Biodistribution and pharmacokinetics of a telodendrimer micellar paclitaxel nanoformulation in a mouse xenograft model of ovarian cancer

Wenwu Xiao1, Juntao Luo2, Teesta Jain3, John Riggs3, Harry P Tseng1, Paul T Henderson3, Simon R Cherry4, Douglas Rowland4, Kit S Lam1,31Department of Biochemistry and Molecular Medicine, UC Davis Cancer Center, University of California Davis, Sacramento, CA; 2Department of Pharmacology, SUNY Upstate Cancer Research Institute, SUNY Upstate Medical University, Syracuse, NY; 3Department of Internal Medicine, Division of Hematology and Oncology, 4Department of Biomedical Engineering, UC Davis Cancer Center, University of California Davis, Davis, CABackground: A multifunctional telodendrimer-based micelle system was characterized for delivery of imaging and chemotherapy agents to mouse tumor xenografts. Previous optical imaging studies demonstrated qualitatively that these classes of nanoparticles, called nanomicelles, preferentially accumulate at tumor sites in mice. The research reported herein describes the detailed quantitative imaging and biodistribution profiling of nanomicelles loaded with a cargo of paclitaxel.Methods: The telodendrimer was covalently labeled with 125I and the nanomicelles were loaded with 14C-paclitaxel, which allowed measurement of pharmacokinetics and biodistribution in the mice using microSPECT/CT imaging and liquid scintillation counting, respectively.Results: The radio imaging data showed preferential accumulation of nanomicelles at the tumor site along with a slower clearance rate than paclitaxel formulated in Cremophor EL (Taxol®). Liquid scintillation counting confirmed that 14C-labeled paclitaxel sequestered in nanomicelles had increased uptake by tumor tissue and slower pharmacokinetics than Taxol.Conclusion: Overall, the results indicate that nanomicelle-formulated paclitaxel is a potentially superior formulation compared with Taxol in terms of water solubility, pharmacokinetics, and tumor accumulation, and may be clinically useful for both tumor imaging and improved chemotherapy applications.Keywords: telodendrimer, nanomicelle, paclitaxel, microSPECT/CT, imaging guided drug deliver

Simulating the WFIRST coronagraph Integral Field Spectrograph

A primary goal of direct imaging techniques is to spectrally characterize the atmospheres of planets around other stars at extremely high contrast levels. To achieve this goal, coronagraphic instruments have favored integral field spectrographs (IFS) as the science cameras to disperse the entire search area at once and obtain spectra at each location, since the planet position is not known a priori. These spectrographs are useful against confusion from speckles and background objects, and can also help in the speckle subtraction and wavefront control stages of the coronagraphic observation. We present a software package, the Coronagraph and Rapid Imaging Spectrograph in Python (crispy) to simulate the IFS of the WFIRST Coronagraph Instrument (CGI). The software propagates input science cubes using spatially and spectrally resolved coronagraphic focal plane cubes, transforms them into IFS detector maps and ultimately reconstructs the spatio-spectral input scene as a 3D datacube. Simulated IFS cubes can be used to test data extraction techniques, refine sensitivity analyses and carry out design trade studies of the flight CGI-IFS instrument. crispy is a publicly available Python package and can be adapted to other IFS designs.Comment: 15 page

Doping dependence of upper critical field and Hall resistivity in LaFeAsO1-xFx

The electrical resistivity (Rxx) and Hall resistivity (Rxy) of LaFeAsO1-xFx have been measured over a wide fluorine doping range 0 =< x =< 0.14 using 60 T pulsed magnets. While the superconducting phase diagram (Tc, x) displays the classic dome-shaped structure, we find that the resistive upper critical field (Hc2) increases monotonically with decreasing fluorine concentration, with the largest Hc2 >= 75 T for x = 0.05. This is reminiscent of the composition dependence in high-Tc cuprates and might correlate with opening of a pseudo-gap in the underdoped region. Further, the temperature dependence of Hc2(T) for superconducting samples can be understood in terms of multi-band superconductivity. Rxy data for non-superconducting samples show non-linear field dependence, which is also consistent with a multi-carrier scenario.Comment: 15 pages, 5 figures, Accepted by PR

Recruitment, augmentation and apoptosis of rat osteoclasts in 1,25-(OH)2D3 response to short-term treatment with 1,25-dihydroxyvitamin D3in vivo

