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Ferroptosis, a form of regulated cell death that is driven by iron-dependent phospholipid peroxidation, has been implicated in multiple diseases, including cancer1-3, degenerative disorders4 and organ ischaemia-reperfusion injury (IRI)5,6. Here, using genome-wide CRISPR-Cas9 screening, we identified that the enzymes involved in distal cholesterol biosynthesis have pivotal yet opposing roles in regulating ferroptosis through dictating the level of 7-dehydrocholesterol (7-DHC)-an intermediate metabolite of distal cholesterol biosynthesis that is synthesized by sterol C5-desaturase (SC5D) and metabolized by 7-DHC reductase (DHCR7) for cholesterol synthesis. We found that the pathway components, including MSMO1, CYP51A1, EBP and SC5D, function as potential suppressors of ferroptosis, whereas DHCR7 functions as a pro-ferroptotic gene. Mechanistically, 7-DHC dictates ferroptosis surveillance by using the conjugated diene to exert its anti-phospholipid autoxidation function and shields plasma and mitochondria membranes from phospholipid autoxidation. Importantly, blocking the biosynthesis of endogenous 7-DHC by pharmacological targeting of EBP induces ferroptosis and inhibits tumour growth, whereas increasing the 7-DHC level by inhibiting DHCR7 effectively promotes cancer metastasis and attenuates the progression of kidney IRI, supporting a critical function of this axis in vivo. In conclusion, our data reveal a role of 7-DHC as a natural anti-ferroptotic metabolite and suggest that pharmacological manipulation of 7-DHC levels is a promising therapeutic strategy for cancer and IRI.
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Deshidrocolesteroles , Ferroptosis , Humanos , Membrana Celular/metabolismo , Colesterol/biosíntesis , Colesterol/metabolismo , Sistemas CRISPR-Cas/genética , Deshidrocolesteroles/metabolismo , Genoma Humano , Enfermedades Renales/metabolismo , Membranas Mitocondriales/metabolismo , Metástasis de la Neoplasia , Neoplasias/metabolismo , Neoplasias/patología , Fosfolípidos/metabolismo , Daño por Reperfusión/metabolismoRESUMEN
Increased adipose tissue lipogenesis is associated with enhanced insulin sensitivity. Mice overexpressing the Glut4 glucose transporter in adipocytes have elevated lipogenesis and increased glucose tolerance despite being obese with elevated circulating fatty acids. Lipidomic analysis of adipose tissue revealed the existence of branched fatty acid esters of hydroxy fatty acids (FAHFAs) that were elevated 16- to 18-fold in these mice. FAHFA isomers differ by the branched ester position on the hydroxy fatty acid (e.g., palmitic-acid-9-hydroxy-stearic-acid, 9-PAHSA). PAHSAs are synthesized in vivo and regulated by fasting and high-fat feeding. PAHSA levels correlate highly with insulin sensitivity and are reduced in adipose tissue and serum of insulin-resistant humans. PAHSA administration in mice lowers ambient glycemia and improves glucose tolerance while stimulating GLP-1 and insulin secretion. PAHSAs also reduce adipose tissue inflammation. In adipocytes, PAHSAs signal through GPR120 to enhance insulin-stimulated glucose uptake. Thus, FAHFAs are endogenous lipids with the potential to treat type 2 diabetes.
