Nifurtimox Is Effective Against Neural Tumor Cells and Is Synergistic with Buthionine Sulfoximine.

Children with aggressive neural tumors have poor survival rates and novel therapies are needed. Previous studies have identified nifurtimox and buthionine sulfoximine (BSO) as effective agents in children with neuroblastoma and medulloblastoma. We hypothesized that nifurtimox would be effective against other neural tumor cells and would be synergistic with BSO. We determined neural tumor cell viability before and after treatment with nifurtimox using MTT assays. Assays for DNA ladder formation and poly-ADP ribose polymerase (PARP) cleavage were performed to measure the induction of apoptosis after nifurtimox treatment. Inhibition of intracellular signaling was measured by Western blot analysis of treated and untreated cells. Tumor cells were then treated with combinations of nifurtimox and BSO and evaluated for viability using MTT assays. All neural tumor cell lines were sensitive to nifurtimox, and IC50 values ranged from approximately 20 to 210 μM. Nifurtimox treatment inhibited ERK phosphorylation and induced apoptosis in tumor cells. Furthermore, the combination of nifurtimox and BSO demonstrated significant synergistic efficacy in all tested cell lines. Additional preclinical and clinical studies of the combination of nifurtimox and BSO in patients with neural tumors are warranted

Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression.

BackgroundNovel therapies are needed for children with high-risk and relapsed neuroblastoma. We hypothesized that MAPK/ERK kinase (MEK) inhibition with the novel MEK1/2 inhibitor binimetinib would be effective in neuroblastoma preclinical models.MethodsLevels of total and phosphorylated MEK and extracellular signal-regulated kinase (ERK) were examined in primary neuroblastoma tumor samples and in neuroblastoma cell lines by Western blot. A panel of established neuroblastoma tumor cell lines was treated with increasing concentrations of binimetinib, and their viability was determined using MTT assays. Western blot analyses were performed to examine changes in total and phosphorylated MEK and ERK and to measure apoptosis in neuroblastoma tumor cells after binimetinib treatment. NF1 protein levels in neuroblastoma cell lines were determined using Western blot assays. Gene expression of NF1 and MEK1 was examined in relationship to neuroblastoma patient outcomes.ResultsBoth primary neuroblastoma tumor samples and cell lines showed detectable levels of total and phosphorylated MEK and ERK. IC50 values for cells sensitive to binimetinib ranged from 8 nM to 1.16 μM, while resistant cells did not demonstrate any significant reduction in cell viability with doses exceeding 15 μM. Sensitive cells showed higher endogenous expression of phosphorylated MEK and ERK. Gene expression of NF1, but not MEK1, correlated with patient outcomes in neuroblastoma, and NF1 protein expression also correlated with responses to binimetinib.ConclusionsNeuroblastoma tumor cells show a range of sensitivities to the novel MEK inhibitor binimetinib. In response to binimetinib, sensitive cells demonstrated complete loss of phosphorylated ERK, while resistant cells demonstrated either incomplete loss of ERK phosphorylation or minimal effects on MEK phosphorylation, suggesting alternative mechanisms of resistance. NF1 protein expression correlated with responses to binimetinib, supporting the use of NF1 as a biomarker to identify patients that may respond to MEK inhibition. MEK inhibition therefore represents a potential new therapeutic strategy for neuroblastoma

Global MHD simulation of flux transfer events at the high-latitude magnetopause observed by the cluster spacecraft and the SuperDARN radar system

A global magnetohydrodynamic numerical simulation is used to study the large-scale structure and formation location of flux transfer events (FTEs) in synergy with in situ spacecraft and ground-based observations. During the main period of interest on the 14 February 2001 from 0930 to 1100 UT the Cluster spacecraft were approaching the Northern Hemisphere high-latitude magnetopause in the postnoon sector on an outbound trajectory. Throughout this period the magnetic field, electron, and ion sensors on board Cluster observed characteristic signatures of FTEs. A few minutes delayed to these observations the Super Dual Auroral Radar Network (SuperDARN) system indicated flow disturbances in the conjugate ionospheres. These “two-point” observations on the ground and in space were closely correlated and were caused by ongoing unsteady reconnection in the vicinity of the spacecraft. The three-dimensional structures and dynamics of the observed FTEs and the associated reconnection sites are studied by using the Block-Adaptive-Tree-Solarwind-Roe-Upwind-Scheme (BATS-R-US) MHD code in combination with a simple open flux tube motion model (Cooling). Using these two models the spatial and temporal evolution of the FTEs is estimated. The models fill the gaps left by measurements and allow a “point-to-point” mapping between the instruments in order to investigate the global structure of the phenomenon. The modeled results presented are in good correlation with previous theoretical and observational studies addressing individual features of FTEs

The origin of Jupiter's outer radiation belt

The intense inner radiation belt at Jupiter (>50 MeV at 1.5 RJ) is generally accepted to be created by radial diffusion of electrons from further away from the planet. However, this requires a source with energies that exceed 1 MeV outside the orbit of the moon Io at 5.9 RJ, which has never been explained satisfactorily. Here we test the hypothesis that this source population could be formed from a very soft energy spectrum, by particle injection processes and resonant electron acceleration via whistler mode chorus waves. We use the British Antarctic Survey Radiation Belt Model to calculate the change in the electron flux between 6.5 and 15 RJ; these are the first simulations at Jupiter combining wave particle interactions and radial diffusion. The resulting electron flux at 100 keV and 1 MeV lies very close to the Galileo Interim Radiation Electron model spectrum after 1 and 10 days, respectively. The primary driver for the increase in the flux is cyclotron resonant acceleration by chorus waves. A peak in phase space density forms such that inside L≈9 radial diffusion transports electrons toward Jupiter, but outside L≈9 radial diffusion acts away from the planet. The results are insensitive to the softness of the initial energy spectrum but do depend on the value of the flux at the minimum energy boundary. We conclude by suggesting that the source population for the inner radiation belt at Jupiter could indeed be formed by wave-particle interactions

