RESUMEN
The Elongator complex was originally identified as an interactor of hyperphosphorylated RNA polymerase II (RNAPII) in yeast and has histone acetyltransferase (HAT) activity. However, the genome-wide regulatory roles of Elongator on transcriptional elongation and histone acetylation remain unclear. We characterized a maize miniature seed mutant, mn7 and map-based cloning revealed that Mn7 encodes one of the subunits of the Elongator complex, ZmELP1. ZmELP1 deficiency causes marked reductions in the kernel size and weight. Molecular analyses showed that ZmELP1 interacts with ZmELP3, which is required for H3K14 acetylation (H3K14ac), and Elongator complex subunits interact with RNA polymerase II (RNAPII) C-terminal domain (CTD). Genome-wide analyses indicated that loss of ZmELP1 leads to a significant decrease in the deposition of H3K14ac and the CTD of phosphorylated RNAPII on Ser2 (Ser2P). These chromatin changes positively correlate with global transcriptomic changes. ZmELP1 mutation alters the expression of genes involved in transcriptional regulation and kernel development. We also showed that the decrease of Ser2P depends on the deposition of Elongator complex-mediated H3K14ac. Taken together, our results reveal an important role of ZmELP1 in the H3K14ac-dependent transcriptional elongation, which is critical for kernel development.
Asunto(s)
Histonas , ARN Polimerasa II , ARN Polimerasa II/genética , ARN Polimerasa II/metabolismo , Histonas/metabolismo , Zea mays/genética , Zea mays/metabolismo , Fosforilación , Acetilación , Estudio de Asociación del Genoma Completo , Saccharomyces cerevisiae/genéticaRESUMEN
Circular RNAs (circRNAs) have been documented to play crucial roles in the biology of various cancers. However, their investigation in melanoma is still at an early stage, particularly as a broader mechanism beyond acting as miRNA sponges needs to be explored. We report here that circFCHO2(hsa_circ_0002490), a circRNA encompassing exons 19 and 20 of the FCHO2 gene, exhibited a consistent overexpression in melanoma tissues. Furthermore, elevated circFCHO2 levels demonstrated a positive correlation with the malignant phenotype and poor prognosis among the 158 melanoma patients studied. Besides, we observed that heightened levels of circFCHO2 promoted melanoma cell proliferation, migration, and invasion in vitro, along with contributing to tumor growth in vivo. Furthermore, we found differences in the secondary structure of circFCHO2 compared to most other circular RNA structures. It has fewer miRNA binding sites, while it has more RNA binding protein binding sites. We therefore speculate that circFCHO2 may have a function of interacting with RNA binding proteins. Mechanistically, it was confirmed by fluorescence in situ hybridization (FISH), RNA-pull down, RNA immunoprecipitation (RIP), and western blotting assays that circFCHO2 interacts with dead end protein homolog 1 (DND1) and reverses the inhibition of the PI3K/AKT signaling pathway by binding to DND1. Our findings reveal that circFCHO2 drives melanoma progression by regulating the PI3K/AKT signaling pathway through direct binding to DND1 and may serve as a potential diagnostic biomarker and therapeutic target for the treatment of melanoma.
Asunto(s)
Proteínas de Unión a Ácidos Grasos , Melanoma , Proteínas de Neoplasias , ARN Circular , Humanos , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Hibridación Fluorescente in Situ , Melanoma/patología , MicroARNs/genética , MicroARNs/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Circular/genética , Proteínas de Neoplasias/genética , Proteínas de Unión a Ácidos Grasos/genéticaRESUMEN
Seven new sugar alcohol-conjugated acyclic sesquiterpenes, acremosides A-G (1-7), were isolated from the cultures of the sponge-associated fungus Acremonium sp. IMB18-086 cultivated with heat-killed Pseudomonas aeruginosa. The structures were determined by comprehensive analyses of 1D and 2D NMR spectroscopic data. The relative configurations were established by J-based configuration analysis and acetonide derivatization. The absolute configurations were elucidated by the Mosher ester method and ECD calculations. The structures of acremosides E-G (5-7) featured the linear sesquiterpene skeleton with a tetrahydrofuran moiety attached to a sugar alcohol. Acremosides A (1) and C-E (3-5) showed significant inhibitory activities against hepatitis C virus (EC50 values of 4.8-8.8 µM) with no cytotoxicity (CC50 of >200 µM).