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Tejido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Ésteres/metabolismo , Ácidos Grasos/metabolismo , Adulto , Animales , Diabetes Mellitus Tipo 2/dietoterapia , Dieta , Ésteres/administración & dosificación , Ésteres/análisis , Ácidos Grasos/administración & dosificación , Ácidos Grasos/análisis , Femenino , Péptido 1 Similar al Glucagón/metabolismo , Transportador de Glucosa de Tipo 4/genética , Transportador de Glucosa de Tipo 4/metabolismo , Humanos , Inflamación/dietoterapia , Insulina/metabolismo , Resistencia a la Insulina , Lipogénesis , Masculino , Espectrometría de Masas , Ratones Endogámicos C57BL , Persona de Mediana Edad , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Gemcitabine-based chemotherapy is a cornerstone of standard care for gallbladder cancer (GBC) treatment. Still, drug resistance remains a significant challenge, influenced by factors such as tumor-associated microbiota impacting drug concentrations within tumors. Enterococcus faecium, a member of tumor-associated microbiota, was notably enriched in the GBC patient cluster. In this study, we investigated the biochemical characteristics, catalytic activity, and kinetics of the cytidine deaminase of E. faecium (EfCDA). EfCDA showed the ability to convert gemcitabine to its metabolite 2',2'-difluorodeoxyuridine. Both EfCDA and E. faecium can induce gemcitabine resistance in GBC cells. Moreover, we determined the crystal structure of EfCDA, in its apo form and in complex with 2', 2'-difluorodeoxyuridine at high resolution. Mutation of key residues abolished the catalytic activity of EfCDA and reduced the gemcitabine resistance in GBC cells. Our findings provide structural insights into the molecular basis for recognizing gemcitabine metabolite by a bacteria CDA protein and may provide potential strategies to combat cancer drug resistance and improve the efficacy of gemcitabine-based chemotherapy in GBC treatment.
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Antimetabolitos Antineoplásicos , Citidina Desaminasa , Desoxicitidina , Resistencia a Antineoplásicos , Enterococcus faecium , Neoplasias de la Vesícula Biliar , Gemcitabina , Humanos , Antimetabolitos Antineoplásicos/metabolismo , Antimetabolitos Antineoplásicos/farmacología , Antimetabolitos Antineoplásicos/uso terapéutico , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/química , Línea Celular Tumoral , Citidina Desaminasa/metabolismo , Citidina Desaminasa/genética , Citidina Desaminasa/química , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/metabolismo , Desoxicitidina/química , Enterococcus faecium/enzimología , Enterococcus faecium/genética , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Neoplasias de la Vesícula Biliar/genética , Neoplasias de la Vesícula Biliar/microbiología , Gemcitabina/metabolismo , Gemcitabina/farmacología , Gemcitabina/uso terapéuticoRESUMEN
BACKGROUND: The progression of gallbladder cancer (GBC) is accompanied by abnormal fatty acid ß-oxidation (FAO) metabolism. Different types of lipids perform various biological functions. This study aimed to determine the role of acyl carnitines in the molecular mechanisms of GBC progression. METHODS: Distribution of lipids in GBC was described by LC-MS-based lipidomics. Cellular localization, expression level and full-length of lncBCL2L11 were detected using fluorescence in situ hybridization (FISH) assays, subcellular fractionation assay and 5' and 3' rapid amplification of the cDNA ends (RACE), respectively. In vitro and in vivo experiments were used to verify the biological function of lncBCL2L11 in GBC cells. Methylated RNA Immunoprecipitation (MeRIP) was performed to detect the methylation levels of lncBCL2L11. RNA pull-down assay and RNA immunoprecipitation (RIP) assay were used to identify lncBCL2L11 interacting proteins. Co-Immunoprecipitation (Co-IP) and Western blot assay were performed to validate the regulatory mechanism of lncBCL2L11 and THO complex. RESULTS: Acylcarnitines were significantly up-regulated in GBC tissues. High serum triglycerides correlated to decreased survival in GBC patients and promoted tumor migration. LncBCL2L11 was identified in the joint analysis of highly metastatic cells and RNA sequencing data. LncBCl2L11 prevented the binding of THOC6 and THOC5 and causes the degradation of THOC5, thus promoting the accumulation of acylcarnitines in GBC cells, leading to the malignant progression of cancer cells. In addition, highly expressed acylcarnitines stabilized the expression of lncBCL2L11 through N6-methyladenosine methylation (m6A), forming a positive feedback regulation in tumor dissemination. CONCLUSIONS: LncBCL2L11 is involved in gallbladder cancer metastasis through FAO metabolism. High lipid intake is associated with poor prognosis of GBC. Therefore, targeting lncBCL2L11 and its pathway-related proteins or reducing lipid intake may be significant for the treatment of GBC patients.
