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OBJECTIVE: Padsevonil (PSL) is a novel antiepileptic drug candidate that inhibits seizure activity in both presynaptic and postsynaptic ways. The pharmacokinetic (PK) profiles and volumetric absorptive microsampling (VAMS) application of PSL in the Chinese population are limited. The objectives of this study were to evaluate the PK profile of PSL and its 2 metabolites, the safety of PSL, and compare the PK profile of PSL from samples collected using the VAMS technique with that of conventional venous samples in healthy Chinese subjects. SUBJECTS AND METHODS: In this randomized, double-blind, placebo-controlled single-dose study, the participants received either 200 mg PSL or placebo. Blood samples for the PK variables were collected using both the traditional venous method and the VAMS Mitra® technique at the scheduled time points. The PK parameters of PSL and 2 metabolites were calculated, and the concentration agreement of VAMS and venous samples were also evaluated. RESULTS: A total of 14 subjects were enrolled. The concentration-time profile of PSL showed rapid absorption with a median tmax of 1.25 h (range: 0.5 to 3.0), followed by an apparent biphasic disposition. For PSL, the geometric means of AUC(0-t), AUC, Cmax, and t1/2 were 6,573 h*ng/mL, 6,588 h*ng/mL, 1,387 ng/mL, and 5.275 h, respectively. The geometric mean body weight-normalized AUC(0-t), AUC, and Cmax w ere 5,712 h *ng/mL, 5,725 h *ng/mL, and 1,205 ng/mL, respectively. The AUC(0-t), AUC, Cmax of PSL and metabolites in VAMS-dried blood were all lower than those in plasma. The Passing-Bablok regression showed that the PSL and metabolite concentrations obtained by VAMS analysis were comparable to those obtained by plasma at some time points. The most frequently reported treatment-emergent adverse events (TEAEs) were somnolence and dizziness. There were no serious TEAEs, severe TEAEs, discontinuations due to TEAEs, or deaths reported during this study. No clinically significant laboratory, vital signs, electrocardiograph (ECG), or physical examination results were reported. CONCLUSIONS: PSL has a favorable PK profile after single-dose oral administration and good safety properties in healthy Chinese volunteers. The regression analysis results of VAMS and plasma indicated that the application of VAMS for therapeutic drug monitoring in novel antiepileptic drug development is promising and needs further validation. [ABSTRACT FROM AUTHOR]

Acute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation involving RAR[Alpha] and one of four fusion partners: PML, PLZF, NPM, and NuMA genes. To study the leukemogenic potential of the fusion genes in vivo, we generated transgenic mice with PLZF-RAR[Alpha] and NPM-RAR[Alpha]. PLZF-RAR[Alpha] transgenic animals developed chronic myeloid leukemia-like phenotypes at an early stage of life (within 3 months in five of six mice), whereas three NPM-RAR[Alpha] transgenic mice showed a spectrum of phenotypes from typical APL to chronic myeloid leukemia relatively late in life (from 12 to 15 months). In contrast to bone marrow cells from PLZFRAR[Alpha] transgenic mice, those from NPM-RAR[Alpha] transgenic mice could be induced to differentiate by all-trans-retinoic acid (ATRA). We also studied RARE binding properties and interactions between nuclear corepressor SMRT and various fusion proteins in response to ATRA. Dissociation of SMRT from different receptors was observed at ATRA concentrations of 0.01 [[micro]molar], 0.1 [[micro]molar], and 1.0 [[micro]molar] for RAR[Alpha]-RXR[Alpha], NPM-RAR[Alpha], and PML-RAR[Alpha], respectively, but not observed for PLZF-RAR[Alpha] even in the presence of 10 [[micro]molar] ATRA. We also determined the expression of the tissue factor gene in transgenic mice, which was detected only in bone marrow cells of mice expressing the fusion genes. These data clearly establish the leukemogenic role of PLZF-RAR[Alpha] and NPM-RAR[Alpha] and the importance of fusion receptor/corepressor interactions in the pathogenesis as well as in determining different clinical phenotypes of APL.

