The SMAC mimetic LCL-161 selectively targets JAK2V617F mutant cells.

Background:Evasion from programmed cell death is a hallmark of cancer and can be achieved in cancer cells by overexpression of inhibitor of apoptosis proteins (IAPs). Second mitochondria-derived activator of caspases (SMAC) directly bind to IAPs and promote apoptosis; thus, SMAC mimetics have been investigated in a variety of cancer types. particularly in diseases with high inflammation and NFĸB activation. Given that elevated TNFα levels and NFĸB activation is a characteristic feature of myeloproliferative neoplasms (MPN), we investigated the effect of the SMAC mimetic LCL-161 on MPN cell survival in vitro and disease development in vivo. Methods:To investigate the effect of the SMAC mimetic LCL-161 in vitro, we utilized murine and human cell lines to perform cell viability assays as well as primary bone marrow from mice or humans with JAK2V617F-driven MPN to interrogate myeloid colony formation. To elucidate the effect of the SMAC mimetic LCL-161 in vivo, we treated a JAK2V617F-driven mouse model of MPN with LCL-161 then assessed blood counts, splenomegaly, and myelofibrosis. Results:We found that JAK2V617F-mutated cells are hypersensitive to the SMAC mimetic LCL-161 in the absence of exogenous TNFα. JAK2 kinase activity and NFĸB activation is required for JAK2V617F-mediated sensitivity to LCL-161, as JAK or NFĸB inhibitors diminished the differential sensitivity of JAK2V617F mutant cells to IAP inhibition. Finally, LCL-161 reduces splenomegaly and may reduce fibrosis in a mouse model of JAK2V617F-driven MPN. Conclusion:LCL-161 may be therapeutically useful in MPN, in particular when exogenous TNFα signaling is blocked. NFĸB activation is a characteristic feature of JAK2V617F mutant cells and this sensitizes them to SMAC mimetic induced killing even in the absence of TNFα. However, when exogenous TNFα is added, NFĸB is activated in both mutant and wild-type cells, abolishing the differential sensitivity. Moreover, JAK kinase activity is required for the differential sensitivity of JAK2V617F mutant cells, suggesting that the addition of JAK2 inhibitors to SMAC mimetics would detract from the ability of SMAC mimetics to selectively target JAK2V617F mutant cells. Instead, combination therapy with other agents that reduce inflammatory cytokines but preserve JAK2 signaling in mutant cells may be a more beneficial combination therapy in MPN

Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons

The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions

The Eighth Data Release of the Sloan Digital Sky Survey: First Data from SDSS-III

The Sloan Digital Sky Survey (SDSS) started a new phase in August 2008, with new instrumentation and new surveys focused on Galactic structure and chemical evolution, measurements of the baryon oscillation feature in the clustering of galaxies and the quasar Ly alpha forest, and a radial velocity search for planets around ~8000 stars. This paper describes the first data release of SDSS-III (and the eighth counting from the beginning of the SDSS). The release includes five-band imaging of roughly 5200 deg^2 in the Southern Galactic Cap, bringing the total footprint of the SDSS imaging to 14,555 deg^2, or over a third of the Celestial Sphere. All the imaging data have been reprocessed with an improved sky-subtraction algorithm and a final, self-consistent photometric recalibration and flat-field determination. This release also includes all data from the second phase of the Sloan Extension for Galactic Understanding and Evolution (SEGUE-2), consisting of spectroscopy of approximately 118,000 stars at both high and low Galactic latitudes. All the more than half a million stellar spectra obtained with the SDSS spectrograph have been reprocessed through an improved stellar parameters pipeline, which has better determination of metallicity for high metallicity stars.Comment: Astrophysical Journal Supplements, in press (minor updates from submitted version

The Ninth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the SDSS-III Baryon Oscillation Spectroscopic Survey

The Sloan Digital Sky Survey III (SDSS-III) presents the first spectroscopic data from the Baryon Oscillation Spectroscopic Survey (BOSS). This ninth data release (DR9) of the SDSS project includes 535,995 new galaxy spectra (median z=0.52), 102,100 new quasar spectra (median z=2.32), and 90,897 new stellar spectra, along with the data presented in previous data releases. These spectra were obtained with the new BOSS spectrograph and were taken between 2009 December and 2011 July. In addition, the stellar parameters pipeline, which determines radial velocities, surface temperatures, surface gravities, and metallicities of stars, has been updated and refined with improvements in temperature estimates for stars with T_eff<5000 K and in metallicity estimates for stars with [Fe/H]>-0.5. DR9 includes new stellar parameters for all stars presented in DR8, including stars from SDSS-I and II, as well as those observed as part of the SDSS-III Sloan Extension for Galactic Understanding and Exploration-2 (SEGUE-2). The astrometry error introduced in the DR8 imaging catalogs has been corrected in the DR9 data products. The next data release for SDSS-III will be in Summer 2013, which will present the first data from the Apache Point Observatory Galactic Evolution Experiment (APOGEE) along with another year of data from BOSS, followed by the final SDSS-III data release in December 2014.Comment: 9 figures; 2 tables. Submitted to ApJS. DR9 is available at http://www.sdss3.org/dr

