2,671 research outputs found
Receptor tyrosine kinase inhibitors negatively impact on pro-reparative characteristics of human cardiac progenitor cells
Receptor tyrosine kinase inhibitors improve cancer survival but their cardiotoxicity requires investigation. We investigated these inhibitors' effects on human cardiac progenitor cells in vitro and rat heart in vivo. We applied imatinib, sunitinib or sorafenib to human cardiac progenitor cells, assessing cell viability, proliferation, stemness, differentiation, growth factor production and second messengers. Alongside, sunitinib effects were assessed in vivo. Inhibitors decreased (\u1d631 < 0.05) cell viability, at levels equivalent to 'peak' (24 h; imatinib: 91.5 ± 0.9%; sunitinib: 83.9 ± 1.8%; sorafenib: 75.0 ± 1.6%) and 'trough' (7 days; imatinib: 62.3 ± 6.2%; sunitinib: 86.2 ± 3.5%) clinical plasma levels, compared to control (100% viability). Reduced (\u1d631 < 0.05) cell cycle activity was seen with imatinib (29.3 ± 4.3% cells in S/G2/M-phases; 50.3 ± 5.1% in control). Expression of PECAM-1, Nkx2.5, Wnt2, linked with cell differentiation, were decreased (\u1d631 < 0.05) 2, 2 and 6-fold, respectively. Expression of HGF, p38 and Akt1 in cells was reduced (\u1d631 < 0.05) by sunitinib. Second messenger (p38 and Akt1) blockade affected progenitor cell phenotype, reducing c-kit and growth factor (HGF, EGF) expression. Sunitinib for 9 days (40 mg/kg, i.p.) in adult rats reduced (\u1d631 < 0.05) cardiac ejection fraction (68 ± 2% \u1d637\u1d634. baseline (83 ± 1%) and control (84 ± 4%)) and reduced progenitor cell numbers. Receptor tyrosine kinase inhibitors reduce cardiac progenitor cell survival, proliferation, differentiation and reparative growth factor expression
Turbulence and particle acceleration in collisionless supernovae remnant shocks: II- Cosmic-ray transport
Supernovae remnant shock waves could be at the origin of cosmic rays up to
energies in excess of the knee (eV) if the magnetic
field is efficiently amplified by the streaming of accelerated particles in the
shock precursor. This paper follows up on a previous paper \citep{pell05} which
derived the properties of the MHD turbulence so generated, in particular its
anisotropic character, its amplitude and its spectrum. In the present paper, we
calculate the diffusion coefficients, also accounting for compression through
the shock, and show that the predicted three-dimensional turbulence spectrum
(with and the
wavenumber components along and perpendicular to the shock normal) generally
leads to Bohm diffusion in the parallel direction. However, if the anisotropy
is constrained by a relation of the form ,
which arises when the turbulent energy cascade occurs at a constant rate
independent of scale, then the diffusion coefficient loses its Bohm scaling and
scales as in isotropic Kolmogorov turbulence. We show that these diffusion
coefficients allow to account for X-ray observations of supernova remnants.
This paper also calculates the modification of the Fermi cycle due to the
energy lost by cosmic rays in generating upstream turbulence and the
concomittant steepening of the energy spectrum. Finally we confirm that cosmic
rays can produced an amplified turbulence in young SNr during their free
expansion phase such that the maximal energy is close to the knee and the
spectral index is close to 2.3 in the warm phase of the interstellar mediumComment: 13 pages, 4 figures, accepted for publication in Astronomy &
Astrophysics main journa
Transplantation of Skeletal Muscle-Derived Sca-1⁺/PW1⁺/Pax7⁻ Interstitial Cells (PICs) Improves Cardiac Function and Attenuates Remodeling in Mice Subjected to Myocardial Infarction
We have previously shown that skeletal muscle-derived Sca-1⁺/PW1⁺/Pax7⁻ interstitial cells (PICs) are multi-potent and enhance endogenous repair and regeneration. Here, we investigated the regenerative potential of PICs following intramyocardial transplantation in mice subjected to an acute myocardial infarction (MI). MI was induced through the ligation of the left anterior descending coronary artery in 8-week old male C57BL/6 mice. 5 × 10⁵ eGFP-labelled PICs (MI + PICs; n = 7) or PBS (MI-PBS; n = 7) were injected intramyocardially into the border zone. Sham mice (n = 8) were not subjected to MI, or the transplantation of PICs or PBS. BrdU was administered via osmotic mini-pump for 14 days. Echocardiography was performed prior to surgery (baseline), and 1-, 3- and 6-weeks post-MI and PICs transplantation. Mice were sacrificed at 6 weeks post-MI + PICs transplantation, and heart sections were analysed for fibrosis, hypertrophy, engraftment, proliferation, and differentiation of PICs. A significant (\u1d631 < 0.05) improvement in ejection fraction (EF) and fractional shortening was observed in the MI-PICs group, compared to MI + PBS group at 6-weeks post MI + PICs transplantation. Infarct size/fibrosis of the left ventricle significantly (\u1d631 < 0.05) decreased in the MI-PICs group (14.0 ± 2.5%), compared to the MI-PBS group (32.8 ± 2.2%). Cardiomyocyte hypertrophy in the border zone significantly (\u1d631 < 0.05) decreased in the MI-PICs group compared to the MI-PBS group (330.0 ± 28.5 µM2 vs. 543.5 ± 26.6 µm2), as did cardiomyocyte apoptosis (0.6 ± 0.9% MI-PICs vs. 