Asunto(s)
Acremonium , Sesquiterpenos , Sesquiterpenos/farmacología , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificación , Animales , Estructura Molecular , Acremonium/química , Antivirales/farmacología , Antivirales/química , Antivirales/aislamiento & purificación , Poríferos/química , Hepacivirus/efectos de los fármacos , Humanos , Pseudomonas aeruginosa/efectos de los fármacosRESUMEN
BACKGROUND: Gliomas differ from meningiomas in their margins, most of which are not separated from the surrounding tissue by a distinct interface. PURPOSE: To characterize the margins of gliomas quantitatively based on the margin sharpness coefficient (MSC) is significant for clinical judgment and invasive analysis of gliomas. MATERIAL AND METHODS: The data for this study used magnetic resonance image (MRI) data from 67 local patients and 15 open patients to quantify the intensity of changes in the glioma margins of the brain using MSC. The accuracy of MSC was assessed by consistency analysis and Bland-Altman test analysis, as well as invasive correlations using receiver operating characteristic (ROC) and Spearman correlation coefficients for subjects. RESULTS: In grading the tumors, the mean MSC values were significantly lower for high-grade gliomas (HGG) than for low-grade gliomas (LGG). The concordance correlation between the measured gradient and the actual gradient was high (HGG: 0.981; LGG: 0.993), and the Bland-Altman mean difference at the 95% confidence interval (HGG: -0.576; LGG: 0.254) and the limits of concordance (HGG: 5.580; LGG: 5.436) indicated no statistical difference. The correlation between MSC and invasion based on the margins of gliomas showed an AUC of 0.903 and 0.911 for HGG and LGG, respectively. The mean Spearman correlation coefficient of the MSC versus the actual distance of invasion was -0.631 in gliomas. CONCLUSION: The relatively low MSC on the blurred margins and irregular shape of gliomas may help in benign-malignant differentiation and invasion prediction of gliomas and has potential application for clinical judgment.
Asunto(s)
Neoplasias Encefálicas , Glioma , Imagen por Resonancia Magnética , Humanos , Glioma/diagnóstico por imagen , Glioma/patología , Imagen por Resonancia Magnética/métodos , Femenino , Masculino , Persona de Mediana Edad , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Adulto , Anciano , Clasificación del Tumor , Adulto Joven , Adolescente , Estudios Retrospectivos , Anciano de 80 o más AñosRESUMEN
OBJECTIVE: To provide surgical references for selecting appropriate parotidectomy incisions, reviewing modified approaches, incision designs, and associated complications. METHODS: We have systematically searched 5 medical literature databases examining parotidectomy incision designs and postoperative complications from 2008 to 2021. RESULTS: There are a total of 9 novel incision designs: 1) posterior auricular hairline incision (PAHI); 2) combined preauricular and retroauricular incision (CPRI); 3) V-shaped incision (VI); 4) N-shaped incision (NI); 5) postaural incision (PI); 6) preauricular crutch incision (PCI); and 7) endaural incision (EI). Simultaneously, there are a total of 8 postoperative complications: 1) infection; 2) salivary fistula; 3) facial nerve palsy/paresis; 4) ear lobule numbness; 5) Frey syndrome; 6) facial deformity; 7) hematoma; and 8) tumor reoccurrence. CONCLUSIONS: Over the last decade, a surge in modified parotidectomy incisions has been witnessed in clinical practice. This expansion is attributed to rapid technical advancements and a deeper understanding of anatomy and histopathology. These modified approaches contribute significantly to improving cosmetic outcomes, minimizing associated complications, and enhancing patient satisfaction.
