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Highly sensitive detection of low-frequency EGFR-L858R mutation is particularly important in guiding targeted therapy of nonsmall-cell lung carcinoma (NSCLC). To this end, a ligase chain reaction (LCR)-based electrochemical biosensor (e-LCR) with an inverted sandwich-type architecture was provided by combining a cooperation of lambda exonuclease-RecJf exonuclease (λ-RecJf exo). In this work, by designing a knife-like DNA substrate (an overhang ssDNA part referred to the "knife arm") and introducing the λ-RecJf exo, the unreacted DNA probes in the LCR were specially degraded while only the ligated products were preserved, after which the ligated knife-like DNA products were hybridized with capture probes on the gold electrode surface through the "knife arms", forming the inverted sandwich-type DNA structure and bringing the methylene blue-label close to the electrode surface to engender the electrical signal. Finally, the sensitivity of the e-LCR could be improved by 3 orders of magnitude with the help of the λ-RecJf exo, and due to the mutation recognizing in the ligation site of the employed ligase, this method could detect EGFR-L858R mutation down to 0.01%, along with a linear range of 1 fM-10 pM and a limit detection of 0.8 fM. Further, the developed method could distinguish between L858R positive and negative mutations in cultured cell samples, tumor tissue samples, and plasma samples, whose accuracy was verified by the droplet digital PCR, holding a huge potential in liquid biopsy for precisely guiding individualized-treatment of NSCLC patients with advantages of high sensitivity, low cost, and adaptability to point-of-care testing.
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Most known chemiluminescence (CL) systems are flash-type that generate weak luminescence and decline quickly after dozens of seconds, while the glow-type CL systems have stable emission for an extended period to achieve accurate quantitation. In this work, a long-term CL system based on hydrazine-hydrate (N2H4·H2O) modified carbon quantum dots (N-CQDs) as a luminescent probe, with K2S2O8 and H2O2 as co-reactants, was proposed. The CL emission enhanced by H2O2 increased 18-fold more than that of N-CQDs and K2S2O8 direct reaction, and decayed by 5% of the maximum intensity over 700 s. In the reaction system, K2S2O8 and H2O2 co-reactants can promote each other to continuously generate corresponding radicals (â¢OH, O2â¢-, 1O2), which in turn trigger the CL emission of N-CQDs. This phenomenon was identified as the primary cause for the production of persistent CL. In addition, a stable and selective CL sensor based on the N-CQDs-K2S2O8-H2O2 CL enhancing system was developed for ascorbic acid quantitation in the linear range from 0.1 to 10.0 mM with a detection limit of 0.036 mM. The method has been applied to the analysis of tablet samples and holds potential in pharmaceutical analysis field.
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[This corrects the article DOI: 10.3389/fnagi.2017.00409.].
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There is a lack of a systematic understanding of the specific mechanism of action of DL0410 in AD treatment. In this study, the combination of RNA-seq and proteomics was firstly employed to uncover the mechanism of action of DL0410 in APP/PS1 transgenic mice. The results of behavioral tests showed that oral administration of DL0410 for 8 weeks improved memory and cognition of APP/PS1 mice. DL0410 significantly reduced ß-amyloid deposition and resulted in significant upregulation of synaptophysin, PSD95 and NMDAR/ CaMKâ ¡ signaling pathway in the hippocampus and cortex, indicating that DL0410 improved synaptic plasticity in APP/PS1 mice, which agrees with the results of RNA-seq and proteomics. Furthermore, the enrichment results of differentially expressed genes identified by RNA-seq and proteomics demonstrate the potential protective effects of DL0410 against oxidative stress and mitochondrial dysfunction. As expected, DL0410 dose-dependently ameliorated oxidative damage and markedly increased the expression of PGC-1α, TFAM, SOD1 and SOD2. Mitochondrial high-resolution respirometry results revealed that mitochondrial respiratory function was significantly improved in APP/PS1 mice administered with DL0410. In addition, DL0410 treatment reduced oxidative damage, strengthened antioxidant system and improved mitochondrial function in Aß-induced HT22 cells. Altogether, our findings suggest the potential of DL0410 as a novel candidate for AD treatment.
