Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 68
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Pharm ; 17(2): 683-694, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-31913047

RESUMO

Plant-based saponins are amphipathic glycosides composed of a hydrophobic aglycone backbone covalently bound to one or more hydrophilic sugar moieties. Recently, the endosomal escape activity of triterpenoid saponins has been investigated as a potentially powerful tool for improved cytosolic penetration of protein drugs internalized by endocytic uptake, thereby greatly enhancing their pharmacological effects. However, only a few saponins have been studied, and the paucity in understanding the structure-activity relationship of saponins imposes significant limitations on their applications. To address this knowledge gap, 12 triterpenoid saponins with diverse structural side chains were screened for their utility as endosomolytic agents. These compounds were used in combination with a toxin (MAP30-HBP) comprising a type I ribosome-inactivating protein fused to a cell-penetrating peptide. Suitability of saponins as endosomolytic agents was assessed on the basis of cytotoxicity, endosomal escape promotion, and synergistic effects on toxins. Five saponins showed strong endosomal escape activity, enhancing MAP30-HBP cytotoxicity by more than 106 to 109 folds. These saponins also enhanced the apoptotic effect of MAP30-HBP in a pH-dependent manner. Additionally, growth inhibition of MAP30-HBP-treated SMMC-7721 cells was greater than that of similarly treated HeLa cells, suggesting that saponin-mediated endosomolytic effect is likely to be cell-specific. Furthermore, the structural features and hydrophobicity of the sugar side chains were analyzed to draw correlations with endosomal escape activity and derive predictive rules, thus providing new insights into structure-activity relationships of saponins. This study revealed new saponins that can potentially be exploited as efficient cytosolic delivery reagents for improved therapeutic drug effects.

2.
Eur J Heart Fail ; 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31808279

RESUMO

AIMS: The performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in diagnosing acute decompensated heart failure (ADHF) among patients presenting with breathlessness is markedly impaired in the presence of atrial fibrillation (AF). We evaluated the diagnostic performance of mid-regional pro-adrenomedullin (MR-proADM) and cardiac troponin T as possible alternative markers for discrimination of ADHF in this setting. METHODS AND RESULTS: Breathless patients (n = 1107) were prospectively and contemporaneously recruited in emergency departments in Singapore and New Zealand. The diagnoses of ADHF and presence of AF were adjudicated by two clinician specialists, blinded to MR-proADM, NT-proBNP and high-sensitivity cardiac troponin T (hs-cTnT) results. MR-proADM exhibited strong discrimination of ADHF with little change in performance irrespective of the presence of AF (area under the curve 0.83 in non-AF vs. 0.76 in AF) compared to NT-proBNP (0.91 vs. 0.71) and hs-cTnT (0.83 vs. 0.62), respectively. The accuracy of MR-proADM (73.3%) for diagnosing ADHF among patients with AF was superior to both NT-proBNP (61.6%) and hs-cTnT (64.6%). The superior performance of MR-proADM remained apparent when data from Singapore and New Zealand were analysed separately. CONCLUSION: In the presence of AF, MR-proADM showed greater discrimination and accuracy, and less impairment in performance compared to that in non-AF cases, for the diagnosis of ADHF, compared to the guideline-endorsed NT-proBNP.

3.
Rev Sci Instrum ; 90(7): 076108, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31370467

RESUMO

A vast majority of syringe pumps operate on stepper motors, which limits their effectiveness for precision fluid delivery using estimation algorithms. Such a system also hampers the ability to ascertain if the infusion or aspiration instruction has been correctly carried out in the event of power interruptions. To address this issue, a linear servo based actuator system is described to provide absolute indications of the plunger position. System performance in terms of linearity and reliability of plunger translation were verified using a camera tracking system with syringe capacities ranging from 3 to 50 ml and at syringe plunger speeds ranging from 1 to 6.6 mm/s when distilled water was used as the medium. In investigations involving more viscous liquids, the system revealed similarly linear characteristics with 50% glycerol-water (v/v), but cyclical stick-slip behavior with Freund's adjuvant.