Asunto(s)
Neoplasias de la Parótida , Humanos , Neoplasias de la Parótida/cirugía , Complicaciones Posoperatorias/etiología , Glándula Parótida/cirugía , Herida Quirúrgica/cirugíaRESUMEN
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common metabolic disease of the liver, characterized by hepatic steatosis in more than 5% of hepatocytes. However, despite the recent approval of the first drug, resmetirom, for the management of metabolic dysfunction-associated steatohepatitis, decades of target exploration and hundreds of clinical trials have failed, highlighting the urgent need to find new druggable targets for the discovery of innovative drug candidates against MASLD. Here, we found that glutathione S-transferase alpha 1 (GSTA1) expression was negatively associated with lipid droplet accumulation in vitro and in vivo. Overexpression of GSTA1 significantly attenuated oleic acid-induced steatosis in hepatocytes or high-fat diet-induced steatosis in the mouse liver. The hepatoprotective and anti-inflammatory drug bicyclol also attenuated steatosis by upregulating GSTA1 expression. A detailed mechanism showed that GSTA1 directly interacts with fatty acid binding protein 1 (FABP1) and facilitates the degradation of FABP1, thereby inhibiting intracellular triglyceride synthesis by impeding the uptake and transportation of free fatty acids. Conclusion: GSTA1 may be a good target for the discovery of innovative drug candidates as GSTA1 stabilizers or enhancers against MASLD.
Asunto(s)
Proteínas de Unión a Ácidos Grasos , Hígado Graso , Glutatión Transferasa , Regulación hacia Arriba , Glutatión Transferasa/metabolismo , Glutatión Transferasa/genética , Animales , Humanos , Ratones , Proteínas de Unión a Ácidos Grasos/metabolismo , Proteínas de Unión a Ácidos Grasos/genética , Hígado Graso/metabolismo , Hígado Graso/tratamiento farmacológico , Regulación hacia Arriba/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Hígado/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Masculino , Ratones Endogámicos C57BL , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Ácido Oléico/metabolismo , Células Hep G2 , Triglicéridos/metabolismo , IsoenzimasRESUMEN
Drought stress is a serious factor affecting crop growth and production worldwide. The circadian clock has been identified as key to improving regional adaptability of plants. However, our understanding of the contribution of the circadian clock to drought response and the impacts of drought stress on the circadian clock in plants is still limited. To explore the interactions between the circadian clock and drought stress, foxtail millet seedlings were treated with simulated drought (20% polyethylene glycol-6000) treatment starting at the day (DD) onset zeitgeber time 0 (ZT0, lights on) and at the night (DN) onset zeitgeber time 16 (ZT16, lights off). A high temporal-resolution transcriptomic investigation was performed using DD and DN samples collected at intervals of 2 or 4 h within a 24-h drought-treatment period. Overall, we identified 13 294 drought-responsive genes (DRGs). Among these DRGs, 7931 were common between DD and DN samples, 2638 were specific to DD, and 2725 were specific to DN. Additionally, we identified 1257 circadian genes, of which 67% were DRGs. Interestingly, with drought treatment starting at the day for 8, 12 or 16 h, the circadian phase shifted to 12 h. We also found that the circadian clock led to different day and night drought-responsive pathways. The identification of DRG_Clock (DRG and circadian clock) and DRG_NonClock (DRG and not circadian clock) genes provides a reference for selecting candidate drought resistance genes. Our work reveals the temporal drought-response process and crosstalk between drought stress and the circadian clock in foxtail millet.
Asunto(s)
Relojes Circadianos , Setaria (Planta) , Relojes Circadianos/genética , Sequías , Regulación de la Expresión Génica de las Plantas/genética , Proteínas de Plantas/metabolismo , Setaria (Planta)/metabolismo , Estrés Fisiológico/genética , TranscriptomaRESUMEN