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Carnitina/análogos & derivados , Neoplasias de la Vesícula Biliar , Humanos , Neoplasias de la Vesícula Biliar/genética , Hibridación Fluorescente in Situ , ARN , Lípidos , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Proteínas Nucleares/metabolismo , Proteínas de Unión al ARN/genéticaRESUMEN
Transcranial ultrasound imaging assumes a growing significance in the detection and monitoring of intracranial lesions and cerebral blood flow. Accurate solution of partial differential equation (PDE) is one of the prerequisites for obtaining transcranial ultrasound wavefields. Grid-based numerical solvers such as finite difference (FD) and finite element methods have limitations including high computational costs and discretization errors. Purely data-driven methods have relatively high demands on training datasets. The fact that physics-informed neural network can only target the same model limits its application. In addition, compared to time-domain approaches, frequency-domain solutions offer advantages of reducing computational complexity and enabling stable and accurate inversions. Therefore, we introduce a framework called FD-embedded UNet (FEUNet) for solving frequency-domain transcranial ultrasound wavefields. The PDE error is calculated using the optimal 9-point FD operator, and it is integrated with the data-driven error to jointly guide the network iterations. We showcase the effectiveness of this approach through experiments involving idealized skull and brain models. FEUNet demonstrates versatility in handling various input scenarios and excels in enhancing prediction accuracy, especially with limited datasets and noisy information. Finally, we provide an overview of the advantages, limitations, and potential avenues for future research in this study.
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Sistemas de Computación , Cabeza , Ultrasonografía , Redes Neurales de la Computación , CráneoRESUMEN
In this paper, we use the improved event study method to analyze the changes in the systemic risk trends of various financial sectors after the outbreak of COVID-19. The analysis is based on the daily return data of 45 Chinese financial institutions from January 2, 2019, to November 30, 2020. The improved event study method is also used to explore the horizontal, trend, and public opinion effects of the systemic risk. The empirical analysis results show that: (1) the occurrence of COVID-19 will increase the level and volatility of systemic risk in the financial industry. (2) After the outbreak of COVID-19, there is no horizontal effect in all financial industries. The banking and securities industries have significant and longer-lasting positive trend effects, and from the perspective of trend effects, in the face of external shocks, the banking industry is more stable than the securities industry. (3) After the outbreak of COVID-19, the banking and securities industries have a public opinion effect, which is gradually weakened; but there is no public opinion effect in the insurance industry.
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Gallbladder carcinoma (GBC) is a vicious and invasive disease. The major challenge in the clinical treatment of GBC is the lack of a suitable prognosis method. Chemokine receptors such as CXCR3, CXCR4 and CXCR7 play vital roles in the process of tumour progression and metastasis. Their expression levels and distribution are proven to be indicative of the progression of GBC, but are hard to be decoded by conventional pathological methods, and therefore, not commonly used in the prognosis of GBC. In this study, we developed a computer-aided image analysis method, which we used to quantitatively measure the expression levels of CXCR3, CXCR4 and CXCR7 in the nuclei and cytoplasm of glandular and interstitial cells from a cohort of 55 GBC patients. We found that CXCR3, CXCR4 and CXCR7 expressions are associated with the clinicopathological variables of GBC. Cytoplasmic CXCR3, nuclear CXCR7 and cytoplasmic CXCR7 were significant predictive factors of histology invasion, whereas cytoplasmic CXCR4 and nuclear CXCR4 were significantly correlated with T and N stage and were associated with the overall survival and disease-free survival. These results suggest that the quantification and localisation of CXCR3, CXCR4 and CXCR7 expressions in different cell types should be considered using computer-aided assessment to improve the accuracy of prognosis in GBC.
