Particle-Filter-Based Fault Diagnosis for the Startup Process of an Open-Cycle Liquid-Propellant Rocket Engine.

This study introduces a fault diagnosis algorithm based on particle filtering for open-cycle liquid-propellant rocket engines (LPREs). The algorithm serves as a model-based method for the startup process, accounting for more than 30% of engine failures. Similar to the previous fault detection and diagnosis (FDD) algorithm for the startup process, the algorithm in this study is composed of a nonlinear filter to generate residuals, a residual analysis, and a multiple-model (MM) approach to detect and diagnose faults from the residuals. In contrast to the previous study, this study makes use of the modified cumulative sum (CUSUM) algorithm, widely used in change-detection monitoring, and a particle filter (PF), which is theoretically the most accurate nonlinear filter. The algorithm is confirmed numerically using the CUSUM and MM methods. Subsequently, the FDD algorithm is compared with an algorithm from a previous study using a Monte Carlo simulation. Through a comparative analysis of algorithmic performance, this study demonstrates that the current PF-based FDD algorithm outperforms the algorithm based on other nonlinear filters.

How to improve data quality in dog eye tracking.

Pupil-corneal reflection (P-CR) eye tracking has gained a prominent role in studying dog visual cognition, despite methodological challenges that often lead to lower-quality data than when recording from humans. In the current study, we investigated if and how the morphology of dogs might interfere with tracking of P-CR systems, and to what extent such interference, possibly in combination with dog-unique eye-movement characteristics, may undermine data quality and affect eye-movement classification when processed through algorithms. For this aim, we have conducted an eye-tracking experiment with dogs and humans, and investigated incidences of tracking interference, compared how they blinked, and examined how differential quality of dog and human data affected the detection and classification of eye-movement events. Our results show that the morphology of dogs' face and eye can interfere with tracking methods of the systems, and dogs blink less often but their blinks are longer. Importantly, the lower quality of dog data lead to larger differences in how two different event detection algorithms classified fixations, indicating that the results of key dependent variables are more susceptible to choice of algorithm in dog than human data. Further, two measures of the Nyström & Holmqvist (Behavior Research Methods, 42(4), 188-204, 2010) algorithm showed that dog fixations are less stable and dog data have more trials with extreme levels of noise. Our findings call for analyses better adjusted to the characteristics of dog eye-tracking data, and our recommendations help future dog eye-tracking studies acquire quality data to enable robust comparisons of visual cognition between dogs and humans.

Eye tracking: empirical foundations for a minimal reporting guideline.

In this paper, we present a review of how the various aspects of any study using an eye tracker (such as the instrument, methodology, environment, participant, etc.) affect the quality of the recorded eye-tracking data and the obtained eye-movement and gaze measures. We take this review to represent the empirical foundation for reporting guidelines of any study involving an eye tracker. We compare this empirical foundation to five existing reporting guidelines and to a database of 207 published eye-tracking studies. We find that reporting guidelines vary substantially and do not match with actual reporting practices. We end by deriving a minimal, flexible reporting guideline based on empirical research (Section "An empirically based minimal reporting guideline").

Stable maintenance of the Mre11-Rad50-Nbs1 complex is sufficient to restore the DNA double-strand break response in cells lacking RecQL4 helicase activity.

The proper cellular response to DNA double-strand breaks (DSBs) is critical for maintaining the integrity of the genome. RecQL4, a DNA helicase of which mutations are associated with Rothmund-Thomson syndrome (RTS), is required for the DNA DSB response. However, the mechanism by which RecQL4 performs these essential roles in the DSB response remains unknown. Here, we show that RecQL4 and its helicase activity are required for maintaining the stability of the Mre11-Rad50-Nbs1 (MRN) complex on DSB sites during a DSB response. We found using immunocytochemistry and live-cell imaging that the MRN complex is prematurely disassembled from DSB sites in a manner dependent upon Skp2-mediated ubiquitination of Nbs1 in RecQL4-defective cells. This early disassembly of the MRN complex could be prevented by altering the ubiquitination site of Nbs1 or by expressing a deubiquitinase, Usp28, which sufficiently restored homologous recombination repair and ATM, a major checkpoint kinase against DNA DSBs, activation abilities in RTS, and RecQL4-depleted cells. These results suggest that the essential role of RecQL4 in the DSB response is to maintain the stability of the MRN complex on DSB sites and that defects in the DSB response in cells of patients with RTS can be recovered by controlling the stability of the MRN complex.