BACKGROUND: Determination of H3 K27M mutation in diffuse midline glioma (DMG) is key for prognostic assessment and stratifying patient subgroups for clinical trials. MRI can noninvasively depict morphological and metabolic characteristics of H3 K27M mutant DMG. PURPOSE: This study aimed to develop a deep learning (DL) approach to noninvasively predict H3 K27M mutation in DMG using T2-weighted images. STUDY TYPE: Retrospective and prospective. POPULATION: For diffuse midline brain gliomas, 341 patients from Center-1 (27 ± 19 years, 184 males), 42 patients from Center-2 (33 ± 19 years, 27 males) and 35 patients (37 ± 18 years, 24 males). For diffuse spinal cord gliomas, 133 patients from Center-1 (30 ± 15 years, 80 males). FIELD STRENGTH/SEQUENCE: 5T and 3T, T2-weighted turbo spin echo imaging. ASSESSMENT: Conventional radiological features were independently reviewed by two neuroradiologists. H3 K27M status was determined by histopathological examination. The Dice coefficient was used to evaluate segmentation performance. Classification performance was evaluated using accuracy, sensitivity, specificity, and area under the curve. STATISTICAL TESTS: Pearson's Chi-squared test, Fisher's exact test, two-sample Student's t-test and Mann-Whitney U test. A two-sided P value <0.05 was considered statistically significant. RESULTS: In the testing cohort, Dice coefficients of tumor segmentation using DL were 0.87 for diffuse midline brain and 0.81 for spinal cord gliomas. In the internal prospective testing dataset, the predictive accuracies, sensitivities, and specificities of H3 K27M mutation status were 92.1%, 98.2%, 82.9% in diffuse midline brain gliomas and 85.4%, 88.9%, 82.6% in spinal cord gliomas. Furthermore, this study showed that the performance generalizes to external institutions, with predictive accuracies of 85.7%-90.5%, sensitivities of 90.9%-96.0%, and specificities of 82.4%-83.3%. DATA CONCLUSION: In this study, an automatic DL framework was developed and validated for accurately predicting H3 K27M mutation using T2-weighted images, which could contribute to the noninvasive determination of H3 K27M status for clinical decision-making. EVIDENCE LEVEL: 2 Technical Efficacy: Stage 2.
Asunto(s)
Neoplasias Encefálicas , Aprendizaje Profundo , Glioma , Neoplasias de la Médula Espinal , Masculino , Humanos , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Histonas/genética , Estudios Retrospectivos , Estudios Prospectivos , Mutación , Glioma/diagnóstico por imagen , Glioma/genética , Imagen por Resonancia Magnética , Neoplasias de la Médula Espinal/diagnóstico por imagen , Neoplasias de la Médula Espinal/genéticaRESUMEN
OBJECTIVES: To assess the value of coordinatized lesion location analysis (CLLA), in empowering ROI-based imaging diagnosis of gliomas by improving accuracy and generalization performances. METHODS: In this retrospective study, pre-operative contrasted T1-weighted and T2-weighted MR images were obtained from patients with gliomas from three centers: Jinling Hospital, Tiantan Hospital, and the Cancer Genome Atlas Program. Based on CLLA and ROI-based radiomic analyses, a fusion location-radiomics model was constructed to predict tumor grades, isocitrate dehydrogenase (IDH) status, and overall survival (OS). An inter-site cross-validation strategy was used for assessing the performances of the fusion model on accuracy and generalization with the value of area under the curve (AUC) and delta accuracy (ACC) (ACCtesting-ACCtraining). Comparisons of diagnostic performances were performed between the fusion model and the other two models constructed with location and radiomics analysis using DeLong's test and Wilcoxon signed ranks test. RESULTS: A total of 679 patients (mean age, 50 years ± 14 [standard deviation]; 388 men) were enrolled. Based on tumor location probabilistic maps, fusion location-radiomics models (averaged AUC values of grade/IDH/OS: 0.756/0.748/0.768) showed the highest accuracy in contrast to radiomics models (0.731/0.686/0.716) and location models (0.706/0.712/0.740). Notably, fusion models ([median Delta ACC: - 0.125, interquartile range: 0.130]) demonstrated improved generalization than that of radiomics model ([- 0.200, 0.195], p = 0.018). CONCLUSIONS: CLLA could empower ROI-based radiomics diagnosis of gliomas by improving the accuracy and generalization of the models. CLINICAL RELEVANCE STATEMENT: This study proposed a coordinatized lesion location analysis for glioma diagnosis, which could improve the performances of the conventional ROI-based radiomics model in accuracy and generalization. KEY POINTS: ⢠Using coordinatized lesion location analysis, we mapped anatomic distribution patterns of gliomas with specific pathological and clinical features and constructed glioma prediction models. ⢠We integrated coordinatized lesion location analysis into ROI-based analysis of radiomics to propose new fusion location-radiomics models. ⢠Fusion location-radiomics models, with the advantages of being less influenced by variabilities, improved accuracy, and generalization performances of ROI-based radiomics models on predicting the diagnosis of gliomas.
