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BackgroundCircular RNAs (circRNAs) are pivotal regulators of various human cancers and circ-ERBB2 is abnormally expressed in breast cancer cells. However, the role and mechanism of circ-ERBB2 in HER2-positive breast cancer are still unknown.MethodsThe circ-ERBB2 expressions in the tumor tissues of HER2-positive breast cancer patients were tested using quantitative real-time PCR. The circ-ERBB2 function was investigated by cell counting kit 8 assay, Transwell, flow cytometry and Western blot. Mechanistically, fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down and dual-luciferase reporter gene assays were conducted to confirm the interaction between circ-ERBB2 and miR-136-5p or miR-198 in HER2-positive breast cancer cells.ResultsCirc-ERBB2 was elevated in the tumor tissues of HER2-positive breast cancer patients. Functionally, the interference with circ-ERBB2 repressed HER2-positive breast cancer cell proliferation, migration, invasion and accelerated cell apoptosis. Furthermore, the mechanistic analysis corroborated that circ-ERBB2 acted as a competing endogenous RNA for miR-136-5p or miR-198 to relieve the repressive influence of miR-136-5p or miR-198 on its target transcription factor activator protein 2C (TFAP2C). Meanwhile, in vivo assays further corroborated the oncogenic function of circ-ERBB2 in HER2-positive breast cancer.ConclusionsCirc-ERBB2 accelerated HER2-positive breast cancer progression through the circ-ERBB2/miR-136-5p/TFAP2C axis or the circ-ERBB2/miR-198/TFAP2C axis.

Severe sepsis is an important cause of mortality and morbidity in critically ill children. Meropenem is a broad-spectrum antibiotic commonly used to treat sepsis. Current meropenem dosage recommendations for children on continuous renal replacement therapy are extrapolated from pharmacokinetic (PK) studies done in adults. Our study aims to determine the optimal dosing in critically ill septic children receiving continuous renal replacement therapy. A prospective single-center PK study was performed in 9 children in the intensive care unit on continuous renal replacement therapy. Meropenem concentrations were measured from blood and effluent fluid samples. A population PK model was developed using nonlinear mixed-effects modeling software (NONMEM, AstraZeneca UK Ltd, Cheshire, UK). Monte Carlo simulations were performed. The PK/pharmacodynamic target aimed for plasma concentrations above minimum inhibitory concentration of 4 mg/L for 100% of dosing interval (100%ƒT>MIC ). A 2-compartment model best characterized meropenem PK. Mean (range) clearance and elimination half-life was 0.091 L/h/kg (0.04-0.157) and 3.9 hours (2.1-7.5), respectively. Dosing of 40 mg/kg/dose every 12 hours over 30 minutes achieved PK/PD target in only 32% while 20 mg/kg every 8 hours over 4 hours or 40 mg/kg every 8 hours over 2 hours achieved 100% ƒT>MIC target for at least 90% of simulated patients.

To explore the effect of smoking on the histological subtype and prognosis of patients with lung adenocarcinoma (LAC) in China.According to the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society(IASLC/ATS/ERS)classification, 266 donors with primary LAC were reclassified. The correlation between clinicopathological factors including smoking status and the histological subtype was analyzed, and survival analysis was used to analyze the prognosis of primary LAC.There were four main histological subtypes including acinar predominant adenocarcinoma (APA) 30.1%, papillary predominant adenocarcinoma (PPA) 26.7%, solid predominant adenocarcinoma (SPA) 25.9%, and lepidic predominant adenocarcinoma (LPA) 11.7%.Smoking was associated with the histological subtype.The proportion of smokers was significantly higher than non-smokers in the SPA group, and the proportion of non-smokers was higher in other subtypes group. Cox regression model showed that the histological subtype and TNM stage were the independent predictors of prognostic in all patients.TNM stage was the predictor of postoperative survival in both smokers and non-smokers, and histological subtypes was the predictor only in smokers (Smoking is associated with SPA subtype, which affect the prognosis of primary LAC.