ATM activation is impaired in human cells defective in RecQL4 helicase activity.

RecQL4 has been shown to be involved in DNA replication and repair, but its role in DNA damage checkpoint pathway has not been reported. Here, we show that RecQL4 plays an important role in the activation of ataxia telangiectasia mutated (ATM)-dependent checkpoint pathway in human cells. Cells depleted with RecQL4 or Rothmund-Thomson syndrome cells showed significant impairment in the activation of ATM and the downstream effector proteins such as checkpoint kinase 2 and p53 after DNA damage. This defect was recovered with the expression of wild type RecQL4 but not any mutant RecQL4 proteins with defective helicase activities. While RecQL4 failed to show any direct interaction with ATM, it stably interacted with the Mre11-Rad50-Nbs1 complex that is essential for the activation of ATM and was localized on the DNA damage foci. Thus, our results suggest that the helicase activity of RecQL4 plays an important role in the activation of ATM-dependent checkpoint pathway against DNA double strand breaks in human cells.

Porous Silicone Polymeric Composites Filled with Hollow Silica Particles: Thermal Conductivity, Thermal Stability and Mechanical Properties.

Porous silicone composites containing different types and volume fractions of hollow silica particles (HSPs) were prepared and characterized in terms of thermal insulation performance, thermal stability, and tensile and dynamic mechanical properties. The comparative study on measured and theoretical thermal conductivity of porous silicone/HSP composites was performed. Dependence of shell thickness, defined as the ratio (η) of internal (ri) to outer (r0) radius, and volume fraction (Φ) of HSPs on the thermal insulation performance of composites was predicted theoretically by Felske model. Tensile properties and dynamic mechanical measurements showed the incorporation of HSPs led to mechanical reinforcement in the silicone composites. Theh Guth and Gold equation showed mechanical reinforcement of porous silicone/HSP composites was primarily due to the hydrodynamic effect of HSPs in the silicone matrix at low HSP contents (Φ < 0.5).

Gentamicin-intercalated smectite as a new therapeutic option for Helicobacter pylori eradication.

Objectives: Novel antibacterial strategies against Helicobacter pylori are needed because H. pylori strains are acquiring resistance to antibiotics. We evaluated the efficacy of gentamicin-intercalated smectite hybrid (S-GEN)-based treatment regimens in a murine model of H. pylori infection. Methods: Two groups of 10 rats were administered either smectite or S-GEN to measure coverage of the gastric mucosa. To evaluate anti-H. pylori efficacy, mice were divided into eight groups of 10 mice each given different treatments, and H. pylori eradication was assessed by a Campylobacter-like organism (CLO) test and H. pylori PCR of the gastric mucosa, and H. pylori antigen and H. pylori PCR analysis of mouse faeces. The levels of proinflammatory cytokines were examined. Results: S-GEN was retained in the gastric mucosal layer with a >60% distribution ratio for up to 1 h, and the S-GEN-based triple regimen decreased bacterial burden in vivo compared with that of untreated mice or mice treated with other regimens. The cure rates in the CLO test and H. pylori PCR from gastric mucosa were 70%, 60%, 80%, 50%, 60% and 60% in Groups III-VIII, respectively. Those for H. pylori PCR in the faeces of mice were 90% and 100% in Group III with standard therapy and Group V with triple therapy including S-GEN, respectively. S-GEN triple therapy also reduced the levels of proinflammatory cytokines. Conclusions: These results suggest that S-GEN is a promising and effective therapeutic agent for the treatment of H. pylori infection.