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Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Presenilina-1 , Animales , Masculino , Ratones , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Transgénicos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Presenilina-1/genética , Proteómica/métodos , RNA-SeqRESUMEN
Considering the high probability of recurrence or metastasis after thyroidectomy, it is meaningful to develop a rapid, sensitive and specific method for monitoring thyrophyma-related biomarkers. In this study, a homogeneous electrochemiluminescence immunoassay (HO-ECLIA) coupled with magnetic beads (MBs)-based enrichment tactic was established for the determination of thyrophyma-related thyroglobulin (Tg). Importantly, owing to the abundant surface groups and good biocompatibility of carbon quantum dots (CQDs), the incorporation of CQDs onto the Tg antigen surface was achieved, resulting in the formation of Tg-encapsulated CQDs (CQDs-Tg), which served not only as an ECL probe but as a biorecognition element. Under optimal experimental conditions, the proposed platform demonstrated a wide linear range from 0.01 to 100 ng·mL-1 with a detection limit of 6.9 pg·mL-1 (S/N = 3), and performed well in real serum sample analysis against interference. Collectively, the proposed platform exhibited the rapid response, satisfactory sensitivity and specificity toward Tg in complex serum milieu, and held a considerable potential for clinical prognosis monitoring of thyrophyma.
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Técnicas Electroquímicas , Inmunoensayo , Tiroglobulina , Humanos , Carbono/química , Técnicas Electroquímicas/métodos , Inmunoensayo/métodos , Límite de Detección , Mediciones Luminiscentes/métodos , Puntos Cuánticos/química , Tiroglobulina/sangreRESUMEN
Gold nanostructures and a Nafion modified screen-printed carbon electrode (Nafion/AuNS/SPCE) were developed to assess the cell viability of Parkinson's disease (PD) cell models. The electrochemical measurement of cell viability was reflected by catecholamine neurotransmitter (represented by dopamine) secretion capacity, followed by a traditional tetrazolium-based colorimetric assay for confirmation. Due to the capacity to synthesize, store, and release catecholamines as well as their unlimited homogeneous proliferation, and ease of manipulation, pheochromocytoma (PC12) cells were used for PD cell modeling. Commercial low-differentiated and highly-differentiated PC12 cells, and home-made nerve growth factor (NGF) induced low-differentiated PC12 cells (NGF-differentiated PC12 cells) were included in the modeling. This approach achieved sensitive and rapid determination of cellular modeling and intervention states. Notably, among the three cell lines, NGF-differentiated PC12 cells displayed the enhanced neurotransmitter secretion level accompanied with attenuated growth rate, incremental dendrites in number and length that were highly resemble with neurons. Therefore, it was selected as the PD-tailorable modeling cell line. In short, the electrochemical sensor can be used to sensitively determine the biological function of neuron-like PC12 cells with negligible destruction and to explore the protective and regenerative impact of various substances on nerve cell model.
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Neoplasias de las Glándulas Suprarrenales , Polímeros de Fluorocarbono , Enfermedad de Parkinson , Ratas , Animales , Catecolaminas/metabolismo , Células PC12 , Factor de Crecimiento Nervioso , Evaluación Preclínica de Medicamentos , NeurotransmisoresRESUMEN
Flubendazole, an FDA-approved anthelmintic, has been predicted to show strong VEGFR2 inhibitory activity in silico screening combined with in vitro experimental validation, and it has shown anti-cancer effects on some human cancer cell lines, but little is known about the anti-angiogenesis effects and anti-prostate cancer effects. In this study, we analyzed the binding modes and kinetic analysis of flubendazole with VEGFR2 and first demonstrated that flubendazole suppressed VEGF-stimulated cell proliferation, wound-healing migration, cell invasion and tube formation of HUVEC cells, and decreased the phosphorylation of extracellular signal-regulated kinase and serine/threonine kinase Akt, which are the downstream proteins of VEGFR2 that are important for cell growth. What's more, our results showed that flubendazole decreased PC-3 cell viability and proliferation ability, and suppressed PC-3 cell wound healing migration and invasion across a Matrigel-coated Transwell membrane in a concentration-dependent manner. The antiproliferative effects of flubendazole were due to induction of G2-M phase cell cycle arrest in PC-3 cells with decreasing expression of the Cyclin D1 and induction of cell apoptosis with the number of apoptotic cells increased after flubendazole treatment. These results indicated that flubendazole could exert anti-angiogenic and anticancer effects by inhibiting cell cycle and inducing cell apoptosis.
