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BACKGROUND: Disease-modifying antirheumatic drugs (DMARDs) are widely used for treating rheumatoid arthritis (RA). However, there are no established biomarkers to predict a patient's response to these therapies. Prostanoids, encompassing prostaglandins, prostacyclins, and thromboxanes, are potent lipid mediators implicated in RA progression. Nevertheless, the influence of DMARDs on prostanoid biosynthesis in RA patients remains poorly understood. This study aims to assess the impact of various DMARDs on urinary prostanoids levels and to explore whether urinary prostanoid profiles correlate with disease activity or response to therapy. METHODS: This study included 152 Swedish female patients with early RA, all rheumatoid factor (RF) positive, enrolled in the NORD-STAR trial (registration number: NCT01491815). Participants were randomized into four therapeutic regimes: methotrexate (MTX) combined with (i) prednisolone (arm ACT), (ii) TNF-α blocker certolizumab pegol (arm CZP), (iii) CTLA-4Ig abatacept (arm ABA), or (iv) IL-6R blocker tocilizumab (arm TCZ). Urine samples, collected before start of treatment and at 24 weeks post-treatment, were analyzed for tetranor-prostaglandin E metabolite (tPGEM), tetranor-prostaglandin D metabolite (tPGDM), 2,3-dinor thromboxane B2 (TXBM), 2,3-dinor-6-keto prostaglandin F1a (PGIM), leukotriene E4 (LTE4) and 12-hydroxyeicosatetraenoic acid (12-HETE) using liquid chromatography-mass spectrometry (LC-MS). Generalized estimating equation (GEE) models were used to analyze the change in urinary eicosanoids and their correlations to clinical outcomes. RESULTS: Patients receiving MTX combined with CZP or TCZ exhibited significant elevations in urinary tPGEM and TXBM levels after 24 weeks of treatment. Other eicosanoids did not show significant alterations in response to any treatment. Baseline urinary eicosanoid levels did not correlate with baseline clinical disease activity index (CDAI) levels, nor with changes in CDAI from baseline to week 24. Their levels were also similar between patients who achieved CDAI remission and those with active disease at week 24. CONCLUSIONS: Treatment with anti-TNF or anti-IL6R agents in early RA patients leads to an increased systemic production of proinflammatory and prothrombotic prostanoids. However, urinary eicosanoid levels do not appear to be predictive of the response to DMARDs therapy.
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Antirreumáticos , Artritis Reumatoide , Dimaprit/análogos & derivados , Humanos , Femenino , Prostaglandinas , Antirreumáticos/uso terapéutico , Inhibidores del Factor de Necrosis Tumoral , Artritis Reumatoide/tratamiento farmacológico , Metotrexato , Certolizumab PegolRESUMEN
OBJECTIVE: The performance of sarcopenia diagnosis using adductor pollicis muscle thickness (APMT) has been reported. However, the relationship between APMT and low skeletal muscle mass index (SMI) is unclear. The purpose of this study is to investigate the relationship between APMT and low SMI and APMT performance to diagnose low SMI in community-dwelling older women undergoing outpatient rehabilitation. METHODS: This study included 65 older women (mean age: 86.4 years). Subjects were received outpatient rehabilitation one to three times a week. The main outcomes were low SMI as diagnosed using the Asian working group for sarcopenia 2019 and APMT. Logistic regression analysis was performed with low SMI as the dependent variable, APMT, and propensity score calculated using age, sex, number of medications, and updated Charlson comorbidity index as the independent variable. A receiver operating characteristic (ROC) curve of APMT for low SMI was created. A cut-off value was calculated using the Youden index. RESULTS: Among the 65 subjects, 45 (69.2 %) had low SMI. The results of the logistic regression analysis showed a significant association between APMT and low SMI (odds ratio: 0.482 {95 % confidence interval [CI]: 0.313-0.744}). The cut-off value of APMT calculated from the ROC curve was 13 mm. The sensitivity and specificity of this cut-off value were 0.800 (95 % CI: 0.654-0.904) (36 out of 45 subjects) and 0.850 (95 % CI: 0.621-0.968) (17 out of 20 subjects), respectively. The positive predictive value, negative predictive value, and area under the curve were 0.923 (95 % CI: 0.791-0.984), 0.654 (95 % CI: 0.443-0.828), and 0.843 (95 % CI: 0.731-0.955), respectively. The APMT cut-off value of 13 mm is good to identify low SMI. CONCLUSIONS: The results of this study show that APMT is associated with low SMI. Furthermore, the cut-off value of APMT for diagnosing low SMI was 13 mm. The APMT cut-off value of 13 mm is good to identify low SMI. Our findings indicate that measuring APMT is useful for diagnosing low SMI in community-dwelling older women undergoing outpatient rehabilitation.