Comparison of attitudes towards death and perceptions of do-not-resuscitate orders between older Korean adults residing in a facility and at home.

The purpose of this study was to compare and analyse attitudes towards death and perceptions of do-not-resuscitate (DNR) orders between the elderly living in a facility and those living at home, in order to provide basic data for effective nursing interventions to help the elderly prepare for death in a positive manner. The subjects of this study were 300 persons over 65 years old who lived in a facility or home in Seoul or Gyeonggi Province, South Korea, and data were collected from 1 April to 15 August 2012. Descriptive analysis, χ(2)-test, and ANCOVA were conducted on the data using the SPSS version 20.0 program. With regard to attitudes towards death, the elderly in a facility reported that physical pain relief was most necessary for a comfortable death, and the elderly living at home reported that psychological stability was most required. With regard to perceptions of DNR orders, most of the participants agreed that DNR is sometimes necessary (institution: 86.7%, home: 78.7%). About 8% more of the elderly living in a facility considered DNR to sometimes be necessary compared with the elderly living at home. In conclusion, the elderly living in a facility were interested in physical pain relief or physical health, and the elderly living at home were focused on psychological stability or psychological health. Based on the findings, basic data for development of effective nursing interventions to help the elderly prepare for death in a positive manner can be provided.

Disruption of polycomb repressor complex-mediated gene silencing reactivates HIV-1 provirus in latently infected cells.

OBJECTIVES: Persistent HIV-1 infections are characterized by a long silent infection period in resting CD4+ T cells, which allows them to escape the host immune response. Several HIV-1 latency mechanisms have been reported, but the molecular mechanism underlying polycomb repressor complex (PRC)-mediated HIV-1 latency remains poorly understood. METHODS: Expression of PRC proteins in latent cells was measured by Western blot. Knockdowns of PRC genes were conducted by the specific siRNA and methylations at H3K27 on the proviral LTR were investigated by ChIP assay. RESULTS: PRC proteins (EED, BMI-1, and RNF2) were dramatically downregulated in latent cells after PMA treatment. The downregulation of PRC proteins was followed by a decrease in the methylation of H3K27 and ubiquitination of H2AK119 in the PMA-treated latent cells. siRNA knockdowns of EED and BMI-1 also enhanced HIV-1 reactivation significantly in latently infected cells. By contrast, proteasomal inhibitor MG132 successfully abrogated the PMA-induced downregulation of PRCs. In particular, di-/tri-methylations of histone-3 in the proviral LTR was absent from latent cells after PMA treatment. CONCLUSIONS: This study shows that PRC is strongly related to the control of HIV-1 latency and that PRC-breaking agents may be helpful for purging HIV-1 from latent reservoirs.

Assessing the role of cold front passage and synoptic patterns on air pollution in the Korean Peninsula.

Various numerical experiments using WRF (Weather Research & Forecasting Model) and CMAQ (Community Multiscale Air Quality Modeling System) were performed to analyze the phenomenon of rapidly high concentration PM2.5 after the passage of a cold front in an area with limited local emissions. The episode period was from January 14 to 23, 2018, and analysis was conducted by dividing it into two stages according to the characteristics of changes in PM2.5 concentrations during the period. Through the analysis of observational data during the episode period, we confirmed meteorological impacts (decrease in temperature, increase in wind speed and relative humidity) and an increase in air pollution (PM10 and PM2.5) attributed to the passage of a cold front. Using CMAQ's IPR (Integrated Process Rate) analysis, the contribution of the horizontal advection process was observed in transporting PM2.5 to Gangneung at higher altitudes, and the PM2.5 concentrations at the surface increased because the vertical advection process was influenced by the terrain. Notably, in Stage 2 (64 µg·m-3), a higher contribution of the vertical advection process compared to Stage 1 (35 µg·m-3) was observed, which is attributed to the differences in synoptic patterns following the passage of the cold front. During Stage 2, following the cold front, atmospheric stability (dominance of high-pressure system) led to air subsidence and the presence of a temperature inversion layer, creating favorable meteorological conditions for the accumulation of air pollutants. This study offers the mechanisms of air pollution over the Korean Peninsula under non-stationary meteorological conditions, particularly in relation to the passage of the cold front (low-pressure system). Notably, the influence of a cold front can vary according to the synoptic patterns that develop following its passage.

