Interfacing polymeric scaffolds with primary pancreatic ductal adenocarcinoma cells to develop 3D cancer models

We analyzed the interactions between human primary cells from pancreatic ductal adenocarcinoma (PDAC) and polymeric scaffolds to develop 3D cancer models useful for mimicking the biology of this tumor. Three scaffold types based on two biocompatible polymeric formulations, such as poly(vinyl alcohol)/gelatin (PVA/G) mixture and poly(ethylene oxide terephthalate)/poly(butylene terephthalate) (PEOT/PBT) copolymer, were obtained via different techniques, namely, emulsion and freeze-drying, compression molding followed by salt leaching, and electrospinning. In this way, primary PDAC cells interfaced with different pore topographies, such as sponge-like pores of different shape and size or nanofiber interspaces. The aim of this study was to investigate the influence played by the scaffold architecture over cancerous cell growth and function. In all scaffolds, primary PDAC cells showed good viability and synthesized tumor-specific metalloproteinases (MMPs) such as MMP-2, and MMP-9. However, only sponge-like pores, obtained via emulsion-based and salt leaching-based techniques allowed for an organized cellular aggregation very similar to the native PDAC morphological structure. Differently, these cell clusters were not observed on PEOT/PBT electrospun scaffolds. MMP-2 and MMP-9, as active enzymes, resulted to be increased in PVA/G and PEOT/PBT sponges, respectively. These findings suggested that spongy scaffolds supported the generation of pancreatic tumor models with enhanced aggressiveness. In conclusion, primary PDAC cells showed diverse behaviors while interacting with different scaffold types that can be potentially exploited to create stage-specific pancreatic cancer models likely to provide new knowledge on the modulation and drug susceptibility of MMPs

CLASH-VLT: Insights on the mass substructures in the Frontier Fields Cluster MACS J0416.1-2403 through accurate strong lens modeling

We present a detailed mass reconstruction and a novel study on the substructure properties in the core of the CLASH and Frontier Fields galaxy cluster MACS J0416.1-2403. We show and employ our extensive spectroscopic data set taken with the VIMOS instrument as part of our CLASH-VLT program, to confirm spectroscopically 10 strong lensing systems and to select a sample of 175 plausible cluster members to a limiting stellar mass of log(M_*/M_Sun) ~ 8.6. We reproduce the measured positions of 30 multiple images with a remarkable median offset of only 0.3" by means of a comprehensive strong lensing model comprised of 2 cluster dark-matter halos, represented by cored elliptical pseudo-isothermal mass distributions, and the cluster member components. The latter have total mass-to-light ratios increasing with the galaxy HST/WFC3 near-IR (F160W) luminosities. The measurement of the total enclosed mass within the Einstein radius is accurate to ~5%, including systematic uncertainties. We emphasize that the use of multiple-image systems with spectroscopic redshifts and knowledge of cluster membership based on extensive spectroscopic information is key to constructing robust high-resolution mass maps. We also produce magnification maps over the central area that is covered with HST observations. We investigate the galaxy contribution, both in terms of total and stellar mass, to the total mass budget of the cluster. When compared with the outcomes of cosmological $N$-body simulations, our results point to a lack of massive subhalos in the inner regions of simulated clusters with total masses similar to that of MACS J0416.1-2403. Our findings of the location and shape of the cluster dark-matter halo density profiles and on the cluster substructures provide intriguing tests of the assumed collisionless, cold nature of dark matter and of the role played by baryons in the process of structure formation.Comment: 26 pages, 22 figures, 7 tables; accepted for publication in the Astrophysical Journal. A high-resolution version is available at https://sites.google.com/site/vltclashpublic/publications/Grillo_etal_2014.pd

An Improved Calculation of the Non-Gaussian Halo Mass Function

The abundance of collapsed objects in the universe, or halo mass function, is an important theoretical tool in studying the effects of primordially generated non-Gaussianities on the large scale structure. The non-Gaussian mass function has been calculated by several authors in different ways, typically by exploiting the smallness of certain parameters which naturally appear in the calculation, to set up a perturbative expansion. We improve upon the existing results for the mass function by combining path integral methods and saddle point techniques (which have been separately applied in previous approaches). Additionally, we carefully account for the various scale dependent combinations of small parameters which appear. Some of these combinations in fact become of order unity for large mass scales and at high redshifts, and must therefore be treated non-perturbatively. Our approach allows us to do this, and to also account for multi-scale density correlations which appear in the calculation. We thus derive an accurate expression for the mass function which is based on approximations that are valid over a larger range of mass scales and redshifts than those of other authors. By tracking the terms ignored in the analysis, we estimate theoretical errors for our result and also for the results of others. We also discuss the complications introduced by the choice of smoothing filter function, which we take to be a top-hat in real space, and which leads to the dominant errors in our expression. Finally, we present a detailed comparison between the various expressions for the mass functions, exploring the accuracy and range of validity of each.Comment: 28 pages, 13 figures; v2: text reorganized and some figured modified for clarity, results unchanged, references added. Matches version published in JCA