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Dimaprit/análogos & derivados , Estado Nutricional , Sarcopenia , Humanos , Femenino , Anciano , Anciano de 80 o más Años , Sarcopenia/diagnóstico , Evaluación Nutricional , Vida Independiente , Pacientes Ambulatorios , Músculo Esquelético/patologíaRESUMEN
Background: Microsoft Windows Security is a recently implemented safeguard for the Windows operating systems, including the latest versions of Windows10 and 11. However, there is a major shortcoming in this system to stop Advanced Persistent Threat (APT). These are government-financed groups that are funded to attack other government entities. Following the initial security breach, the hacked Windows device is used to access the rest of the network devices in order to transfer data to external storage (Exfiltration). Methods: In this work, we have tested the Microsoft Windows Security system using MITRE CALDERA and ATT&CK frameworks and explain how APT groups are able to bypass Windows Security. Results: In this study we used "54ndc47" agent through GoLang feature in MITRE CALDERA platform to test and bypass Microsoft Windows Security systems (MS Windows 10). Through it, we were able to bypass the Windows Security system and display entire files in the victim's device. Conclusions: In this paper, we have provided recommendations to Microsoft to improve their Windows Security tool through the use of Artificial intelligence (AI).
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Inteligencia Artificial , Programas Informáticos , Dimaprit/análogos & derivadosRESUMEN
A "signal-on" dual-mode aptasensor based on photoelectrochemical (PEC) and electrochemical (EC) signals was established for kanamycin (Kana) assay by using a novel Z-scheme AgBr/AgI-Ag-CNTs composite as sensing platform, an aptamer structure switch, and K3[Fe(CN)6] as photoelectron acceptor and electrochemical signal indicator. The aptamer structure switch was designed to obtain a "signal-off" state, which included an extended Kana aptamer (APT), one immobilized probe (P1), and one blocking probe (P2) covalently linked with graphdiyne oxide (GDYO) nanosheets. P1, P2, and aptamer formed the double helix structure, which resulted in the inhibited photocurrent intensity because of the weak conductivity of double helix layer and serious electrostatic repulsion of GDYO towards K3[Fe(CN)6]. In the presence of Kana, APT specifically bound to the target and dissociated from P1 and P2, and thus, a "signal-on" state was initiated by releasing P2-GDYO from the platform. Based on the sensing platform and the aptamer structure switch, the dual-mode aptasensor realized the linear determination ranges of 1.0 pM-2.0 µM with a detection limit (LOD) of 0.4 pM (for PEC method) and 10 pM-5.0 µM with a LOD of 5 pM (for EC method). The aptasensor displayed good application potential for Kana test in real samples.
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Aptámeros de Nucleótidos , Técnicas Biosensibles , Aptámeros de Nucleótidos/química , Técnicas Biosensibles/métodos , Dimaprit/análogos & derivados , Grafito , Kanamicina/química , ÓxidosRESUMEN
BACKGROUND: Oxidative stress from excess reactive oxygen species (ROS) is a hypothesized contributor to preterm birth. Per- and polyfluoroalkyl substances (PFAS) exposure is reported to generate ROS in laboratory settings, and is linked to adverse birth outcomes globally. However, to our knowledge, the relationship between PFAS and oxidative stress has not been examined in the context of human pregnancy. OBJECTIVE: To investigate the associations between prenatal PFAS exposure and oxidative stress biomarkers among pregnant people. METHODS: Our analytic sample included 428 participants enrolled in the Illinois Kids Development Study and Chemicals In Our Bodies prospective birth cohorts between 2014 and 2019. Twelve PFAS were measured in second trimester serum. We focused on seven PFAS that were detected in >65 % of participants. Urinary levels of 8-isoprostane-prostaglandin-F2α, prostaglandin-F2α, 2,3-dinor-8-iso-PGF2α, and 2,3-dinor-5,6-dihydro-8-iso-PGF2α were measured in the second and third trimesters as biomarkers of oxidative stress. We fit linear mixed-effects models to estimate individual associations between PFAS and oxidative stress biomarkers. We used quantile g-computation and Bayesian kernel machine regression (BKMR) to assess associations between the PFAS mixture and averaged oxidative stress biomarkers. RESULTS: Linear mixed-effects models showed that an interquartile range increase in perfluorooctane sulfonic acid (PFOS) was associated with an increase in 8-isoprostane-prostaglandin-F2α (ß = 0.10, 95 % confidence interval = 0, 0.20). In both quantile g-computation and BKMR, and across all oxidative stress biomarkers, PFOS contributed the most to the overall mixture effect. The six remaining PFAS were not significantly associated with changes in oxidative stress biomarkers. CONCLUSIONS: Our study is the first to investigate the relationship between PFAS exposure and biomarkers of oxidative stress during human pregnancy. We found that PFOS was associated with elevated levels of oxidative stress, which is consistent with prior work in animal models and cell lines. Future research is needed to understand how prenatal PFAS exposure and maternal oxidative stress may affect fetal development.