Asunto(s)
Neoplasias Encefálicas , Glioma , Masculino , Humanos , Persona de Mediana Edad , Neoplasias Encefálicas/patología , Imagen por Resonancia Magnética/métodos , Estudios Retrospectivos , Glioma/patología , Isocitrato Deshidrogenasa/genética , Encéfalo/patología , Poder PsicológicoRESUMEN
To explore the potential use of CDK inhibitors in pancreatic ductal adenocarcinoma (PDAC) therapy, a series of novel 2-((4-sulfamoylphenyl)amino)-pyrrolo[2,3-d]pyrimidine derivatives was designed, synthesised, and investigated for inhibition on both CDK kinase activity and cellular proliferation of pancreatic cancer. Most of new sulphonamide-containing derivatives demonstrated strong inhibitory activity on CDK9 and obvious anti-proliferative activity in cell culture. Moreover, two new compounds suppressed cell proliferation of multiple human pancreatic cancer cell lines. The most potent compound 2g inhibited cancer cell proliferation by blocking Rb phosphorylation and induced apoptosis via downregulation of CDK9 downstream proteins Mcl-1 and c-Myc in MIA PaCa-2 cells. CDK9 knockdown experiment suggests its anti-proliferative activity is mainly mediated by CDK9. Additionally, 2g displayed moderate tumour inhibition effect in AsPC-1 derived xenograft mice model. Altogether, this study provided a new start for further optimisation to develop potential CDK inhibitor candidates for PDAC treatment by alone or combination use.
Asunto(s)
Antineoplásicos , Neoplasias Pancreáticas , Humanos , Ratones , Animales , Línea Celular Tumoral , Antineoplásicos/farmacología , Puntos de Control del Ciclo Celular , Neoplasias Pancreáticas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proliferación Celular , Apoptosis , Pirimidinas/farmacología , Neoplasias PancreáticasRESUMEN
OBJECTIVE: To observe the radiological characteristics of Neuronal Intranuclear Inclusion Disease (NIID) on lesion locations and diffusion property using quantitative imaging analysis. METHODS: Visual inspection and quantitative analyses were performed on MRI data from 31 retrospectively included patients with NIID. Frequency heatmaps of lesion locations on T2WI and DWI were generated using voxel-wise analysis. Gray matter volume (GMV), white matter volume (WMV) and diffusion property of apparent diffusion coefficient (ADC) values of patients were voxel-wisely compared with healthy controls. Moreover, the ADC values within the DWI-detected lesion were compared with those within the adjacent cortical gray matter and white matter. Voxel-based lesion symptom mapping (VLSM) techniques, were used to determine the relationship between DWI lesion location and disease durations. RESULTS: By visual inspection on the imaging findings, we proposed an "cockscomb flower sign" for describing the radiological feature of DWI hyperintensity within the corticomedullary junction. A "T2WI-DWI mismatch of spatial distribution" pattern was also revealed with visual inspection and frequency heatmaps, for describing the feature of a wider lesion distribution covering white matter shown on T2WI than that on DWI. Voxel-based morphometry comparison revealed that wildly reduced GMV and WMV, both the lesion areas detected by DWI and T2WI demonstrated ADC increase in patients. Furthermore, the ADC values within the DWI-detected lesion were intermediate between the adjacent cortex and the deep white matter with highest ADC. VLSM analysis revealed that frontal lobe, parietal lobe and internal capsule damage were associated with higher NIID durations. CONCLUSION: NIID features with "cockscomb flower-like" DWI hyperintensity in area of corticomedullary junction, based on a "T2WI-DWI mismatch of spatial distribution" of lesion locations. The pathological substrate of corticomedullary junction hyperintensity on DWI, can not be explained as diffusion restriction. These typical radiological features of brain MRI would be helpful for diagnosis of NIID.