According to the reclassification of lung adenocarcinoma (LAC) proposed in 2011, solid predominant lung adenocarcinoma (SPA) has been associated with poor outcomes for LAC patients. However, the prognostic value of the presence of solid subtype remains unclear. Besides, there is little data about the roles of microRNA (miRNA) in solid subtype of LAC. In this study, 243 LAC patients were classified into solid subtype positive and negative groups (S+ LAC, n=134 and S- LAC, n=109) according to whether the solid subtype was more than 5% of the tumor component or not. We analyzed the relationship between solid subtype and patients' outcome by univariate and multivariate analyses. Solid subtype was proved to be significantly associated with the 5-year overall survival and played as an independent prognostic factor for stage I-III invasive LAC patients. Then miRNA microarray was used to identify differentially expressed miRNAs in solid subtype, resulting in 31 differential miRNAs. Quantitative reverse transcription-PCR (QRT-PCR) was used to validate 4 key miRNAs (miR-133b, miR-155-5p, miR-124-3p, miR-145-5p). Further, CCK-8 and transwell assays were performed to validate the impact of one dysregulated miRNA (miR-133b) on LAC cell function. Interestingly, while miR-133b could significantly inhibit the proliferation of A549 and SPC-A1, it showed no effect on the migration or invasion of LAC cell lines. These results suggest that solid subtype can exert independent prognostic impact on LAC patients, and 4 important dysregulated miRNAs in solid subtype of LAC may be involved in the malignancy of S+LAC, thus may further have clinical perspective for S+ LAC in the future.

The joint observation of GW170817 and GRB 170817A indicated that short gamma-ray bursts (SGRBs) can originate from binary neutron star mergers. Moreover, some SGRBs could be detected off-axis, while the SGRB jets are highly structured. Then, by assuming an universal angular distribution of the jet emission for all SGRBs, we re-produce the flux and redshift distributions of the cosmological SGRBs detected by {\it Swift} and {\it Fermi}. For self-consistency, this angular distribution is simultaneously constrained by the luminosity and event rate of GRB 170817A. As a result, it is found that the universal jet structure of SGRBs could approximately have a two-Gaussian profile. Meanwhile, the intrinsic luminosity function (LF) of the on-axis emission of the jets can be simply described by a single power law with a low-luminosity exponential cutoff. The usually discovered broken-power-law apparent LF for relatively high luminosities can naturally result from the coupling of the intrinsic LF with the angular distribution of the jet emission, as the viewing angles to the SGRBs are arbitrarily distributed., Comment: 9 pages, 8 figures, accepted for publication in ApJ

By employing a simple semi-analytical star formation model where the formation rates of Population (Pop) I/II and III stars can be calculated, respectively, we account for the number distribution of gamma-ray bursts (GRBs) with high pseudo-redshifts that was derived from an empirical luminosity-indictor relationship. It is suggested that a considerable number of Pop III GRBs could exist in the present sample of Swift GRBs. By further combining the implication for the star formation history from the optical depth of the CMB photons, it is also suggested that only a very small fraction 0.6% of Pop III GRBs could have triggered the Swift BAT. These results could provide an useful basis for estimating future detectability of Pop III stars and their produced transient phenomena., 5 pages, 3 figures, 1 table, accepted for publication in New Astronomy

Mergers of compact binaries, such as binary neutron stars (BNSs), neutron star-black hole binaries (NSBHs), and binary black holes (BBHs), are expected to be the best candidates for the sources of gravitational waves (GWs) and the leading theoretical models for short gamma-ray bursts (SGRBs). Based on the observations of SGRBs, we could derive the merger rates of these compact binaries, and study the stochastic GW backgrounds (SGWBs) or the co-detection rates of GWs associate with SGRBs (GW-SGRBs). But before that, the most important thing is to derive the GW spectrum from a single GW source. Usually, GW spectrum from a circular orbit binary is assumed. However, observations of the large spatial offsets of SGRBs from their host galaxies imply that SGRB progenitors may be formed by the dynamical processes, and will merge with residual eccentricities. The orbital eccentricity has important effect on GW spectra, and therefore on the SGWB and GW-SGRB co-detection rate. Our results show that the power spectra of the SGWBs from eccentric compact binaries are greatly suppressed at low frequencies. Especially, SGWBs from binaries with high residual eccentricities will hard to be detected (above the detection frequency of $\sim100~\rm Hz$). For the co-detection rates of GW-SGRB events, they could be $\sim1.4$ times higher than the circular case within some particular ranges of $e_{\rm r}$ , but greatly reduced for high residual eccentricities (e.g., $e_{\rm r}>0.1$ for BNSs). In general, the BBH progenitors produce 200 and 10 times higher GW-SGRB events than the BNS and NSBH progenitors, respectively. Therefore, binaries with low residual eccentricities and high total masses will easier to be detected by aLIGO., 9 pages, 4 figures, 1 table, accepted by MNRAS