First Measurement of the Ti (e,e′) X Cross Section at Jefferson Lab

To probe CP violation in the leptonic sector using GeV energy neutrino beams in current and future experiments using argon detectors, precise models of the complex underlying neutrino and antineutrino interactions are needed. The E12-14-012 experiment at Jefferson Lab Hall A was designed to perform a combined analysis of inclusive and exclusive electron scatterings on both argon (N=22) and titanium (Z=22) nuclei using GeV-energy electron beams. The measurement on titanium nucleus provides essential information to understand the neutrino scattering on argon, large contribution to which comes from scattering off neutrons. Here we report the first experimental study of electron-titanium scattering as double-differential cross section at beam energy E=2.222 GeV and electron-scattering angle θ=15.541^{∘}, measured over a broad range of energy transfer, spanning the kinematical regions in which quasielastic scattering and delta production are the dominant reaction mechanisms. The data provide valuable new information needed to develop accurate theoretical models of the electromagnetic and weak cross sections of these complex nuclei in the kinematic regime of interest to neutrino experiments.National Science Foundation (U.S.) (CAREER Grant PHY-1352106

First Measurement of the Ti(e,e′)X(e,e^\prime){\rm X} Cross Section at Jefferson Lab

To probe CP violation in the leptonic sector using GeV energy neutrino beams in current and future experiments using argon detectors, precise models of the complex underlying neutrino and antineutrino interactions are needed. The E12-14-012 experiment at Jefferson Lab Hall A was designed to perform a combined analysis of inclusive and exclusive electron scatterings on both argon ($N = 22$) and titanium ($Z = 22$) nuclei using GeV energy electron beams. The measurement on titanium nucleus provides essential information to understand the neutrino scattering on argon, large contribution to which comes from scattering off neutrons. Here we report the first experimental study of electron-titanium scattering as double differential cross section at beam energy $E=2.222$ GeV and electron scattering angle $\theta = 15.541$ deg, measured over a broad range of energy transfer, spanning the kinematical regions in which quasielastic scattering and delta production are the dominant reaction mechanisms. The data provide valuable new information needed to develop accurate theoretical models of the electromagnetic and weak cross sections of these complex nuclei in the kinematic regime of interest to neutrino experiments.Comment: 6 pages, 5 figures. Version published in Physical Review

Measurement of the Ar(e,e′^\prime p) and Ti(e,e′^\prime p) cross sections in Jefferson Lab Hall A

The E12-14-012 experiment, performed in Jefferson Lab Hall A, has collected exclusive electron-scattering data (e,e$^\prime$p) in parallel kinematics using natural argon and natural titanium targets. Here, we report the first results of the analysis of the data set corresponding to beam energy of 2,222 MeV, electron scattering angle 21.5 deg, and proton emission angle -50 deg. The differential cross sections, measured with $\sim$4% uncertainty, have been studied as a function of missing energy and missing momentum, and compared to the results of Monte Carlo simulations, obtained from a model based on the Distorted Wave Impulse Approximation.Comment: 14 pages, 8 figures (submitted to PRC

Measurement of the Cross Sections for Inclusive Electron Scattering in the E12-14-012 Experiment at Jefferson Lab

The E12-14-012 experiment performed at Jefferson Lab Hall A has collected inclusive electron-scattering data for different targets at the kinematics corresponding to beam energy 2.222 GeV and scattering angle 15.54°. Here we present a comprehensive analysis of the collected data and compare the double-differential cross sections for inclusive scattering of electrons, extracted using solid targets (aluminum, carbon, and titanium) and a closed argon-gas cell. The data extend over broad range of energy transfer, where quasielastic interaction, Δ-resonance excitation, and inelastic scattering yield contributions to the cross section. The double-differential cross sections are reported with high precision (∼3%) for all targets over the covered kinematic range

Discrimination of n-3 Rich Oils by Gas Chromatography

Exploring the capabilities of instrumental techniques for discriminating n-3 rich oils derived from animals is a very important though much neglected area that was emphasized more than 100 years ago. In this study the potential of gas chromatography (GC) for discriminating full fatty acid methyl ester (FAME) profiles from fish (cod liver and salmon) and marine mammal (seal and whale) oils is evaluated by means of principal component analysis (PCA). The FAME profiles from plant oils such as rapeseed, linseed and soy oils and seven different brands of n-3 supplements are also used in the discrimination process. The results from the PCA plots can reliably distinguish between plant, n-3 supplements, fish and marine mammal oils. By removing the contribution of the n-3 supplements and plant oils it is possible to discriminate between types of fish and marine animal oils. GC offers a rapid, simple and convenient means of discriminating oils from different species, brands and grades

Determination of the Titanium Spectral Function From (e, e\u27p) Data

The E12-14-012 experiment, performed in Jefferson Lab Hall A, has measured the (e,e′p) cross section in parallel kinematics using a natural titanium target. In this paper, we report the analysis of the dataset obtained in different kinematics for our solid natural titanium target. Data were obtained in a range of missing momentum and missing energy between 15 ≲ pm ≲ 250  MeV/c and 12 ≲ Em ≲ 80  MeV, respectively, and using an electron beam energy of 2.2 GeV. We measured the reduced cross section with ∼7% accuracy as a function of both missing momentum and missing energy. Our Monte Carlo simulation, including both a model spectral function and the effects of final-state interactions, satisfactorily reproduces the data