Docetaxel-Loaded Pluronic P123 Polymeric Micelles: in Vitro and in Vivo Evaluation

In this work, novel docetaxel (DTX) -loaded Tween 80-free Pluronic P123 (P123) micelles with improved therapeutic effect were developed. The freeze-dried DTX-loaded P123 micelles (DTX-micelles) were analyzed by HPLC, TEM and DLS to determine the DTX loading, micelle morphology, size, respectively. The in vitro cytotoxic activity of DTX-micelles in HepG2, A549 and malignant melanoma B16 cells were evaluated by MTT assay. The corresponding in vivo antitumor efficacy was assessed in Kunming mice bearing B16 tumor after intravenous administration. The DTX-loading and efficiency into the micelles were 2.12 ± 0.09% and 86.34 ± 3.32%, respectively. The DTX-micelles were spherical with a mean particle size of 50.7 nm and size distribution from 22 to 84 nm, which suggested that they should be able to selectively accumulate in solid tumors by means of EPR effect, with a zeta potential of −12.45 ± 3.24 mV. The in vitro release behavior of DTX from DTX-micelles followed the Weibull equation. Compared with Duopafei®, DTX-micelles showed higher cytotoxicity against HepG2 (P < 0.01), A549 (P < 0.05) and B16 (P < 0.01) cells. In addition, DTX-micelles exhibited remarkable antitumor activity and reduced toxicity on B16 tumor in vivo. The tumor inhibition rates (TIR) of DTX-micelles was 91.6% versus 76.3% of Duopafei® (P < 0.01). These results suggested that P123 micelles might be considered as an effective DTX delivery system

Endothelial ether lipids link the vasculature to blood pressure, behavior, and neurodegeneration

Vascular disease contributes to neurodegeneration, which is associated with decreased blood pressure in older humans. Plasmalogens, ether phospholipids produced by peroxisomes, are decreased in Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders. However, the mechanistic links between ether phospholipids, blood pressure, and neurodegeneration are not fully understood. Here, we show that endothelium-derived ether phospholipids affect blood pressure, behavior, and neurodegeneration in mice. In young adult mice, inducible endothelial-specific disruption of PexRAP, a peroxisomal enzyme required for ether lipid synthesis, unexpectedly decreased circulating plasmalogens. PexRAP endothelial knockout (PEKO) mice responded normally to hindlimb ischemia but had lower blood pressure and increased plasma renin activity. In PEKO as compared with control mice, tyrosine hydroxylase was decreased in the locus coeruleus, which maintains blood pressure and arousal. PEKO mice moved less, slept more, and had impaired attention to and recall of environmental events as well as mild spatial memory deficits. In PEKO hippocampus, gliosis was increased, and a plasmalogen associated with memory was decreased. Despite lower blood pressure, PEKO mice had generally normal homotopic functional connectivity by optical neuroimaging of the cerebral cortex. Decreased glycogen synthase kinase-3 phosphorylation, a marker of neurodegeneration, was detected in PEKO cerebral cortex. In a co-culture system, PexRAP knockdown in brain endothelial cells decreased glycogen synthase kinase-3 phosphorylation in co-cultured astrocytes that was rescued by incubation with the ether lipid alkylglycerol. Taken together, our findings suggest that endothelium-derived ether lipids mediate several biological processes and may also confer neuroprotection in mice

PF-05280014 (a trastuzumab biosimilar) plus paclitaxel compared with reference trastuzumab plus paclitaxel for HER2-positive metastatic breast cancer: a randomised, double-blind study

BACKGROUND: This randomised, double-blind study compared PF-05280014 (a trastuzumab biosimilar) with reference trastuzumab (Herceptin®) sourced from the European Union (trastuzumab-EU), when each was given with paclitaxel as first-line treatment for HER2-positive metastatic breast cancer. METHODS: Between 4 April 2014 and 22 January 2016, 707 participants were randomised 1:1 to receive intravenous PF-05280014 plus paclitaxel (PF-05280014 group; n = 352) or trastuzumab-EU plus paclitaxel (trastuzumab-EU group; n = 355). PF-05280014 or trastuzumab-EU was administered weekly (first dose 4 mg/kg, subsequent doses 2 mg/kg), with the option to change to a 3-weekly regimen (6 mg/kg) from Week 33. Treatment with PF-05280014 or trastuzumab-EU could continue until disease progression. Paclitaxel (starting dose 80 mg/m2 ) was administered on Days 1, 8 and 15 of 28-day cycles for at least six cycles or until maximal benefit of response. The primary endpoint was objective response rate (ORR), evaluating responses achieved by Week 25 and confirmed by Week 33, based on blinded central radiology review. RESULTS: The risk ratio for ORR was 0.940 (95% CI: 0.842–1.049). The 95% CI fell within the pre-specified equivalence margin of 0.80–1.25. ORR was 62.5% (95% CI: 57.2–67.6%) in the PF-05280014 group and 66.5% (95% CI: 61.3–71.4%) in the trastuzumab-EU group. As of data cut-off on 11 January 2017 (using data up to 378 days post-randomisation), there were no notable differences between groups in progression-free survival (median: 12.16 months in the PF-05280014 group vs. 12.06 months in the trastuzumab-EU group; 1-year rate: 54% vs. 51%) or overall survival (median: not reached in either group; 1-year rate: 89.31% vs. 87.36%). Safety outcomes and immunogenicity were similar between the treatment groups. CONCLUSION: When given as first-line treatment for HER2-positive metastatic breast cancer, PF-05280014 plus paclitaxel demonstrated equivalence to trastuzumab-EU plus paclitaxel in terms of ORR. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT0198967

