Autophagy is a potential target for the treatment of triple negative breast cancer (TNBC). Because of a lack of targeted therapies for TNBC, it is vital to find optimal agents that avoid ...chemoresistance and metastasis. Flavopereirine has anti-proliferation ability in cancer cells, but whether it regulates autophagy in breast cancer cells remains unclear. A Premo™ Tandem Autophagy Sensor Kit was used to image the stage at which flavopereirine affects autophagy by confocal microscopy. A plasmid that constitutively expresses p-AKT and siRNA targeting p38 mitogen-activated protein kinase (MAPK) was used to confirm the related signaling pathways by Western blot. We found that flavopereirine induced microtubule-associated protein 1 light chain 3 (LC3)-II accumulation in a dose- and time-dependent manner in MDA-MB-231 cells. Confocal florescent images showed that flavopereirine blocked autophagosome fusion with lysosomes. Western blotting showed that flavopereirine directly suppressed p-AKT levels and mammalian target of rapamycin (mTOR) translation. Recovery of AKT phosphorylation decreased the level of p-p38 MAPK and LC3-II, but not mTOR. Moreover, flavopereirine-induced LC3-II accumulation was partially reduced in MDA-MB-231 cells that were transfected with p38 MAPK siRNA. Overall, flavopereirine blocked autophagy via LC3-II accumulation in autophagosomes, which was mediated by the AKT/p38 MAPK signaling pathway.
Neutrophil extracellular traps (NETs) are net-like chromatin fibers that can trap and kill microorganisms. Although several anti-inflammatory effects of intravenous anesthetics have been reported, it ...has not been investigated whether intravenous anesthetics influence NET formation.
To compare the effects of four intravenous anesthetics (propofol, thiamylal sodium, midazolam, and ketamine) on phorbol myristate acetate (PMA)-induced NET formation and analyze the associated signaling pathways.
PMA-stimulated NETs formed in the absence or presence of intravenous anesthetics were stained with SYTOX Green and then quantified. Inhibitors were applied to investigate the related mechanism, which was confirmed by western blotting, and ROS were detected.
The neutrophils incubated with propofol showed the lowest degree of NET formation compared with those incubated with the other intravenous anesthetics. Propofol significantly reduced the level of myeloperoxidase (MPO)-derived HOCl but not that of superoxide. Aminopyrine, an MPO inhibitor, markedly decreased the number of PMA-induced NETs, indicating the involvement of HOCl in the inhibitory effect of propofol on NET formation. According to western blotting results, the level of p-ERK was reduced by propofol during PMA-induced NET formation. The ERK inhibitor PD98059 decreased NET formation but did not inhibit PMA-induced HOCl generation, and aminopyrine did not reduce ERK phosphorylation.
Through this study, we define a new anti-inflammatory effect of intravenous anesthetics. Of the four intravenous anesthetics tested, propofol was the most potent inhibitor of NET formation. Moreover, propofol resulted in a decrease in PMA-induced NET formation by two independent mechanisms: inhibition of HOCl and p-ERK.
Staphylococcus lugdunensis can cause community- and healthcare-associated infections. This study investigated the molecular characteristics of S. lugdunensis isolates collected at our hospital and ...compared the characteristics of the infectious and commensal isolates.
We collected the S. lugdunensis isolates between 2003 and 2013. The antimicrobial resistance test, SCCmec typing, accessory gene regulator (agr) typing, pulsed-field gel electrophoresis (PFGE), and δ-like hemolysin activity were performed.