RESUMEN
PURPOSE: EphA2 is a key factor underlying invasive propensity of gliomas, and is associated with poor prognosis of tumors. We aimed to develop a radiomics-based imaging index for predicting EphA2 expression in diffuse gliomas, and further estimating its value for grading of tumors. METHODS: A total of 182 patients with diffuse gliomas were included. All subjects underwent pre-operative MRI and post-operative pathological diagnosis. EphA2 expression of tumors was scored on pathological sections with immunohistochemical staining using monoclonal EphA2 antibody. MRI radiomics features were extracted from three-dimensional contrast-enhanced T1-weighted imaging and diffusion kurtosis imaging. Predictive models were constructed using machine learning-based radiomics features selection and three classifiers for predicting EphA2 expression and tumor grade. Features of best EphA2 expression model were subsequently used to construct another model of tumor grading. For each model, 146 cases (80%) were randomly picked as training and the rest 36 (20%) were testing cohorts. EphA2 expression was further correlated to the radiomics features in both grade models using Spearman's correlation. RESULTS: Logistic regression model presented highest performance for predicting EphA2 expression (AUC: 0.836/0.724 in training/validation set). Tumor gradings model guided by features from EphA2 expression model demonstrated comparable performance (AUC: 0.930/0.983) to that constructed directly using imaging radiomics features (AUC: 0.960/0.977). Two radiomics features which included in both LR-grade models showed strong correlation (P < 0.05) with EphA2 expression. CONCLUSION: The expression of EphA2 in gliomas could be predicted by radiomics features extracted from diffusion kurtosis MRI, which could also be used to assist tumor grading.
Asunto(s)
Neoplasias Encefálicas , Carcinoma Hepatocelular , Eritropoyetina , Glioma , Neoplasias Hepáticas , Encéfalo , Neoplasias Encefálicas/diagnóstico por imagen , Glioma/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Receptores de Eritropoyetina , Estudios RetrospectivosRESUMEN
Zelkovamycins F and G (1 and 2), two new natural cyclic octapeptides possessing the unprecedented nonproteinogenic amino acid residues l-α-methyl-threonine and l-α-methyl-allo-threonine, respectively, along with four new analogues, zelkovamycins H-K (3-6), were identified from the endophytic Kitasatospora sp. CPCC 204717. Their structures were elucidated by detailed analysis of NMR and HRESIMS/MS spectroscopic data. The configurations of amino acid residues were determined by Marfey's analysis combined with NMR calculations. Compounds 1, 2, and 4 showed potent antibacterial activity against methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis. The structure-activity relationship study revealed that the 2-methyl-3-oxobutyrine and sarcosine residues played important roles in their antibacterial activities. Zelkovamycin (7) and zelkovamycin E (8) exhibited significant antiviral activity against the hepatitis C virus.
Asunto(s)
Staphylococcus aureus Resistente a Meticilina , Streptomycetaceae , Antibacterianos/química , Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , TreoninaRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and there is no specific drug to treat it. Recent results showed that 17-beta-hydroxysteroid dehydrogenase type 13 (HSD17B13) is associated with liver diseases, but these conclusions are controversial. Here, we showed that HSD17B13 was more highly expressed in the livers of NAFLD patients, and high expression was induced in the livers of murine NAFLD models and cultural hepatocytes treated using various etiologies. The high HSD17B13 expression in the hepatocytes facilitated the progression of NAFLD by directly stabilizing the intracellular lipid drops and by indirectly activating hepatic stellate cells. When HSD17B13 was overexpressed in the liver, it aggravated liver steatosis and fibrosis in mice fed with a high-fat diet, while down-regulated the high expression of HSD17B13 by short hairpin RNAs produced a therapeutic effect in the NAFLD mice. We concluded that high HSD17B13 expression is a good target for the development of drugs to treat NAFLD.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Animales , Dieta Alta en Grasa/efectos adversos , Células Estrelladas Hepáticas/metabolismo , Hepatocitos/metabolismo , Humanos , Ratones , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
Transforming growth factor beta (TGF-ß) plays an important role in the viral liver disease progression via controlling viral propagation and mediating inflammation-associated responses. However, the antiviral activities and mechanisms of TGF-ß isoforms, including TGF-ß1, TGF-ß2 and TGF-ß3, remain unclear. Here, we demonstrated that all of the three TGF-ß isoforms were increased in Huh7.5 cells infected by hepatitis C virus (HCV), but in turn, the elevated TGF-ß isoforms could inhibit HCV propagation with different potency in infectious HCV cell culture system. TGF-ß isoforms suppressed HCV propagation through interrupting several different stages in the whole HCV life cycle, including virus entry and intracellular replication, in TGF-ß/SMAD signalling pathway-dependent and TGF-ß/SMAD signalling pathway-independent manners. TGF-ß isoforms showed additional anti-HCV activities when combined with each other. However, the elevated TGF-ß1 and TGF-ß2, not TGF-ß3, could also induce liver fibrosis with a high expression of type I collagen alpha-1 and α-smooth muscle actin in LX-2 cells. Our results showed a new insight into TGF-ß isoforms in the HCV-related liver disease progression.