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Neoplasias de la Vesícula Biliar/genética , Regulación Neoplásica de la Expresión Génica , Receptores CXCR3/genética , Receptores CXCR4/genética , Receptores CXCR/genética , Núcleo Celular/metabolismo , Neoplasias de la Vesícula Biliar/patología , Humanos , Estadificación de Neoplasias , Receptores CXCR/metabolismo , Receptores CXCR3/metabolismo , Receptores CXCR4/metabolismoRESUMEN
Ganglioside is an important class of lipid species involved in intercellular signaling and various diseases, especially for neurodegenerative diseases. Systematic ganglioside profiling is challenging because of their naturally low abundance and highly diverse species. Herein, a new data-independent acquisition and parallel reaction monitoring (DIA/PRM) method with superior sensitivity was developed. The untargeted DIA acquisition consecutively records all the precursor ion and fragment ions at the same time, while the targeted PRM analysis with versatile higher collisional dissociation generates full MS/MS spectra for structure elucidation and verification. As compared with traditional data-dependent acquisition (DDA), the DIA/PRM method unbiasedly detected the majority of abundant ganglioside species and as low as 50 pg of ganglioside in an untargeted manner. Gangliosides in four kinds of biological samples including the mouse brain, mouse plasma, HeLa cell, and human colon cancer tissue were systematically identified, and low-abundance ganglioside species were further extended on the basis of linear chromatography retention rules of the most frequently detected ganglioside species. A total of 383 ganglioside features were defined with 329 of them derived from 32 ganglioside species. Taking advantage of the high-resolution MS analysis, rare ganglioside species were further elucidated according to their characteristic fragment ions and neutral losses. In total, 18 gangliosides with a ceramide carbon number from 20 to 25 and modified gangliosides, including 18 acetylated, 8 diacetylated, 1 phosphorylated, 36 N-glycolyneuraminic acid (NeuGc)-containing, and 7 di-NeuGc-containing gangliosides, were newly identified. The developed DIA/PRM method therefore generated a rich ganglioside resource for further functional exploration and is a unique alternative for DDA analysis for global ganglioside profiling in various biological systems.
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Gangliósidos/metabolismo , Lipidómica/métodos , Métodos Analíticos de la Preparación de la Muestra , Animales , Encéfalo/metabolismo , Neoplasias del Colon/metabolismo , Gangliósidos/sangre , Células HeLa , Humanos , RatonesRESUMEN
OBJECTIVES: Patients with gallbladder carcinoma (GBC) lack effective treatment methods largely due to the inadequacy of both molecular characterisation and potential therapeutic targets. We previously uncovered a spectrum of genomic alterations and identified recurrent mutations in the ErbB pathway in GBC. Here, we aimed to study recurrent mutations of genes and pathways in a larger cohort of patients with GBC and investigate the potential mechanisms and clinical significance of these mutations. DESIGN: We performed whole-exome sequencing (WES) in 157 patients with GBC. Functional experiments were applied in GBC cell lines to explore the oncogenic roles of ERBB2/ERBB3 hotspot mutations, their correlation with PD-L1 expression and the underlying mechanisms. ERBB inhibitors and a PD-L1 blocker were used to evaluate the anticancer activities in co-culture systems in vitro and in vivo. RESULTS: WES identified ERBB2 and ERBB3 mutations at a frequency of 7%-8% in the expanded cohort, and patients with ERBB2/ERBB3 mutations exhibited poorer prognoses. A set of in vitro and in vivo experiments revealed increased proliferation/migration on ERBB2/ERBB3 mutation. Ectopic expression of ERBB2/ERBB3 mutants upregulated PD-L1 expression in GBC cells, effectively suppressed normal T-cell-mediated cytotoxicity in vitro through activation of the PI3K/Akt signalling pathway and contributed to the growth and progression of GBC in vivo. Treatment with an ERBB2/ERBB3 inhibitor or a PD-L1 monoclonal antibody reversed these immunosuppressive effects, and combined therapy revealed promising therapeutic activities. CONCLUSIONS: ERBB2/ERBB3 mutations may serve as useful biomarkers in identifying patients who are sensitive to ERBB2/ERBB3 inhibitors and PD-L1 monoclonal antibody treatment. TRIAL REGISTRATION NUMBER: NCT02442414;Pre-results.