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Ácidos Alcanesulfónicos , Contaminantes Ambientales , Fluorocarburos , Nacimiento Prematuro , Ácidos Alcanesulfónicos/toxicidad , Animales , Teorema de Bayes , Biomarcadores , Dimaprit/análogos & derivados , Contaminantes Ambientales/efectos adversos , Femenino , Fluorocarburos/toxicidad , Humanos , Recién Nacido , Estrés Oxidativo , Embarazo , Nacimiento Prematuro/inducido químicamente , Estudios Prospectivos , Especies Reactivas de OxígenoRESUMEN
Infectious diseases caused by viruses have attracted global concern owing to their rapid spread and catastrophic consequences. Therefore, developing fast and reliable on-site virus detection methods is essential for the prevention and treatment of virus-related diseases. In this study, immunoassays on a membrane, combining virus preconcentration with nanoparticle-based signal amplification, were used to realize the rapid and accurate visual detection of viruses. The biotin-streptavidin scaffolds for target virus preconcentration were established on a membrane, and subsequently a Zika aptamer (Apt) immobilized on the membrane recognized and captured the nonstructural protein 1 of Zika virus (ZIKV-NS1). The probe for detection was synthesized by conjugating the Zika Apt with a high level of horseradish peroxidase on gold nanoparticles. The ZIKV-loaded membrane was incubated with the probes, and the viral signal was amplified as the signal of horseradish peroxidase. In the presence of 3,3,5',5'-tetramethyl benzidine and hydrogen peroxide, the green color of the probe-coated membrane indicated the level of ZIKV-NS1. Our developed method could reach a detection limit of 5 ng mL-1, and the whole procedure could be completed within 1 h. Analyses of rabbit serum and environmental water samples demonstrated that an immunoassay-based approach on the membrane could accurately determine the level of ZIKV-NS1 against the complicated matrix. Our results suggest that this virus detection method has a high potential for application in clinical and environmental settings.
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Nanopartículas del Metal , Infección por el Virus Zika , Virus Zika , Animales , Biotina , Dimaprit/análogos & derivados , Oro/química , Peroxidasa de Rábano Silvestre , Peróxido de Hidrógeno , Nanopartículas del Metal/química , Conejos , Estreptavidina , Proteínas no Estructurales Virales/análisis , Agua , Virus Zika/química , Infección por el Virus Zika/diagnóstico , Infección por el Virus Zika/prevención & controlRESUMEN
The benefits of potent antithrombotic therapy usually come at the expense of a higher risk of bleeding. The efficacy and safety of ticagrelor in elderly East Asian populations remains debated due to the concerns about the imbalance of ischemic and bleeding risks. This study aimed to compare the impact of clopidogrel with ticagrelor on clinical outcomes in East Asian patients aged ≥75 years with acute coronary syndrome (ACS) using data from an institutional registry. We assessed the treatment effect of ticagrelor versus clopidogrel based on propensity scores and multivariate Cox proportional hazards models. A total of 2775 ACS patients were included, of which 235 (8.5%) were treated with ticagrelor. The primary efficacy outcome occurred in 11.9% of patients treated with ticagrelor versus 8.8% treated with clopidogrel. There was no significant association between treatment with ticagrelor and a lower risk of the primary efficacy outcome (p = .156). However, the incidences of all-cause death (hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.02 to 2.79) and major bleeding (adjusted HR 2.20, 95% CI 1.06 to 4.56) were significantly higher in patients treated with ticagrelor than clopidogrel. In elderly patients with ACS from East Asia, the efficacy of clopidogrel was comparable to ticagrelor, while ticagrelor is associated with an increased risk of mortality and major bleeding.
What is the context?Current guidelines recommend ticagrelor over clopidogrel for patients with acute coronary syndrome (ACS).There are no specific guidelines concerning the elderly, and data on optimal antiplatelet therapy in elderly are quite scarce.Further study was necessary to identify the efficacy and safety of ticagrelor and clopidogrel in elderly patients from East Asian populations which are reported to be at a higher risk of bleeding.What is new?The risk of major adverse cardiac events did not differ significantly between clopidogrel versus ticagrelor in patients aged ≥75 years from East Asia, while the use of ticagrelor might be associated with increased risk of mortality and major bleeding events.Analyses after propensity score matching showed consistent results on the safety and efficacy of clopidogrel versus ticagrelor.The benefit of potent P2Y12 inhibitor ticagrelor over clopidogrel is questionable in elderly East Asian patients with ACS.What is the impact? This study provides more information on the use of potent antiplatelet therapy in older patients from Asia. The individual assessment of ischemic and bleeding risk is necessary to guide decision-making on DAPT rather than applying the recommendations of guidelines directly.