Background Although much is known about the regulation of osteoclast (OC) formation and activity, little is known about OC senescence. In particular, the fate of of OC seen after 1,25-(OH)2D3 administration in vivo is unclear. There is evidence that the normal fate of OC is to undergo apoptosis (programmed cell death). We have investigated the effect of short-term application of high dose 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) on OC apoptosis in an experimental rat model. Methods OC recruitment, augmentation and apoptosis was visualised and quantitated by staining histochemically for tartrate resistant acid phosphatase (TRAP), double staining for TRAP/ED1 or TRAP/DAPI, in situ DNA fragmentation end labelling and histomorphometric analysis. Results Short-term treatment with high-dose 1,25-(OH)2D3 increased the recruitment of OC precursors in the bone marrow resulting in a short-lived increase in OC numbers. This was rapidly followed by an increase in the number of apoptotic OC and their subsequent removal. The response of OC to 1,25-(OH)2D3 treatment was dose and site dependent; higher doses producing stronger, more rapid responses and the response in the tibiae being consistently stronger and more rapid than in the vertebrae. Conclusions This study demonstrates that (1) after recruitment, OC are removed from the resorption site by apoptosis (2) the combined use of TRAP and ED1 can be used to identify OC and their precursors in vivo (3) double staining for TRAP and DAPI or in situ DNA fragmentation end labelling can be used to identify apoptotic OC in vivo

WFIRST CGI Integral Field Spectrograph Performance and Post-Processing in the OS6 Observing Scenario

The WFIRST coronagraph instrument (CGI) will have an integral field spectrograph (IFS) backend to disperse the entire field of view at once and obtain spatially-resolved, low-resolution spectra of the speckles and science scene. The IFS will be key to understanding the spectral nature of the speckles, obtain science spectra of planets and disks, and will be used for broadband wavefront control. In order to characterize, predict, and optimize the performance of the instrument, we present a detailed model of the IFS in the context of the new OS6 observing scenario. The simulation includes spatial, spectral, and temporal variations of the speckle field on the IFS detector plane, which allows us to explore several post-processing methods and assess what gains can be expected. The simulator includes the latest models of the detector behavior when operating in photon-counting mode

Two-dimensional Dirac fermions in a topological insulator: transport in the quantum limit

Pulsed magnetic fields of up to 55T are used to investigate the transport properties of the topological insulator Bi_2Se_3 in the extreme quantum limit. For samples with a bulk carrier density of n = 2.9\times10^16cm^-3, the lowest Landau level of the bulk 3D Fermi surface is reached by a field of 4T. For fields well beyond this limit, Shubnikov-de Haas oscillations arising from quantization of the 2D surface state are observed, with the \nu =1 Landau level attained by a field of 35T. These measurements reveal the presence of additional oscillations which occur at fields corresponding to simple rational fractions of the integer Landau indices.Comment: 5 pages, 4 figure

Pion-Nucleon Scattering in a Large-N Sigma Model

We review the large-N_c approach to meson-baryon scattering, including recent interesting developments. We then study pion-nucleon scattering in a particular variant of the linear sigma-model, in which the couplings of the sigma and pi mesons to the nucleon are echoed by couplings to the entire tower of I=J baryons (including the Delta) as dictated by large-N_c group theory. We sum the complete set of multi-loop meson-exchange \pi N --> \pi N and \pi N --> \sigma N Feynman diagrams, to leading order in 1/N_c. The key idea, reviewed in detail, is that large-N_c allows the approximation of LOOP graphs by TREE graphs, so long as the loops contain at least one baryon leg; trees, in turn, can be summed by solving classical equations of motion. We exhibit the resulting partial-wave S-matrix and the rich nucleon and Delta resonance spectrum of this simple model, comparing not only to experiment but also to pion-nucleon scattering in the Skyrme model. The moral is that much of the detailed structure of the meson-baryon S-matrix which hitherto has been uncovered only with skyrmion methods, can also be described by models with explicit baryon fields, thanks to the 1/N_c expansion.Comment: This LaTeX file inputs the ReVTeX macropackage; figures accompany i

Elgin on understanding:How does it involve know-how, endorsement and factivity?

In Chapter 3 of True Enough, Elgin (2017) outlines her view of objectual understanding, focusing largely on its non-factive nature and the extent to which a certain kind of know-how is required for the “grasping” component of understanding. I will explore four central issues that feature in this chapter, concentrating on (1) the role of know-how, (2) the concept of endorsement, (3) Elgin’s critique of the factivity constraint on understanding, and (4) how we might use aspects of Elgin’s framework to inform related debates on the norm of assertion

Computational Micromodel for Epigenetic Mechanisms

Characterization of the epigenetic profile of humans since the initial breakthrough on the human genome project has strongly established the key role of histone modifications and DNA methylation. These dynamic elements interact to determine the normal level of expression or methylation status of the constituent genes in the genome. Recently, considerable evidence has been put forward to demonstrate that environmental stress implicitly alters epigenetic patterns causing imbalance that can lead to cancer initiation. This chain of consequences has motivated attempts to computationally model the influence of histone modification and DNA methylation in gene expression and investigate their intrinsic interdependency. In this paper, we explore the relation between DNA methylation and transcription and characterize in detail the histone modifications for specific DNA methylation levels using a stochastic approach