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Angiogénesis , Mebendazol/análogos & derivados , Factor A de Crecimiento Endotelial Vascular , Humanos , Células PC-3 , Factor A de Crecimiento Endotelial Vascular/metabolismo , Cinética , Movimiento Celular , Proliferación Celular , Inhibidores de la Angiogénesis/farmacología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
BACKGROUND: Predicting the prognosis of primary percutaneous coronary intervention(PPCI) in ST-segment elevation myocardial infarction (STEMI) patients in the perioperative period is of great clinical significance. The inflammatory response during the perioperative period is also an important factor. This study aimed to investigate the dynamic changes in the systemic immune inflammatory index (SII) during the perioperative period of PPCI and evaluate its predictive value for in-hospital and out-of-hospital outcomes in patients with STEMI. METHODS: This retrospective study included 324 consecutive patients with STEMI who were admitted to the cardiac care unit. Blood samples were collected before PPCI, 12 h (T1), 24 h, 48 h after PPCI, the last time before hospital discharge (T2), and 1 month after hospital discharge. The SII was calculated as (neutrophils×platelets)/lymphocytes. Based on whether the primary endpoint occurred, we divided the patients into event and non-event groups. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors that might influence the occurrence of the primary endpoint. Dynamic curves of SII were plotted, and receiver operating characteristic (ROC) curves were drawn for each node to calculate the optimal critical value, sensitivity, and specificity to assess their predictive ability for in-hospital and out-of-hospital courses. Kaplan-Meier curves were used to analyze the differences in survival rates at different SII inflammation levels. RESULTS: High levels of SII were individually related to the occurrence of the in-hospital period and long-term outcomes during the post-operative follow-up of STEMI patients (in-hospital SII: T1:OR 1.001,95%CI 1.001-1.001, P < 0.001; SII following hospital discharge: T1M: OR 1.008,95%CI 1.006-1.010, P < 0.001). Patients with high SII levels had lower survival rates than those with low SII levels. The analysis showed that the SII 12 h after (T1) and SII 1 month (T1M) had excellent predictive values for the occurrence of in-hospital and out-of-hospital outcomes, respectively (AUC:0.896, P < 0.001; AUC:0.892, P < 0.001). CONCLUSION: There is a significant relationship between the dynamic status of SII and prognosis in patients with STEMI. This study found that the 12 h and SII 1 month affected in-hospital and out-of-hospital outcomes, respectively. Consequently, we focused on the dynamic changes in the SII.
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Infarto del Miocardio con Elevación del ST , Humanos , Pronóstico , Estudios Retrospectivos , Plaquetas , Unidades de Cuidados CoronariosRESUMEN
In this study, source water, finished water, and tap water were sampled monthly from two large drinking water treatment plants in Wuhan city, China for 12 months where physicochemical and microbiological parameters were measured, and the complex monitoring data was analyzed using single-factor assessment method, entropy weight water quality index (EWQI), and multivariate statistical techniques (i.e., cluster analysis (CA), discriminant analysis, and correlation analysis). The results of the single-factor assessment method showed that the total nitrogen pollution was the main problem in the source water quality, and the finished and tap water met the required quality standards. The EWQI values indicated that the overall quality of the source, finished, and tap water samples was "Excellent." In addition, strengthening monitoring of parameters with high entropy weights, including Pb, Hg, sulfide, Cr in surface water and Hg, aerobic bateria count, and As in drinking water, were suggested, as they were prone to drastic changes. Spatial CA grouped the finished and tap water samples from the same plant into a cluster. Temporal CA grouped 12 sampling times of source water into Cluster 1 (June), Cluster 2 (April-May, and July-November), and Cluster 3 (December-March). Concerning finished and tap water, except the October was regrouped, the result of temporal CA was consistent to that of the source water. Based on similar characteristics of water samples, monitoring sites and frequency can be optimized. Moreover, stepwise discriminant analysis indicated that the spatiotemporal variations in water quality among CA-groups were enough to be explained by four or five parameters, which provided a basis for the selection of monitoring parameters. The results of correlation analysis showed that few pairwise correlations were both significant (P < 0.05) and stable across sampling sites, suggesting that the number of monitoring parameters was difficult to reduce through substitution. In summary, this study illustrates the usefulness of EWQI and the multivariate statistical techniques in the water quality assessment and monitoring strategy optimization.