4.
Microsc Res Tech ; 82(10): 1741-1747, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31295381

RESUMO

In this work a single glycerol-water mixture, determined to be most apt at 30% (wt/vol), was used to immobilize Drosophila samples as well as to create a liquid lens for smartphone magnification viewing. This provides the advantage of being able to observe immobilized insects directly in the field rather than in the laboratory. In order to avoid having bubbles in the liquid lens and immobilizing medium that hinder visibility, an approach was developed where a stable pendant drop is moved in tandem with the dispensing tip by gravity and stopped abruptly so that sufficient momentum is transferred to the drop for its dislodgement. With 30% glycerol-water (wt/vol) mixtures, applying a minimal stroke of 10 mm with longitudinal impact delivered a momentum of 0.1464 N/s that allowed transfer of a preselected liquid volume for the processes.


Assuntos
Drosophila/anatomia & histologia , Entomologia/instrumentação , Entomologia/métodos , Microscopia/instrumentação , Microscopia/métodos , Smartphone , Animais
5.
J Am Coll Cardiol ; 73(11): 1300-1313, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30898206

RESUMO

BACKGROUND: Clinicians need improved tools to better identify nonacute heart failure with preserved ejection fraction (HFpEF). OBJECTIVES: The purpose of this study was to derive and validate circulating microRNA signatures for nonacute heart failure (HF). METHODS: Discovery and validation cohorts (N = 1,710), comprised 903 HF and 807 non-HF patients from Singapore and New Zealand (NZ). MicroRNA biomarker panel discovery in a Singapore cohort (n = 546) was independently validated in a second Singapore cohort (Validation 1; n = 448) and a NZ cohort (Validation 2; n = 716). RESULTS: In discovery, an 8-microRNA panel identified HF with an area under the curve (AUC) 0.96, specificity 0.88, and accuracy 0.89. Corresponding metrics were 0.88, 0.66, and 0.77 in Validation 1, and 0.87, 0.58, and 0.74 in Validation 2. Combining microRNA panels with N-terminal pro-B-type natriuretic peptide (NT-proBNP) clearly improved specificity and accuracy from AUC 0.96, specificity 0.91, and accuracy 0.90 for NT-proBNP alone to corresponding metrics of 0.99, 0.99, and 0.93 in the discovery and 0.97, 0.96, and 0.93 in Validation 1. The 8-microRNA discovery panel distinguished HFpEF from HF with reduced ejection fraction with AUC 0.81, specificity 0.66, and accuracy 0.72. Corresponding metrics were 0.65, 0.41, and 0.56 in Validation 1 and 0.65, 0.41, and 0.62 in Validation 2. For phenotype categorization, combined markers achieved AUC 0.87, specificity 0.75, and accuracy 0.77 in the discovery with corresponding metrics of 0.74, 0.59, and 0.67 in Validation 1 and 0.72, 0.52, and 0.68 in Validation 2, as compared with NT-proBNP alone of AUC 0.71, specificity 0.46, and accuracy 0.62 in the discovery; with corresponding metrics of 0.72, 0.44, and 0.57 in Validation 1 and 0.69, 0.48, and 0.66 in Validation 2. Accordingly, false negative (FN) (81% Singapore and all NZ FN cases were HFpEF) as classified by a guideline-endorsed NT-proBNP ruleout threshold, were correctly reclassified by the 8-microRNA panel in the majority (72% and 88% of FN in Singapore and NZ, respectively) of cases. CONCLUSIONS: Multi-microRNA panels in combination with NT-proBNP are highly discriminatory and improved specificity and accuracy in identifying nonacute HF. These findings suggest potential utility in the identification of nonacute HF, where clinical assessment, imaging, and NT-proBNP may not be definitive, especially in HFpEF.