BACKGROUND A population pharmacokinetic model for phenytoin in Asian pediatric patients was developed to determine the influence of concurrent medications, patient demographics, and blood biochemistry on the pharmacokinetic profile of phenytoin. METHODS Retrospective clinical data were obtained from 66 patients (age, 1-16 years) for the determination of pharmacokinetic parameters of phenytoin using WinNonmix. Data from 49 patients (74.2%) were allocated in the "index" group, and the other 17 patients (25.8%) in the "validation" group. Models were compared by final log likelihood, mean error as a measure of bias, and root-mean-squared error as a measure of precision. RESULTS The Michaelis-Menten constant (km) and volume of distribution (V) were fixed at 9.08 mg/L and 1.23 L/kg, respectively. The saturated elimination rate (V × Vmax) of phenytoin was then found to be 0.525 mg/kg per hour (352.9 4 mg/d for a 28.0 kg individual). Patients' body surface area (in square meter) and catalytic activities of liver enzymes aspartate aminotransferase (U/L) and alkaline phosphatase (U/L) appeared to have significant correlation with Vmax, whereas coadministrating drugs with phenytoin did not yield any significant effect. The final model for the saturated elimination rate was (Equation is included in full-text article.) In validation of the final model, the mean error was found to be -0.805 (95% confidence interval, -3.67 to 2.06), and the root-mean-squared error was 7.92 (95% confidence interval, 3.41-12.43). CONCLUSIONS The obtained results indicated the need to consider patients' body surface area and the catalytic activities of liver enzymes aspartate aminotransferase and alkaline phosphatase when dosing phenytoin. Based on the population pharmacokinetic parameters, a nomogram was subsequently developed for dose individualization of phenytoin in Asian pediatric patients.

Purpose In light of the increasing usage of the newer antiepileptic drugs (AEDs) in other countries, we reviewed the prescribing pattern of AEDs in Singapore over the last 10 years (2000–2009). Methods A retrospective review of pharmacy dispensing records solicited from the only children's hospital in Singapore was performed to analyze the trend in AEDs prescribing in the last 10 years. We also examined the correlation between the serum concentrations of valproic acid (VPA), the most-prescribed AED, and seizure control. Descriptive and inferential statistical analyses were then performed on the findings. Results A total of 41 671 prescriptions on AEDs were retrieved and analyzed. Despite the introduction of the second-generation AEDs, the first generation AEDs still dominate epilepsy treatment in Asian children, with VPA being the mostly prescribed AED (about 40% of the total AEDs usage). The majority of patients (62.8%) were on monotherapy. The mean VPA serum concentration in patients with good seizure control was 68.6 µg/ml (SD = 26.4 µg/ml; range = 12.2–138.0 µg/ml), which was statistically higher than the mean VPA concentration of 57.7 µg/ml (SD = 27.1 µg/ml; range = 11.1-149.0 µg/ml) in patients with poor seizure control (p

In this paper, a generalization of the positive-definite and skew-Hermitian splitting (GPSS) iteration is considered for solving non-Hermitian and positive definite systems of linear equations. Theoretical analysis shows that the GPSS method converges unconditionally to the exact solution of the linear system, with the upper bound of its convergence factor dependent only on the spectrum of the positive-definite splitting matrices. In some situations, this new scheme can outperform the Hermitian and skew-Hermitian splitting (HSS) method, the positive-definite and skew-Hermitian splitting (PSS) method, and the generalized HSS method (GHSS) and can be used as an efficient preconditioner. Numerical experiments using discretization of convection-diffusion-reaction equations demonstrate the effectiveness of the new method.

