated on-site by bioaugmentation original marine bacteria with Pseudoalteromonas sp. SCSE709-6 (P. sp. SCSE709-6) to prevent marine pollution. In the batch experiments, P. sp. SCSE709-6 was effective in nutrient removal, which was not closely related to the amount of inoculation. In the on-board continuous experiments, the systems inoculated with P. sp. SCSE709-6 possessed excellent TP removal ability (removal rate: 80.93% for T3 and 88.39% for T4). The inoculum of P. sp. SCSE709-6 changed the microbial community structure and increased the similarity of microbial communities. P. sp. SCSE709-6 had a significant influence on the performance and microbial community of the systems. This study strongly proposes that the P. sp. SCSE709-6 is a promising alternative in saline black water treatment, which has great significance to the practice of on-board seawater flushing toilet.
Assuntos
Microbiota , Pseudoalteromonas/metabolismo , Purificação da Água/métodos , Água do MarRESUMO
Treatment of metal complex dye wastewater has attracted growing attention due to the degradation-resistant, high cost and potential hazards of current techniques. This study reported a marine bacterium (Pseudoalteromonas sp CF10-13) with potential performance in decolorization and degradation of a metal complex dye-Naphthol Green B (NGB) at wide ranges of salinity, dye concentration and alkalinity under anaerobic conditions. It was inferred that the secretion of electron mediators in soluble extracellular metabolites by P. sp CF10-13 played important roles in NGB decolorization and degradation through extracellular electron transfer. Naphthalenesulfonate, the major structure in NGB molecule, was further degraded into low-toxic benzamide. Black stable iron-sulfur nanoparticles were formed endogenously avoiding H2S releasing, exogenous sulfur addition and metal sludge in accumulation. Accordingly, this study provided a cost-effective and eco-friendly biodegradation method to refractory NGB, further promoting the understanding of dye resources recovery.
Assuntos
Compostos Férricos/metabolismo , Ferro/metabolismo , Nanopartículas Metálicas , Naftalenossulfonatos/metabolismo , Pseudoalteromonas/metabolismo , Enxofre/metabolismo , Biodegradação Ambiental , Complexos de Coordenação/metabolismoRESUMO
OBJECTIVES: Rare cases of clonally related histiocytic sarcoma (HS) following B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) have been reported to date. METHODS: We present a patient with HS, which appeared as a breast mass 12 months after the initial diagnosis of B-ALL. RESULTS: Both HS and the B-ALL shared IGH-MYC and IGK gene rearrangements. Next-generation sequencing and whole-exome sequencing (WES) studies detected 35 common mutations, as well as mutations unique to B-ALL (16) and HS (15), including BRAF D594G. The patient achieved complete remission of B-ALL, but HS failed to respond to many cycles of intensive chemotherapy regimens. A partial response was achieved with sorafenib, a BRAF-targeted therapy. CONCLUSIONS: To our knowledge, this is the first study to demonstrate by WES that clonally related B-ALL and HS arise through divergent evolution from a common precursor. We present our findings together with a discussion of the previously reported cases of HS in patients with B-ALL.