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Antígeno B7-H1/genética , Secuenciación del Exoma , Neoplasias de la Vesícula Biliar/genética , Neoplasias de la Vesícula Biliar/inmunología , Receptor ErbB-2/genética , Anticuerpos Monoclonales/farmacología , Antígeno B7-H1/efectos de los fármacos , Línea Celular Tumoral , Análisis Mutacional de ADN , Femenino , Genómica , Humanos , Masculino , Terapia Molecular Dirigida , Medición de Riesgo , Sensibilidad y Especificidad , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUNDS: Long non-coding RNAs (lncRNAs) are essential factors that regulate tumor development and metastasis via diverse molecular mechanisms in a broad type of cancers. However, the pathological roles of lncRNAs in gallbladder carcinoma (GBC) remain largely unknown. Here we discovered a novel lncRNA termed lncRNA Highly expressed in GBC (lncRNA-HGBC) which was upregulated in GBC tissue and aimed to investigate its role and regulatory mechanism in the development and progression of GBC. METHODS: The expression level of lncRNA-HGBC in GBC tissue and different cell lines was determined by quantitative real-time PCR. The full length of lncRNA-HGBC was obtained by 5' and 3' rapid amplification of the cDNA ends (RACE). Cellular localization of lncRNA-HGBC was detected by fluorescence in situ hybridization (FISH) assays and subcellular fractionation assay. In vitro and in vivo assays were preformed to explore the biological effects of lncRNA-HGBC in GBC cells. RNA pull-down assay, mass spectrometry, and RNA immunoprecipitation (RIP) assay were used to identify lncRNA-HGBC-interacting proteins. Dual luciferase reporter assays, AGO2-RIP, and MS2-RIP assays were performed to verify the interaction between lncRNA-HGBC and miR-502-3p. RESULTS: We found that lncRNA-HGBC was upregulated in GBC and its upregulation could predict poor survival. Overexpression or knockdown of lncRNA-HGBC in GBC cell lines resulted in increased or decreased, respectively, cell proliferation and invasion in vitro and in xenografted tumors. LncRNA-HGBC specifically bound to RNA binding protein Hu Antigen R (HuR) that in turn stabilized lncRNA-HGBC. LncRNA-HGBC functioned as a competitive endogenous RNA to bind to miR-502-3p that inhibits target gene SET. Overexpression, knockdown or mutation of lncRNA-HGBC altered the inhibitory effects of miR-502-3p on SET expression and downstream activation of AKT. Clinically, lncRNA-HGBC expression was negatively correlated with miR-502-3p, but positively correlated with SET and HuR in GBC tissue. CONCLUSIONS: Our study demonstrates that lncRNA-HGBC promotes GBC metastasis via activation of the miR-502-3p-SET-AKT cascade, pointing to lncRNA-HGBC as a new prognostic predictor and a therapeutic target.
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Proteínas de Unión al ADN/genética , Proteína 1 Similar a ELAV/genética , Neoplasias de la Vesícula Biliar/genética , Regulación Neoplásica de la Expresión Génica , Chaperonas de Histonas/genética , MicroARNs/genética , Proteínas Proto-Oncogénicas c-akt/genética , ARN Largo no Codificante/genética , Adulto , Anciano , Biomarcadores de Tumor , Línea Celular Tumoral , Proliferación Celular , Proteínas de Unión al ADN/metabolismo , Progresión de la Enfermedad , Femenino , Neoplasias de la Vesícula Biliar/metabolismo , Neoplasias de la Vesícula Biliar/patología , Chaperonas de Histonas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARNRESUMEN
A test strip has been developed for the rapid detection of the illegal additive ethyl anthranilate (EA) in wine. The detection scheme is based on a combination of photonic crystal based detection and molecular imprinting based recognition. The resulting molecularly imprinted photonic crystal (MIPC) undergoes a gradual color change from green to yellow to red upon binding of EA. A semi-quantitative colorimetric card can be used to estimate the content of EA, either visually or by making use of an optical fiber spectrometer. A linear relationship was found between the Bragg diffraction peak shift and the concentration of EA in the range from 0.1 mM to 10 mM. The detection limit is 10 µM. The test has been successfully used to screening for the presence of EA in grape wine. The test strip is selective, and can be re-used after re-activation. Graphical abstract Schematic representation of the fabrication and application of the molecularly imprinted photonic crystal (MIPC) based test trip. The resulting MIPC undergoes a gradual color change from green to yellow to red upon binding of the illegal wine additive ethyl anthranilate (EA).