Scale-Dependent Non-Gaussianity as a Generalization of the Local Model

We generalize the local model of primordial non-Gaussianity by promoting the parameter fNL to a general scale-dependent function fNL(k). We calculate the resulting bispectrum and the effect on the bias of dark matter halos, and thus the extent to which fNL(k) can be measured from the large-scale structure observations. By calculating the principal components of fNL(k), we identify scales where this form of non-Gaussianity is best constrained and estimate the overlap with previously studied local and equilateral non-Gaussian models.Comment: Accepted to JCAP. 22 pages, 4 figure

CLASH-VLT: A Highly Precise Strong Lensing Model of the Galaxy Cluster RXC J2248.7-4431 (Abell S1063) and Prospects for Cosmography

We perform a comprehensive study of the total mass distribution of the galaxy cluster RXCJ2248 ($z=0.348$) with a set of high-precision strong lensing models, which take advantage of extensive spectroscopic information on many multiply lensed systems. In the effort to understand and quantify inherent systematics in parametric strong lensing modelling, we explore a collection of 22 models where we use different samples of multiple image families, parametrizations of the mass distribution and cosmological parameters. As input information for the strong lensing models, we use the CLASH HST imaging data and spectroscopic follow-up observations, carried out with the VIMOS and MUSE spectrographs, to identify bona-fide multiple images. A total of 16 background sources, over the redshift range $1.0-6.1$, are multiply lensed into 47 images, 24 of which are spectroscopically confirmed and belong to 10 individual sources. The cluster total mass distribution and underlying cosmology in the models are optimized by matching the observed positions of the multiple images on the lens plane. We show that with a careful selection of a sample of spectroscopically confirmed multiple images, the best-fit model reproduces their observed positions with a rms of $0.3$ in a fixed flat $\Lambda$CDM cosmology, whereas the lack of spectroscopic information lead to biases in the values of the model parameters. Allowing cosmological parameters to vary together with the cluster parameters, we find (at $68\%$ confidence level) $\Omega_m=0.25^{+0.13}_{-0.16}$ and $w=-1.07^{+0.16}_{-0.42}$ for a flat $\Lambda$CDM model, and $\Omega_m=0.31^{+0.12}_{-0.13}$ and $\Omega_\Lambda=0.38^{+0.38}_{-0.27}$ for a universe with $w=-1$ and free curvature. Using toy models mimicking the overall configuration of RXCJ2248, we estimate the impact of the line of sight mass structure on the positional rms to be $0.3\pm 0.1$.(ABRIDGED)Comment: 23 pages, 13 figures, accepted for publication in A&

CLASH-VLT: The mass, velocity-anisotropy, and pseudo-phase-space density profiles of the z=0.44 galaxy cluster MACS 1206.2-0847

We use an unprecedented data-set of about 600 redshifts for cluster members, obtained as part of a VLT/VIMOS large programme, to constrain the mass profile of the z=0.44 cluster MACS J1206.2-0847 over the radial range 0-5 Mpc (0-2.5 virial radii) using the MAMPOSSt and Caustic methods. We then add external constraints from our previous gravitational lensing analysis. We invert the Jeans equation to obtain the velocity-anisotropy profiles of cluster members. With the mass-density and velocity-anisotropy profiles we then obtain the first determination of a cluster pseudo-phase-space density profile. The kinematics and lensing determinations of the cluster mass profile are in excellent agreement. This is very well fitted by a NFW model with mass M200=(1.4 +- 0.2) 10^15 Msun and concentration c200=6 +- 1, only slightly higher than theoretical expectations. Other mass profile models also provide acceptable fits to our data, of (slightly) lower (Burkert, Hernquist, and Softened Isothermal Sphere) or comparable (Einasto) quality than NFW. The velocity anisotropy profiles of the passive and star-forming cluster members are similar, close to isotropic near the center and increasingly radial outside. Passive cluster members follow extremely well the theoretical expectations for the pseudo-phase-space density profile and the relation between the slope of the mass-density profile and the velocity anisotropy. Star-forming cluster members show marginal deviations from theoretical expectations. This is the most accurate determination of a cluster mass profile out to a radius of 5 Mpc, and the only determination of the velocity-anisotropy and pseudo-phase-space density profiles of both passive and star-forming galaxies for an individual cluster [abridged]Comment: A&A in press; 22 pages, 19 figure

CLASH-VLT: Substructure in the galaxy cluster MACS J1206.2-0847 from kinematics of galaxy populations