Histone deactylase inhibitor SAHA induces a synergistic HIV-1 reactivation by 12-O-tetradecanoylphorbol-13-acetate in latently infected cells.

OBJECTIVES: Recent studies have reported that human immunodeficiency virus type 1 (HIV-1) proviruses are strongly suppressed in the unique epigenetic environments caused by chromatin modifications such as acetylation and methylation. Therefore, optimized therapeutic strategies directed against the virus reservoir using these epigenetic modifying agents (EMAs) should cure HIV infection. METHODS: Cytotoxicity and HIV-1 reactivation were determined using the PrestoBlue™ Cell Viability Reagent and p24 HIV ELISA, respectively. RESULTS: EMAs, including histone deacetylase inhibitors (VPA and SAHA), DNA methyltransferase inhibitor (5'-Aza-CdR), histone methyltransferase inhibitor (ADOX) and 12-O-tetradecanoylphorbol-13-acetate (TPA), were used to reactivate proviruses in HIV-1 latently infected cells. The effect of monotreatment with these EMAs on HIV-1 reactivation was VPA or SAHA > 5'-Aza-CdR > ADOX. Even though cotreatment with these potential HIV-1 reactivating agents did not show any significant reactivation effects in HIV-1 latently infected cells, employing SAHA under TPA treatment demonstrated a dramatic synergistic effect on purging HIV-1 proviruses in all HIV-1 latently infected cells via the ERK and AP-1 pathways. CONCLUSIONS: These results suggest that the combined approaches of EMAs, cotreatment of SAHA and TPA, could provide an effective way to lead a decline of HIV-1 reservoirs in patients.

Performance comparisons of the three data assimilation methods for improved predictability of PM2·5: Ensemble Kalman filter, ensemble square root filter, and three-dimensional variational methods.

To improve the predictability of concentrations of atmospheric particulate matter, a data assimilation (DA) system using ensemble square root filter (EnSRF) has been developed for the Community Multiscale Air Quality (CMAQ) model. The EnSRF DA method is a deterministic variant of the ensemble Kalman filter (EnKF) method, which means that unlike the EnKF method, it does not add random noise to the observations. To compare the performances of the EnSRF with those of other DA methods, such as EnKF and 3DVAR (three-dimensional variational), these three methods were applied to the same CMAQ model simulations with identical experimental settings. This is the first attempt in the field of chemical DA to compare the EnKF and EnSRF methods. An identical set of surface fine particulate matter (PM2.5) were assimilated every 6 h by all the DA methods over a CMAQ domain of East Asia, during the period from 01 May to 11 June 2016. In parallel with 'reanalysis experiments', we also carried out '48 h prediction experiments' using the optimized initial conditions produced by the three DA methods. Detailed analyses among the three DA methods were then carried out by comparing both the reanalysis and the prediction outputs with the observed surface PM2.5 over four regions (i.e., South Korea, the Beijing-Tianjin-Hebei (BTH) region, Shandong province, and Liaoning province). The comparison results revealed that the EnSRF produced the best reanalysis and prediction fields in terms of several statistical metrics. For example, when the 3DVAR, EnKF, and EnSRF methods were used, averaged normalized mean biases (NMBs) decreased by (57.6, 85.6, and 91.8) % in reanalyses and (39.7, 87.6, and 91.5) % in first-day predictions, compared to the CMAQ control experiment (i.e., without DA) over South Korea, respectively. Also, over the three Chinese regions, the EnSRF method outperformed the EnKF and 3DVAR methods.