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Gallbladder cancer (GBC) is the most common malignant tumor of the biliary tract system. Epithelial-mesenchymal transition (EMT) plays a vital role in the process of tumor metastasis. Mesenchymal-like cells can serve as a source of cancer stem cells, which can confer the EMT phenotype. Placental growth factor (PLGF) belongs to the vascular endothelial growth factor family and plays a vital role in cancer. However, the underlying molecular mechanisms about the influence of PLGF on EMT in GBC remain unknown. Here we show that PLGF expression levels were higher in GBC tissues than in normal adjacent tissues and were associated with poor prognosis in GBC patients. Exogenous PLGF enhanced the migration, invasion, and tumorsphere formation of GBC cells. Conversely, knockdown of PLGF decreased the aggressive phenotype of GBC cells. Mechanistically, exogenous PLGF upregulated microRNA-19a (miR-19a) expression through the activation of c-MYC. Moreover, Spearman's correlation analysis showed a positive pairwise correlation among PLGF, c-MYC, and miR-19a expression in GBC tissues. Taken together, these results suggest that PLGF promotes EMT and tumorsphere formation through inducing miR-19a expression by upregulating c-MYC. Thus, PLGF could be a promising molecular therapeutic target for GBC.
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Neoplasias de la Vesícula Biliar/patología , MicroARNs/fisiología , Factor de Crecimiento Placentario/fisiología , Proteínas Proto-Oncogénicas c-myc/fisiología , Adulto , Anciano , Animales , Línea Celular Tumoral , Transición Epitelial-Mesenquimal , Femenino , Neoplasias de la Vesícula Biliar/mortalidad , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Invasividad Neoplásica , Metástasis de la NeoplasiaRESUMEN
BACKGROUND/AIMS: The role of ZFX in tumourigenesis is unclear. We aimed to study ZFX expression, regulation, and function and the clinical implications of this protein in human pancreatic cancer (PCa). METHODS: One hundred and twenty patients with histologically confirmed PCa who underwent surgery were recruited for this study. Tumour samples and PCa cell lines were used to examine ZFX. Various cell functions related to tumourigenesis were assessed. In vivo mouse tumour xenografts were used to confirm the in vitro results. RESULTS: Patients with ZFX-positive tumours had worse overall survival than patients with ZFX-negative tumours. The depletion of ZFX using lentiviral shRNAs significantly inhibited cell proliferation by inducing cell cycle arrest in G0/G1 phase and resulted in increased cell apoptosis and invasive repression. In vivo studies confirmed that ZFX promoted tumour growth. Mechanistically, MAPK pathway activation was involved in the oncogenic functions of ZFX. CONCLUSIONS: ZFX acts as a putative oncogene in PCa and could be a novel therapeutic target for this disease.