6.
Mater Sci Eng C Mater Biol Appl ; 96: 599-605, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30606571

RESUMO

Superhydrophobic substrates facilitate low adhesion for biological liquid handling but are hampered by wetting state changes due to condensation. Here, meshed near-superhydrophobic substrates, that are easier to produce than two-tiered architecture substrates, are shown to provide good immunity to wetting state changes while imbuing high positional resistance to roll-off by tilting when tested with 5 and 10 µL volume drops (18° and 13° respectively) of human IgG antibodies in aqueous solution at both room temperature and 4 °C. Pneumatic actuation was applied to elicit horizontal drop movement over the near-SH surface without any fragmentation, wherein higher velocities can be achieved when smaller drops and higher air pressures are used (0.385 m/s at 33 mbar with the 5 µL drop). A non-contact mode of translating a protein drop towards a highly viscous oil-based adjuvant dispensed from a steel tip allowed for both drops to be combined and aspirated back up into the tip such that subsequent repeated cycles of pendant drop formation and upward aspiration allows for effective mixing to achieve a stable emulsion. The findings here advance the development of devices that enable improved antigen-adjuvant preparation by reducing the amount of reagents required and product losses from surface adsorption.


Assuntos
Interações Hidrofóbicas e Hidrofílicas , Imunoglobulina G/química , Emulsões , Humanos
7.
Cells ; 8(12)2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31888288

RESUMO

Circulating microRNAs offer attractive potential as epigenetic disease biomarkers by virtue of their biological stability and ready accessibility in liquid biopsies. Numerous clinical cohort studies have revealed unique microRNA profiles in different disease settings, suggesting utility as markers with diagnostic and prognostic applications. Given the complex network of microRNA functions in modulating gene expression and post-transcriptional modifications, the circulating microRNA landscape in disease may reflect pathophysiological status, providing valuable information for delineating distinct subtypes and/or stages of complex diseases. Heart failure (HF) is an increasingly significant global health challenge, imposing major economic liability and health care burden due to high hospitalization, morbidity, and mortality rates. Although HF is defined as a syndrome characterized by symptoms and findings on physical examination, it may be further differentiated based on left ventricular ejection fraction (LVEF) and categorized as HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). The presenting clinical syndromes in HFpEF and HFrEF are similar but mortality differs, being somewhat lower in HFpEF than in HFrEF. However, while HFrEF is responsive to an array of therapies, none has been shown to improve survival in HFpEF. Herein, we review recent HF cohort studies focusing on the distinct microRNA profiles associated with HF subtypes to reveal new insights to underlying mechanisms and explore the possibility of exploiting these differences for diagnostic/prognostic applications.

8.
Rev Sci Instrum ; 89(10): 106102, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30399692

RESUMO

The ability to conduct en-route centrifugation of samples improves quality and timeliness in the pre-analytical phase. This is demonstrated here on a quadcopter whereby the propellers were adapted to house and apply centrifugal forces to sample-containing capillary tubes instead of incorporating a centrifuge. Tests revealed the ability of the method to separate non-homogenized milk into a cream portion and a skim milk portion, and human whole blood into plasma, buffy coat, and red blood cell components.

9.
Sci Rep ; 8(1): 7055, 2018 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-29728596

RESUMO

Natriuretic Peptide Receptor 3 (NPR3), the clearance receptor for extracellular bio-active natriuretic peptides (NPs), plays important roles in the homeostasis of body fluid volume and vascular tone. Using luciferase reporter and antagomir-based silencing assays, we demonstrated that the expression of NPR3 could be modulated by microRNA-143 (miR-143-3p), a microRNA species with up-regulated circulating concentrations in clinical heart failure. The regulatory effect of miR-143 on NPR3 expression was further evidenced by the reciprocal relationship between miR-143 and NPR3 levels observed in hypoxia-treated human cardiac cells and in left ventricular tissue from rats undergoing experimental myocardial infarction. Further analysis indicated elevation of miR-143 in response to hypoxic challenge reflects transcriptional activation of the miR-143 host gene (MIR143HG). This was corroborated by demonstration of the induction of host gene promoter activity upon hypoxic challenge. Moreover, miR-143 was shown to enhance its own expression by increasing MIR143HG promoter activity, as well as targeting the expressions of NPPA, NPPC, NR3C2, and CRHR2 in cardiac cells. Taken together, these findings suggest that the elevation of miR-143 upon hypoxic insult may be part of a microRNA-based feed forward loop that results in fine tuning the levels of NPs and neurohormonal receptors in cardiac cell lineages.