Novel Mutations Conferring Amoxicillin Resistance in Helicobacter pylori in South Korea.

Helicobacter pylori is the primary causative agent of gastritis, gastric ulcers, duodenal ulcers, gastric cancer, and peripheral B-cell lymphoma. H. pylori eradication often fails due to elevated antibiotic resistance. However, no previous studies have thoroughly examined amoxicillin resistance. Here, the objective was to identify clinical strains of H. pylori with amoxicillin resistance and to analyze single-nucleotide polymorphisms (SNPs) associated with amoxicillin resistance. From March 2015 to June 2019, genotypic and phenotypic amoxicillin resistance was analyzed using an E-test and whole-genome sequencing (WGS). Analysis of 368 clinical strains confirmed amoxicillin resistance in 31 strains (resistance rate of 8.7%). The genomes were extracted from nine resistant (<0.125 mg/L) strains, and WGS was performed for genetic analysis. WGS analysis identified SNPs present in pbp1a, pbp2, nhaC, hofH, hofC, and hefC in all nine isolates. Some of these genes may be related to amoxicillin resistance. A total of six SNPs (A69V, V374L, S414R, T503I, A592D, and R435Q) were identified in PBP2 of H-8, the most resistant strain. We predict that these six SNPs are associated with high amoxicillin resistance. Amoxicillin resistance should be considered in the clinical setting for the treatment failure of H. pylori eradication.

Irreversible HER2 inhibitors overcome resistance to the RSL3 ferroptosis inducer in non-HER2 amplified luminal breast cancer.

Ferroptosis, a form of programed cell death, can be promoted by inhibitors of the xCT transporter (erastin) or GPX4 (RSL3). We found that GPX4, but not the xCT transporter, is selectively elevated in luminal breast cancer. Consistent with this observation, the majority of luminal breast cancer cell lines are exquisitely sensitive to RSL3 with limited sensitivity to erastin. In RSL3-resistant, but not sensitive, luminal breast cancer cell lines, RSL3 induces HER2 pathway activation. Irreversible HER2 inhibitors including neratinib reversed RSL3 resistance in constitutively RSL3-resistant cell lines. Combination treatment with RSL3 and neratinib increases ferroptosis through mitochondrial iron-dependent reactive oxygen species production and lipid peroxidation. RSL3 also activated replication stress and concomitant S phase and G2/M blockade leading to sensitivity to targeting the DNA damage checkpoint. Together, our data support the exploration of RSL3 combined with irreversible HER2 inhibitors in clinical trials.

Prevalence of carbapenemase producing Enterobacterales colonization and risk factor of clinical infection.

BACKGROUND: Carbapenemase-producing Enterobacterales (CPE) are global concerns in infection control, and the number of CPE outbreaks in hospitals is increasing despite the strengthening of contact precautions. This study aimed to confirm the prevalence and transition rate of CPE infection from stool surveillance culture and to identify the acquisition pathway of CPE. METHODS: This is a longitudinal review of patients with stool surveillance cultures at a tertiary center in Seoul, South Korea, from July 2018 to June 2020. Pulsed-field gel electrophoresis, multi-locus sequence typing, and whole genome sequencing were performed for carbapenemase-producing Klebsiella pneumoniae and Escherichia coli strains. RESULTS: Among 1620 patients who had undergone stool CPE surveillance cultures, only 7.1% of active surveillance at the Emergency Room (ER) and 4.4% of universal surveillance in the Intensive Care Unit (ICU) were stool CPE positive. The transition rates from stool carriers to clinical CPE infections were 29.4% in the ER and 31.3% in the ICU. However, it was significantly high (55.0%) in the initial stool CPE-negative ICU patients. Among the initial stool CPE-positive patients, hypertension (61% vs. 92.3%, P = 0.004), malignancy (28.8% vs. 53.8%, P = 0.027), and mechanical ventilation (25.4% vs. 53.8%, P = 0.011) were significant risk factors for clinical CPE infection. Molecular typing revealed that sequence type (ST) 307 and ST 395 were dominant in K. pneumoniae, and ST 410 was dominant in E. coli isolates. CONCLUSIONS: Active surveillance showed a higher detection rate than universal stool CPE screening, and one-third of positive stool CPE specimens ultimately developed subsquent clinical CPE infection. According to the molecular typing of the identified CPE strains, in-hospital spread prevailed over external inflow, and the transition rate to clinical CPE was particularly high in the ICU. Therefore, in order to control CPE propagation, not only active surveillance to block inflow from outside, but also continuous ICU monitoring within the hospital is necessary.

