Cancer therapeutic potential of combinatorial immuno- and vaso-modulatory interventions

Currently, most of the basic mechanisms governing tumor-immune system interactions, in combination with modulations of tumor-associated vasculature, are far from being completely understood. Here, we propose a mathematical model of vascularized tumor growth, where the main novelty is the modeling of the interplay between functional tumor vasculature and effector cell recruitment dynamics. Parameters are calibrated on the basis of different in vivo immunocompromised Rag1-/- and wild-type (WT) BALB/c murine tumor growth experiments. The model analysis supports that tumor vasculature normalization can be a plausible and effective strategy to treat cancer when combined with appropriate immuno-stimulations. We find that improved levels of functional tumor vasculature, potentially mediated by normalization or stress alleviation strategies, can provide beneficial outcomes in terms of tumor burden reduction and growth control. Normalization of tumor blood vessels opens a therapeutic window of opportunity to augment the antitumor immune responses, as well as to reduce the intratumoral immunosuppression and induced-hypoxia due to vascular abnormalities. The potential success of normalizing tumor-associated vasculature closely depends on the effector cell recruitment dynamics and tumor sizes. Furthermore, an arbitrary increase of initial effector cell concentration does not necessarily imply a better tumor control. We evidence the existence of an optimal concentration range of effector cells for tumor shrinkage. Based on these findings, we suggest a theory-driven therapeutic proposal that optimally combines immuno- and vaso-modulatory interventions

Why one-size-fits-all vaso-modulatory interventions fail to control glioma invasion: in silico insights

There is an ongoing debate on the therapeutic potential of vaso-modulatory interventions against glioma invasion. Prominent vasculature-targeting therapies involve functional tumour-associated blood vessel deterioration and normalisation. The former aims at tumour infarction and nutrient deprivation medi- ated by vascular targeting agents that induce occlusion/collapse of tumour blood vessels. In contrast, the therapeutic intention of normalising the abnormal structure and function of tumour vascular net- works, e.g. via alleviating stress-induced vaso-occlusion, is to improve chemo-, immuno- and radiation therapy efficacy. Although both strategies have shown therapeutic potential, it remains unclear why they often fail to control glioma invasion into the surrounding healthy brain tissue. To shed light on this issue, we propose a mathematical model of glioma invasion focusing on the interplay between the mi- gration/proliferation dichotomy (Go-or-Grow) of glioma cells and modulations of the functional tumour vasculature. Vaso-modulatory interventions are modelled by varying the degree of vaso-occlusion. We discovered the existence of a critical cell proliferation/diffusion ratio that separates glioma invasion re- sponses to vaso-modulatory interventions into two distinct regimes. While for tumours, belonging to one regime, vascular modulations reduce the tumour front speed and increase the infiltration width, for those in the other regime the invasion speed increases and infiltration width decreases. We show how these in silico findings can be used to guide individualised approaches of vaso-modulatory treatment strategies and thereby improve success rates

A dose-volume histogram based decision-support system for dosimetric comparison of radiotherapy treatment plans

Background: The choice of any radiotherapy treatment plan is usually made after the evaluation of a few preliminary isodose distributions obtained from different beam configurations. Despite considerable advances in planning techniques, such final decision remains a challenging task that would greatly benefit from efficient and reliable assessment tools. Methods: For any dosimetric plan considered, data on dose-volume histograms supplied by treatment planning systems are used to provide estimates on planning target coverage as well as on sparing of organs at risk and the remaining healthy tissue. These partial metrics are then combined into a dose distribution index (DDI), which provides a unified, easy-to-read score for each competing radiotherapy plan. To assess the performance of the proposed scoring system, DDI figures for fifty brain cancer patients were retrospectively evaluated. Patients were divided in three groups depending on tumor location and malignancy. For each patient, three tentative plans were designed and recorded during planning, one of which was eventually selected for treatment. We thus were able to compare the plans with better DDI scores and those actually delivered. Results: When planning target coverage and organs at risk sparing are considered as equally important, the tentative plan with the highest DDI score is shown to coincide with that actually delivered in 32 of the 50 patients considered. In 15 (respectively 3) of the remaining 18 cases, the plan with highest DDI value still coincides with that actually selected, provided that organs at risk sparing is given higher priority (respectively, lower priority) than target coverage. Conclusions: DDI provides a straightforward and non-subjective tool for dosimetric comparison of tentative radiotherapy plans. In particular, DDI readily quantifies differences among competing plans with similar-looking dose-volume histograms and can be easily implemented for any tumor type and localization, irrespective of the planning system and irradiation technique considered. Moreover, DDI permits to estimate the dosimetry impact of different priorities being assigned to sparing of organs at risk or to better target coverag