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Agua Potable , Mercurio , Contaminantes Químicos del Agua , Calidad del Agua , Agua Potable/análisis , Monitoreo del Ambiente/métodos , Entropía , Análisis Multivariante , China , Mercurio/análisis , Contaminantes Químicos del Agua/análisis , Abastecimiento de AguaRESUMEN
BACKGROUND: Ankle sprain causes proprioceptor injuries and prolonged joint deafferentation, which might lead to maladaptive neuroplasticity in patients with chronic ankle instability (CAI), especially in the cerebellum. Previous studies have indicated the impairment of superior cerebellar peduncle (SCP), but the inferior cerebellar peduncle (ICP) and middle cerebellar peduncle (MCP) have not been fully analyzed. HYPOTHESIS: The cerebellar peduncles of participants with CAI would have altered fractional anisotropy (FA) and orientation dispersion index (ODI) in comparison with healthy controls without ankle injury history. In addition, FA and ODI would be correlated with the duration or severity of the sensorimotor deficits in CAI. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 3. METHODS: A group of 27 participants with CAI and 26 healthy controls underwent diffusion-weighted imaging scanning, with the cerebellar peduncles as the regions of interest. The measures obtained by single-shell diffusion tensor imaging and the multishell neurite orientation dispersion and density imaging were used. Correlation analyses were performed to examine the potential relationship between the FA/ODI and both the normalized Y-balance scores and the durations of ankle instability. RESULTS: The ipsilateral ICP of the injured ankle in participants with CAI showed significantly lower FA (Cohen d 95% CI, -1.33 to -0.21; P = 0.04) and marginally significant higher ODI (Cohen d 95% CI, 0.10 to 1.20, P = 0.08) when compared with the same measures in the control group, with the ODI being positively correlated with the duration of ankle instability (r = 0.42, P = 0.03). CONCLUSION: The ICP in participants with CAI exhibited impaired integrity and a trend of abnormally organized neurites in comparison with a healthy control group. CLINICAL RELEVANCE: The impairments of ICP might be an ongoing part of the pathological process of CAI, having the potential to become a target for the diagnostic evaluation of this clinical entity.
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Traumatismos del Tobillo , Inestabilidad de la Articulación , Humanos , Imagen de Difusión Tensora/métodos , Estudios Transversales , Tobillo , Cerebelo/diagnóstico por imagen , Cerebelo/patología , Imagen de Difusión por Resonancia Magnética , Inestabilidad de la Articulación/diagnóstico por imagen , Inestabilidad de la Articulación/patologíaRESUMEN
BACKGROUND: The combination of drug delivery with immune checkpoint targeting has been extensively studied in cancer therapy. However, the clinical benefit for patients from this strategy is still limited. B7 homolog 3 protein (B7-H3), also known as CD276 (B7-H3/CD276), is a promising therapeutic target for anti-cancer treatment. It is widely overexpressed on the surface of malignant cells and tumor vasculature, and its overexpression is associated with poor prognosis. Herein, we report B7H3 targeting doxorubicin (Dox)-conjugated gold nanocages (B7H3/Dox@GNCs) with pH-responsive drug release as a selective, precise, and synergistic chemotherapy-photothermal therapy agent against non-small-cell lung cancer (NSCLC). RESULTS: In vitro, B7H3/Dox@GNCs exhibited a responsive release of Dox in the tumor acidic microenvironment. We also demonstrated enhanced intracellular uptake, induced cell cycle arrest, and increased apoptosis in B7H3 overexpressing NSCLC cells. In xenograft tumor models, B7H3/Dox@GNCs exhibited tumor tissue targeting and sustained drug release in response to the acidic environment. Wherein they synchronously destroyed B7H3 positive tumor cells, tumor-associated vasculature, and stromal fibroblasts. CONCLUSION: This study presents a dual-compartment targeted B7H3 multifunctional gold conjugate system that can precisely control Dox exposure in a spatio-temporal manner without evident toxicity and suggests a general strategy for synergistic therapy against NSCLC.