In total, 118 S. lugdunensis isolates were collected, of which 67 (56.8%) were classified into the infection group and 51 (43.2%) into the commensal group. The oxacillin resistance rate was 36.4%. The most common SCCmec types were SCCmec types V (51.4%) and II (32.6%). In total, 34 pulsotypes were identified. The PFGE typing revealed five clones (pulsotypes A, J, M, N, and P) at our hospital. Pulsotypes A and N caused the spread of high oxacillin resistance. In total, 10.2% (12 of 118) of the isolates lacked δ-like hemolysin activity. Compared with the infection group, the commensal group showed a higher percentage of multiple drug resistance and carried a higher percentage of SCCmec type II (11 of 22, 50% and 3 of 21, 14.3%) and a lower percentage of SCCmec type V (8 of 22, 36.4% and 14 of 21, 66.7%). The commensal group (27 PFGE types) showed higher genetic diversity than did the infection group (20 PFGE types). No difference was observed in the distribution of the five main pulsotypes, agr typing, and the presence of δ-like hemolysin activity between the two groups.
Five main clones were identified at our hospital. The commensal group showed higher genetic diversity, had a higher percentage of multidrug resistance, and carried a higher percentage of SCCmec type II and a lower percentage of SCCmec type V than did the infection group.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Exogenous arginine is required for growth in some argininosuccinate synthetase (ASS)-deficient cancers. Arginine deiminase (ADI) inhibits growth in various ASS-deficient cancers by depleting ...arginine. The efficacy of pegylated ADI (ADI-PEG20) in relapsed/refractory/poor-risk acute myeloid leukemia (AML) was evaluated in 43 patients in a prospective, phase II trial (NCT01910012 (10/07/2013), https://clinicaltrials.gov/ct2/show/NCT01910012?term = ADI-PEG20&rank = 12 ). Despite almost all pre-treatment tumor samples showing ASS deficiency, the best response among 21 evaluable patients was complete response (CR) in 2 (9.5%) and stable disease in 7 (33.3%), yielding a disease control rate (DCR) of 42.9%. The response durations of the two patients with CR were 7.5 and 8.8 months. DCR was correlated with a median of 8 weeks of arginine depletion to ≤10 μM. Using whole transcriptome sequencing, we compared gene expression profiling of pre- and post-treatment bone marrow samples of the two responders and three non-responders. The expression levels of some markers for AML subtypes and c-MYC regulated genes were considered potential predictors of response to ADI-PEG20. These results suggest that ASS deficiency is a prerequisite but not a sufficient condition for response to ADI-PEG20 monotherapy in AML. Predictive biomarkers and mechanistic explorations will be critical for identifying appropriate patients for future AML trials of ADI-PEG20.
Endothelial nitric oxide synthase (eNOS) is localized in caveole and has important effects on caveolar coordination through its interaction with caveolin-1 (Cav-1), which supports normal functioning ...of vascular endothelial cells. However, the relationship between genotypic polymorphisms of e-NOS and Cav-1 genes and ischemic stroke (IS) remains lesser reported. This hospital-based case-control study aimed to determine the genetic polymorphisms of the eNOS (Glu298Asp) and Cav-1 (G14713A and T29107A) genes in association with susceptibility risk in patients who had suffered from a large artery atherosclerotic (LAA) stroke. Genotyping determination for these variant alleles was performed using the TaqMan assay. The distributions of observed allelic and genotypic frequencies for the polymorphisms were in Hardy-Weinberg equilibrium in healthy controls. The risk for an LAA stroke in the Asp298 variant was 1.72 (95% CI = 1.09-2.75) versus Glu298 of the eNOS. In the GA/AA (rs3807987) variant, it was 1.79 (95% CI = 1.16-2.74) versus GG and in TA/AA (rs7804372) was 1.61 (95% CI = 1.06-2.43) versus TT of the Cav-1, respectively. A tendency toward an increased LAA stroke risk was significant in carriers with the eNOS Glu298Asp variant in conjunction with the G14713 A and T29107A polymorphisms of the Cav-1 (aOR = 2.03, P-trend = 0.002). A synergistic effect between eNOS and Cav-1 polymorphisms on IS risk elevation was significantly influenced by alcohol drinking, heavy cigarette smoking (P-trend<0.01), and hypercholesterolemia (P-trend < 0.001). In conclusion, genotypic polymorphisms of the eNOS Glu298Asp and Cav-1 14713A/29107A polymorphisms are associated with the elevated risk of LAA stroke among Han Chinese in Taiwan.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A simulation scheme was developed to explore the light distribution of full-color micron-scale light-emitting diode (LED) arrays. The influences of substrate thickness, patterning, and cutting angle ...of the substrate on several important features, such as light field pattern, light extraction efficiency, and color variation, were evaluated numerically. An experiment was conducted; the results were consistent with simulation results for a 225 × 125 µm
miniLED and those for an 80 × 80 µm
microLED. Based on the simulation results, the light extraction efficiency of LED devices with a substrate increases by 67.75% over the extraction efficiency of those without a substrate. The light extraction efficiency of LED devices with a substrate increases by 113.55% when an additional patterned design is used on green and blue chips. The calculated large angle Δu'v' can be as low as 0.015 for miniLED devices.