2.8 ± 0.8% MI-PBS). The number of BrdU+ cardiomyocytes was significantly (\u1d631 < 0.05) increased in the infarct/border zone of the MI-PICs group (7.0 ± 3.3%), compared to the MI-PBS group (1.7 ± 0.5%). The proliferation index (total BrdU+ cells) was significantly increased in the MI-PICs group compared to the MI-PBS group (27.0 ± 3.4% vs. 7.6 ± 1.0%). PICs expressed and secreted pro-survival and reparative growth factors, supporting a paracrine effect of PICs during recovery/remodeling. Skeletal muscle-derived PICs show significant reparative potential, attenuating cardiac remodelling following transplantation into the infarcted myocardium. PICs can be easily sourced from skeletal muscle and therefore show promise as a potential cell candidate for supporting the reparative and regenerative effects of cell therapie
Detection of BRAF mutations in the tumour and serum of patients enrolled in the AZD6244 (ARRY-142886) advanced melanoma phase II study
Aged-senescent cells contribute to impaired heart regeneration
Aging leads to increased cellular senescence and is associated with decreased potency of tissue-specific stem/progenitor cells. Here, we have done an extensive analysis of cardiac progenitor cells (CPCs) isolated from human subjects with cardiovascular disease, aged 32-86 years. In aged subjects (>70 years old), over half of CPCs are senescent (p16INK4A , SA-β-gal, DNA damage γH2AX, telomere length, senescence-associated secretory phenotype [SASP]), unable to replicate, differentiate, regenerate or restore cardiac function following transplantation into the infarcted heart. SASP factors secreted by senescent CPCs renders otherwise healthy CPCs to senescence. Elimination of senescent CPCs using senolytics abrogates the SASP and its debilitative effect in vitro. Global elimination of senescent cells in aged mice (INK-ATTAC or wild-type mice treated with D + Q senolytics) in vivo activates resident CPCs and increased the number of small Ki67-, EdU-positive cardiomyocytes. Therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and restore the regenerative capacity of the heart
A Broadband Study of the Emission from the Composite Supernova Remnant MSH 11-62
MSH 11-62 (G291.1-0.9) is a composite supernova remnant for which radio and
X-ray observations have identified the remnant shell as well as its central
pulsar wind nebula. The observations suggest a relatively young system
expanding into a low density region. Here we present a study of MSH 11-62 using
observations with the Chandra, XMM-Newton, and Fermi observatories, along with
radio observations from the Australia Telescope Compact Array (ATCA). We
identify a compact X-ray source that appears to be the putative pulsar that
powers the nebula, and show that the X-ray spectrum of the nebula bears the
signature of synchrotron losses as particles diffuse into the outer nebula.
Using data from the Fermi LAT, we identify gamma-ray emission originating from
MSH 11-62. With density constraints from the new X-ray measurements of the
remnant, we model the evolution of the composite system in order to constrain
the properties of the underlying pulsar and the origin of the gamma-ray
emission.Comment: 12 Pages, 12 figures. Accepted for publication in the Astrophysical
Journa
Topical Issues for Particle Acceleration Mechanisms in Astrophysical Shocks
Particle acceleration at plasma shocks appears to be ubiquitous in the
universe, spanning systems in the heliosphere, supernova remnants, and
relativistic jets in distant active galaxies and gamma-ray bursts. This review
addresses some of the key issues for shock acceleration theory that require
resolution in order to propel our understanding of particle energization in
astrophysical environments. These include magnetic field amplification in shock
ramps, the non-linear hydrodynamic interplay between thermal ions and their
extremely energetic counterparts possessing ultrarelativistic energies, and the
ability to inject and accelerate electrons in both non-relativistic and
relativistic shocks. Recent observational developments that impact these issues
are summarized. While these topics are currently being probed by
astrophysicists using numerical simulations, they are also ripe for
investigation in laboratory experiments, which potentially can provide valuable
insights into the physics of cosmic shocks.Comment: 13 pages, no figures. Invited review, accepted for publication in
Astrophysics and Space Science, as part of the HEDLA 2006 conference
proceeding
Gas Accretion and Galactic Chemical Evolution: Theory and Observations
This chapter reviews how galactic inflows influence galaxy metallicity. The
goal is to discuss predictions from theoretical models, but particular emphasis
is placed on the insights that result from using models to interpret
observations. Even as the classical G-dwarf problem endures in the latest round
of observational confirmation, a rich and tantalizing new phenomenology of
relationships between , , SFR, and gas fraction is emerging both in
observations and in theoretical models. A consensus interpretation is emerging
in which star-forming galaxies do most of their growing in a quiescent way that
balances gas inflows and gas processing, and metal dilution with enrichment.