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Síndrome Coronario Agudo , Intervención Coronaria Percutánea , Síndrome Coronario Agudo/terapia , Anciano , Clopidogrel/uso terapéutico , Dimaprit/análogos & derivados , Fibrinolíticos/uso terapéutico , Hemorragia/epidemiología , Hemorragia/etiología , Humanos , Inhibidores de Agregación Plaquetaria/efectos adversos , Sistema de Registros , Ticagrelor/uso terapéutico , Resultado del TratamientoRESUMEN
Immune checkpoint blockade (ICB) has been hailed as the hope for conquering cancer as ICB could produce a significant and durable response to tumor cells. However, the high cost and severe side effects of ICB drugs limited their application for further anticancer therapy. Here, we developed a photoactivated immunotherapy nanoplatform (Apt@AuNC). This nanoplatform could target tumor tissues via enhanced penetration retention (EPR) effect and the aptamer (Apt) could be released from Apt@AuNC in tumor sites via illumination. The immune system in the tumor area was then activated after the combination of Apt and PD-1 protein. The heat generated from AuNC was able to continue killing tumor cells. This nanoplatform could not only achieve the precise immunotherapy but also significantly facilitate the anticancer efficacy.
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Aptámeros de Nucleótidos , Neoplasias , Aptámeros de Nucleótidos/farmacología , Aptámeros de Nucleótidos/uso terapéutico , Línea Celular Tumoral , Dimaprit/análogos & derivados , Oro/farmacología , Oro/uso terapéutico , Humanos , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Nanoestructuras , Neoplasias/tratamiento farmacológico , Receptor de Muerte Celular Programada 1RESUMEN
The overexpression of specific biomarkers in serum is closely related to diseases, and accurate and sensitive detection of them is beneficial for the early diagnosis and treatment of cancer. In this study, we developed a novel surface-enhanced Raman spectroscopy (SERS)-based aptasensor to detect the prostate-specific antigen biomarkers, consisting of total prostate-specific antigen (PSA) and free prostate-specific antigen (f-PSA). A composite structure containing arrays of polystyrene colloidal sphere @Ag shell (PS@Ag) was fabricated as a SERS-active chip. A complementary DNA probe (SH-DNA) and PSA aptamer (Apt) were immobilised stepwise on the chip, followed by the binding of a Raman reporter methylene blue (MB) to the guanine base of the aptamer. PSA-Apt recognition causes the release of MB-Apt and a decrease in the SERS intensity of MB on the chip, which correlates with the PSA concentration. The proposed biosensor has high spectral reproducibility, selectivity, and sensitivity and successfully determines the PSA levels in serum samples collected from prostate cancer patients, demonstrating great potential for clinical diagnosis.
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Aptámeros de Nucleótidos , Técnicas Biosensibles , Nanopartículas del Metal , Neoplasias de la Próstata , Aptámeros de Nucleótidos/química , Biomarcadores de Tumor , Técnicas Biosensibles/métodos , ADN Complementario , Dimaprit/análogos & derivados , Oro/química , Guanina , Humanos , Límite de Detección , Masculino , Nanopartículas del Metal/química , Azul de Metileno , Poliestirenos , Próstata , Antígeno Prostático Específico , Neoplasias de la Próstata/diagnóstico , Reproducibilidad de los Resultados , Espectrometría Raman/métodosRESUMEN
BACKGROUND: Drug resistance of pathogens and immunosuppression are the main causes of clinical stagnation of osteomyelitis. The ideal treatment strategy for osteomyelitis is to achieve both efficient antibacterial and bone healing through spatiotemporal modulation of immune microenvironment. METHODS: In this study, a bilayer hydrogel based on genetically engineered polypeptide AC10A and AC10ARGD was prepared by self-assembly. Ag2S QDs@DSPE-mPEG2000-Ce6/Aptamer (AD-Ce6/Apt) was loaded in the top layer AC10A hydrogel (AA) for antibacterial, and bone marrow-derived mesenchymal stem cells (BMSCs) were loaded in the lower layer AC10ARGD hydrogel (MAR) for bone healing. The AD-Ce6/Apt can be released from the AA hydrogel to target S. aureus before bacterial biofilm formation and achieved significant bactericidal effect under irradiation with a 660 nm laser. Moreover, AD-Ce6/Apt can induce M1 type polarization of macrophages to activate the immune system and eliminate residual bacteria. Subsequently, BMSCs released from the MAR hydrogel can differentiate into osteoblasts and promote the formation of an anti-inflammatory microenvironment by regulating the M2 type polarization of macrophages. The bilayer AA-MAR hydrogel possessed good biocompatibility. RESULTS: The in vitro and in vivo results showed that the AA-MAR hydrogel not only realized efficient photodynamic therapy of S. aureus infection, but also promoted the transformation of immune microenvironment to fulfill the different needs of each stage, which ultimately improved bone regeneration and mechanical properties post-surgery. CONCLUSION: This work presents an approach for spatiotemporal modulation of immune microenvironment in the treatment of osteomyelitis.