The edge of the M87 halo and the kinematics of the diffuse light in the Virgo cluster core

We present high resolution FLAMES/VLT spectroscopy of intracluster planetary nebula (ICPN) candidates, targeting three new fields in the Virgo cluster core with surface brightness down to mu_B = 28.5. Based on the projected phase space information we separate the old and 12 newly-confirmed PNs into galaxy and intracluster components. The M87 PNs are confined to the extended stellar envelope of M87, within a projected radius of ~ 160 kpc, while the ICPNs are scattered across the whole surveyed region between M87 and M86. The velocity dispersions determined from the M87 PNs at projected radii of 60 kpc and 144 kpc show that the galaxy's velocity dispersion profile decreases in the outer halo, down to 78 +/- 25 km/s. A Jeans model for the M87 halo stars in the gravitational potential traced by the X-ray emission fits the observed velocity dispersion profile only if the stellar orbits are strongly radially anisotropic (beta ~= 0.4 at r ~= 10 kpc increasing to 0.8 at the outer edge), and if additionally the stellar halo is truncated at ~= 150 kpc average elliptical radius. From the spatial and velocity distribution of the ICPNs we infer that M87 and M86 are falling towards each other and that we may be observing them just before the first close pass. The inferred luminosity-specific PN numbers for the M87 halo and the ICL are in the range of values observed for old (> 10 Gyr) stellar populations (abridged).Comment: Accepted for publication in Astronomy and Astrophysics. 16 pages, 14 figures and 4 table

The Second INTEGRAL AGN Catalogue

The INTEGRAL mission provides a large data set for studying the hard X-ray properties of AGN and allows testing of the unified scheme for AGN. We present analysis of INTEGRAL IBIS/ISGRI, JEM-X, and OMC data for 199 AGN supposedly detected by INTEGRAL above 20 keV. The data analysed here allow a significant spectral extraction on 148 objects and an optical variability study of 57 AGN. The slopes of the hard X-ray spectra of Seyfert 1 and Seyfert~2 galaxies are found to be consistent within the uncertainties, whereas higher cut-off energies and lower luminosities are measured for the more absorbed / type 2 AGN. The intermediate Seyfert 1.5 objects exhibit hard X-ray spectra consistent with those of Seyfert 1. When applying a Compton reflection model, the underlying continua appear the same in Seyfert 1 and 2 with photon index 2, and the reflection strength is about R = 1, when assuming different inclination angles. A significant correlation is found between the hard X-ray and optical luminosity and the mass of the central black hole in the sense that the more luminous objects appear to be more massive. There is also a general trend toward the absorbed sources and type 2 AGN having lower Eddington ratios. The black holemass appears to form a fundamental plane together with the optical and X-ray luminosity of the form Lv being proportional to Lx^0.6 M^0.2, similar to that found between radio luminosity Lr, Lx, and M. The unified model for Seyfert galaxies seems to hold, showing in hard X-rays that the central engine is the same in Seyfert 1 and 2, but seen under different inclination angles and absorption. (Abridged)Comment: 26 pages, 16 figures, accepted for publication in A&A. Corrections by language editor included in version

Electron transport properties of sub-3-nm diameter copper nanowires

Density functional theory and density functional tight-binding are applied to model electron transport in copper nanowires of approximately 1 nm and 3 nm diameters with varying crystal orientation and surface termination. The copper nanowires studied are found to be metallic irrespective of diameter, crystal orientation and/or surface termination. Electron transmission is highly dependent on crystal orientation and surface termination. Nanowires oriented along the [110] crystallographic axis consistently exhibit the highest electron transmission while surface oxidized nanowires show significantly reduced electron transmission compared to unterminated nanowires. Transmission per unit area is calculated in each case, for a given crystal orientation we find that this value decreases with diameter for unterminated nanowires but is largely unaffected by diameter in surface oxidized nanowires for the size regime considered. Transmission pathway plots show that transmission is larger at the surface of unterminated nanowires than inside the nanowire and that transmission at the nanowire surface is significantly reduced by surface oxidation. Finally, we present a simple model which explains the transport per unit area dependence on diameter based on transmission pathways results