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Factores de Transcripción de Tipo Kruppel/metabolismo , Neoplasias Pancreáticas/patología , Animales , Apoptosis , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Femenino , Puntos de Control de la Fase G1 del Ciclo Celular , Humanos , Estimación de Kaplan-Meier , Factores de Transcripción de Tipo Kruppel/antagonistas & inhibidores , Factores de Transcripción de Tipo Kruppel/genética , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidad , Pronóstico , Interferencia de ARN , ARN Interferente Pequeño/metabolismoRESUMEN
The authors describe a method for the determination of carbonyl pollutants adsorbed on ambient particulate matter (diameter < 2.5 µm; PM2.5). 2,4-Dinitrophenylhydrazine (DNPH) was used to derivatize carbonyl compounds. Magnetic molecularly imprinted polymers (MMIPs) selective for 2,4-DNPH were synthesized to remove excess of the derivatization reagent 2,4-DNPH. Micellar electrokinetic chromatography (MEKC) was then applied to the separation of DNPH-derivatized carbonyl compounds. The increased sensitivity of MEKC with UV detection and the sample cleanup resulted in drastically reduced sampling times (15 min) with detection limits ranging from 0.005-0.068 µg·m-3 for different carbonyls. The method was applied to continuous monitoring of carbonyl compounds on ambient PM 2.5 for two consecutive months. The concentrations and gas-to-particle ratios of carbonyls were determined, and a statistical method was used to evaluate the correlation among different carbonyls. It was observed that the total concentration of carbonyls, especially of multi-carbon carbonyls, increases with the level of air pollution. The level of isovaleraldehyde rises sharply and accounts for 37% of total carbonyls on days with extremely humid haze. The ratio of acetaldehyde to propionaldehyde (C2/C3) decreases with the duration and heaviness of haze conditions. Results indicate that anthropogenic emissions and the characteristics of the atmosphere (e.g. temperature, sunlight, and relative humidity) are the main factors that lead to abnormally high levels of isovaleraldehyde and other carbonyls in ambient PM 2.5. Graphical abstract Schematic of a method for the determination of carbonyl pollutants adsorbed on ambient fine particle of type PM2.5. Magnetic molecularly imprinted polymers (MMIPs) were synthesized to remove the excess derivatization reagent (2,4-DNPH) in air sample prior to CE separation.
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Embracing the fact that one can recover certain signals and images from far fewer measurements than traditional methods use, compressive sensing (CS) provides solutions to huge amounts of data collection in phased array-based material characterization. This article describes how a CS framework can be utilized to effectively compress ultrasonic phased array images in time and frequency domains. By projecting the image onto its Discrete Cosine transform domain, a novel scheme was implemented to verify the potentiality of CS for data reduction, as well as to explore its reconstruction accuracy. The results from CIVA simulations indicate that both time and frequency domain CS can accurately reconstruct array images using samples less than the minimum requirements of the Nyquist theorem. For experimental verification of three types of artificial flaws, although a considerable data reduction can be achieved with defects clearly preserved, it is currently impossible to break Nyquist limitation in the time domain. Fortunately, qualified recovery in the frequency domain makes it happen, meaning a real breakthrough for phased array image reconstruction. As a case study, the proposed CS procedure is applied to the inspection of an engine cylinder cavity containing different pit defects and the results show that orthogonal matching pursuit (OMP)-based CS guarantees the performance for real application.
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Metformin is the most commonly used drug for type 2 diabetes and has potential benefit in treating and preventing cancer. Previous studies indicated that membrane proteins can affect the antineoplastic effects of metformin and may be crucial in the field of cancer research. However, the antineoplastic effects of metformin and its mechanism in gallbladder cancer (GBC) remain largely unknown. In this study, the effects of metformin on GBC cell proliferation and viability were evaluated using the Cell Counting Kit-8 (CCK-8) assay and an apoptosis assay. Western blotting was performed to investigate related signaling pathways. Of note, inhibition, knockdown and upregulation of the membrane protein Chloride intracellular channel 1 (CLIC1) can affect GBC resistance in the presence of metformin. Our data demonstrated that metformin apparently inhibits the proliferation and viability of GBC cells. Metformin promoted cell apoptosis and increased the number of early apoptotic cells. We found that metformin can exert growth-suppressive effects on these cell lines via inhibition of p-Akt activity and the Bcl-2 family. Notably, either dysfunction or downregulation of CLIC1 can partially decrease the antineoplastic effects of metformin while upregulation of CLIC1 can increase drug sensitivity. Our findings provide experimental evidence for using metformin as an antitumor treatment for gallbladder carcinoma.