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Doxorrubicina , Neoplasias Pulmonares , Nanopartículas , Terapia Fototérmica , Humanos , Antígenos B7 , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Liberación de Fármacos , Oro , Concentración de Iones de Hidrógeno , Hipertermia Inducida , Neoplasias Pulmonares/tratamiento farmacológico , Fototerapia , Terapia Fototérmica/métodos , Microambiente Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Animales , Ratones , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In recent years, electrochemiluminescence resonance energy transfer (ECL-RET) with low background signal and high specificity has attracted much attention among researchers. Herein, we established a novel ECL-RET biosensor for PML/RARα fusion gene detection. In this ECL-RET system, carbon dots (CDs) with low toxicity and prominent electrochemical activity were used as donor and Au@Ag2S core-shell nanoparticles (Au@Ag2S NPs) were employed as ECL acceptor. The Au@Ag2S NPs possessed a wide ultraviolet-visible (UV-vis) absorption spectrum between 500 nm and 700 nm, which completely overlapped with the ECL spectrum of CDs. Furthermore, the CDs-decorated poly-amidoamine/reduced graphene oxide (CDs/PAMAM/rGO) nanocomposites were prepared to improve the ECL signals and served as a substrate to stably load capture probe deoxyribonucleic acid (DNA). Based on the ECL-RET biosensing strategy, the Au@Ag2S NPs-labeled assistant probes and target DNA could pair with capture probes to form the sandwich-type DNA structure and the distance between donor and accepter was closed, leading to quenching of the ECL signal of CDs. The ECL-RET biosensor represented eminent analytical performance for PML/RARα fusion gene detection with a wide linear relationship from 5 fM to 500 pM and a low detection limit of 0.72 fM, which provided a novel technical means and theoretical basis for detection and diagnosis of acute promyelocytic leukemia.
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Nanocompuestos , Nanopartículas , Carbono , Transferencia de Energía , ADNRESUMEN
Pterostilbene, an important analogue of the star molecule resveratrol and a novel compound naturally occurring in blueberries and grapes, exerts a significant neuroprotective effect on cerebral ischemia/reperfusion (I/R), but its mechanism is still unclear. This study aimed to follow the molecular mechanisms behind the potential protective effect of pterostilbene against I/R induced injury. For fulfilment of our aim, we investigated the protective effects of pterostilbene on I/R injury caused by middle cerebral artery occlusion (MCAO) in vivo and oxygen-glucose deprivation (OGD) in vitro. Machine learning models and molecular docking were used for target exploration and validated by western blotting. Pterostilbene significantly reduced the cerebral infarction volume, improved neurological deficits, increased cerebral microcirculation and improved blood-brain barrier (BBB) leakage. Machine learning models confirmed that the stroke target MMP-9 bound to pterostilbene, and molecular docking demonstrated the strong binding activity. We further found that pterostilbene could depolymerize stress fibers and maintain the cytoskeleton by effectively increasing the expression of the non-phosphorylated actin depolymerizing factor (ADF) in the early stage of I/R. In the late stage of I/R, pterostilbene could activate the Wnt pathway and inhibit the expression of MMP-9 to decrease the degradation of the extracellular basement membrane (BM) and increase the expression of junction proteins. In this study, we explored the protective mechanisms of pterostilbene in terms of both endothelial cytoskeleton and extracellular matrix. The early and late protective effects jointly maintain BBB stability and attenuate I/R injury, showing its potential to be a promising drug candidate for the treatment of ischemic stroke.