We study the redshift evolution of the luminosity function (LF) and redshift selection effect of long gamma-ray bursts (LGRBs). The method is to fit the observed peak flux and redshift distributions, simultaneously. To account for the complex triggering algorithm of Swift, we use a flux triggering efficiency function. We find evidence supporting an evolving LF, where the break luminosity scales as $L_b\propto (1+z)^{\tau}$, with $\tau =3.5^{+0.4}_{-0.2}$ and $\tau =0.8^{+0.1}_{-0.08}$ for two kind of LGRB rate models. The corresponding local GRB rates are $\dot{R}(0)=0.86^{+0.11}_{-0.08} \yr^{-1}\Gpc^{-3}$ and $\dot{R}(0)= 0.54^{+0.25}_{-0.07} \yr^{-1}\Gpc^{-3}$, respectively. Furthermore, by comparing the redshift distribution between the observed one and our mocked one, we find that the redshift detection efficiency of the flux triggered GRBs decreases with redshift. Especially, a great number of GRBs miss their redshifts in the redshift range of $1, Comment: 8 pages, 4 figures, 1 table, accepted by MNRAS

Febrile illness-related epilepsy syndrome is a catastrophic epileptic encephalopathy that is highly refractory to most antiepileptic drugs leading to high morbidity and mortality. The authors report the use of a pediatric infusion protocol of continuous intravenous magnesium sulfate for the control of seizures in 2 children with febrile illness-related epilepsy syndrome refractory to multiple antiepileptic drugs in a pediatric intensive care unit of a tertiary care children’s hospital. Both patients, 2 and 16 years of age, respectively, were treated with continuous magnesium sulfate infusion. Serum magnesium concentrations ranging from 2.1 to 5 mmol/L were achieved. Seizure reduction and cessation were noted in 1 patient with magnesium more than 3.0 mmol/L. No significant adverse effects were observed. Magnesium sulfate infusions can be safely used in pediatric refractory status epilepticus. Magnesium sulfate can be considered in the management of children with febrile illness-related epilepsy syndrome.

The development of metastases involves the dissociation of cells from the primary tumor, penetrating the basement membrane, invasion and exiting from the vasculature to seed, and finally colonizing in distant tissues. The formation of brain metastasis (BM) in lung adenocarcinoma remains poorly understood. We examined the differential microRNA (miRNA) expression profiles of 5 primary and 3 brain metastatic lung adenocarcinoma samples by Agilent miRNA Microarrays. Five upregulated miRNAs (miRs-9*, -1471, 718, 3656, 720) and 3 downregulated miRNAs (miRs-214, -145 and -23a) were detected. The 4 most significantly deregulated miRNAs (miR-145, miR-214, miR-9* and miR-1471) were validated in the additional 43 samples (35 primary and 8 brain metastatic lung adenocarcinoma samples) using TaqMan quantitative PCR. By functional assay, we found that the expression of miR-145 can regulate the ability of proliferation of A549 and SPC-A1 cells in vitro, but is not related to lymph node metastasis, migration and invasion. These results suggest that miR-145 may have a cell type-specific function and play important roles in the process of BM from lung adenocarcinoma.

The determination of luminosity function (LF) of gamma-ray bursts (GRBs) is of an important role for the cosmological applications of the GRBs, which is however hindered seriously by some selection effects due to redshift measurements. In order to avoid these selection effects, we suggest to calculate pseudo-redshifts for Swift GRBs according to the empirical L-E_p relationship. Here, such a $L-E_p$ relationship is determined by reconciling the distributions of pseudo- and real redshifts of redshift-known GRBs. The values of E_p taken from Butler's GRB catalog are estimated with Bayesian statistics rather than observed. Using the GRB sample with pseudo-redshifts of a relatively large number, we fit the redshift-resolved luminosity distributions of the GRBs with a broken-power-law LF. The fitting results suggest that the LF could evolve with redshift by a redshift-dependent break luminosity, e.g., L_b=1.2\times10^{51}(1+z)^2\rm erg s^{-1}. The low- and high-luminosity indices are constrained to 0.8 and 2.0, respectively. It is found that the proportional coefficient between GRB event rate and star formation rate should correspondingly decrease with increasing redshifts., 5 pages, 5 figures, accepted for publication in ApJL