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Antineoplásicos/farmacología , Canales de Cloruro/metabolismo , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Neoplasias de la Vesícula Biliar/metabolismo , Metformina/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Pseudotargeted metabolic profiling is a novel strategy combining the advantages of both targeted and untargeted methods. The strategy obtains metabolites and their product ions from quadrupole time-of-flight (Q-TOF) MS by information-dependent acquisition (IDA) and then picks targeted ion pairs and measures them on a triple-quadrupole MS by multiple reaction monitoring (MRM). The picking of ion pairs from thousands of candidates is the most time-consuming step of the pseudotargeted strategy. Herein, a systematic and automated approach and software (MRM-Ion Pair Finder) were developed to acquire characteristic MRM ion pairs by precursor ions alignment, MS(2) spectrum extraction and reduction, characteristic product ion selection, and ion fusion. To test the reliability of the approach, a mixture of 15 metabolite standards was first analyzed; the representative ion pairs were correctly picked out. Then, pooled serum samples were further studied, and the results were confirmed by the manual selection. Finally, a comparison with a commercial peak alignment software was performed, and a good characteristic ion coverage of metabolites was obtained. As a proof of concept, the proposed approach was applied to a metabolomics study of liver cancer; 854 metabolite ion pairs were defined in the positive ion mode from serum. Our approach provides a high throughput method which is reliable to acquire MRM ion pairs for pseudotargeted metabolomics with improved metabolite coverage and facilitate more reliable biomarkers discoveries.
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Metabolómica/métodos , Carcinoma Hepatocelular/metabolismo , Cromatografía Líquida de Alta Presión , Humanos , Neoplasias Hepáticas/metabolismo , Espectrometría de Masas , Reproducibilidad de los Resultados , Programas InformáticosRESUMEN
With the rapid demand for high-performance energy storage systems, lithium-ion batteries (LiBs) have emerged as the predominant technology in various applications. However, ensuring the safety and reliability of these batteries remains a critical challenge. Ultrasound-based detection, as a non-destructive and effective method for monitoring the internal state of LiBs, has gradually emerged as a valuable tool to enhance battery safety, reliability, and performance. This paper provides a review of recent advancements in the field of acoustic detection for LiBs, delving into the fundamental principles and mechanisms governing the propagation of acoustic signals within these batteries. This paper reviews the correlation between these acoustic signals and the operational status of the battery, as well as the association with internal side reactions during abnormal conditions. The strengths and limitations of current ultrasound-based detection methods are emphasized, offering insights to guide researchers, engineers, and industry professionals in advancing the field. The review aims to foster the development of robust ultrasound-based detection solutions for the next generation of energy storage systems.
RESUMEN
OBJECTIVES: Pancreatic carcinoid tumor (PCT) is described as a malignant form of carcinoid tumors. However, the epidemiology and prognostic factors for PCT are poorly understood. MATERIALS AND METHODS: The data of 2447 PCT patients were included in this study from the Surveillance, Epidemiology, and End Results database and randomly divided into a training cohort (1959) and a validation cohort (488). The epidemiology of PCT was calculated, and independent prognostic factors were identified to construct a prognostic nomogram for predicting long-term disease-specific survival (DSS) among PCT patients. RESULTS: The incidence of PCT increased remarkably from 2000 to 2018. The 1-, 5-, and 10-year DSS rates were 96.4%, 90.3%, and 86.5%, respectively. Age at diagnosis, stage, surgery, radiotherapy, and chemotherapy were identified as independent prognostic factors to construct a prognostic nomogram. The C -indices; area under the receiver operating characteristic curves for predicting 1-, 5-, and 10-year DSS, and calibration plots of the nomogram in both cohorts indicated a high discriminatory accuracy, preferable survival predictive ability, and optimal concordances, respectively. CONCLUSIONS: The incidence of PCT has increased rapidly since 2000. In addition, we established a practical, effective, and accurate prognostic nomogram for predicting the long-term DSS of PCT patients.