Assuntos
Regulação da Expressão Gênica , MicroRNAs/genética , Miócitos Cardíacos/metabolismo , Interferência de RNA , Receptores do Fator Natriurético Atrial/genética , Regiões 3' não Traduzidas , Animais , Biomarcadores , Estudos de Casos e Controles , Linhagem Celular , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipóxia/genética , Hipóxia/metabolismo , MicroRNAs/sangue , Modelos Biológicos , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Regiões Promotoras Genéticas , Ratos , Receptores do Fator Natriurético Atrial/metabolismo , Fatores de Transcrição , Transcrição Genética
10.
Biochem Mol Biol Educ ; 46(3): 245-252, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29488323

RESUMO

The appreciation and understanding of gas generation through processes is vital in biochemical education. In this work, an augmented reality tool is reported to depict the redox reaction between hydrogen peroxide and sodium hypochlorite solutions, two ubiquitous oxidizing agents, to create oxygen, a combustible gas. As it operates out of smartphones or tablets, students are able to conduct the exercise collaboratively, respond in a manner similar to an actual physical experiment, and able to depict the oxygen volume changes in relation to the volume of hydrogen peroxide of different concentrations used. The tool offers to help students acquire bench skills by limiting handing risks and to mitigate possible student anxiety on handling chemical materials and implements in the laboratory. The feedback received from Year 11 and 12 high school student participants in an outreach exercise indicate the overall effectiveness of this tool. © 2018 by The International Union of Biochemistry and Molecular Biology, 46(3):245-252, 2018.


Assuntos
Peróxido de Hidrogênio/química , Oxigênio/química , Aprendizagem Baseada em Problemas , Hipoclorito de Sódio/química , Estudantes , Compreensão , Humanos , Instituições Acadêmicas
11.
Anal Biochem ; 545: 1-3, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29307634

RESUMO

Autonomous systems for sample transport to the laboratory for analysis can be improved in terms of timeliness, cost and error mitigation in the pre-analytical testing phase. Drones have been reported for outdoor sample transport but incorporating devices on them to attain homogenous mixing of reagents during flight to enhance sample processing timeliness is limited by payload issues. It is shown here that flipping maneuvers conducted with quadcopters are able to facilitate complete and gentle mixing. This capability incorporated during automated sample transport serves to address an important factor contributing to pre-analytical variability which ultimately impacts on test result reliability.


Assuntos
Testes Imediatos , Impressão Tridimensional , Biomarcadores/análise , Humanos , Testes Imediatos/economia , Impressão Tridimensional/economia , Impressão Tridimensional/instrumentação
12.
Cell Rep ; 22(1): 299-312, 2018 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-29298430

RESUMO

The large number of mutations identified across all cancers represents an untapped reservoir of targets that can be useful for therapeutic targeting if highly selective, mutation-specific reagents are available. We report here our attempt to generate such reagents: monoclonal antibodies against the most common R175H, R248Q, and R273H hotspot mutants of the tumor suppressor p53. These antibodies recognize their intended specific alterations without any cross-reactivity against wild-type (WT) p53 or other p53 mutants, including at the same position (as exemplified by anti-R248Q antibody, which does not recognize the R248W mutation), evaluated by direct immunoblotting, immunoprecipitation, and immunofluorescence methods on transfected and endogenous proteins. Moreover, their clinical utility to diagnose the presence of specific p53 mutants in human tumor microarrays by immunohistochemistry is also shown. Together, the data demonstrate that antibodies against specific single-amino-acid alterations can be generated reproducibly and highlight their utility, which could potentially be extended to therapeutic settings.


Assuntos
Anticorpos Monoclonais Murinos/química , Especificidade de Anticorpos , Mutação , Proteína Supressora de Tumor p53/imunologia , Animais , Anticorpos Monoclonais Murinos/imunologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Medicina de Precisão , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/genética
13.
ACS Omega ; 3(8): 9310-9317, 2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31459064

RESUMO

Facile creation of multiple drops at appropriate volumes on surfaces without the use of sophisticated instrumentation facilitates downstream evaporative preconcentration of liquid samples for analytical purposes. In this work, a superhydrophobic (SH) substrate comprising wells with a perforated mesh base was developed for simultaneous drop creation in a quick and convenient manner. In contrast to the method of pouring liquid directly over the SH wells, consistent liquid filling was readily achieved by a simple immersion approach. This method works well even for challenging situations where well diameters are smaller than 3.4 mm. Despite the poor liquid-retention properties of SH surfaces, inverting the wells did not result in liquid detachment under gravitational force, indicating strong pinning effects afforded by the well architecture. The perforated base of the well allowed the liquid to be completely removed from the well by compressed air. High-speed camera image processing was used to study the evolution of drop contact angle and displacement with time. It was found that the liquid body was able to undergo strong oscillations. Optical spectroscopy was used to confirm the ability of evaporative preconcentration of silver nanoparticles.