We constrain the warm dark matter (WDM) particle mass with the observations of cosmic reionization and CMB optical depth. We suggest that the GWs from stellar mass black holes (BHs) could give a further constraint on WDM particle mass for future observations. The star formation rates (SFRs) of Population I/II (Pop I/II) and Population III (Pop III) stars are also derived. If the metallicity of the universe have been enriched beyond the critical value of $Z_{\rm crit}=10^{-3.5}Z_{\odot}$, the star formation shift from Pop III to Pop I/II stars. Our results show that the SFRs are quite dependent on the WDM particle mass, especially at high redshifts. Combing with the reionization history and CMB optical depth derived from the recent \emph{Planck} mission, we find that the current data requires the WDM particle mass in a narrow range of $1 < m_x < 3$ keV. Furthermore, we suggest that the stochastic gravitational wave background (SGWB) produced by stellar BHs could give a further constraint on the WDM particle mass for future observations. For $m_{x}=3$ keV with Salpeter (Chabrier) initial mass function (IMF), the SGWB from Pop I/II BHs has a peak amplitude of $��_{\rm GW}\approx2.8\times 10^{-9}~(5.0\times 10^{-9})$ at $f= 316 {\rm Hz}$, while the GW radiation at $f, 11 pages, 5 figures, accepted for publication in ApJ

By phenomenologically describing the high-redshift star formation history, i.e., $\dot{\rho}_{*}(z)\propto[(1+z)/4.5]^{-\alpha}$, and semi-analytically calculating the fractions of high-redshift Pop I/II and Pop III stars, we investigate the contributions from both high-redshfit Pop I/II and Pop III stars to the observed near-infrared ($3 \mu\rm m, Comment: 6 pages, 5 figures, published in SCIENCE CHINA Physics, Mechanics and Astronomy

In light of the increasing usage of the newer antiepileptic drugs (AEDs) in other countries, we reviewed the prescribing pattern of AEDs in Singapore over the last 10 years (2000-2009).A retrospective review of pharmacy dispensing records solicited from the only children's hospital in Singapore was performed to analyze the trend in AEDs prescribing in the last 10 years. We also examined the correlation between the serum concentrations of valproic acid (VPA), the most-prescribed AED, and seizure control. Descriptive and inferential statistical analyses were then performed on the findings.A total of 41 671 prescriptions on AEDs were retrieved and analyzed. Despite the introduction of the second-generation AEDs, the first generation AEDs still dominate epilepsy treatment in Asian children, with VPA being the mostly prescribed AED (about 40% of the total AEDs usage). The majority of patients (62.8%) were on monotherapy. The mean VPA serum concentration in patients with good seizure control was 68.6 µg/ml (SD = 26.4 µg/ml; range = 12.2-138.0 µg/ml), which was statistically higher than the mean VPA concentration of 57.7 µg/ml (SD = 27.1 µg/ml; range = 11.1-149.0 µg/ml) in patients with poor seizure control (p 0.0001).With VPA being the most prescribed AED in our clinical practice, and the finding in this study that with careful classification of the patients' condition, serum concentrations of VPA generally correlate well with the seizure control, the correct dose titration of VPA with therapeutic drug monitoring is still of paramount importance.

Febrile illness-related epilepsy syndrome is a catastrophic epileptic encephalopathy that is highly refractory to most antiepileptic drugs leading to high morbidity and mortality. The authors report the use of a pediatric infusion protocol of continuous intravenous magnesium sulfate for the control of seizures in 2 children with febrile illness-related epilepsy syndrome refractory to multiple antiepileptic drugs in a pediatric intensive care unit of a tertiary care children’s hospital. Both patients, 2 and 16 years of age, respectively, were treated with continuous magnesium sulfate infusion. Serum magnesium concentrations ranging from 2.1 to 5 mmol/L were achieved. Seizure reduction and cessation were noted in 1 patient with magnesium more than 3.0 mmol/L. No significant adverse effects were observed. Magnesium sulfate infusions can be safely used in pediatric refractory status epilepticus. Magnesium sulfate can be considered in the management of children with febrile illness-related epilepsy syndrome.