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Hidrogeles , Osteomielitis , Antibacterianos/química , Antibacterianos/farmacología , Dimaprit/análogos & derivados , Humanos , Hidrogeles/química , Osteomielitis/tratamiento farmacológico , Péptidos/farmacología , Staphylococcus aureusRESUMEN
BACKGROUND: The optimal duration of antiplatelet therapy (APT) after coronary stenting in patients at high bleeding risk (HBR) presenting with an acute coronary syndrome remains unclear. OBJECTIVES: The objective of this study was to investigate the safety and efficacy of an abbreviated APT regimen after coronary stenting in an HBR population presenting with acute or recent myocardial infarction. METHODS: In the MASTER DAPT trial, 4,579 patients at HBR were randomized after 1 month of dual APT (DAPT) to abbreviated (DAPT stopped and 11 months single APT or 5 months in patients with oral anticoagulants) or nonabbreviated APT (DAPT for minimum 3 months) strategies. Randomization was stratified by acute or recent myocardial infarction at index procedure. Coprimary outcomes at 335 days after randomization were net adverse clinical outcomes events (NACE); major adverse cardiac and cerebral events (MACCE); and type 2, 3, or 5 Bleeding Academic Research Consortium bleeding. RESULTS: NACE and MACCE did not differ with abbreviated vs nonabbreviated APT regimens in patients with an acute or recent myocardial infarction (n = 1,780; HR: 0.83; 95% CI: 0.61-1.12 and HR: 0.86; 95% CI: 0.62-1.19, respectively) or without an acute or recent myocardial infarction (n = 2,799; HR: 1.03; 95% CI: 0.77-1.38 and HR: 1.13; 95% CI: 0.80-1.59; Pinteraction = 0.31 and 0.25, respectively). Bleeding Academic Research Consortium 2, 3, or 5 bleeding was significantly reduced in patients with or without an acute or recent myocardial infarction (HR: 0.65; 95% CI: 0.46-0.91 and HR: 0.71; 95% CI: 0.54-0.92; Pinteraction = 0.72) with abbreviated APT. CONCLUSIONS: A 1-month DAPT strategy in patients with HBR presenting with an acute or recent myocardial infarction results in similar NACE and MACCE rates and reduces bleedings compared with a nonabbreviated DAPT strategy. (Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated Versus Prolonged DAPT Regimen [MASTER DAPT]; NCT03023020).
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Infarto del Miocardio , Intervención Coronaria Percutánea , Anticoagulantes/uso terapéutico , Dimaprit/análogos & derivados , Quimioterapia Combinada , Hemorragia/inducido químicamente , Hemorragia/epidemiología , Humanos , Infarto del Miocardio/tratamiento farmacológico , Intervención Coronaria Percutánea/métodos , Inhibidores de Agregación Plaquetaria/efectos adversos , Polímeros , Stents , Resultado del TratamientoRESUMEN
A Golgi protein 73 (GP73) colorimetric biosensor based on the reduced graphene oxide-carboxymethyl chitosan-hemin/platinum@palladium nanoparticles (RGO-CMCS-Hemin/Pt@Pd NPs) with peroxidase-like activity was constructed. The RGO-CMCS-Hemin/Pt@Pd NPs with high peroxidase-like activity were successfully synthesized under mild conditions. Then, the aminylated GP73 aptamer (Apt) was bound to the RGO-CMCS-Hemin/Pt@Pd NPs to form the recognition probe. Another unmodified GP73 aptamer (AptI) was served as the capture probe. In the presence of target GP73, the capture probe and the recognition probe specifically bind to GP73 and form a RGO-CMCS-Hemin/Pt@Pd NP-Apt/GP73/AptI sandwich-type structure, which can oxidase the colorless 3,3',5,5'-tetramethylbenzidine (TMB) into blue oxTMB in the presence of H2O2. GP73 detection was achieved by measuring the peak UV absorption at 652 nm. Under the optimum conditions, the GP73 concentration was linearly related to the absorbance intensity in the range 10.0-110.0 ng/mL, and the limit of detection (LOD) was 4.7 ng/mL. The proposed colorimetric biosensor was successfully applied to detect GP73 in spiked human serum samples with recoveries of 98.2-107.0% and RSDs of 1.90-5.44%, demonstrating the excellent potential for highly sensitive GP73 detection in clinical detection. A colorimetric biosensor for visual determination of GP73 based on RGO-CMCS-Hemin/Pt@Pd NPs nanozyme with peroxidase-like activity was designed. The GP73 biosensor responses linearly from 10.0-110.0 ng/mL with LOD of 4.7 ng/mL, and shows acceptable specificity and good recovery.