14.
Langmuir ; 33(48): 13892-13898, 2017 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-29116806

RESUMO

Valves used to control liquid filling and draining processes from storage typically need to be actuated. Here, we show that similar flow enabling and restricting operations can be achieved through millimeter scale holes that function according to the amount of hydrostatic pressure applied without any other intervention. This phenomena is exhibited using receptacles where the base is made of either a hydrophilic or superhydrophobic substrate with hole sizes ranging from 1.0-2.0 mm. The construction is such that the drainage flow velocities are of the same order in both substrates and follow Torricelli's law trends. Nevertheless, the primary mechanisms responsible for resisting the onset of flow in each substrate are different; nonbreaching of the advancing contact angle threshold in the former, and stable maintenance of an elastic-like deformation of the liquid-gas interface that is connected to the surrounding plastron in the latter. These differences are demonstrated using an upward jet of water delivered to the orifice, where a discharging flow from the hydrophilic base occurred before the threshold hydrostatic pressure condition was attained, while liquid from the jet is subsumed into the liquid body of the receptacle with the superhydrophobic base without any leakage. These findings portend advantages in simplicity and robustness for a myriad of liquid-related processes.

15.
Eur J Heart Fail ; 19(12): 1638-1647, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28849609

RESUMO

AIMS: Circulating biomarkers are important in the diagnosis, risk stratification and management of patients with heart failure (HF). Given the current lack of biomarkers in HF with preserved ejection fraction (HFpEF), we aimed to investigate the prognostic performance of the newly developed high-sensitivity (hs) assays for cardiac troponin I (hsTnI) compared with troponin T (hsTnT) for adverse events in HFpEF vs. HF with reduced ejection fraction (HFrEF). Findings in these two HF subgroups were also compared with those in the recently defined HF with mid-range ejection fraction (HFmrEF) subgroup. METHODS AND RESULTS: Both hsTnI and hsTnT were measured in 1096 patients with HFrEF [left ventricular ejection fraction (LVEF) <50%; n = 853] or HFpEF (LVEF ≥50%; n = 243) enrolled in the Singapore Heart Failure Outcomes and Phenotypes (SHOP) study. Both troponin assays were more strongly associated with the composite endpoint (all-cause mortality or first rehospitalization for HF) in HFpEF than in HFrEF. The hsTnT assay provided the greatest additional prognostic value in HFpEF in comparison with hsTnI and NT-proBNP. TnI was more strongly associated with composite events in men with HFpEF [hazard ratio (HR) 3.33, 95% confidence interval (CI) 1.82-6.09; P < 0.001 per standard deviation (SD) increase in log-transformed hsTnI] than in women with HFpEF (HR 1.35, 95% CI 0.94-1.93; P = 0.10 per SD increase in log-transformed hsTnI). CONCLUSIONS: There is a potential role for the prognostic use of high-sensitivity troponin assays, particularly hsTnT, in men and women with HFpEF. The predictive association of hsTnI with outcome appears strongest in men with HFpEF.