OBJECTIVE: Current evidence of the maternal, perinatal and neonatal outcomes in twin pregnancies among mothers with advanced age is unclear, especially for mothers with age above 40 years. MATERIALS AND METHODS: A systematic search was conducted using the PubMed, Scopus, and Google Scholar databases. Studies that were observational in design or analysed retrospective data were considered for inclusion. The included studies had to be conducted in twin pregnancies and should have documented the effect of maternal age on obstetric and/ or neonatal outcomes. Statistical analysis was performed using STATA software. RESULTS: A total of 20 studies were considered for inclusion. All the studies were based on retrospective data. Compared to mothers aged under 40 years, those with advanced age (≥40 years) had increased risk of caesarean delivery [RR 1.20, 95% CI: 1.05, 1.37], gestational hypertension [RR 2.71, 95% CI: 1.72, 4.27], gestational diabetes mellitus [RR 2.03, 95% CI: 1.28, 3.21], preterm birth [RR 2.47, 95% CI: 1.09, 5.80], neonatal admission to intensive care unit [RR 1.78, 95% CI: 1.21, 2.64] and perinatal and/or neonatal mortality [RR 5.76, 95% CI: 1.11, 29.7]. The risk of gestational diabetes mellitus [RR 1.52, 95% CI: 1.21, 1.90] and having caesarean delivery [RR 1.19, 95% CI: 1.10, 1.28] was higher in mothers with ≥35 years of age, compared to those <35 years. There were no significant differences in the risk of adverse neonatal outcomes among the mothers with age ≥35 years. However, in these mothers, the risk of perinatal/ neonatal mortality [RR 0.82, 95% CI: 0.76, 0.88] was comparatively lower than in mothers under 35 years of age. There appeared no significant risk of advanced maternal age for postpartum haemorrhage, hospitalization during pregnancy and premature rupture of membranes. CONCLUSIONS: The increased risk of maternal, neonatal and perinatal outcomes in mothers with advanced age highlights the need for close follow-up, early detection and management of medical complications in twin pregnancies. [ABSTRACT FROM AUTHOR]

PbO–MgO–Nb2O5–TiO2 (PMNT) pyrochlore thin films were prepared on Pt-coated silicon substrates by radio-frequency magnetron sputtering and postdeposition annealing method. Very interestingly, these pyrochlore-structured PMNT thin films exhibited ultralow dielectric losses, with a typical loss tangent as low as 0.001, and relatively high dielectric constants, typically [variant_greek_epsilon]r∼170. It was found that the relative permittivity slightly but continuously increased upon cooling without any signature of a structural phase transition, displaying a quantum paraelectriclike behavior; meanwhile, the PMNT pyrochlore thin films did not show any noticeable dielectric dispersion in the real part of permittivity over a wide temperature range (77–400 K). Their dielectric responses could, however, be efficiently tuned by applying a dc electric field. A maximum applied bias field of 1 MV/cm resulted in a ∼20% tunability of the dielectric permittivity, giving rise to a fairly large coefficient of the dielectric nonlinearity, ∼2.5×109 J C-4 m-5. Moreover, the PMNT pyrochlore films exhibited superior electrical insulation properties with a relatively high breakdown field (Ebreakdown∼1.5 MV/cm) and a very low leakage current density of about 8.2×10-7 A/cm2 obtained at an electric field intensity as high as 500 kV/cm. [ABSTRACT FROM AUTHOR]

Dielectric properties of Ba0.7Sr0.3TiO3 (BST) thin films, which were prepared on silicon-based substrates by ion beam sputtering and postdeposition annealing method, were systematically investigated in different electrode configurations of metal-insulator-metal and coplanar interdigital capacitors. It was found that a large dielectric anisotropy exists in the films with better in-plane dielectric properties (higher dielectric permittivity and tunability) than those along the out-of-plane direction. The observed anisotropic dielectric responses are explained qualitatively in terms of a thermal strain effect that is related to dissimilar film strains along the in-plane and out-of-plane directions. Another reason for the dielectric anisotropy is due to different influences of the interfacial low-dielectric layer between the BST film and the substrate (metal electrode). [ABSTRACT FROM AUTHOR]