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Daño por Reperfusión , Accidente Cerebrovascular , Humanos , Metaloproteinasa 9 de la Matriz/genética , Barrera Hematoencefálica , Simulación del Acoplamiento Molecular , Infarto Cerebral , Isquemia , Reperfusión , Daño por Reperfusión/tratamiento farmacológico , Membrana BasalRESUMEN
Since microRNAs (miRNAs) are predictors of tumorigenesis, accurate identification and quantification of miRNAs with highly similar sequences are expected to reflect tumor diagnosis and treatment. In this study, a highly selective and sensitive electrochemiluminescence (ECL) biosensor was constructed for miRNAs determination based on Y-shaped junction structure equipped with locked nucleic acids (LNA), graphene oxide-based nanocomposite to enrich luminophores, and conductive matrix. Specifically, two LNA-modified probes were designed for specific miRNA recognition, that is, a dual-amine functionalized hairpin capture probe and a signal probe. A Y-shaped DNA junction structure was generated on the electrode surface upon miRNA hybridizing across the two branches, so as to enhance the selectivity. Carbon quantum dots-polyethylene imine-graphene oxide (CQDs-PEI-GO) nanocomposites were developed to enrich luminophores CQDs, and thus enhancing the ECL intensity. For indirect signal amplification, an electrochemically activated poly(2-aminoterephthalic acid) (ATA) film decorated with gold nanoparticles was prepared on electrode as an effective matrix to accelerate the electron transfer. The fabricated ECL biosensor achieved sensitive determination of miRNA-222 with a limit-of-detection (LOD) as low as 1.95 fM (S/N = 3). Notably, Y-shaped junction structures equipped with LNA probes endowed ECL biosensor with salient single-base discrimination ability and anti-interference capacity. Overall, the proposed Y-shaped ECL biosensor has considerable promise for clinical biomarker determination.
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Técnicas Biosensibles , Nanopartículas del Metal , MicroARNs , Puntos Cuánticos , MicroARNs/genética , Carbono/química , Puntos Cuánticos/química , Oro/química , Mediciones Luminiscentes , Nanopartículas del Metal/química , ADN/química , Sondas de Ácido Nucleico , Polietileneimina/química , Técnicas ElectroquímicasRESUMEN
INTRODUCTION: Patients with end-stage renal disease receiving hemodialysis (HD) have a high morbidity and mortality rate associated with pulmonary hypertension (PH). A nomogram was developed to predict all-cause mortality in HD patients with PH. In this study, we aimed to validate the usefulness of this nomogram. METHODS: A total of 274 HD patients with PH were hospitalized at the Affiliated Hospital of Xuzhou Medical University between January 2014 and June 2019 and followed up for 3 years. Echocardiography detected PH when the peak tricuspid regurgitation velocity (TRV) was more than 2.8 m/s. To evaluate the all-cause mortality for long-term HD patients with PH, Cox regression analysis was performed to determine the factors of mortality that were included in the prediction model. Next, the area under the receiver-operating characteristic curve (AUC-ROC) was used to assess the predictive power of the model. Calibration plots and decision curve analysis (DCA) were used to assess the accuracy of the prediction results and the clinical utility of the model. RESULTS: The all-cause mortality rate was 29.20% throughout the follow-up period. The nomogram comprised six commonly available predictors: age, diabetes mellitus, cardiovascular disease, hemoglobin, left ventricular ejection fraction, and TRV. The 1-year, 2-year, and 3-year AUC-ROC values were 0.842, 0.800, and 0.781, respectively. The calibration curves revealed excellent agreement with the nomogram, while the DCA demonstrated favorable clinical practicability. CONCLUSION: The first developed nomogram for predicting all-cause mortality in HD patients with PH could guide clinical decision-making and intervention planning.