Plasma efavirenz concentrations in HIV-infected patients with tuberculosis (TB) may be affected by cytochrome P450 (CYP) 2B6 single-nucleotide polymorphisms and concurrent rifampicin use. We aimed to ...investigate the effects of CYP2B6 G516T polymorphisms and concomitant rifampicin use on the plasma efavirenz concentrations in HIV-infected Taiwanese.
HIV-infected patients with or without TB who had received combination antiretroviral therapy containing efavirenz (600 mg daily) for two weeks or greater were enrolled for determinations of CYP2B6 G516T polymorphism and plasma efavirenz concentrations with the use of polymerase-chain-reaction restriction fragment-length polymorphism and high-performance liquid chromatography, respectively.
From October 2009 to August 2012, 171 HIV-infected patients, including 18 with TB, were enrolled 113 (66.1%) with CYP2B6 G516G, 55 (32.2%) GT, and 3 (1.8%) TT genotype. Patients receiving rifampicin had a significantly lower median plasma efavirenz concentration than the control group (2.16 vs 2.92 mg/L, P = 0.003); however, all patients achieved target plasma concentration (>1 mg/L). Patients with GT or TT genotype had a significantly higher plasma concentration than those with GG genotype (2.50 vs 3.47 mg/L for GT genotype and 8.78 mg/L for TT genotype, P<0.001). Plasma efavirenz concentration >4 mg/L was noted in 38 (22.2%) patients, which was associated with a lower weight (per 10-kg increase, odds ratio, 0.52; 95% confidence interval, 0.33-0.83) and GT or TT genotype (odds ratio, 4.35; 95% confidence interval, 1.97-9.59) in multivariate analysis.
Despite combination with rifampicin, sufficient plasma efavirenz concentrations can be achieved in HIV-infected Taiwanese with TB who receive efavirenz 600 mg daily. Carriage of CYP2B6 516 GT and TT genotypes and a lower weight are associated with higher plasma efavirenz concentrations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Sequential addition of tenofovir disoproxil fumarate (TDF) is often needed for patients coinfected with HIV and hepatitis B virus (HBV) who develop HBV resistance to lamivudine after combination ...antiretroviral therapy (cART) containing only lamivudine for HBV. We aimed to assess the virological response of HBV to add-on TDF in patients coinfected with lamivudine-resistant HBV.
Between November 2010 and December 2014, 33 HIV/HBV-coinfected patients with lamivudine-resistant HBV and 56 with lamivudine-susceptible HBV were prospectively included. TDF plus lamivudine was used to substitute zidovudine or abacavir plus lamivudine contained in cART in patients with lamivudine-resistant HBV infection, while patients with lamivudine-susceptible HBV infection received TDF plus lamivudine as backbone of cART. Serial determinations of plasma HBV DNA load, HBV serologic markers, and liver and renal functions were performed after initiation of TDF-containing cART.