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Técnicas Biosensibles , Quitosano , Nanopartículas del Metal , Quitosano/química , Colorimetría , Dimaprit/análogos & derivados , Grafito , Hemina , Humanos , Peróxido de Hidrógeno/química , Nanopartículas del Metal/química , Paladio/química , Peroxidasa/química , Peroxidasas , Platino (Metal)/químicaRESUMEN
PURPOSE: Chemical exchange saturation transfer (CEST) imaging measurement depends not only on the labile proton concentration and pH-dependent exchange rate but also on experimental conditions, including the relaxation delay and radiofrequency (RF) saturation time. Our study aimed to extend a quasi-steady-state (QUASS) solution to a modified multi-slice CEST MRI sequence and test if it provides enhanced pH imaging after acute stroke. METHODS: Our study derived the QUASS solution for a modified multislice CEST MRI sequence with an unevenly segmented RF saturation between image readout and signal averaging. Numerical simulation was performed to test if the generalized QUASS solution corrects the impact of insufficiently long relaxation delay, primary and secondary saturation times, and multi-slice readout. In addition, multiparametric MRI scans were obtained after middle cerebral artery occlusion, including relaxation and CEST Z-spectrum, to evaluate the performance of QUASS CEST MRI in a rodent acute stroke model. We also performed Lorentzian fitting to isolate multi-pool CEST contributions. RESULTS: The QUASS analysis enhanced pH-weighted magnetization transfer asymmetry contrast over the routine apparent CEST measurements in both contralateral normal (-3.46% ± 0.62% (apparent) vs. -3.67% ± 0.66% (QUASS), P < 0.05) and ischemic tissue (-5.53% ± 0.68% (apparent) vs. -5.94% ± 0.73% (QUASS), P < 0.05). Lorentzian fitting also showed significant differences between routine and QUASS analysis of ischemia-induced changes in magnetization transfer, amide, amine, guanidyl CEST, and nuclear Overhauser enhancement (-1.6 parts per million) effects. CONCLUSION: Our study demonstrated that generalized QUASS analysis enhanced pH MRI contrast and improved quantification of the underlying CEST contrast mechanism, promising for further in vivo applications.
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Protones , Accidente Cerebrovascular , Algoritmos , Amidas , Aminas , Dimaprit/análogos & derivados , Humanos , Concentración de Iones de Hidrógeno , Interpretación de Imagen Asistida por Computador/métodos , Imagen por Resonancia Magnética/métodos , Accidente Cerebrovascular/diagnóstico por imagenRESUMEN
Endowing bone regeneration materials with both stem cell recruitment and osteoinduction properties is a key factor in promoting osseointegration of titanium (Ti) implants. In this study, Apt19s-grafted oxidized hyaluronic acid (OHA) was deposited onto a protein-mediated biomineralization hydroxyapatite (HAp) coating of Ti. HAp was achieved by the treatment of lysozyme and tris(2-carboxyethyl) phosphonate mixture and then soaked in calcium ion (Ca2+) solution to obtain functional Ti substrate (Ti/HAp/OHA-Apt). In vitro studies confirmed that Ti/HAp/OHA-Apt could effectively maintain the sustained release of Apt19s from Ti for 7 days. The released Apt19s significantly enhanced the migration of bone marrow mesenchymal stem cells (MSCs), which was reflected by the experiment of transwell assay, wound healing, and zymogram detection. Compared with pure Ti, Ti/HAp/OHA-Apt was able to adjust the adsorption of functional proteins at the Ti-based interface to expose their active sites, which significantly increased the expression of adhesion-associated proteins (vinculin and tensin) in MSCs to promote their adhesion on Ti-based interface. In vitro cell experiments of alkaline phosphatase activity staining, mineralization detection, and expression of osteogenesis-related genes showed that Ti/HAp/OHA-Apt significantly enhanced the osteogenic differentiation ability of MSCs, which may be highly related to the porous structure of hydroxyapatite on Ti interface. In vivo test of Micro-CT, H&E staining, and histochemical staining further confirmed that Ti/HAp/OHA-Apt was able to promote MSC recruitment at the peri-implant interface to form new bone. This work provides a new approach to develop functional Ti-based materials for bone defect repair.
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Células Madre Mesenquimatosas , Organofosfonatos , Fosfatasa Alcalina/metabolismo , Calcio/metabolismo , Diferenciación Celular , Preparaciones de Acción Retardada/farmacología , Dimaprit/análogos & derivados , Durapatita/química , Ácido Hialurónico/farmacología , Muramidasa/metabolismo , Oseointegración , Osteogénesis , Propiedades de Superficie , Tensinas/metabolismo , Titanio/química , Vinculina/metabolismoRESUMEN
The use of functional DNA nanostructures as carriers to ship proteins through solid-state nanopores has recently seen substantial growth in single-protein-molecule detection (SPMD), driven by the potential of this methodology and implementations that it may enable. Ultrasmall nanopores have exhibited obvious advantages in spatiotemporal biological detection due to the appropriate nanoconfined spaces and unique properties. Herein, a 6.8 nm DNA tetrahedron (TDN) with a target-specific DNA aptamer (TDN-apt) was engineered to carry the representative target of acetylcholinesterase (AChE) through an ultrasmall nanopipet with a 30 nm orifice, underpinning the advanced SPMD of AChE with good performance in terms of high selectivity, low detection limit (0.1 fM), and especially superior signal-to-noise ratio (SNR). The kinetic interaction between TDN-apt and AChE was studied and the practical applicability of the as-developed SPMD toward real samples was validated using serum samples from patients with Alzheimer's disease. This work not only presented a feasible SPMD solution toward low-abundance proteins in complex samples and but also was envisioned to inspire more interest in the design and implementation of synergized DNA nanostructure-ultrasmall nanopore systems for future SPMD development.