Asunto(s)
Hepacivirus/efectos de los fármacos , Hepacivirus/crecimiento & desarrollo , Hepatitis C/virología , Transducción de Señal , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/farmacología , Secuencia de Aminoácidos , Antivirales/farmacología , Línea Celular Tumoral , Hepatitis C/patología , Humanos , Conformación Proteica en Hélice alfa , Dominios y Motivos de Interacción de Proteínas , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/farmacología , ARN Viral , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Factor de Crecimiento Transformador beta2/metabolismo , Factor de Crecimiento Transformador beta2/farmacología , Factor de Crecimiento Transformador beta3/metabolismo , Factor de Crecimiento Transformador beta3/farmacología , Internalización del Virus/efectos de los fármacosRESUMEN
Glioma is the most common malignant brain tumor and classification of low grade glioma (LGG) and high grade glioma (HGG) is an important reference of making decisions on patient treatment options and prognosis. This work is largely done manually by pathologist based on an examination of whole slide image (WSI), which is arduous and heavily dependent on doctors' experience. In the World Health Organization (WHO) criteria, grade of glioma is closely related to hypercellularity, nuclear atypia and necrosis. Inspired by this, this paper designed and extracted cell density and atypia features to classify LGG and HGG. First, regions of interest (ROI) were located by analyzing cell density and global density features were extracted as well. Second, local density and atypia features were extracted in ROI. Third, balanced support vector machine (SVM) classifier was trained and tested using 10 selected features. The area under the curve (AUC) and accuracy (ACC) of 5-fold cross validation were 0.92 ± 0.01 and 0.82 ± 0.01 respectively. The results demonstrate that the proposed method of locating ROI is effective and the designed features of density and atypia can be used to predict glioma grade accurately, which can provide reliable basis for clinical diagnosis.
Asunto(s)
Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/diagnóstico por imagen , Glioma/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Clasificación del Tumor , Máquina de Vectores de SoporteRESUMEN
OBJECTIVE: To investigate the clinical efficacy of autologous bone marrow mesenchymal stem cell (BMSC) transplantation in the treatment of knee osteoarthritis (OA) and its effect on the expression of serum TNF-α and IL-6. METHODS: The clinical data of 86 patients with knee OA treated in the Shanghai East Hospital Tongji University from March 2015 to March 2017 were analyzed retrospectively. Observation group (treated with intraarticular injection of autologous BMSC); Control group (treated with arthroscopic debridement and injected with sodium hyaluronate). The patients were followed up for 1 year after treatment, the clinical efficacy was evaluated by the Lysholm Knee Scale (Lysholm), Visual analog scale (VAS), and the expression of serum TNF-α and IL-6 was detected by ELISA. RESULTS: The expression of TNF-α and IL-6 at 6 and 12 months after surgery was significantly lower than that before surgery (P<0.05). CONCLUSIONS: The Lysholm score and total effective rate of knee OA patients underwent BMSC transplantation are better than that of joint debridement, while the VAS score was lower than that of joint debridement. Meanwhile, BMSC transplantation seems to reduce the postoperative inflammatory reaction.