Neuronal differentiation drives the antitumor activity of mitogen-activated protein kinase kinase (MEK) inhibition in glioblastoma.

Background: Epidermal growth factor receptor (EGFR) amplification is found in nearly 40%-50% of glioblastoma cases. Several EGFR inhibitors have been tested in glioblastoma but have failed to demonstrate long-term therapeutic benefit, presumably because of acquired resistance. Targeting EGFR downstream signaling with mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) inhibitors would be a more effective approach to glioblastoma treatment. We tested the therapeutic potential of MEK1/2 inhibitors in glioblastoma using 3D cultures of glioma stem-like cells (GSCs) and mouse models of glioblastoma. Methods: Several MEK inhibitors were screened in an unbiased high-throughput platform using GSCs. Cell death was evaluated using flow cytometry and Western blotting (WB) analysis. RNA-seq, real-time quantitative polymerase chain reaction, immunofluorescence, and WB analysis were used to identify and validate neuronal differentiation. Results: Unbiased screening of multiple MEK inhibitors in GSCs showed antiproliferative and apoptotic cell death in sensitive cell lines. An RNA-seq analysis of cells treated with trametinib, a potent MEK inhibitor, revealed upregulation of neurogenesis and neuronal differentiation genes, such as achaete-scute homolog 1 (ASCL1), delta-like 3 (DLL3), and neurogenic differentiation 4 (NeuroD4). We validated the neuronal differentiation phenotypes in vitro and in vivo using selected differentiation markers (ß-III-tubulin, ASCL1, DLL3, and NeuroD4). Oral treatment with trametinib in an orthotopic GSC xenograft model significantly improved animal survival, with 25%-30% of mice being long-term survivors. Conclusions: Our findings demonstrated that MEK1/2 inhibition promotes neuronal differentiation in glioblastoma, a potential additional mechanism of action of MEK1/2 inhibitors. Thus, MEK inhibitors could be efficacious in glioblastoma patients with activated EGFR/MAPK signaling.

Numerical study on advective fog formation and its characteristic associated with cold water upwelling.

Recent rapid industrial development in the Korean Peninsula has increased the impacts of meteorological disasters on marine and coastal environments. In particular, marine fog driven by summer cold water masses can inhibit transport and aviation; yet a lack of observational data hinders our understanding of this phenomena. The present study aimed to analyze the differences in cold water mass formation according to sea surface temperature (SST) resolution and its effects on the occurrence and distribution of sea fog over the Korean Peninsula from June 23-July 1, 2016, according to the Weather Research and Forecasting model. Data from the Final Operational Model Global Tropospheric Analyses were provided at 1° and 0.25° resolutions and NOAA real-time global SST (RTG-SST) data were provided at 0.083°. While conventional analyses have used initial SST distributions throughout the entire simulation period, small-scale, rapidly developing oceanic phenomena (e.g., cold water masses) lasting for several days act as an important mediating factor between the lower atmosphere and sea. RTG-SST was successful at identifying fog presence and maintained the most extensive horizontal distribution of cold water masses. In addition, it was confirmed that the difference in SST resolution led to varying sizes and strengths of the warm pools that provided water vapor from the open sea area to the atmosphere. On examining the horizontal water vapor transport and the vertical structure of the generated sea fog using the RTG-SST, water vapors were found to be continuously introduced by the southwesterly winds from June 29 to 30, creating a fog event throughout June 30. Accordingly, high-resolution SST data must be input into numerical models whenever possible. It is expected that the findings of this study can contribute to the reduction of ship accidents via the accurate simulation of sea fog.