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Aptámeros de Nucleótidos , Nanoporos , Acetilcolinesterasa , ADN/química , Dimaprit/análogos & derivados , Humanos , Relación Señal-RuidoRESUMEN
Simultaneous isolation of various circulating tumor cell (CTC) subtypes from whole blood is useful in cancer diagnosis and prognosis. Microfluidic affinity separation devices are promising for CTC separation because of their high throughput capacity and automatability. However, current affinity agents, such as antibodies (mAbs) and aptamers (Apts) alone, are still suboptimal for efficient, consistent, and versatile cell analysis. By introducing a hybrid affinity agent, i.e., an aptamer-antibody (Apt-mAb) conjugate, we developed a universal and regenerative microchip with high efficiency and non-invasiveness in the separation and profiling of various CTCs from blood. The Apt-mAb conjugate consists of a monoclonal antibody that specifically binds the target cell receptor and a surface-bound aptamer that recognizes the conserved Fc region of the mAb. The aptamer then indirectly links the surface functionalization of the microfluidic channels to the mAbs. This hybrid affinity agent and the microchip platform may be widely useful for various bio-particle separations in different biological matrices. Further, the regeneration capability of the microchip improves data consistency between multiple uses and minimizes plastic waste while promoting environmental sustainability. STATEMENT OF SIGNIFICANCE: A hybrid affinity agent, Apt-mAb, consisting of a universal aptamer (Apt) that binds the conserved Fc region of monoclonal antibodies (mAbs) was developed. The invented nano-biomaterial combines the strengths and overcomes the weakness of both Apts and mAbs, thus changing the paradigm of affinity separation of cell subtypes. When Apt-mAb was used to fabricate microfluidic chips using a "universal screwdriver" approach, the microchip could be easily tuned to bind any cell type, exhibiting great universality. Besides high sensitivity and selectivity, the superior regenerative capacity of the microchips makes them reusable, which provides improved consistency and repeatability in cell profiling and opens a new approach towards in vitro diagnostic point-of-care testing devices with environmental sustainability and cost-effectiveness.
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Aptámeros de Nucleótidos , Técnicas Analíticas Microfluídicas , Células Neoplásicas Circulantes , Anticuerpos Monoclonales , Línea Celular Tumoral , Separación Celular , Dimaprit/análogos & derivados , Humanos , Microfluídica , Células Neoplásicas Circulantes/patología , PlásticosRESUMEN
BACKGROUND: Existing predictive scores for early identification of children at high risk of developing asthma include invasive procedures, and hence have limited utility in a primary care setting. The Leicestershire respiratory cohort (LRC) has developed a noninvasive asthma prediction tool (APT) for children with promising results. We aimed to perform its external validation in the French general population Étude Longitudinale Française depuis l'Enfance (ELFE) cohort. METHODS: Predictive scores were determined at Age 1 and the primary outcome of asthma was defined as parental reporting of "asthma ever or "wheezing in the past 12 months" at Age 5. Logistic regression was used to calculate the odds ratio (OR) and performance measures, and discriminative performance was reported using the receiver operating curve and area under curve (AUC). Calibration was assessed using Hosmer-Lemeshow goodness-of-fit test and visualized with a calibration plot. Overall performance was determined using Brier scores. RESULTS: Of the 10,689 children analyzed: 84.9% were at low, 13.1% medium, and 2% at high risk of developing asthma at Age 5. Children in the medium-risk category were three times more likely to develop asthma (OR = 3.3, 95% confidence interval [CI] = 2.97-3.78) whereas 13 times more likely in the high-risk category (OR = 13.8, 95% CI = 10.2-18.8). The tool's AUC was comparable: LRC 0.74 versus ELFE 0.68; as were the Brier scores LRC 0.16 versus ELFE 0.14. The tool's performance was robust to changes in inclusion criteria and outcome definitions. CONCLUSIONS AND RELEVANCE: Results of the present study and previous validation studies performed in high-risk populations provide a comprehensive measure of the effectiveness of the APT, providing encouragement for its application by general practitioners.