Models that explicitly invoke this idea via equilibrium conditions can be used
to infer inflow rates from observations, while models that do not assume
equilibrium growth tend to recover it self-consistently. Mergers are an overall
subdominant mechanism for delivering fresh gas to galaxies, but they trigger
radial flows of previously-accreted gas that flatten radial gas-phase
metallicity gradients and temporarily suppress central metallicities. Radial
gradients are generically expected to be steep at early times and then
flattened by mergers and enriched inflows of recycled gas at late times.
However, further theoretical work is required in order to understand how to
interpret observations. Likewise, more observational work is needed in order to
understand how metallicity gradients evolve to high redshifts.Comment: Invited review to appear in Gas Accretion onto Galaxies, Astrophysics
and Space Science Library, eds. A. J. Fox & R. Dav\'e, to be published by
Springer. 29 pages, 2 figure
Adult cardiac stem cells are multipotent and robustly myogenic: c-kit expression is necessary but not sufficient for their identification
Multipotent adult resident cardiac stem cells (CSCs) were first identified by the expression of c-kit, the stem cell factor receptor. However, in the adult myocardium c-kit alone cannot distinguish CSCs from other c-kit-expressing (c-kitpos) cells. The adult heart indeed contains a heterogeneous mixture of c-kitpos cells, mainly composed of mast and endothelial/progenitor cells. This heterogeneity of cardiac c-kitpos cells has generated confusion and controversy about the existence and role of CSCs in the adult heart. Here, to unravel CSC identity within the heterogeneous c-kit-expressing cardiac cell population, c-kitpos cardiac cells were separated through CD45-positive or -negative sorting followed by c-kitpos sorting. The blood/endothelial lineage-committed (Lineagepos) CD45posc-kitpos cardiac cells were compared to CD45neg(Lineageneg/Linneg) c-kitpos cardiac cells for stemness and myogenic properties in vitro and in vivo. The majority (~90%) of the resident c-kitpos cardiac cells are blood/endothelial lineage-committed CD45posCD31posc-kitpos cells. In contrast, the LinnegCD45negc-kitpos cardiac cell cohort, which represents 10% of the total c-kitpos cells, contain all the cardiac cells with the properties of adult multipotent CSCs. These characteristics are absent from the c-kitneg and the blood/endothelial lineage-committed c-kitpos cardiac cells. Single Linnegc-kitpos cell-derived clones, which represent only 1–2% of total c-kitpos myocardial cells, when stimulated with TGF-β/Wnt molecules, acquire full transcriptome and protein expression, sarcomere organisation, spontaneous contraction and electrophysiological properties of differentiated cardiomyocytes (CMs). Genetically tagged cloned progeny of one Linnegc-kitpos cell when injected into the infarcted myocardium, results in significant regeneration of new CMs, arterioles and capillaries, derived from the injected cells. The CSC’s myogenic regenerative capacity is dependent on commitment to the CM lineage through activation of the SMAD2 pathway. Such regeneration was not apparent when blood/endothelial lineage-committed c-kitpos cardiac cells were injected. Thus, among the cardiac c-kitpos cell cohort only a very small fraction has the phenotype and the differentiation/regenerative potential characteristics of true multipotent CSCs
Radio emission from Supernova Remnants
The explosion of a supernova releases almost instantaneously about 10^51 ergs
of mechanic energy, changing irreversibly the physical and chemical properties
of large regions in the galaxies. The stellar ejecta, the nebula resulting from
the powerful shock waves, and sometimes a compact stellar remnant, constitute a
supernova remnant (SNR). They can radiate their energy across the whole
electromagnetic spectrum, but the great majority are radio sources. Almost 70
years after the first detection of radio emission coming from a SNR, great
progress has been achieved in the comprehension of their physical
characteristics and evolution. We review the present knowledge of different
aspects of radio remnants, focusing on sources of the Milky Way and the
Magellanic Clouds, where the SNRs can be spatially resolved. We present a brief
overview of theoretical background, analyze morphology and polarization
properties, and review and critical discuss different methods applied to
determine the radio spectrum and distances. The consequences of the interaction
between the SNR shocks and the surrounding medium are examined, including the
question of whether SNRs can trigger the formation of new stars. Cases of
multispectral comparison are presented. A section is devoted to reviewing
recent results of radio SNRs in the Magellanic Clouds, with particular emphasis
on the radio properties of SN 1987A, an ideal laboratory to investigate
dynamical evolution of an SNR in near real time. The review concludes with a
summary of issues on radio SNRs that deserve further study, and analyzing the
prospects for future research with the latest generation radio telescopes.Comment: Revised version. 48 pages, 15 figure
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