Assuntos
Insuficiência Cardíaca/sangue , Volume Sistólico/fisiologia , Troponina I/sangue , Troponina T/sangue , Idoso , Biomarcadores/sangue , Feminino , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Prevalência , Prognóstico , Singapura/epidemiologia , Função Ventricular Esquerda
16.
Int J Mol Sci ; 18(7)2017 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-28672880

RESUMO

The ankyrin repeat domain 1 (ANKRD1) protein is a cardiac-specific stress-response protein that is part of the muscle ankyrin repeat protein family. ANKRD1 is functionally pleiotropic, playing pivotal roles in transcriptional regulation, sarcomere assembly and mechano-sensing in the heart. Importantly, cardiac ANKRD1 has been shown to be highly induced in various cardiomyopathies and in heart failure, although it is still unclear what impact this may have on the pathophysiology of heart failure. This review aims at highlighting the known properties, functions and regulation of ANKRD1, with focus on the underlying mechanisms that may be involved. The current views on the actions of ANKRD1 in cardiovascular disease and its utility as a candidate cardiac biomarker with diagnostic and/or prognostic potential are also discussed. More studies of ANKRD1 are warranted to obtain deeper functional insights into this molecule to allow assessment of its potential clinical applications as a diagnostic or prognostic marker and/or as a possible therapeutic target.


Assuntos
Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Animais , Repetição de Anquirina , Biomarcadores , Proteínas de Transporte/metabolismo , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Cardiopatias/etiologia , Cardiopatias/metabolismo , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Humanos , Proteínas Musculares/química , Proteínas Nucleares/química , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Transporte Proteico , Proteólise , Proteínas Repressoras/química
17.
J Am Heart Assoc ; 6(6)2017 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-28611096

RESUMO

BACKGROUND: Thymosin beta-4 (TB4) is an X-linked gene product with cardioprotective properties. Little is known about plasma concentration of TB4 in heart failure (HF), and its relationship with other cardiovascular biomarkers. We sought to evaluate circulating TB4 in HF patients with preserved (HFpEF) or reduced (HFrEF) ejection fraction compared to non-HF controls. METHODS AND RESULTS: TB4 was measured using a liquid chromatography and mass spectrometry assay in age- and sex-matched HFpEF (n=219), HFrEF (n=219) patients, and controls (n=219) from a prospective nationwide study. Additionally, a 92-marker multiplex proximity extension assay was measured to identify biomarker covariates. Compared with controls, plasma TB4 was elevated in HFpEF (985 [421-1723] ng/mL versus 1401 [720-2379] ng/mL, P<0.001), but not in HFrEF (1106 [556-1955] ng/mL, P=0.642). Stratifying by sex, only women (1623 [1040-2625] ng/mL versus 942 [386-1891] ng/mL, P<0.001), but not men (1238.5 [586-1967] ng/mL versus 1004 [451-1538] ng/mL, P=1.0), had significantly elevated TB4 in the setting of HFpEF. Adjusted for New York Heart Association class, N-terminal pro B-type natriuretic peptide, age, and myocardial infarction, hazard ratio to all-cause mortality is significantly higher in women with elevated TB4 (1.668, P=0.036), but not in men (0.791, P=0.456) with HF. TB4 is strongly correlated with a cluster of 7 markers from the proximity extension assay panel, which are either X-linked, regulated by sex hormones, or involved with NF-κB signaling. CONCLUSIONS: We show that plasma TB4 is elevated in women with HFpEF and has prognostic information. Because TB4 can preserve EF in animal studies of cardiac injury, the relation of endogenous, circulating TB4 to X chromosome biology and differential outcomes in female heart disease warrants further study.


Assuntos
Insuficiência Cardíaca/sangue , Volume Sistólico/fisiologia , Timosina/sangue , Idoso , Biomarcadores/sangue , Cromatografia Líquida , Progressão da Doença , Feminino , Seguimentos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Espectrometria de Massas , Proteínas dos Microfilamentos , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores Sexuais
18.
Biochim Biophys Acta Mol Basis Dis ; 1863(8): 2031-2040, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28065846