In the effort to understand the link between the structure of galaxy clusters and their galaxy populations, we focus on MACSJ1206.2-0847 at z~0.44 and probe its substructure in the projected phase space through the spectrophotometric properties of a large number of galaxies from the CLASH-VLT survey. Our analysis is mainly based on an extensive spectroscopic dataset of 445 member galaxies, mostly acquired with VIMOS@VLT as part of our ESO Large Programme, sampling the cluster out to a radius ~2R200 (4 Mpc). We classify 412 galaxies as passive, with strong Hdelta absorption (red and blue galaxies, and with emission lines from weak to very strong. A number of tests for substructure detection are applied to analyze the galaxy distribution in the velocity space, in 2D space, and in 3D projected phase-space. Studied in its entirety, the cluster appears as a large-scale relaxed system with a few secondary, minor overdensities in 2D distribution. We detect no velocity gradients or evidence of deviations in local mean velocities. The main feature is the WNW-ESE elongation. The analysis of galaxy populations per spectral class highlights a more complex scenario. The passive galaxies and red strong Hdelta galaxies trace the cluster center and the WNW-ESE elongated structure. The red strong Hdelta galaxies also mark a secondary, dense peak ~2 Mpc at ESE. The emission line galaxies cluster in several loose structures, mostly outside R200. The observational scenario agrees with MACS J1206.2-0847 having WNW-ESE as the direction of the main cluster accretion, traced by passive galaxies and red strong Hdelta galaxies. The red strong Hdelta galaxies, interpreted as poststarburst galaxies, date a likely important event 1-2 Gyr before the epoch of observation. The emission line galaxies trace a secondary, ongoing infall where groups are accreted along several directions.Comment: A&A accepted, 19 pages, 30 figures, minor language change

CLASH-VLT: Dissecting the Frontier Fields Galaxy Cluster MACS J0416.1-2403 with ∼800\sim800 Spectra of Member Galaxies

We present VIMOS-VLT spectroscopy of the Frontier Fields cluster MACS~J0416.1-2403 (z=0.397). Taken as part of the CLASH-VLT survey, the large spectroscopic campaign provided more than 4000 reliable redshifts, including ~800 cluster member galaxies. The unprecedented sample of cluster members at this redshift allows us to perform a highly detailed dynamical and structural analysis of the cluster out to ~2.2$r_{200}$ (~4Mpc). Our analysis of substructures reveals a complex system composed of a main massive cluster ($M_{200}$~0.9$\times 10^{15} M_{\odot}$) presenting two major features: i) a bimodal velocity distribution, showing two central peaks separated by $\Delta V_{rf}$~1100 km s$^{-1}$ with comparable galaxy content and velocity dispersion, ii) a projected elongation of the main substructures along the NE-SW direction, with a prominent subclump ~600 kpc SW of the center and an isolated BCG approximately halfway between the center and the SW clump. We also detect a low mass structure at z~0.390, ~10' S of the cluster center, projected at ~3Mpc, with a relative line-of-sight velocity of $\Delta V_{rf}$~-1700 km s$^{-1}$. The cluster mass profile that we obtain through our dynamical analysis deviates significantly from the "universal" NFW, being best fit by a Softened Isothermal Sphere model instead. The mass profile measured from the galaxy dynamics is found to be in relatively good agreement with those obtained from strong and weak lensing, as well as with that from the X-rays, despite the clearly unrelaxed nature of the cluster. Our results reveal overall a complex dynamical state of this massive cluster and support the hypothesis that the two main subclusters are being observed in a pre-collisional phase, in line with recent findings from radio and deep X-ray data. With this article we also release the entire redshift catalog of 4386 sources in the field of this cluster.Comment: Accepted for publication on ApJS. Revised to match the accepted version; 21 pages, 18 figures, 9 tables. The CLASH-VLT spectroscopic catalogs are publicly available at: http://sites.google.com/site/vltclashpublic

Extragalactic Radio Continuum Surveys and the Transformation of Radio Astronomy

Next-generation radio surveys are about to transform radio astronomy by discovering and studying tens of millions of previously unknown radio sources. These surveys will provide new insights to understand the evolution of galaxies, measuring the evolution of the cosmic star formation rate, and rivalling traditional techniques in the measurement of fundamental cosmological parameters. By observing a new volume of observational parameter space, they are also likely to discover unexpected new phenomena. This review traces the evolution of extragalactic radio continuum surveys from the earliest days of radio astronomy to the present, and identifies the challenges that must be overcome to achieve this transformational change.Comment: To be published in Nature Astronomy 18 Sept 201

Optimal MHC-II-restricted tumor antigen presentation to CD4+ T helper cells: the key issue for development of anti-tumor vaccines

Present immunoprevention and immunotherapeutic approaches against cancer suffer from the limitation of being not “sterilizing” procedures, as very poor protection against the tumor is obtained. Thus newly conceived anti-tumor vaccination strategies are urgently needed. In this review we will focus on ways to provide optimal MHC class II-restricted tumor antigen presentation to CD4+ T helper cells as a crucial parameter to get optimal and protective adaptive immune response against tumor. Through the description of successful preventive or therapeutic experimental approaches to vaccinate the host against the tumor we will show that optimal activation of MHC class II-restricted tumor specific CD4+ T helper cells can be achieved in various ways. Interestingly, the success in tumor eradication and/or growth arrest generated by classical therapies such as radiotherapy and chemotherapy in some instances can be re-interpreted on the basis of an adaptive immune response induced by providing suitable access of tumor-associated antigens to MHC class II molecules. Therefore, focussing on strategies to generate better and suitable MHC class II–restricted activation of tumor specific CD4+ T helper cells may have an important impact on fighting and defeating cancer