Maser emission from SiO isotopologues traces the innermost 100 AU around Radio Source I in Orion BN/KL

We have used the Very Large Array (VLA) at 7 mm wavelength to image five rotational transitions (J=1-0) from three SiO isotopologues towards Orion BN/KL: 28SiO v=0,1,2; and 29SiO and 30SiO v=0. For the first time, we have mapped the 29SiO and 30SiO J=1-0 emission, established the maser nature of the emission, and confirmed association with the deeply embedded high-mass young stellar object commonly denoted radio Source I. The 28SiO v=0 maser emission shows a bipolar structure that extends over ~700 AU along a northeast-southwest axis, and we propose that it traces a bipolar outflow driven by Source I. The high-brightness isotopic SiO maser emission imaged with a ~0.2 arcsec resolution has a more compact distribution, generally similar to that of the 28SiO v=1,2 emission, and it probably traces bulk gas flows in a region of diameter <100 AU centered on Source I. On small scales of <10 AU, however, compact 29SiO/30SiO v=0 and 28SiO v=1,2 emission features may be offset from one another in position and line-of-sight velocity. From a radiative transfer analysis based on a large velocity gradient (LVG) pumping model, we derive similar temperatures and densities for the optimum excitation of both 29SiO/30SiO v=0 and 28SiO v=1,2 masers, significantly higher than required for 28SiO v=0 maser excitation. In order to account for the small-scale differences among the isotopologues (v=0) and the main species (v=1,2), follow-up radiative transfer modeling that incorporates non-local line overlap among transitions of all SiO isotopic species may be required.Comment: 10 pages, 3 figures, accepted for publication by Ap

High-excitation OH and H_2O lines in Markarian 231: the molecular signatures of compact far-infrared continuum sources

The ISO/LWS far-infrared spectrum of the ultraluminous galaxy Mkn 231 shows OH and H_2O lines in absorption from energy levels up to 300 K above the ground state, and emission in the [O I] 63 micron and [C II] 158 micron lines. Our analysis shows that OH and H_2O are radiatively pumped by the far-infrared continuum emission of the galaxy. The absorptions in the high-excitation lines require high far-infrared radiation densities, allowing us to constrain the properties of the underlying continuum source. The bulk of the far-infrared continuum arises from a warm (T_dust=70-100 K), optically thick (tau_100micron=1-2) medium of effective diameter 200-400 pc. In our best-fit model of total luminosity L_IR, the observed OH and H2O high-lying lines arise from a luminous (L/L_IR~0.56) region with radius ~100 pc. The high surface brightness of this component suggests that its infrared emission is dominated by the AGN. The derived column densities N(OH)>~10^{17} cm^{-2} and N(H_2O)>~6x10^{16} cm^{-2} may indicate XDR chemistry, although significant starburst chemistry cannot be ruled out. The lower-lying OH, [C II] 158 micron, and [O I] 63 micron lines arise from a more extended (~350 pc) starburst region. We show that the [C II] deficit in Mkn 231 is compatible with a high average abundance of C+ because of an extreme overall luminosity to gas mass ratio. Therefore, a [C II] deficit may indicate a significant contribution to the luminosity by an AGN, and/or by extremely efficient star formation.Comment: 16 pages, 6 figures, accepted for publication in The Astrophysical Journa

Constraints on the H2O formation mechanism in the wind of carbon-rich AGB stars

Context. The recent detection of warm H$_2$O vapor emission from the outflows of carbon-rich asymptotic giant branch (AGB) stars challenges the current understanding of circumstellar chemistry. Two mechanisms have been invoked to explain warm H$_2$O vapor formation. In the first, periodic shocks passing through the medium immediately above the stellar surface lead to H$_2$O formation. In the second, penetration of ultraviolet interstellar radiation through a clumpy circumstellar medium leads to the formation of H$_2$O molecules in the intermediate wind. Aims. We aim to determine the properties of H$_2$O emission for a sample of 18 carbon-rich AGB stars and subsequently constrain which of the above mechanisms provides the most likely warm H$_2$O formation pathway. Methods, Results, and Conclusions. See paper