RESUMO

Heart failure (HF) is a widely prevalent syndrome imposing a significant burden of morbidity and mortality world-wide. Differential circulating microRNA profiles observed in HF cohorts suggest the diagnostic utility of microRNAs as biomarkers. Given their function in fine tuning gene expression, alternations in microRNA landscape could reflecting the underlying mechanisms of disease and present potential therapeutic targets. Using multiple computational target predicting algorithms together with the luciferase-based reporting platform, the interactions between HF-related microRNAs and the 3' untranslated regions (3'UTRs) of neurohormone associated genes were examined and compared. Our results indicate that although in silico prediction provides an overview of possible microRNA-mRNA target pairs, less than half of the predicted interactions were experimentally confirmed by reporter assays in HeLa cells. Thus, the establishment of microRNA/3'UTR reporters is essential to systemically evaluate the roles of microRNAs for signaling cascades of interest, including cardiovascular neurohormonal signaling. The physiological relevance of HF-related microRNAs on the expression of putative gene targets was further established by using gain-of-function assays in two human cardiac-derived cells. Our findings, for the first time, provide direct evidence of the regulatory effects of HF-related microRNAs on the neurohormonal signaling in cardiac cells. More importantly, our study presents a rational approach to further exploring microRNA profiling data in deciphering the role of microRNA in complex syndromes such as HF. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren & Megan Yingmei Zhang.


Assuntos
Regiões 3' não Traduzidas , Regulação da Expressão Gênica , Insuficiência Cardíaca , MicroRNAs , Transdução de Sinais/genética , Perfilação da Expressão Gênica , Células HeLa , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo
19.
ACS Omega ; 2(9): 6211-6222, 2017 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31457866

RESUMO

Drops with larger volumes placed over a superhydrophobic (SH) surface with a hole do not fall through unless they are evaporated to a size that is small enough. This feature offers the ability to preconcentrate samples for biochemical analysis. In this work, the influence of pinning on the behavior of drops placed on a 0.1 mm thick SH substrate with a 2 mm diameter hole as they evaporated was investigated. With 16 µL of water dispensed, the sessile drop component volume was initially higher than that of the overhanging drop component and maintained this until the later stages where almost identical shapes were attained and full evaporation was achieved without falling off the hole. With 15 µL of water dispensed, the volume of the sessile drop was initially higher than that of the overhanging drop component but the liquid body was able to squeeze through the hole after 180 s due to the contact line not having sufficient pinning strength when it encountered the edge of the hole. This resulted in the liquid body either falling through the hole or remaining pinned with an oval-like shape. When it did not fall-off, the liquid body had volume and contact angle characteristics for the sessile drop and overhanging drop components that were reversed. In the later stages, however, nearly identical shapes were again attained and full evaporation was achieved without falling off the hole. The effects of pinning, despite the substrate being SH, offer another path toward achieving practical outcomes with liquid bodies without the need for chemical surface functionalization. Similarities and differences could be seen in the behavior of a sessile drop on a SH plate that was inclined at 30° to the horizontal and evaporated.

20.
Eur J Heart Fail ; 19(2): 209-217, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27620387

RESUMO

AIMS: This study was conducted to test the diagnostic performance of NT-proBNP for discrimination of acute decompensated heart failure (ADHF) among breathless patients presenting in an Asian compared with a Western centre. METHODS AND RESULTS: Patients with breathlessness were prospectively and contemporaneously recruited in Emergency Departments in Singapore and New Zealand (NZ). The diagnosis of ADHF was adjudicated by two clinician specialists. A total of 606 patients were recruited in Singapore and 500 in NZ. The discriminative power of NT-proBNP for ADHF was superior in Singapore compared with NZ [area under the curve (AUC) 0.926 vs. 0.866; P = 0.012] both overall and among selected subgroups stratified according to age, renal function, body mass index, and presence or absence of AF or diabetes. Previously established cut-off point values of plasma NT-proBNP yielded comparable sensitivity and negative predictive values, but superior specificity and accuracy in Singapore compared with NZ. The difference in test performance was driven by the younger age (median age 56 years vs. 73 years; P < 0.001), associated with better renal function (estimated glomerular filtration rate 89 vs. 62 mL/min/1.73 m2 ; P < 0.001), and lower prevalence of AF (9.7% vs. 25.7%; P < 0.001) in acutely breathless patients in Singapore. CONCLUSION: Considering emerging evidence of a lower average age of presentation with ADHF over most of Asia compared with Western countries, NT-proBNP is likely to be more accurate when applied in Asian centres than in the West.


Assuntos
Grupo com Ancestrais do Continente Asiático , Grupo com Ancestrais do Continente Europeu , Insuficiência Cardíaca/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Serviço Hospitalar de Emergência , Feminino , Insuficiência Cardíaca/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Singapura
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA