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Oncolytic viral (OV) therapy, which uses genetically engineered tumor-targeting viruses, is being increasingly used in cancer clinical trials due to the direct cytolytic effects of this treatment that appear to provoke a robust immune response against the tumor. As OVs enter tumor cells, intrinsic host defenses have the potential to hinder viral replication and spread within the tumor mass. In this report, we show that histone deacetylase 6 (HDAC6) in tumor cells appears to alter the trafficking of post-entry OVs from the nucleus toward lysosomes. In glioma cell lines and glioma-stem-like cells, HDAC6 inhibition (HDAC6i) by either pharmacologic or genetic means substantially increased replication of oncolytic herpes simplex virus type 1 (oHSV). Moreover, HDAC6i increased shuttling of post-entry oHSV to the nucleus. In addition, electron microscopic analysis revealed that post-entry oHSVs are preferentially taken up into glioma cells through the endosomal pathway rather than via fusion at the cell surface. Together, these findings illustrate a mechanism of glioma cell defense against an incoming infection by oHSV and identify possible approaches to enhance oHSV replication and subsequent lysis of tumor cells.

The Cherenkov Telescope Array (CTA), the new generation very high-energy gamma-ray observatory, will improve the flux sensitivity of the current Cherenkov telescopes by an order of magnitude over a continuous range from about 10 GeV to above 100 TeV. With tens of telescopes distributed in the Northern and Southern hemispheres, the large effective area and field of view coupled with the fast pointing capability make CTA a crucial instrument for the detection and understanding of the physics of transient, short-timescale variability phenomena (e.g. Gamma-Ray Bursts, Active Galactic Nuclei, gamma-ray binaries, serendipitous sources). The key CTA system for the fast identification of flaring events is the Real-Time Analysis (RTA) pipeline, a science alert system that will automatically detect and generate science alerts with a maximum latency of 30 seconds with respect to the triggering event collection and ensure fast communication to/from the astrophysics community. According to the CTA design requirements, the RTA search for a true transient event should be performed on multiple time scales (from minutes to hours) with a sensitivity not worse than three times the nominal CTA sensitivity. Given the CTA requirement constraints on the RTA efficiency and the fast response ability demanded by the transient science, we perform a preliminary evaluation of the RTA sensitivity as a function of the CTA high-level technical performance (e.g. effective area, point spread function) and the observing time. This preliminary approach allows the exploration of the complex parameter space defined by the scientific and technological requirements, with the aim of defining the feasibility range of the input parameters and the minimum background rejection capability of the RTA pipeline., In Proceedings of the 34th International Cosmic Ray Conference (ICRC2015), The Hague, The Netherlands. All CTA contributions at arXiv:1508.05894

Overexpression of ATAD2 (ATPase family, AAA domain containing 2) has been linked to disease severity and progression in a wide range of cancers, and is implicated in the regulation of several drivers of cancer growth. Little is known of the dependence of these effects upon the ATAD2 bromodomain, which has been categorized as among the least tractable of its class. The absence of any potent, selective inhibitors limits clear understanding of the therapeutic potential of the bromodomain. Here, we describe the discovery of a hit from a fragment-based targeted array. Optimization of this produced the first known micromolar inhibitors of the ATAD2 bromodomain.

Glioblastoma (GB) remains the most aggressive primary brain malignancy. Adoptive transfer of chimeric antigen receptor (CAR)-modified immune cells has emerged as a promising anti-cancer approach, yet the potential utility of CAR-engineered natural killer (NK) cells to treat GB has not been explored. Tumors from approximately 50% of GB patients express wild-type EGFR (wtEGFR) and in fewer cases express both wtEGFR and the mutant form EGFRvIII; however, previously reported CAR T cell studies only focus on targeting EGFRvIII. Here we explore whether both wtEGFR and EGFRvIII can be effectively targeted by CAR-redirected NK cells to treat GB. We transduced human NK cell lines NK-92 and NKL and primary NK cells with a lentiviral construct harboring a second generation CAR targeting both wtEGFR and EGFRvIII and evaluated the anti-GB efficacy of EGFR-CAR-modified NK cells. EGFR-CAR-engineered NK cells displayed enhanced cytolytic capability and IFN-γ production when co-cultured with GB cells or patient-derived GB stem cells in an EGFR-dependent manner. In two orthotopic GB xenograft mouse models, intracranial administration of NK-92-EGFR-CAR cells resulted in efficient suppression of tumor growth and significantly prolonged the tumor-bearing mice survival. These findings support intracranial administration of NK-92-EGFR-CAR cells represents a promising clinical strategy to treat GB.

© 2015. The American Astronomical Society. All rights reserved. We present the analysis of the radio jet evolution of the radio galaxy 3C 120 during a period of prolonged γ-ray activity detected by the Fermi satellite between 2012 December and 2014 October. We find a clear connection between the γ-ray and radio emission, such that every period of γ-ray activity is accompanied by the flaring of the millimeter very long baseline interferometry (VLBI) core and subsequent ejection of a new superluminal component. However, not all ejections of components are associated with γ-ray events detectable by Fermi. Clear γ-ray detections are obtained only when components are moving in a direction closer to our line of sight. This suggests that the observed γ-ray emission depends not only on the interaction of moving components with the millimeter VLBI core, but also on their orientation with respect to the observer. Timing of the γ-ray detections and ejection of superluminal components locate the γ-ray production to within ∼0.13 pc from the millimeter VLBI core, which was previously estimated to lie about 0.24 pc from the central black hole. This corresponds to about twice the estimated extension of the broad line region, limiting the external photon field and therefore suggesting synchrotron self Compton as the most probable mechanism for the production of the γ-ray emission. Alternatively, the interaction of components with the jet sheath can provide the necessary photon field to produced the observed γ-rays by Compton scattering., his research has been supported by the Spanish Ministry of Science and Innovation grants AYA2010-14844, and AYA2013-40825 P, and by the Regional Government of Andalucia (Spain) grant P09-FQM-4784. This research was partly supported by the Russian Foundation for Basic Research grant 13-02-12103 and by the Academy of Finland project 274477.

著者人数：11名, Accepted: 2005-06-13, 資料番号: SA1000579000

Glioblastoma Multiforme (GBM) is an aggressive brain cancer for which there is no effective treatment. Oncolytic HSV vectors (oHSV) are attenuated lytic viruses that have shown promise in the treatment of human GBM models in animals. Although proven safe for treatment of GBM in patients, oHSVs efficacy has been limited, a consequence of poor intra-tumoral virus replication and spread. To counter these limitations, we have developed oHSVs whose selective replication in GBM cells does not rely on defective genes. This was accomplished by (i) full retargeting of oHSV to utilize the epidermal growth factor receptor (EGFR) for infection of human GBM tumor cells and (ii) further vector engineering to modify the essential HSV immediate early gene (ICP4) for sensitivity to repression by the microRNA mir-124. Mir-124 is highly expressed in neurons but virtually absent in GBM and highly conserved among different species. The mir-124-regulated vector was unable to replicate in nude mice following intracranial inoculation supporting vector safety and was shown to be effective (50-60% long term survival) in the treatment of human GBM in nude mice. To enhance vector intra-tumor vector spread, our EGFR retargeted-mir-124 controlled vector was further modified by vector arming with the matrix metalloproteinase gene encoding MMP9. MMP9 degrades collagen type IV, a major component of the extracellular matrix (ECM) and basement membranes of glioblastomas but absent in normal brain tissue. Studies are ongoing to determine whether MMP9 expression enhances vector spread in GBM neurospheres and as a therapeutic agent for enhanced treatment of human GBM in animals.

We have carried out a systematic analysis of all the AGN brighter than 1 Jansky at 5 GHz available in the BeppoSAX public archive. Our sample includes a total of 26 Radio-Loud AGN, 10 of which are Broad Line Radio Galaxies (BLRGs), 4 Steep Spectrum Radio Quasars (SSRQs) and 12 Flat Spectrum Radio Quasars (FSRQs). Our analysis shows spectral differences (spectral slopes, column densities and reprocessed features) among the different classes of radio-loud AGN. In addition, when compared to Seyfert 1 galaxies, BLRGs appear to have weaker iron lines. Possible reasons responsible for the observed X-ray spectral differences are investigated.

Several techniques have been developed to deliver DNA directly into mammalian cells, spanning in difficulty from simple mixing procedures to complex systems requiring expensive equipment. Viral vectors have proven able to deliver genes into mammalian cells with high efficiency and low toxicity. In particular, herpes simplex virus type-1 (HSV-1) amplicon vectors are well suited for gene transfer studies as they can infect many cell types, both non-dividing and dividing, have a large transgene capacity and are easy to manipulate. For some applications, it may be desirable to target gene delivery to specific cell populations or to transduce normally non-susceptible cells. This can be achieved by modifying one or more of the glycoproteins found in the viral envelope. Glycoprotein C (gC) has a well-characterized heparan sulfate binding domain (HSBD) necessary for HSV binding to cells. Replacing this region with unique ligands can result in less efficient binding to natural target cells and increase binding to cells which express receptors for these ligands. A method to retarget amplicon vectors by replacing gC HSBD with a model ligand, the hexameric histidine-tag, is described, as well as means to evaluate the binding of modified vector as compared to wild-type virus to cells with or without the appropriate receptor, in this case, a his-tag pseudo-receptor. This protocol demonstrates increased binding of modified virus to receptor-positive cells (at levels greater than wild-type) with no loss of infectivity. Retargeted vectors can provide an additional tool for increasing the efficiency of gene delivery to specific cell types.

Expression of specific peptide epitopes on the surface of virions has significant potential for studying viral biology and designing vectors for targeted gene therapy. In this study, an HSV-1 amplicon plasmid expressing a modified glycoprotein C (gC), in which the heparan sulfate binding domain was replaced with a His-tag, was used in generating HSV-1 virions. Western blot analysis demonstrated the presence of modified gC in the purified virions. The amplicon vectors were packaged using a gC-, lacZ+ helper virus to generate a mixture of high-titer helper virus (lacZ+) and amplicon vectors (GFP+), which expressed modified gC in the virion envelope. His-tagged virions bound to 293 6H cells expressing a cell surface pseudo-His-tag receptor four-fold more efficiently than to parental 293 cells and also proved more effective than wild-type virus in binding to both cell types. Binding resulted in productive infection by the modified virions with expression of reporter genes and cytopathic effect comparable to those of wild-type virions. Thus, not only can HSV-1 tropism be manipulated to recognize a non-herpes simplex binding receptor, but it is also possible to increase the infective capacity of the vectors beyond that of the wild-type virus via specific ligand receptor combinations.

We report the hard X-ray spectrum of the Coma cluster obtained using the PDS data of two independent BeppoSAX observations performed with a time interval of about three years. In both the spectra a non thermal excess with respect to the thermal emission is present at a confidence level of ~ 3.4 sigma. The combined spectrum obtained by adding up the two spectra allows a measurement of the excess at the level of ~ 4.8 sigma at energies above 20 keV. The analysis of the full BeppoSAX data set provides a revised non-thermal X-ray flux which is slightly lower than that previously estimated (Fusco-Femiano et al. 1999) and in agreement with that measured by two RXTE observations. The analysis of the offset fields in our Coma observations provides a possible flux determination of the BL Lac object 1ES 1255+244., Comment: 14 Pages, 1 figure. Accepted for publication on ApJ Letters

Europe is one of the major partners building the International Space Station (ISS) and European industry, together with ESA, is responsible for many station components including the Columbus Orbital Facility, the Automated Transport Vehicle, two connecting modules and the European Robotic Arm. Together with this impressive list of contributions there is a strong desire within the ESA Member States to benefit from this investment by utilizing the unique capabilities of the ISS to perform world-class science. XEUS is one of the astronomical applications being studied by ESA to utilize the capabilities of the ISS. XEUS will be a long-term X-ray observatory with an initial mirror area of 6 m 2 at 1 keV that will be expanded to 30 m 2 following a visit to the ISS. The 1 keV spatial resolution is expected to be 2–5″ half-energy-width. XEUS will consist of separate detector and mirror spacecraft (MSC) aligned by active control to provide a focal length of 50 m. A new detector spacecraft, complete with the next generation of instruments, will also be added after visiting the ISS. The limiting 0.1–2.5 keV sensitivity will then be 4 × 10 −18 erg cm −2 s −1 , around 200 times better than XMM-Newton, allowing XEUS to study the properties of the hot baryons and dark matter at high redshift.

The XMM-Newton satellite has revealed extended X-ray emission from the eastern radio lobe of the Fanaroff-Riley II Radio Galaxy Pictor A. The X-ray spectrum, accumulated on a region covering about half the entire radio lobe, is well described by both a thermal model and a power law. The X-ray emission could be thermal and produced by circum-galactic gas shocked by the expanding radio lobe or, alternatively, by Inverse Compton (IC) of cosmic microwave background photons by relativistic electrons in the lobe. The latter possibility seems to be supported by the good agreement between the lobe-average synchrotron radio index and the X-ray energy slope. However, if this is the case, the magnetic field, as deduced from the comparison of the IC X-ray and radio fluxes, is more than a factor 2 below the equipartition value estimated in the same X-ray region., Comment: 8 pages, 5 figures; accepted for publication in ApJ

We report the BeppoSAX observations of 6 Flat Spectrum Radio Quasars. Three of them have a clear detection up to 100 keV with the PDS instrument. For 4 objects the X-ray spectrum is satisfactorily fitted by a power-law continuum with Galactic absorption. 2251+158 show the presence of absorption higher than the galactic value, while the spectrum of the source 0208-512 shows a complex structure, with evidence of absorption at low energy. We construct the Spectral Energy Distributions adding historical data to the broad band X-ray spectra obtained with $Beppo$SAX and reproduce them with a one-zone Synchrotron-Inverse Compton model (including both SSC and External Compton). The implications are briefly discussed., Comment: 5 figures; ApJ, in press

We briefly review BeppoSAX observations of X-ray bright radio-galaxies. Their X-ray spectra are quite varied, and perhaps surprisingly, any similarity between radio-loud AGN and Seyfert galaxies is the exception rather than the rule. When detected, reprocessing features (iron line and reflection) are generally weak, suggesting two possible scenarios: either: (1) non-thermal (jet?) radiation dilutes the X-ray emission from the disk in radio-loud objects, or (2) the solid angle subtended by the X-ray reprocessing material is smaller in radio-loud than in radio-quiet AGN due to different characteristics of the accretion disk itself., Comment: 6 pages, to appear in `Life Cycles of Radio Galaxies', ed. J. Biretta et al., New Astronomy Reviews

We present BeppoSAX spectra of the extremely luminous and massive object η Car observed in a very broad X-ray range (0.1-200 keV) during high state (December 1996) and egress from the last low state (March 1998). Both spectra are composed of at least two components, a soft one with kT s < 0.7 keV, and a hard with kT h = 4.7 keV. We found in March 1998 a large flux defect in the 1.5-4 keV range, while the flux remained constant below 1.5 keV and above 5 keV. We attribute this defect to a x3.5 increase of the absorbing matter in front of the hard component, while its temperature and unabsorbed luminosity were nearly the same in the two epochs. In December 1996 the PDS X-ray flux in the 13-20 keV range is larger than the extrapolated hard spectrum, indicating the presence of an even harder additional component, which possibly declined during the March 1998 low state. Conversely, we find that at that time, the flux of the 6.7 keV iron line was 40% stronger. Coordinated optical and NIR spectroscopic observations indicate that in March 1998 η Car was still in a state of low excitation of the emission line spectrum, with extended P Cygni absorptions. These results indicate that after the X-ray flux minimum, the hard component recovered its high state luminosity more rapidly than the high ionization spectral lines, but in the meantime it was partly occulted by a large amount of absorbing matter placed in front of the source. These results are discussed in the framework of the proposed binary model of η Car.

Genes encoding subunits of the mammalian SWI/SNF (BAF) ATP-dependent chromatin remodeling complexes are mutated in over 20% of human cancer. Specific subunits are mutated in specific malignancies, highlighting their tissue-specific protective roles; moreover, synthetic lethal screens have uncovered genetic- and lineage-based features which confer dependence on specific mSWI/SNF subunits. As combinatorial complexity represents a major challenge, identification of specialized mSWI/SNF configurations, subunit-specific functions, binding restrictions, and exclusivity relationships is critical for understanding oncogenic mechanisms and for the selection of appropriate therapeutic agents targeting mSWI/SNF complex subunits. Here, we discover that BRD9, a recently identified mSWI/SNF subunit, defines a novel complex configuration distinct from BAF and PBAF, which we term non-canonical BAF, or ncBAF. We used biochemical methods to isolate BRD9-containing complexes and find that BRD9 selectively marks a sub-stoichiometric group of mSWI/SNF complexes of smaller molecular weight that lack several members of canonical BAF complexes such as BAF47 and ARID1A. Moreover, chemoproteomics using a BRD9 inhibitor (GSK) isolates only ncBAF and does not resolve BAF-specific or PBAF-specific components, including the highly related bromodomain-containing subunit BRD7. We further identified regions of BRD9 and BRD7 that confer specificity of these subunits to ncBAF and PBAF complexes, respectively, resolving their mSWI/SNF binding domains. Using genome-wide ChIP-seq and RNA-seq experiments, we determined that ncBAF complexes target a distinct subset of all mSWI/SNF complex target genes and, consistent with previous studies, maintain proliferation of AML cells. Finally, we applied a newly- generated approach to deriving functional relationships within and between protein complex families from shRNA and CRISPR-based genetic screening datasets across hundreds of cancer cell lines to explore ncBAF-specific subunits. We find that ncBAF-specific complex subunits form a distinct functional module, supporting biochemical studies and pointing to the specific and divergent functions of the ncBAF configuration. Cancers of hematologic origin collectively exhibit the most significant responses to perturbation of three ncBAF subunits including BRD9, substantiating previous small molecule screening efforts using BRD9 bromodomain inhibitors. These data demonstrate that ncBAF complexes represent a novel BAF complex composition with distinct function in cancer. Citation Format: Brittany C. Michel, Joshua Pan, Robin M. Meyers, Paola Grandi, Phillip G. Humphreys, Neil G. Garton, Rab K. Prinja, Cigall Kadoch. BRD9 defines a novel mammalian SWI/SNF (BAF) complex configuration which supports proliferation in AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1020. doi:10.1158/1538-7445.AM2017-1020

The Large Area Telescope on board the Fermi Gamma-ray Space Telescope detected a strong gamma-ray flare on 2011 May 15 from a source identified as 4C 49.22, a flat spectrum radio quasar also known as S4 1150+49. This blazar, characterised by a prominent radio-optical-X-ray jet, was in a low gamma-ray activity state during the first years of Fermi observations. Simultaneous observations during the quiescent, outburst and post-flare gamma-ray states were obtained by Swift, Planck and optical-IR-radio telescopes (INAOE, Catalina CSS, VLBA, Metsahovi). The flare is observed from microwave to X-ray bands with correlated variability and the Fermi, Swift and Planck data for this FSRQ show some features more typical of BL Lac objects, like the synchrotron peak in the optical band that outshines the thermal blue-bump emission, and the X-ray spectral softening. Multi-epoch VLBA observations show the ejection of a new component close in time with the GeV gamma-ray flare. The radio-to-gamma-ray spectral energy distribution is modeled and fitted successfully for the outburst and the post-flare epochs using either a single flaring blob with two emission processes (synchrotron self Compton, and external-radiation Compton), and a two-zone model with SSC-only mechanism., 20 pages, 12 figures and 12 tables and accepted by MNRAS

The Cherenkov Telescope Array (CTA) observatory will be one of the biggest ground-based very-high-energy (VHE) gamma-ray observatory. CTA will achieve a factor of 10 improvement in sensitivity from some tens of GeV to beyond 100 TeV with respect to existing telescopes. The CTA observatory will be capable of issuing alerts on variable and transient sources to maximize the scientific return. To capture these phenomena during their evolution and for effective communication to the astrophysical community, speed is crucial. This requires a system with a reliable automated trigger that can issue alerts immediately upon detection of gamma-ray flares. This will be accomplished by means of a Real-Time Analysis (RTA) pipeline, a key system of the CTA observatory. The latency and sensitivity requirements of the alarm system impose a challenge because of the anticipated large data rate, between 0.5 and 8 GB/s. As a consequence, substantial efforts toward the optimization of high-throughput computing service are envisioned. For these reasons our working group has started the development of a prototype of the Real-Time Analysis pipeline. The main goals of this prototype are to test: (i) a set of frameworks and design patterns useful for the inter-process communication between software processes running on memory; (ii) the sustainability of the foreseen CTA data rate in terms of data throughput with different hardware (e.g. accelerators) and software configurations, (iii) the reuse of non-real-time algorithms or how much we need to simplify algorithms to be compliant with CTA requirements, (iv) interface issues between the different CTA systems. In this work we focus on goals (i) and (ii).

Replication protein A (RP-A) is involved in DNA replication, repair and recombination. It has been demonstrated that RP-A clusters in foci prior to DNA replication and redistributes over chromatin during S-phase. Here, we show that RP-A foci also form in response to DNA double-strand (ds) breaks produced on Xenopus laevis sperm nuclei by restriction enzymes and then reconstituted with Xenopus egg high-speed extracts. Ku86 co-localizes with RP-A in the same foci. An unscheduled RP-A-dependent DNA synthesis takes place overlapping with RP-A and Ku86 foci. Immunoelectron-microscopy analysis reveals that these foci correspond to spherical bodies up to 300 nm in diameter, which contain RP-A, Ku86 and DNA. In an independent in vitro assay, we incubated linear dsDNA bound to magnetic beads with Xenopus egg extracts. Here, also RP-A and Ku cluster in foci as seen through immunofluorescence. Both proteins appear to enrich themselves in sequences near the ends of the DNA molecules and influence ligation efficiency of ds linear DNA to these ends. Thus, the Xenopus in vitro system allows for the generation of specific DNA ds breaks, RP-A and Ku can be used as markers for these lesions and the repair of this type of DNA damage can be studied under conditions of a normal nuclear environment.

A nuclear GTPase, Nug1p, was identified in a genetic screen for components linked to 60S ribosomal subunit export. Nug1p cosedimented with nuclear 60S preribosomes and was required for subunit export to the cytoplasm. Tagged Nug1p coprecipitated with proteins of the 60S subunit, late precursors to the 25S and 5.8S rRNAs, and at least 21 nonribosomal proteins. These included a homologous nuclear GTPase, Nug2p, the Noc2p/Noc3p heterodimer, Rix1p, and Rlp7p, each of which was implicated in 60S subunit export. Other known ribosome synthesis factors and proteins of previously unknown function, including the 559 kDa protein Ylr106p, also copurified. Eight of these proteins were copurified with nuclear pore complexes, suggesting that this complex represents the transport intermediate for 60S subunit export.

To date, the in vivo importance of chromatin assembly factors during development in vertebrates is unknown. Chromatin assembly factor 1 (CAF-1) represents the best biochemically characterized factor promoting chromatin assembly during DNA replication or repair in human cell-free systems. Here, we identify a Xenopus homologue of the largest subunit of CAF-1 (p150). Novel dimerization properties are found conserved in both Xenopus and human p150. A region of 36 amino acids required for p150 dimerization was identified. Deletion of this domain abolishes the ability of p150 to promote chromatin assembly in vitro. A dominant-negative interference based on these dimerization properties occurs both in vitro and in vivo. In the embryo, nuclear organization was severely affected and cell cycle progression was impaired during the rapid early cleaving stages of Xenopus development. We propose that the rapid proliferation at early developmental stages necessitates the unique properties of an assembly factor that can ensure a tight coupling between DNA replication or repair and chromatin assembly.

We study a broad-band X-ray observation by BeppoSAX of the broad-line radio galaxy 3C 120. The primary X-ray continuum is well described by a power law with the photon index of Gamma=1.85+-0.05 and a high-energy break or a cutoff. The obtained e-folding energy of about100-300 keV corresponds to kT of about 50 keV in thermal-Compton models. A soft X-ray excess is found at a statistical significance of >98%$ Our physical best-fit model of the excess is optically-thin emission from an extended plasma (with a luminosity of 2% of the total X-ray luminosity), which interpretation is supported by an independent finding of an extended soft X-ray halo in 3C 120. We find a moderate Compton reflection component together with a moderately broad Fe K alpha line with an equivalent width fully consistent with the strength of reflection, indicating their origin in an optically-thick accretion disk extending relatively close to the central black hole. We observe strong spectral variability during our 2-day observation with Gamma varying from 1.7 to 2.0 and correlated with the soft X-ray flux. The variability is very well modeled by thermal Comptonization in a hot plasma irradiated by a variable UV flux. Both a hot patchy corona outflowing with a mildly relativistic velocity away from a cold disk and a hot inner accretion flow overlapping with the cold disk are viable geometries. The presence of an outflow in the first case and an overlap between the hot and cold phases in the second case are required by energy balance and the observed strength of Compton reflection., ApJ, in press, 16 pages, p. 9 is in color

Sensing DNA damage is crucial for the maintenance of genomic integrity and cell cycle progression. The participation of chromatin in these events is becoming of increasing interest. We show that the presence of single-strand breaks and gaps, formed either directly or during DNA damage processing, can trigger the propagation of nucleosomal arrays. This nucleosome assembly pathway involves the histone chaperone chromatin assembly factor 1 (CAF-1). The largest subunit (p150) of this factor interacts directly with proliferating cell nuclear antigen (PCNA), and critical regions for this interaction on both proteins have been mapped. To isolate proteins specifically recruited during DNA repair, damaged DNA linked to magnetic beads was used. The binding of both PCNA and CAF-1 to this damaged DNA was dependent on the number of DNA lesions and required ATP. Chromatin assembly linked to the repair of single-strand breaks was disrupted by depletion of PCNA from a cell-free system. This defect was rescued by complementation with recombinant PCNA, arguing for role of PCNA in mediating chromatin assembly linked to DNA repair. We discuss the importance of the PCNA–CAF-1 interaction in the context of DNA damage processing and checkpoint control.

We report on a ongoing campaign of multiwavelength observations of the superluminous galactic object η Carinae, following its mid 1992 low state. The BeppoSAX LECS and MECS observations of December 1996 detected many sources in the η Car field. η Car itself is by far the brightest, with a multi-component spectrum. The object was in a high state in agreement with ASCA and RossiXTE observations. Optical (LNA), ultraviolet (IUE), and radio observations indicate a general flux modulation following the 5.52 y cycle. A gradual decrease of these fluxes since 1995 are suggestive of the approaching of the next low state.

We present the results from ASCA and OSSE simultaneous observations of the Seyfert 1.5 galaxy MCG+8-11-11 performed in August-September 1995. The ASCA observations indicate a modest flux increase (20%) in 3 days, possibly correlated to a softening of the 0.6-9 keV spectrum. The spectrum is well described by a hard power law (Gamma=1.64) absorbed by a column density slightly larger than the Galactic value, with an iron line at 6.4 keV of EW=400 eV. The simultaneous OSSE data are characterized by a much softer power law with photon index Gamma=3.0, strongly suggesting the presence of a spectral break in the hard X/soft gamma-ray band. A joint fit to OSSE and ASCA data clearly shows an exponential cut-off at about 300 keV, and strong reflection component. MCG+8-11-11 features a spectral break in the underlying continuum unambiguously. This, together with the inferred low compactness of this source, favours thermal or quasi-thermal electron Comptonization in a structured Corona as the leading process of high energy radiation production., 13 pages, + 4 figure.ps AAS LateX [11pt,aasms4]{article} To be published in ApJ, Main Journal

PKS 2155-304, the brightest BL Lac object in the ultraviolet sky, was monitored with the IUE satellite at ~1 hour time-resolution for ten nearly uninterrupted days in May 1994. The campaign, which was coordinated with EUVE, ROSAT, and ASCA monitoring, along with optical and radio observations from the ground, yielded the largest set of spectra and the richest short time scale variability information ever gathered for a blazar at UV wavelengths. The source flared dramatically during the first day, with an increase by a factor ~2.2 in an hour and a half. In subsequent days, the flux maintained a nearly constant level for ~5 days, then flared with ~35% amplitude for two days. The same variability was seen in both short- and long-wavelength IUE light curves, with zero formal lag (~

Optical, near-infrared, and radio observations of the BL Lac object PKS2155-304 were obtained simultaneously with a continuous UV/EUV/X-ray monitoring campaign in 1994 May. Further optical observations were gathered throughout most of 1994. The radio, millimeter, and near-infrared data show no strong correlations with the higher energies. The optical light curves exhibit flickering of 0.2-0.3 mag on timescales of 1-2 days, superimposed on longer timescale variations. Rapid variations of ~0.01 mag/min, which, if real, are the fastest seen to date for any BL Lac object. Small (0.2-0.3 mag) increases in the V and R bands occur simultaneously with a flare seen at higher energies. All optical wavebands (UBVRI) track each other well over the period of observation with no detectable delay. For most of the period the average colors remain relatively constant, although there is a tendency for the colors (in particular B-V) to vary more when the source fades. In polarized light, PKS 2155-304 showed strong color dependence and the highest optical polarization (U = 14.3%) ever observed for this source. The polarization variations trace the flares seen in the ultraviolet flux., 45 pages, latex file with encapsulated postscript, accepted to the Astrophysical Journal

The Cherenkov Telescope Array (CTA) is a new observatory for very high-energy (VHE) gamma rays. CTA has ambitions science goals, for which it is necessary to achieve full-sky coverage, to improve the sensitivity by about an order of magnitude, to span about four decades of energy, from a few tens of GeV to above 100 TeV with enhanced angular and energy resolutions over existing VHE gamma-ray observatories. An international collaboration has formed with more than 1000 members from 27 countries in Europe, Asia, Africa and North and South America. In 2010 the CTA Consortium completed a Design Study and started a three-year Preparatory Phase which leads to production readiness of CTA in 2014. In this paper we introduce the science goals and the concept of CTA, and provide an overview of the project., La lista completa de autores puede consultarse en el documento o en la página web de la revista., Facultad de Ingeniería

The astrophysical journal 765(1), 54 (2013). doi:10.1088/0004-637X/765/1/54, The Large Area Telescope (LAT) on the Fermi Gamma-ray Space Telescope is a pair-conversion telescope designed to detect photons with energies from ≈20 MeV to >300 GeV. The pre-launch response functions of the LAT were determined through extensive Monte Carlo simulations and beam tests. The point-spread function (PSF) characterizing the angular distribution of reconstructed photons as a function of energy and geometry in the detector is determined here from two years of on-orbit data by examining the distributions of γ rays from pulsars and active galactic nuclei (AGNs). Above 3 GeV, the PSF is found to be broader than the pre-launch PSF. We checked for dependence of the PSF on the class of γ-ray source and observation epoch and found none. We also investigated several possible spatial models for pair-halo emission around BL Lac AGNs. We found no evidence for a component with spatial extension larger than the PSF and set upper limits on the amplitude of halo emission in stacked images of low- and high-redshift BL Lac AGNs and the TeV blazars 1ES0229+200 and 1ES0347–121, Published by Univ.11032, Chicago, Ill. [u.a.]

Glioblastoma multiforme (GBM) remains an untreatable human brain malignancy. Despite promising preclinical studies using oncolytic herpes simplex virus (oHSV) vectors, efficacy in patients has been limited by inefficient virus replication in tumor cells. This disappointing outcome can be attributed in part to attenuating mutations engineered into these viruses to prevent replication in normal cells. Alternatively, retargeting of fully replication-competent HSV to tumor-associated receptors has the potential to achieve tumor specificity without impairment of oncolytic activity. Here, we report the establishment of an HSV retargeting system that relies on the combination of two engineered viral glycoproteins, gD and gB, to mediate highly efficient HSV infection exclusively through recognition of the abundantly expressed epidermal growth factor receptor (EGFR) on glioblastoma cells. We demonstrate efficacy in vitro and in a heterotopic tumor model in mice. Evidence for systemically administered virus homing to the tumor mass is presented. Treatment of orthotopic primary human GBM xenografts demonstrated prolonged survival with up to 73% of animals showing a complete response as confirmed by magnetic resonance imaging. Our study describes an approach to HSV retargeting that is effective in a glioma model and may be applicable to the treatment of a broad range of tumor types.

We present multi-wavelength studies of the radio galaxy 3C 120 and the blazar CTA 102 during unprecedented γ-ray flares for both sources. In both studies the analysis of γ-ray data has been compared with a series of 43 GHz VLBA images from the VLBA-BU-BLAZAR program, providing the necessary spatial resolution to probe the parsec scale jet evolution during the high energy events. To extend the radio dataset for 3C 120 we also used 15 GHz VLBA data from the MOJAVE sample. These two objects which represent very different classes of AGN, have similar properties during the γ-ray events. The γ-ray flares are associated with the passage of a new superluminal component through the mm VLBI core, but not all ejections of new components lead to γ-ray events. In both sources γ-ray events occurred only when the new components are moving in a direction closer to our line of sight. We locate the γ-ray dissipation zone a short distance from the radio core but outside of the broad line region, suggesting synchrotron self-Compton scattering as the probable mechanism for the γ-ray production.

Background: Diffuse gliomas are fatal primary brain tumors that are poorly immunogenic. The basis for insufficient anti-tumor immunity in diffuse gliomas is not understood. Gain of function mutations in isocitrate dehydrogenases (IDH1 and IDH2) promote diffuse glioma formation through epigenetic reprogramming of a number of genes, including immune-related genes. Here, we identify epigenetic dysregulation of natural killer (NK) cell ligand genes as significant contributors to immune escape in glioma. Methods: We analyzed the TCGA database for immune gene expression patterns in IDH mutant or wild-type gliomas and identified differentially expressed immune genes. NKG2D ligands expression levels and NK cell-mediated lysis were measured in IDH mutant and wild-type patient-derived glioma stem cells and in genetically engineered astrocytes. Finally, we assessed the impact of hypomethylating agent 5-aza- 2’deoxycytodine (Decitabine) as a potential NK cell sensitizing agent in IDH mutant cells. Results: All IDH mutant glioma stem-like cell lines exhibited significantly lower expression of NKG2D ligands compared with IDH wild-type cells. Consistent with these findings, IDH mutant glioma cells and astrocytes were resistant to NK cell- mediated lysis. The hypomethylating agent Decitabine increased NKG2D ligand expression, and restored NK-mediated lysis of IDH mutant cells in an NKG2D- dependent manner. Conclusions: IDH mutant glioma cells acquire resistance to NK cells through epigenetic silencing of NKG2D ligands ULBP1 and ULPB3. Decitabine-mediated hypomethylation restores ULBP1 and ULBP3 expression in IDH mutant glioma cells and may provide a clinically useful method to sensitize IDH mutant gliomas to NK cell- mediated immune surveillance in patients with IDH mutated diffuse gliomas. Citation Format: Aparna Rao, Xiaoran Zhang, Christopher Deibert, Paola Sette, Tim Chan, Paola Grandi, Nduka Amankulor. IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligands. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3235.

Radio, mm, optical, UV and X-ray light curves of 3C 279 as well as the gamma-ray light curve available since 1991 June are considered. Strong flux correlations are found between the X-ray and the radio-optical region. Variations at 100 MeV are well correlated to the optical and X-ray bands. The variability amplitude, as measured by an average logarithmic dispersion of the available measurements is small in the radio and increases systematically with increasing frequency up to the gamma-ray band, with the possible exception of the X-ray amplitude.

Background Diffuse gliomas are fatal primary brain tumors that are poorly immunogenic. The basis for insufficient anti-tumor immunity in diffuse gliomas is not understood. Mutations in isocitrate dehydrogenases (IDH1 and IDH2) promote diffuse glioma formation through epigenetic reprogramming of a number of genes, including immune-related genes. Here, we identify epigenetic dysregulation of natural killer (NK) cell ligand genes as significant contributors to immune escape in glioma. Methods We analyzed the TCGA database for immune gene expression patterns in IDH mutant or wild-type gliomas and identified differentially expressed immune genes. NKG2D ligands expression levels and NK cell-mediated lysis were measured in patient-derived glioma stem cells and in genetically engineered astrocytes. Finally, we assessed the impact of hypomethylating agent Decitabine as a potential NK cell sensitizing agent in IDH mutant cells. Results All IDH mutant glioma stem-like cell lines exhibited significantly lower expression of NKG2D ligands compared with IDH wild-type cells. Consistent with these findings, IDH mutant glioma cells and astrocytes were resistant to NK cell-mediated lysis. The hypomethylating agent Decitabine increased NKG2D ligand expression, and restored NK- mediated lysis of IDH mutant cells in an NKG2D-dependent manner. Conclusions IDH mutant glioma cells acquire resistance to NK cells through epigenetic silencing of NKG2D ligands ULBP1 and ULPB3. Decitabine-mediated hypomethylation restores ULBP1 and ULBP3 expression in IDH mutant glioma cells and may provide a clinically useful method to sensitize IDH mutant gliomas to NK cell-mediated immune surveillance in patients with IDH mutated diffuse gliomas.

Early phase human clinical trials using several versions of oncolytic herpes simplex virus type 1 (oHSV) have shown promise in the treatment of glioblastoma multiforme, but efficacy has been limited. Impediments to oHSV therapy include poor virus spread due in part to the tumor extracellular matrix, and insufficient replication in tumor cells as a result of attenuating mutations. Thus, our central goal was to improve oncolytic vector delivery, replication, and spread while maintaining safety and tumor specificity. We had already developed a new class of two stage tumor targeted oHSV combining (i) selective infection through tumor-specific receptors and (ii) selective replication based on differential expression of microRNAs (miRs) in tumor and normal cells. We further modified our vector by arming it with the matrix metalloproteinase 9 (MMP9) as a means to reduce vector trapping in the tumor extracellular matrix. MMP9 degrades collagen type IV, a major component of the extracellular matrix (ECM) and basement membranes of glioblastomas. Here we show that: (i) MMP9 expression improves vector spread in GBM neurospheres in vitro; (ii) MMP9 enhances the oncolytic therapeutic efficacy in animal model of human GBM without compromising vector safety.

We analyze Chandra observations of diffuse soft X-ray emission associated with a complete sample of 3CR radio galaxies at z < 0.3. In this paper we focus on the properties of the spectroscopic sub-classes of high excitation galaxies (HEGs) and broad line objects (BLOs). Among the 33 HEGs we detect extended (or possibly extended) emission in about 40% of the sources; the fraction is even higher (8/10) restricting the analysis to the objects with exposure times larger than 10 ks. In the 18 BLOs, extended emission is seen only in 2 objects; this lower detection rate can be ascribed to the presence of their bright X-ray nuclei that easily outshine any genuine diffuse emission. A very close correspondence between the soft X-ray and optical line morphology emerges. We also find that the ratio between [O III] and extended soft X-ray luminosity is confined within a factor of 2 around a median value of 5. Both results are similar to what is seen in Seyfert galaxies. We discuss different processes that could explain the soft X-ray emission and conclude that the photoionization of extended gas, coincident with the narrow line region, is the favored mechanism., Comment: 15 pages, 11 figures. Accepted for publication on A&A

(Abridged) We present the results from new 15 ks Chandra-ACIS and 4.9 GHz Very Large Array observations of 13 galaxies hosting low luminosity AGN. This completes the multiwavelength study of a sample of 51 nearby early-type galaxies described in Capetti & Balmaverde (2005, 2006); Balmaverde & Capetti (2006). The aim of the three previous papers was to explore the connection between the host galaxies and AGN activity in a radio-selected sample. We detect nuclear X-ray emission in eight sources and radio emission in all but one (viz., UGC6985). The new VLA observations improve the spatial resolution by a factor of ten: the presence of nuclear radio sources in 12 of the 13 galaxies confirms their AGN nature. As previously indicated, the behavior of the X-ray and radio emission in these sources depends strongly on the form of their optical surface brightness profiles derived from Hubble Space Telescope imaging, i.e., on their classification as "core", "power-law" or "intermediate" galaxies. With more than twice the number of "power-law" and "intermediate" galaxies compared to previous work, we confirm with a much higher statistical significance that these galaxies lie well above the radio-X-ray correlation established in FRI radio galaxies and the low-luminosity "core" galaxies. This result highlights the fact that the "radio-loud/radio-quiet" dichotomy is a function of the host galaxy's optical surface brightness profile. We present radio-optical-X-ray spectral indices for all 51 sample galaxies. Survival statistics point to significant differences in the radio-to-optical and radio-to-X-ray spectral indices between the "core" and "power-law" galaxies (Gehan's Generalized Wilcoxon test probability "p" for the two classes being statistically similar is, 40 pages, Accepted for publication in AJ

One of the main debated astrophysical problems is the role of the AGN feedback in galaxy formation. It is known that massive black holes have a profound effect on the formation and evolution of galaxies, but how black holes and galaxies communicate is still an unsolved problem. For Radio Galaxies, feedback studies have mainly focused on jet/cavity systems in the most massive and X-ray luminous galaxy clusters. The recent high-resolution detection of warm absorbers in some Broad Line Radio Galaxies allow us to investigate the interplay between the nuclear engine and the surrounding medium from a different perspective. We report on the detection of warm absorbers in two Broad Line Radio Galaxies, 3C 382 and 3C 390.3, and discuss the physical and energetic properties of the absorbing gas. Finally, we attempt a comparison between radio-loud and radio-quiet outflows., To be published in the proceedings of High Energy Phenomena in Relativistic Outflows III (HEPRO III, IJMPCS). 4 pages, 2 figures

We report on the second round of Chandra observations of the 3C snapshot survey developed to observe the complete sample of 3C radio sources with z, Comment: 53 pages, 33 figures, 5 tables, accepted for publication on the ApJ Supplement Series

Successful oncolytic virus treatment of malignant glioblastoma multiforme depends on widespread tumor-specific lytic virus replication and escape from mitigating innate immune responses to infection. Here we characterize a new HSV vector, JD0G, that is deleted for ICP0 and the joint sequences separating the unique long and short elements of the viral genome. We observed that JD0G replication was enhanced in certain glioblastoma cell lines compared to HEL cells, suggesting that a vector backbone deleted for ICP0 may be useful for treatment of glioblastoma. The innate immune response to virus infection can potentially impede oncolytic vector replication in human tumors. Indoleamine-2,3-dioxygenase (IDO) is expressed in response to interferonγ(IFNγ) and has been linked to both antiviral functions and to the immune escape of tumor cells. We observed that IFNγtreatment of human glioblastoma cells induced the expression of IDO and that this expression was quelled by infection with both wild-type and JD0G viruses. The role of IDO in inhibiting virus replication and the connection of this protein to the escape of tumor cells from immune surveillance suggest that IDO downregulation by HSV infection may enhance the oncolytic activity of vectors such as JD0G.

Mutations in isocitrate dehydrogenase 1 and 2 are common in gliomas. 50-80% of WHO II/III gliomas possess IDH1/IDH2 mutation. Methylation-related transcriptional repression is a feature of IDH mutant (IDHmut) tumors. Epigenetic repression of natural killer (NK) cell ligands is a common mechanism of immune escape in cancer, but it is unknown if this occurs in gliomas. We compared IDHmut and IDHwt tumor expression (z-score) and methylation (mean methylation score) data from the TCGA low-grade glioma database, and found two NKG2D ligands (ULBP1, ULBP3) that were downregulated (-0.47, p = 0.02; -1.28, p < 0.01) and hypermethylated (-0.31, p < 0.01; -0.15, p < 0.01) in IDHmut tumors. We validated this finding by measuring ULBP1 and ULBP3 gene expression in cells derived from IDHwt and IDHmut patients and found both genes were repressed in IDHmut cells (-0.85 fold expression, p = 0.01; -0.57 fold expression, p = 0.01). To determine whether repression of NKG2D ligand expression resulted in escape from NK recognition and specific lysis, we these cells with NK cells. We observed significantly (p = 0.03) reduced specific lysis of IDHmut cell (3.62%) as compared to IDHwt cells (24.13%). To determine NK activation, we measured inflammatory cytokine release in co-cultures, no basal release were detected in either tumor or NK monocultures. IDHmut co-cultures has significantly reduced IFN-g (82.08 pg/mL vs 250.1 pg/mL, p = 0.02) and TNF-a (151.2 pg/mL vs 650.2 pg/mL, p < 0.01) release compared to IDHwt co-cultures. To validate that IDHmut immune escape is NKG2D dependent, we blocked NKG2D binding using an antibody. Addition of isotype antibody did not significantly reduce specific lysis in IDHwt co-culture (10.40% vs 10.20%, p = 0.94). Addition of NKG2D blocking antibody to IDHwt significantly reduced specific lysis below isotype (3.34% vs 10.40%, p < 0.01). In conclusion, we were able to demonstrate that IDH mutant gliomas are able to escape from NK immune surveillance through repression of NKG2D ligand expression.