Of 89 patients included, 38.6% tested positive for HBV envelope antigen (HBeAg) at baseline. The plasma HBV DNA level at enrollment of lamivudine-resistant and lamivudine-susceptible group were 6.1 ± 2.2 log10 and 6.0 ± 2.2 log10 copies/mL, respectively (p = 0.895). The cumulative percentage of HBV viral suppression in lamivudine-resistant and lamivudine-susceptible group was 81.8% and 91.1% at 48 weeks, respectively (p = 0.317), which increased to 86.7% and 96.2% at 96 weeks, respectively (p = 0.185). At 48 weeks, 11 patients testing HBeAg-positive at baseline failed to achieve viral suppression. In multivariate analysis, the only factor associated with failure to achieve viral suppression at 48 weeks was higher HBV DNA load at baseline (odds ratio, per 1-log10 copies/mL increase, 1.861; 95% CI, 1.204-2.878). At 48 weeks, HBeAg seroconversion was observed in 5 patients (1 in the lamivudine-resistant group and 4 in the lamivudine-susceptible group; p = 0.166). During the study period, HBsAg levels decreased over time, regardless of lamivudine resistance. Loss of HBsAg was observed in 3 (3.4%) patients in the lamivudine-susceptible group.
Add-on TDF-containing cART in patients coinfected with lamivudine-resistant HBV achieved a similar rate of HBV viral suppression compared to TDF-containing cART as initial regimen in patients coinfected with lamivudine-susceptible HBV. A higher baseline HBV DNA load and HBeAg positivity were associated with failure to achieve HBV viral suppression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Using electronic devices before bedtime impacts sleep quality and has become a major public health issue. This study aims to investigate the associations between electronic devices (EDs) use before ...bedtime and sleep quality in Vietnamese university students. A total of 369 university students from three departments were recruited. Participants completed self-report surveys, including demographic characteristics, lifestyle, ED-use behaviors, the Pittsburgh Sleep Quality Index, and the Center for Epidemiologic Studies Depression Scale. A total of 48.8% of the students experienced poor sleep quality, and 98.1% reported using at least one type of ED every day within two hours before bedtime. Smartphones are the most used devices (92.3%). ED usage within two hours before bedtime (p = 0.031), lack of exercise (p = 0.006), alcohol consumption (p = 0.025), and coffee intake after 4 pm (p = 0.018) were associated with poor sleep quality. ED use near bedtime for a duration longer than 30 min (p = 0.001) and depression (p < 0.001) were associated with poorer sleep quality among university students. ED use near bedtime more than 30 min was significantly associated with poorer sleep quality after adjusting depression status, exercise, and caffeine/alcohol intake in the latter part of the day. This study emphasizes the importance of adequate sleep and restriction of ED use near bedtime, which are necessary for better sleep in university students.
Superspreading events (SSEs) are pivotal in the spread of SARS-CoV-2. This study aimed to investigate an SSE of COVID-19 in a hospital and explore the transmission dynamics and heterogeneity of SSE.
...We performed contact tracing for all close contacts in a cluster. We did nasopharyngeal or throat swabbing for SARS-CoV-2 by real-time RT-PCR. Environmental survey was performed. The epidemiological and clinical characteristics of the SSE were studied.
Patient 1 with congestive heart failure and cellulitis, who had onset of COVID-19 two weeks after hospitalization, was the index case. Patient 1 led to 8 confirmed cases, including four health care workers (HCW). Persons tested positive for SARS-CoV-2 were HCW (n = 4), patient 1's family (n = 2), an accompanying person of an un-infected in-patient (n = 1), and an in-patient admitted before the SSE (n = 1). The attack rate among the HCW was 3.2 % (4/127). Environmental survey confirmed contamination at the bed rails, mattresses, and sink in the room patient 1 stayed, suggesting fomite transmission. The index case's sputum remained positive on illness day 35. Except one asymptomatic patient, at least three patients acquired the infection from the index case at the pre-symptomatic period. The effective reproduction number (Rt) was 0.9 (8/9).
The host factor (heart failure, longer viral shedding), transmissibility of SARS-CoV-2 (Rt, pre-symptomatic transmission), and possible multiple modes of transmission altogether contributed to the SSE. Rapid response and advance deployment of multi-level protection in hospitals could mitigate COVID-19 transmission to one generation, thereby reducing its impact on the healthcare system.
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