Breeding Cool-Season Forage Grasses for a Warming Climate

In many parts of the world, changing climatic conditions are resulting in increased temperatures and more variable precipitation, intensifying the duration and severity of drought, especially in summer. Warming climate is considered one reason for the increasing failure of traditional, summer-active cool-season perennial grasses at the margin of their zone of adaptation in naturally C4 grass-dominated ecosystems of the Southern Great Plains of the USA. Two cool-season perennial forage grasses orchardgrass (Dactylis glomerata L.) and tall fescue (Lolium arundinaceum (Schreb.) Darbysh.) are of major economic and ecological importance in these regions. In 2008, we initiated a breeding program of summer-dormant (Mediterranean) cool-season perennial grasses originating from the Mediterranean Basin, including tall fescue, orchardgrass, and perennial ryegrass. In this publication, we present breeding history and morphological characteristics of cv. Yonatan (also known under research name TAL-02), a new cultivar of summer-dormant tall fescue. Recurrent selection cycles were conducted to develop cv. Yonatan during 2007-2010. Evaluations were performed on several locations across north Texas, Australia and New Zealand during 2015-2020. Yonatan tall fescue has improved forage production and persistence compared with check cultivars Flecha and Chisholm. It also differs from them in terms of wider leaves, earlier maturity, and development of a bulbous storage organ at the base of the tiller. Yonatan is adapted to changing climatic conditions in the Southern Great Plains of the USA, Australia, and New Zealand

Survey of Saturn Z-mode Emission

Because of the role of Z-mode emission in the diffusive scattering and resonant acceleration of electrons, we conduct a survey of intensity in the Saturn inner magnetosphere. Z-mode is primarily observed as “5 kHz” narrowband emission in the lower density regions where the ratio of cyclotron to plasma frequency, fc/fp > 1 to which we limit this study. This occurs at Saturn along the inner edge of the Enceladus torus near the equator and at higher latitudes. We present profiles and parametric fits of intensity as a function of frequency, radius, latitude, and local time. The magnetic field intensity levels are lower than chorus, but the electric field intensities are comparable. We conclude that Z-mode wave-particle interactions may make a significant contribution to electron acceleration in the inner magnetosphere of Saturn, supplementing acceleration produced by chorus emission

Electron acceleration at Jupiter: input from cyclotron-resonant interaction with whistler-mode chorus waves

Jupiter has the most intense radiation belts of all the outer planets. It is not yet known how electrons can be accelerated to energies of 10 MeV or more. It has been suggested that cyclotron-resonant wave-particle interactions by chorus waves could accelerate electrons to a few MeV near the orbit of Io. Here we use the chorus wave intensities observed by the Galileo spacecraft to calculate the changes in electron flux as a result of pitch angle and energy diffusion. We show that, when the bandwidth of the waves and its variation with L are taken into account, pitch angle and energy diffusion due to chorus waves is a factor of 8 larger at L-shells greater than 10 than previously shown. We have used the latitudinal wave intensity profile from Galileo data to model the time evolution of the electron flux using the British Antarctic Survey Radiation Belt (BAS) model. This profile confines intense chorus waves near the magnetic equator with a peak intensity at ∼5° latitude. Electron fluxes in the BAS model increase by an order of magnitude for energies around 3 MeV. Extending our results to L = 14 shows that cyclotron-resonant interactions with chorus waves are equally important for electron acceleration beyond L = 10. These results suggest that there is significant electron acceleration by cyclotron-resonant interactions at Jupiter contributing to the creation of Jupiter's radiation belts and also increasing the range of L-shells over which this mechanism should be considered

Effects of Orbital Degeneracy and Electron Correlation on Charge Dynamics in Perovskite Manganese Oxides

Taking the orbital degeneracy of $e_g$ conduction bands and the Coulomb interaction into account in a double-exchange model, we investigate charge dynamics of perovskite Mn oxides by the Lancz$\ddot{\rm o}$s diagonalization method. In the metallic phase near the Mott insulator, it is found that the optical conductivity for a spin-polarized two-dimensional system exhibits a weight transfer to a broad and incoherent structure within the lower-Hubbard band together with a suppressed Drude weight. It reproduces qualitative feature of the experimental results. As an orbital effect, we find that an anomalous charge correlation at quarter filling suppresses the coherent charge dynamics and signals precursor to the charge ordering.Comment: 4 pages LaTeX including 3 PS figures, to appear in J. Phys. Soc. Jp

Orbital dynamics: The origin of the anomalous optical spectra in ferromagnetic manganites

We discuss the role of orbital degeneracy in the transport properties of perovskite manganites, focusing in particular on the optical conductivity in the metallic ferromagnetic phase at low temperatures. Orbital degeneracy and strong correlations are described by an orbital t-J model which we treat in a slave-boson approach. Employing the memory-function formalism we calculate the optical conductivity, which is found to exhibit a broad incoherent component extending up to bare bandwidth accompanied by a strong suppression of the Drude weight. Further, we calculate the constant of T-linear specific heat. Our results are in overall agreement with experiment and suggest low-energy orbital fluctuations as the origin of the strongly correlated nature of the metallic phase of manganites.Comment: To appear in: Phys. Rev. B 58 (Rapid Communications), 1 November 199