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Hipertensión Pulmonar , Humanos , Hipertensión Pulmonar/complicaciones , Nomogramas , Volumen Sistólico , Función Ventricular Izquierda , Diálisis RenalRESUMEN
BACKGROUND: Although coronavirus disease 2019 (COVID-19) pandemic is still rage worldwide, there are still very limited treatments for human coronaviruses (HCoVs) infections. Xiaochahu decoction (XCHD), which is one of the traditional Chinese medicine (TCM) prescriptions in Qingfeipaidu decoction (QFPDD), is widely used for COVID-19 treatment in China and able to relieve the symptoms of fever, fatigue, anorexia, and sore throat. To explore the role and mechanisms of XCHD against HCoVs, we presented an integrated systems pharmacology framework in this study. METHODS: We constructed a global herb-compound-target (H-C-T) network of XCHD against HCoVs. Multi-level systems pharmacology analyses were conducted to highlight the key XCHD-regulated proteins, and reveal multiple HCoVs relevant biological functions affected by XCHD. We further utilized network-based prediction, drug-likeness analysis, combining with literature investigations to uncover the key ani-HCoV constituents in XCHD, whose effects on anit-HCoV-229E virus were validated using cytopathic effect (CPE) assay. Finally, we proposed potential molecular mechanisms of these compounds against HCoVs via subnetwork analysis. RESULTS: Based on the systems pharmacology framework, we identified 161 XCHD-derived compounds interacting with 37 HCoV-associated proteins. An integrated pathway analysis revealed that the mechanism of XCHD against HCoVs is related to TLR signaling pathway, RIG-I-like receptor signaling pathway, cytoplasmic DNA sensing pathway, and IL-6/STAT3 pro-inflammatory signaling pathway. Five compounds from XCHD, including betulinic acid, chrysin, isoliquiritigenin, schisandrin B, and (20R)-Ginsenoside Rh1 exerted inhibitory activity against HCoV-229E virus in Huh7 cells using in vitro CPE assay. CONCLUSION: Our work presented a comprehensive systems pharmacology approach to identify the effective molecules and explore the molecular mechanism of XCHD against HCoVs.
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COVID-19 , Coronavirus , Humanos , Tratamiento Farmacológico de COVID-19 , Farmacología en RedRESUMEN
High-capacity Li-rich layered oxides (LLOs) suffer from severe structure degradation due to the utilization of hybrid anion- and cation-redox activity. The native post-cycled structure, composed of progressively densified defective spinel layer (DSL) and intrinsic cations mixing, is deemed as the hindrance of the rapid and reversible de/intercalation of Li+ . Herein, the artificial post-cycled structure consisting of artificial DSL and inner cations mixing is in situ constructed, which would act as a shield against the irreversible oxygen emission and undesirable transition metal migration by suppressing anion redox activity and modulating cation mixing. Eventually, the modified DSL-2% Li-rich cathode demonstrates remarkable electrochemical properties with a high discharge capacity of 187 mAh g-1 after 500 cycles at 2 C, and improved voltage stability. Even under harsh operating conditions of 50 °C, DSL-2% can provide a high discharge capacity of 168 mAh g-1 after 250 cycles at 2 C, which is much higher than that of pristine LLO (92 mAh g-1 ). Furthermore, the artificial post-cycled structure provides a novel perspective on the role of native post-cycled structure in sustaining the lattice structure of the lithium-depleted region and also provides an insightful universal design principle for highly stable intercalated materials with anionic redox activity.
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Cell viability is essential for predicting drug toxicity and assessing drug effects in drug screening. However, the over/underestimation of cell viability measured by traditional tetrazolium colorimetric assays is inevitable in cell-based experiments. Hydrogen peroxide (H2O2) secreted by living cells may provide more comprehensive information about the cell state. Hence, it is significant to develop a simple and rapid approach for evaluating cell viability by measuring the excreted H2O2. In this work, we developed a dual-readout sensing platform based on optical and digital signals by integrating a light emitting diode (LED) and a light dependent resistor (LDR) into a closed split bipolar electrode (BPE), denoted as BP-LED-E-LDR, for evaluating cell viability by measuring the H2O2 secreted from living cells in drug screening. Additionally, the customized three-dimensional (3D) printed components were designed to adjust the distance and angle between the LED and LDR, achieving stable, reliable and highly efficient signal transformation. It only took 2 min to obtain response results. For measuring the exocytosis H2O2 from living cells, we observed a good linear relationship between the visual/digital signal and logarithmic function of MCF-7 cell counts. Furthermore, the fitted half inhibitory concentration curve of MCF-7 to doxorubicin hydrochloride obtained by the BP-LED-E-LDR device revealed a nearly identical tendency with the cell counting kit-8 assay, providing an attainable, reusable, and robust analytical strategy for evaluating cell viability in drug toxicology research.