305 research outputs found
Development of targeted therapy for ovarian cancer mediated by a plasmid expressing diphtheria toxin under the control of H19 regulatory sequences
<p>Abstract</p> <p>Background</p> <p>Ovarian cancer ascites fluid (OCAF), contains malignant cells, is usually present in women with an advanced stage disease and currently has no effective therapy. Hence, we developed a new therapy strategy to target the expression of diphtheria toxin gene under the control of H19 regulatory sequences in ovarian tumor cells. H19 RNA is present at high levels in human cancer tissues (including ovarian cancer), while existing at a nearly undetectable level in the surrounding normal tissue.</p> <p>Methods</p> <p>H19 gene expression was tested in cells from OCAF by the in-situ hybridization technique (ISH) using an H19 RNA probe. The therapeutic potential of the toxin vector DTA-H19 was tested in ovarian carcinoma cell lines and in a heterotopic animal model for ovarian cancer.</p> <p>Results</p> <p>H19 RNA was detected in 90% of patients with OCAF as determined by ISH. Intratumoral injection of DTA-H19 into ectopically developed tumors caused 40% inhibition of tumor growth.</p> <p>Conclusion</p> <p>These observations may be the first step towards a major breakthrough in the treatment of human OCAF, while the effect in solid tumors required further investigation. It should enable us to identify likely non-responders in advance, and to treat patients who are resistant to all known therapies, thereby avoiding treatment failure.</p
ORB5: a global electromagnetic gyrokinetic code using the PIC approach in toroidal geometry
This paper presents the current state of the global gyrokinetic code ORB5 as
an update of the previous reference [Jolliet et al., Comp. Phys. Commun. 177
409 (2007)]. The ORB5 code solves the electromagnetic Vlasov-Maxwell system of
equations using a PIC scheme and also includes collisions and strong flows. The
code assumes multiple gyrokinetic ion species at all wavelengths for the
polarization density and drift-kinetic electrons. Variants of the physical
model can be selected for electrons such as assuming an adiabatic response or a
``hybrid'' model in which passing electrons are assumed adiabatic and trapped
electrons are drift-kinetic. A Fourier filter as well as various control
variates and noise reduction techniques enable simulations with good
signal-to-noise ratios at a limited numerical cost. They are completed with
different momentum and zonal flow-conserving heat sources allowing for
temperature-gradient and flux-driven simulations. The code, which runs on both
CPUs and GPUs, is well benchmarked against other similar codes and analytical
predictions, and shows good scalability up to thousands of nodes
Estratégias de modelagem para o Problema do Caixeiro Viajante utilizando o software CPLEX
In this work two mathematical models for the Traveling Salesman Problem (TSP) were implemented using the modeling language of CPLEX software, with the aim to compare computational performance of both models. Computational tests were conducted to compare two differentmethodologies for the modeling of combinatorial optimization problems. On one side, one model is generated in a static way, with all its restrictions, on the other side, the other model is generated in a dynamic way, by the addition of restrictions as needed. Tests showed that the second approach offer significant computational gains
Real-time analysis of the binding of fluorescent VEGFâââ a to VEGFR2 in living cells: Effect of receptor tyrosine kinase inhibitors and fate of internalized agonist-receptor complexes
Vascular endothelial growth factor (VEGF) is an important mediator of angiogenesis. Here we have used a novel stoichiometric protein-labeling method to generate a fluorescent variant of VEGF (VEGFâââ
a-TMR) labeled on a single cysteine within each protomer of the antiparallel VEGF homodimer. VEGFâââ
a-TMR has then been used in conjunction with full length VEGFR2, tagged with the bioluminescent protein NanoLuc, to undertake a real time quantitative evaluation of VEGFR2 binding characteristics in living cells using bioluminescence resonance energy transfer (BRET). This provided quantitative information on VEGF-VEGFR2 interactions. At longer incubation times, VEGFR2 is internalized by VEGFâââ
a-TMR into intracellular endosomes. This internalization can be prevented by the receptor tyrosine kinase inhibitors (RTKIs) cediranib, sorafenib, pazopanib or vandetanib. In the absence of RTKIs, the BRET signal is decreased over time as a consequence of the dissociation of agonist from the receptor in intracellular endosomes and recycling of VEGFR2 back to the plasma membrane
Numerical Calculations of the B1g Raman Spectrum of the Two-Dimensional Heisenberg Model
The B1g Raman spectrum of the two-dimensional S=1/2 Heisenberg model is
discussed within Loudon-Fleury theory at both zero and finite temperature. The
exact T=0 spectrum for lattices with up to 6*6 sites is computed using Lanczos
exact diagonalization. A quantum Monte Carlo (QMC) method is used to calculate
the corresponding imaginary-time correlation function and its first two
derivatives for lattices with up to 16*16 spins. The imaginary-time data is
continued to real frequency using the maximum-entropy method, as well as a fit
based on spinwave theory. The numerical results are compared with spinwave
calculations for finite lattices. There is a surprisingly large change in the
exact spectrum going from 4*4 to 6*6 sites. In the former case there is a
single dominant two-magnon peak at frequency w/J appr. 3.0, whereas in the
latter case there are two approximately equal-sized peaks at w/J appr. 2.7 and
3.9. This is in good qualitative agreement with the spinwave calculations
including two-magnon processes on the same lattices. Both the Lanczos and the
QMC results indicate that the actual infinite-size two-magnon profile is
broader than the narrow peak obtained in spinwave theory, but the positions of
the maxima agree to within a few percent. The higher-order contributions
present in the numerical results are merged with the two-magnon profile and