Potential of Core-Collapse Supernova Neutrino Detection at JUNO

JUNO is an underground neutrino observatory under construction in Jiangmen, China. It uses 20kton liquid scintillator as target, which enables it to detect supernova burst neutrinos of a large statistics for the next galactic core-collapse supernova (CCSN) and also pre-supernova neutrinos from the nearby CCSN progenitors. All flavors of supernova burst neutrinos can be detected by JUNO via several interaction channels, including inverse beta decay, elastic scattering on electron and proton, interactions on C12 nuclei, etc. This retains the possibility for JUNO to reconstruct the energy spectra of supernova burst neutrinos of all flavors. The real time monitoring systems based on FPGA and DAQ are under development in JUNO, which allow prompt alert and trigger-less data acquisition of CCSN events. The alert performances of both monitoring systems have been thoroughly studied using simulations. Moreover, once a CCSN is tagged, the system can give fast characterizations, such as directionality and light curve

Detection of the Diffuse Supernova Neutrino Background with JUNO

As an underground multi-purpose neutrino detector with 20 kton liquid scintillator, Jiangmen Underground Neutrino Observatory (JUNO) is competitive with and complementary to the water-Cherenkov detectors on the search for the diffuse supernova neutrino background (DSNB). Typical supernova models predict 2-4 events per year within the optimal observation window in the JUNO detector. The dominant background is from the neutral-current (NC) interaction of atmospheric neutrinos with 12C nuclei, which surpasses the DSNB by more than one order of magnitude. We evaluated the systematic uncertainty of NC background from the spread of a variety of data-driven models and further developed a method to determine NC background within 15\% with {\it{in}} {\it{situ}} measurements after ten years of running. Besides, the NC-like backgrounds can be effectively suppressed by the intrinsic pulse-shape discrimination (PSD) capabilities of liquid scintillators. In this talk, I will present in detail the improvements on NC background uncertainty evaluation, PSD discriminator development, and finally, the potential of DSNB sensitivity in JUNO

截面形状对早龄期钢管混凝土柱多级加载变形及承载力影响的试验研究

The influence of continuous construction process on the mechanical properties of concrete-filled steel tube (CFST) is mostly considered by introducing an initial stress of steel tube, whilst the multi-level loading process as well as concrete shrinkage and creep at early age are neglected. In order to study the mechanical properties of early-age CFST under multi-level loading, axial compression deformation and ultimate bearing capacity tests of early-age square and circular CFST short columns under and after multi-level loading were performed respectively. The variations of deformation under different multi-level loading schemes as well as ultimate load bearing capacity after multi-level loading were analyzed. The results indicate that the creep deformations of both square and circular CFST under multi-level loading at early age are remarkable. The specimen deformation is significantly affected by the applied loading scheme. In addition, the deformation of circular specimen is found to be smaller than that of square specimen under the same loading condition. The impact of multi-level loading process on the bearing capacity of square and circular CFST short columns at mature stage is limited and can be neglected. The research outcome can serve as a reference for the deformation control and mechanical performance evaluation for CFST under continuous construction

Statistical Model of Normal Contact Stiffness of Fixed Joint Surface during Unloading after First Loading

Based on Kogut and Etsion’s model (KE model), a statistical method is used to establish a model of normal contact stiffness of fixed joint surface during unloading after first loading. Simulation results show that, for the elastoplastic contact, normal contact stiffness of joint surface is the nonlinear function of mean surface separation during loading and unloading and decreases as the separation increases. For different plasticity indexes, the normal contact stiffness of joint surface varies differently following the change of mean surface separation during loading and unloading