Ba0.7Sr0.3TiO3 (BST) thick films with thickness up to 1 μm were deposited on Pt-coated silicon substrates by ion beam sputtering, followed by an annealing treatment. It is demonstrated that pure well-crystallized perovskite phase could be obtained in thick BST films by a low temperature process (535 °C). The BST thick films show highly tunable dielectric properties with tunability (at 800 kV/cm) up to 51.0% and 66.2%, respectively, for the 0.5 and 1 μm thick films. The relationship between strains and dielectric properties was systematically investigated in the thick films. The results suggest that a comparatively larger tensile thermal in-plane strain (0.15%) leads to the degradation in dielectric properties of the 0.5 μm thick film; besides, strong defect-related inhomogeneous strains (∼0.3%) make the dielectric peaks smearing and broadening in the thick films, which, however, preferably results in high figure-of-merit factors over a wide operating temperature range. Moreover, the leakage current behavior in the BST thick films was found to be dominated by the space-charge-limited-current mechanism, irrespective of the film thickness. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Synovial inflammation plays an important role in the pathogenesis of osteoarthritis (OA), and β4GalT1 has been reported to be involved in the inflammatory process. The aim of our study was to investigate the role of β4GalT1 in the progression of inflammation and analyze the association between β4GalT1 and tumor necrosis factor (TNF)-α in human OA fibroblast-like synoviocytes (FLS). PATIENTS AND METHODS: Primary cultured FLS isolated from OA synovial tissues were cultured, and the levels of β4GalT1, TNF-α, MMP-3, p/t-ERK, p/t-JNK, and p/t-P38 were analyzed by Western blotting. An enzyme-linked immunosorbent assay (ELISA) was performed to measure the secretion of TNF-α, interleukin (IL)-1β, and IL-6 in OA-FLS. Immunofluorescence staining was used to examine the co-localization of β4GalT1 and TNF-α or THY1. RT-PCR was used to detect the transfection efficiency of β4GalT1. RESULTS: The expression of β4GalT1 was increased in OA-FLS. β4GalT1 promoted cell invasion, MMP-3 production, and the secretion of TNF-α, IL-1β, and IL-6. si-TNF-α attenuated the β4GalT1-enhanced cell invasion and inflammatory factor secretion in OA-FLS. Furthermore, β4GalT1 increased autocrine TNF-α signaling in OA-FLS. β4GalT1 knockdown successfully decreased autocrine TNF-α activity, while β4GalT1 overexpression increased autocrine TNF-α activity in OA-FLS. Moreover, β4GalT1 enhanced the ERK, JNK, and P38 MAPK signaling pathways through the induction of autocrine TNF-α signaling in OA-FLS. CONCLUSIONS: β4GalT1 may promote the inflammatory progression of OA-FLS by enhancing autocrine TNF-α signaling. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Allergic rhinitis (AR) is a chronic inflammatory disease. This study aimed to investigate the role of microRNA-155 (miR-155) in type-2 innate lymphoid cells (ILC2s) on AR. PATIENTS AND METHODS: Nasal mucosa tissues and peripheral blood samples were collected. mRNA expression of miR-155, interleukin- 25 (IL-25), and interleukin-33 (IL-33) in nasal mucosa tissues was determined using quantitative Real Time-Polymerase Chain Reaction (qRTPCR). The AR model was established by injecting with murine IL-33. The frequency of ILC2s was quantified using flow cytometry. MiR-155 agomir or antagomir was intranasally administrated to mice. MiR-155 and helper T cell 2 (Th2) cytokines were measured with quantitative Real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) or Western blotting, respectively. Hematoxylin and eosin (HE) staining was used for the histopathological examination. RESULTS: Compared with controls, mRNA levels miR-155 (p<0.001), IL-25 (p<0.05), and IL-33 (p<0.001) were increased in nasal mucosa tissues of AR patients and AR mice, and ILC2s ratios were enhanced in human peripheral blood (p<0.0001), which were much higher after intranasal administration with miR-155 agomir (p<0.0001). MiR-155 expression of AR mice was significantly reduced after intranasal administration with miR-155 antagomir (p<0.05). Frequencies of ILC2s in human peripheral blood significantly correlated with miR- 155 (r=0.4803, p=0.0130). MiR-155 up-regulation markedly increased frequencies of nasal rubbing/sneezing and levels of IL-4, IL-5, IL-9, and IL-13. Pathological changes were worsened after miR- 155 agomir and ameliorated after miR-155 antagomir administration. MiR-155 agomir mice (p<0.001) showed higher ILC2s, whereas lower in miR-155 antagomir mice compared to AR mice (p<0.05). CONCLUSIONS: M iR-155 p layed c ritical e ffects on Th2 factor expression and allergic inflammatory response in ILC2 cells in AR. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Mounting evidence has suggested that microRNAs (miRNAs) play crucial roles in the progression of nasopharyngeal carcinoma (NPC). However, the molecular mechanism remains not fully understood. We aimed to examine the expression and biological function of miR-122-5p in NPC. MATERIALS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction was conducted to examine the expression of miR- 122-5p. Cell Counting Kit-8 assay, colony formation assay, wound healing assay and transwell assay were performed to measure cell proliferation, colony formation, migration and invasion. Luciferase reporter assay and Western blot assay were used to confirm the target gene of miR-122-5p. RESULTS: The results showed that miR-122- 5p was significantly downregulated in NPC cell lines. Additionally, it was demonstrated that special AT-rich sequence-binding protein 1 (SATB1) was targeted by miR-122-5p. Furthermore, our results revealed that miR-122-5p inhibits cell proliferation, colony formation, cell migration and cell invasion by targeting SATB1. CONCLUSIONS: Our data suggested that miR- 122-5p functions as a tumor suppressor and may be a therapeutic target for NPC. [ABSTRACT FROM AUTHOR]