extend up to frequencies w/J appr. 7. The first three frequency cumulants of
the spectrum are in excellent agreement with results previously obtained from a
series expansion around the Ising limit. Typical experimental B1g$ spectra for
La2CuO4 are only slightly broader than what we obtain here. The exchange
constant extracted from the peak position is J appr. 1400K, in good agreement
with values obtained from neutron scattering and NMR experiments.Comment: 15 pages, Revtex, 13 PostScript figure
Magnetic and Charge Correlations in La{2-x-y}Nd_ySr_xCuO_4: Raman Scattering Study
Two aspects in connection with the magnetic properties of
La_{2-x-y}Nd_ySr_xCuO_4 single crystals are discussed. The first is related to
long wavelength magnetic excitations in x = 0, 0.01, and 0.03 La_{2-x}Sr_xCuO_4
detwinned crystals as a function of doping, temperature and magnetic field. Two
magnetic modes were observed within the AF region of the phase diagram. The one
at lower energies was identified with the spin-wave gap induced by the
antisymmetric DM interaction and its anisotropic properties in magnetic field
could be well explained using a canonical form of the spin Hamiltonian. A new
finding was a magnetic field induced mode whose dynamics allowed us to discover
a spin ordered state outside the AF order which was shown to persist in a 9 T
field as high as 100 K above the N\'eel temperature T_N for x = 0.01. For these
single magnon excitations we map out the Raman selection rules in magnetic
fields and demonstrate that their temperature dependent spectral weight is
peaked at the N\'eel temperature. The second aspect is related to phononic and
magnetic Raman scattering in La_{2-x-y}Nd_ySr_xCuO_4 with three doping
concentrations: x = 1/8, y = 0; x = 1/8, y = 0.4; and x = 0.01, y = 0. We
observed that around 1/8 Sr doping and independent of Nd concentration there
exists substantial disorder in the tilt pattern of the CuO_6 octahedra in both
the orthorhombic and tetragonal phases which persist down to 10 K and are
coupled to bond disorder in the cation layers. The weak magnitude of existing
charge/spin modulations in the Nd doped structure did not allow us to detect
specific Raman signatures on lattice dynamics or two-magnon scattering around
2200 cm-1.Comment: 26 pages, 22 figure
Real-Time Ligand Binding of Fluorescent VEGF-A Isoforms that Discriminate between VEGFR2 and NRP1 in Living Cells
© 2018 The Author(s) Fluorescent VEGF-A isoforms have been evaluated for their ability to discriminate between VEGFR2 and NRP1 in real-time ligand binding studies in live cells using BRET. To enable this, we synthesized single-site (N-terminal cysteine) labeled versions of VEGF165a, VEGF165b, and VEGF121a. These were used in combination with N-terminal NanoLuc-tagged VEGFR2 or NRP1 to evaluate the selectivity of VEGF isoforms for these two membrane proteins. All fluorescent VEGF-A isoforms displayed high affinity for VEGFR2. Only VEGF165a-TMR bound to NanoLuc-NRP1 with a similar high affinity (4.4 nM). Competition NRP1 binding experiments yielded a rank order of potency of VEGF165a > VEGF189a > VEGF145a. VEGF165b, VEGF-Ax, VEGF121a, and VEGF111a were unable to bind to NRP1. There were marked differences in the kinetic binding profiles of VEGF165a-TMR for NRP1 and VEGFR2. These data emphasize the importance of the kinetic aspects of ligand binding to VEGFR2 and its co-receptors in the dynamics of VEGF signaling. Peach et al. have used fluorescent VEGF-A isoforms to demonstrate that they can discriminate between VEGFR2 and its co-receptor NRP1 in real-time ligand binding studies in live cells. This precision chemical biology approach showed that fluorescent VEGF165a binds more rapidly to NRP1 than VEGFR2
Global turbulence features across marginality and non-local pedestal-core interactions
Spatially non-local aspects of turbulent transport in tokamak plasmas are examined with global gyrokinetic simulations using the ORB5 code. Inspired by very accurate measurements in the TCV tokamak in L-mode, we initialise plasma profiles with constant logarithmic gradients in the core and constant linear gradients in the 'pedestal' (). The main finding is that transport in the core is strongly affected by the presence of pedestal gradients. This non-local pedestal-core coupling appears to be correlated with the appearance of repetitive avalanches that propagate across both pedestal and core regions. Below a certain threshold value in pedestal gradient, no well-defined frequency is found for avalanches. Above this threshold, a well-defined frequency shows up, which roughly matches that of the local geodesic acoustic mode (GAM) frequency near the plasma edge and is thus well below the local GAM frequency in the core: this behaviour is very similar to the global coherent mode structure observed in TCV. Above this threshold in pedestal gradient, the core transport increases sharply: there is therefore a non-locality in marginality. The probability density functions (PDFs) of density, temperature, temperature gradient and potential are found to have nearly Gaussian distributions, whereas the heat flux can have, in the presence of avalanches, a more or less strongly positively skewed PDF, which could be fitted by a log-normal distribution. The skewness of the heat flux is found to be radially and non-locally dependent: its value in the plasma core critically depends on the presence of gradients in the pedestal. The relation flux versus gradient is examined in detail. The local instantaneous flux versus gradient relation shows a hysteresis behaviour during an avalanche but no clear correlation, unlike the flux and zonal flow (ZF) shearing rate, which are anti-correlated: flux is higher when shearing rate is lower. This leads to corrugated time-averaged radial profiles of transport, heat and temperature gradient, with heat diffusivity having local maxima where the ZF shearing rate goes to zero and temperature gradient has local minima. Finally, we show how the flux versus gradient relation can be analysed locally for series of simulations with different averaged gradients
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