Reactogenicity and Immunogenicity of the ChAdOx1 nCOV-19 Coronavirus Disease 2019 Vaccine in South Korean Healthcare Workers.

PURPOSE: The association between reactogenicity and immunogenicity of the ChAdOx1 nCOV-19 is controversial. We aimed to evaluate this association among South Korean healthcare workers (HCWs). MATERIALS AND METHODS: Participants received two doses of the ChAdOx1vaccine 12 weeks apart. Blood samples were tested for anti-severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) spike protein receptor binding domain antibodies about 2 months after the first and second doses using the Elecsys Anti-SARS-CoV-2 S assay kits. Adverse events were noted using an online self-reporting questionnaire. RESULTS: Among the 232 HCWs, pain (85.78% after the first dose vs. 58.62% after the second dose, p<0.001) was the most prominent local reaction, and myalgia or fatigue (84.05% vs. 53.02%, p<0.001) was the most prominent systemic reaction. The frequency of all adverse events was significantly reduced after the second dose. After the first dose, the anti-SARS-CoV-2 S showed significantly higher titer in the group with swelling, itching, fever, and nausea. Also, the anti-SARS-CoV-2 S titer significantly increased as the grade of fever (p=0.007) and duration of fever (p=0.026) increased; however, there was no significant correlation between immunogenicity and adverse event after the second dose. The group with pain after the first dose showed a greater increase in the anti-SARS-CoV-2 S difference between the second and first doses compared to the group without pain (542.2 U/mL vs. 363.8 U/mL, p=0.037). CONCLUSION: The frequency of adverse events occurring after the first dose of the ChAdOx1 was significantly reduced after the second dose. Interestingly, the elevation of anti-SARS-CoV-2 S titer was significantly increased in the group with pain after the first dose.

Norepinephrine induces VEGF expression and angiogenesis by a hypoxia-inducible factor-1α protein-dependent mechanism.

A growing number of studies have demonstrated that physiological factors can influence the progression of several cancers via cellular immune function, angiogenesis and metastasis. Recently, stress-induced catecholamines have been shown to increase the expression of various cancer progressive factors, including vascular endothelial growth factor (VEGF), matrix metalloproteinases and interleukins. However, a detailed mechanism remains to be identified. In this study, we investigated the role of adrenergic receptors and hypoxia-inducible factor (HIF)-1α protein in catecholamine-induced VEGF expression and angiogenesis. Treatment of the cells with norepinephrine (NE) or isoproterenol induced VEGF expression and HIF-1α protein amount in a dose-dependent manner. Induction of VEGF expression by NE was abrogated when the cells were transfected with HIF-1α-specific siRNA. Similarly, adenylate cyclase activator forskolin and cyclic AMP-dependent protein kinase A inhibitor H-89 enhanced and decreased HIF-1α protein amount, respectively. More importantly, conditioned medium of NE-stimulated cancer cells induced angiogenesis in a HIF-1α protein-dependent manner. In addition, pretreatment of cells with propranolol, a ß-adrenergic receptor (AR) blocker, completely abolished induction of VEGF expression and HIF-1α protein amount by NE in all of the tested cancer cells. However, treatment with the α1-AR blocker prazosin inhibited NE-induced HIF-1α protein amount and angiogenesis in SK-Hep1 and PC-3 but not MDA-MB-231 cells. Collectively, our results suggest that ARs and HIF-1α protein have critical roles in NE-induced VEGF expression in cancer cells, leading to stimulation of angiogenesis. These findings will help to understand the mechanism of cancer progression by stress-induced catecholamines and design therapeutic strategies for cancer angiogenesis.