Asunto(s)
Interleucina-6/sangre , Trasplante de Células Madre Mesenquimatosas/métodos , Osteoartritis de la Rodilla/sangre , Osteoartritis de la Rodilla/terapia , Factor de Necrosis Tumoral alfa/sangre , Anciano , Biomarcadores/sangre , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Trasplante Autólogo/métodos , Resultado del TratamientoRESUMEN
PURPOSE: To investigate imaging features of crossed cerebellar diaschisis (CCD) in cerebral gliomas, and its underlying pathophysiological mechanisms. METHODS: Thirty-three pre-surgical patients with cerebral gliomas and 33 healthy controls underwent arterial spin-labeling, diffusion tensor imaging, and high-resolution T1-weighted imaging using MRI, in order to estimate cerebral blood flow (CBF), white matter integrity, and lesion volume, respectively. Asymmetry indices of CBF in the cerebellum were used for evaluating the level of CCD in the patients. These indices were correlated with clinical variables (lesion size and position, tumor histological grade, and CBF asymmetry) and diffusion tensor imaging parameters (fractional anisotropy and number of fibers in the cortico-ponto-cerebellar pathway and across the cerebral hemispheres), respectively. RESULTS: The patients showed decreased CBF in the cerebellar hemisphere contralateral to the supratentorial tumor, and increased CBF asymmetry in the cerebellum (both P < 0.05). CCD levels in high-grade gliomas were higher than those of low-grade gliomas (P < 0.05). CCD levels were negatively correlated with the size of the supratentorial lesions, and positively correlated with FA asymmetry in the cerebral fibers (both P < 0.05). CONCLUSIONS: CCD in cerebral gliomas was specifically associated with tumor histological grade, lesion size, and white matter impairments in the hemisphere ipsilateral to the tumor. The findings implicated that observing CCD might have potential for assisting grading diagnosis of cerebral gliomas.
Asunto(s)
Cerebelo/patología , Glioma/diagnóstico por imagen , Glioma/patología , Imagen por Resonancia Magnética/métodos , Vías Nerviosas/diagnóstico por imagen , Neoplasias Supratentoriales/diagnóstico por imagen , Neoplasias Supratentoriales/patología , Anisotropía , Estudios de Casos y Controles , Circulación Cerebrovascular , Imagen de Difusión por Resonancia Magnética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Marcadores de Spin , Sustancia Blanca/patologíaRESUMEN
A field-scale trial was conducted to investigate the remediation effects of sepiolite on Cd-polluted paddy soils under different moisture managements, using a series of variables (pH and extractable Cd of soil, plant Cd concentration, plant nutrition and enzyme activity in soil). Results revealed that soil pH increased significantly after sepiolite addition, which promoted the reduction in extractable Cd in soil. After applying 0.5-2.5% sepiolite into soil, due to higher pH and lower TCLP Cd concentration, brown rice Cd reduced by 17-67% under continuous flooding, 14-62% under conventional irrigation, and 13-61% under wetting irrigation (pâ¯<â¯0.05). The activities of phosphatase and invertase increased compared with unamended soil (pâ¯<â¯0.05). The available phosphorus in clay treated soil showed a remarkable raise, with a maximum increase by 14.5%, 16.9% and 18.1% under three moisture managements (pâ¯<â¯0.05). The increasing values of enzyme activity and then plant nutrition in soil revealed that clay application improved the ecological condition of Cd-contaminated paddy soil. The sepiolite application in combination with continuous flooding provided an efficient and safe remediation technology for Cd-polluted rice field.
Asunto(s)
Silicatos de Aluminio/análisis , Cadmio/análisis , Silicatos de Magnesio/química , Oryza/química , Contaminantes del Suelo/análisis , Arcilla , Restauración y Remediación Ambiental , Inundaciones , Concentración de Iones de Hidrógeno , Nitrógeno/análisis , Monoéster Fosfórico Hidrolasas/metabolismo , Fósforo/análisis , Potasio/análisis , Suelo/química , beta-Fructofuranosidasa/metabolismoRESUMEN
We examined in situ remediation of sepiolite on cadmium-polluted soils with diverse water regimes, and several variables including brown rice Cd, exchangeable Cd, pH, and available Fe/P. pH, available Fe/P in soils increased gradually during continuous flooding, which contributed to Cd absorption on colloids. In control group (untreated soils), compared to conventional irrigation, brown rice Cd in continuous flooding reduced by 37.9%, and that in wetting irrigation increased by 31.0% (p<0.05). In contrast to corresponding controls, brown rice Cd in sepiolite treated soils reduced by 44.4%, 34.5% and 36.8% under continuous flooding, conventional irrigation and wetting irrigation (p<0.05), and exchangeable Cd in amended soils reduced by 27.5-49.0%, 14.3-40.5%, and 24.9-32.8% under three water management regimes (p<0.05). Compared to corresponding controls, decreasing amplitudes of exchangeable Cd and brown rice Cd in sepiolite treated soils were higher in continuous flooding than in conventional irrigation and wetting irrigation. Continuous flooding management promoted soil Cd immobilization by sepiolite.