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Asma , Área Bajo la Curva , Asma/diagnóstico , Asma/epidemiología , Niño , Preescolar , Estudios de Cohortes , Dimaprit/análogos & derivados , Humanos , Lactante , Ruidos RespiratoriosRESUMEN
Carcinoembryonic antigen (CEA), a lung cancer marker with high sensitivity and specificity, plays vital roles in the early diagnosis of lung cancer. In this paper, an electrochemical biosensor for highly sensitive detection of CEA was constructed, which based on dual signal amplification of electrically mediated atom transfer radical polymerization (eATRP) and polyethyleneimine (PEI) for the first time. Firstly, CEA was captured in a specific recognition manner with CEA aptamer 1 (Apt1), which self-assembled on the electrode via "Au-S" bond. After that, CEA aptamer 2-PEI (Apt2-PEI) was recognized by CEA to form an Apt-antigen-Apt sandwich structure. Next, multiple initiation sites were introduced for the eATRP reaction by the amide reaction. Finally, numerous electroactive monomers, ferrocene methacrylate (FMMA), were grafted onto the modified electrode by eATRP. Under the optimized conditions, there was a wide linear detection range of 10-3 â¼ 102 ng·mL-1, and the limit of detection (LOD) was 70.17 fg·mL-1. Compared to other reported sensors, this electrochemical biosensor used a simpler and more environmentally friendly eATRP, and the use of PEI increased the electron transfer rate. Moreover, the biosensor showed superior analytical performance in the clinical serums and has great promise for early lung cancer diagnosis applications.
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Técnicas Biosensibles , Neoplasias Pulmonares , Amidas , Antígeno Carcinoembrionario , Dimaprit/análogos & derivados , Detección Precoz del Cáncer , Técnicas Electroquímicas , Humanos , Neoplasias Pulmonares/diagnóstico , Metalocenos , Metacrilatos , Polietileneimina/química , PolimerizacionRESUMEN
AIM: To investigate the optimal amide proton transfer (APT) imaging parameters for bladder cancer (BCa), the influence of different protein concentrations and pH values on APT imaging, and to establish the reliability of APT imaging in healthy volunteers and patients with BCa. MATERIALS AND METHODS: The optimal APT imaging parameters for BCa were experimentally optimised using cross-linked bovine serum albumin (BSA) phantoms. BSA phantoms were scanned with different values for the saturation power, saturation duration and number of excitations. Meanwhile, BSA phantoms containing different protein concentrations and solutions of different pH levels were scanned. The interobserver agreement of the asymmetric magnetisation transfer ratio (MTRasym) was assessed in 11 healthy volunteers and 18 patients with BCa. RESULTS: The optimal scanning scheme consisted of 1 excitation, a saturation power of 2 µT, and a saturation time of 2 s. The APT signal intensity increased as the protein concentration increased and as the pH decreased. The MTRasym showed good concordance for all subjects. The MTRasym of BCa tissue was significantly higher (1.81 ± 0.71) than that of bladder wall in healthy volunteers (0.34 ± 0.12) and normal bladder wall in patients with BCa (0.31 ± 0.11; p<0.001). There was no significant difference between the bladder wall of healthy volunteers and the normal bladder wall of patients with BCa. CONCLUSION: APT imaging showed potential value for application in BCa.
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Protones , Neoplasias de la Vejiga Urinaria , Amidas/metabolismo , Dimaprit/análogos & derivados , Estudios de Factibilidad , Humanos , Imagen por Resonancia Magnética/métodos , Reproducibilidad de los Resultados , Albúmina Sérica Bovina , Neoplasias de la Vejiga Urinaria/diagnóstico por imagenRESUMEN
Amide proton transfer (APT)-weighted MRI is a promising molecular imaging technique that has been employed in clinic for detection and grading of brain tumors. MTRasym, the quantification method of APT, is easily influenced by B0 inhomogeneity and causes artifacts. Current model-free interpolation methods have enabled moderate B0 correction for middle offsets, but have performed poorly at limbic offsets. To address this shortcoming, we proposed a practical B0 correction approach that is suitable under time-limited sparse acquisition scenarios and for B1 ≥ 1 µT under 3T. In this study, this approach employed a simplified Lorentzian model containing only two pools of symmetric water and asymmetric solutes, to describe the Z-spectral shape with wide and 'invisible' CEST peaks. The B0 correction was then performed on the basis of the fitted two-pool Lorentzian lines, instead of using conventional model-free interpolation. The approach was firstly evaluated on densely sampled Z-spectra data by using the spline interpolation of all acquired 16 offsets as the gold standard. When only six offsets were available for B0 correction, our method outperformed conventional methods. In particular, the errors at limbic offsets were significantly reduced (n = 8, p < 0.01). Secondly, our method was assessed on the six-offset APT data of nine brain tumor patients. Our MTRasym (3.5 ppm), using the two-pool model, displayed a similar contrast to the vendor-provided B0-orrected MTRasym (3.5 ppm). While the vendor failed in correcting B0 at 4.3 and 2.7 ppm for a large portion of voxels, our method enabled well differentiation of B0 artifacts from tumors. In conclusion, the proposed approach could alleviate analysis errors caused by B0 inhomogeneity, which is useful for facilitating the comprehensive metabolic analysis of brain tumors.