Early phase human clinical trials using several versions of oncolytic herpes simplex virus type 1 (oHSV) have shown promise in the treatment of GBM, but efficacy has been limited. Impediments to oHSV therapy include poor virus spread due in part to the tumor extracellular matrix, and insufficient replication in tumor cells as a result of attenuating mutations. Thus, the central goal of this project is to improve oncolytic vector delivery, replication and spread while maintaining safety and tumor specificity. We have already developed a new class of two stage tumor targeted oHSV combining (i) selective infection through tumor-specific receptors and (ii) selective replication based on differential expression of microRNAs (miRs) in tumor and normal cells. We further modify our vector by arming with the matrix metalloproteinase 9 (MMP9) as a means to reduce vector trapping in the tumor extracellular matrix. Data will be presented on the effect the effect of oHSV on the tumor microenvironment.

We review the high energy properties of Misaligned AGNs associated with gamma-ray sources detected by Fermi in 24 months of survey. Most of them are nearby emission low power radio galaxies (i.e FRIs) which probably have structured jets. On the contrary, high power radio sources (i.e FRIIs) with GeV emission are rare. The small number of FRIIs does not seem to be related to their higher redshifts. Assuming proportionality between the radio core flux and the gamma-ray flux, several of them are expected to be bright enough to be detected above 100 MeV in spite of their distance. We suggest that beaming/jet structural differences are responsible for the detection rate discrepancy observed between FRIs and FRIIs., Comment: To be published in the proceedings of High Energy Phenomena in Relativistic Outflows III (HEPRO III, IJMPCS); 6 pages, 3 figures

NGC 6251 is a luminous radio galaxy ~104 Mpc away that was detected significantly with the Fermi Gamma-ray Space Telescope, and before that with EGRET (onboard the Compton Gamma-ray Observatory). Different observational constraints favor a nuclear origin for the gamma-ray emission. Here we present a study of the spectral energy distribution (SED) of the core of NGC 6251, and give results of modeling in the one-zone synchrotron/SSC framework. The SSC model provides a good description of the radio to gamma-ray emission but, as for other misaligned sources, predicts a lower Lorentz factor (\Gamma~2.4) than typically found when modeling blazars. If the blazar unification scenario is correct, this seems to point to the presence of at least two emitting regions in these objects, one with a higher and one with a lower Lorentz factor. The solution of a structured jet, with a fast moving spine surrounded by a slow layer, is explored and the consequences of the two models for the jet energetics and evolution are discussed., Comment: 11 pages, 4 figures, accepted for publication in Astronomy & Astrophysics

The development of selective histone deacetylase (HDAC) inhibitors with anti-cancer and anti-inflammatory properties remains challenging in large part owing to the difficulty of probing the interaction of small molecules with megadalton protein complexes. A combination of affinity capture and quantitative mass spectrometry revealed the selectivity with which 16 HDAC inhibitors target multiple HDAC complexes scaffolded by ELM-SANT domain subunits, including a novel mitotic deacetylase complex (MiDAC). Inhibitors clustered according to their target profiles with stronger binding of aminobenzamides to the HDAC NCoR complex than to the HDAC Sin3 complex. We identified several non-HDAC targets for hydroxamate inhibitors. HDAC inhibitors with distinct profiles have correspondingly different effects on downstream targets. We also identified the anti-inflammatory drug bufexamac as a class IIb (HDAC6, HDAC10) HDAC inhibitor. Our approach enables the discovery of novel targets and inhibitors and suggests that the selectivity of HDAC inhibitors should be evaluated in the context of HDAC complexes and not purified catalytic subunits.

Herpes simplex virus (HSV) entry into cells is triggered by the binding of envelope glycoprotein D (gD) to a specific receptor, such as nectin-1 or herpesvirus entry mediator (HVEM), resulting in activation of the fusion effectors gB and gH and virus penetration. Here we report the identification of a hyperactive gB allele, D285N/A549T, selected by repeat passage of a gD mutant virus defective for nectin-1 binding through cells that express a gD-binding-impaired mutant nectin-1. The gB allele in a wild-type virus background enabled the use of other nectins as virus entry receptors. In addition, combination of the mutant allele with an epidermal growth factor receptor (EGFR)-retargeted gD gene yielded dramatically increased EGFR-specific virus entry compared to retargeted virus carrying wild-type gB. Entry of the gB mutant virus into nectin-1-bearing cells was markedly accelerated compared to that of wild-type virus, suggesting that the gB mutations affect a rate-limiting step in entry. Our observations indicate that ineffective gD activation can be complemented by hypersensitization of a downstream component of the entry cascade to gD signaling.

We present a long (100 ks) Suzaku observation of one of the X-ray brightest AGN, MCG+8-11-11. These data were complemented with the 54-month Swift BAT spectrum, allowing us to perform a broad-band fit in the 0.6-150 keV range. The fits performed in the 0.6-10 keV band give consistent results with respect to a previous XMM-Newton observation, i.e. the lack of a soft excess, warm absorption along the line of sight, a large Compton reflection component (R~1) and the absence of a relativistic component of the neutral iron K$\alpha$ emission line. However, when the PIN and Swift BAT data are included, the reflection amount drops significantly (R~0.2-0.3), and a relativistic iron line is required, the latter confirmed by a phenomenological analysis in a restricted energy band (3-10 keV). When a self-consistent model is applied to the whole broadband data, the observed reflection component appears to be all associated to the relativistic component of the iron K$\alpha$ line. The resulting scenario, though strongly model-dependent, requires that all the reprocessing spectral components from Compton-thick material must be associated to the accretion disc, and no evidence for the classical pc-scale torus is found. The narrow core of the neutral iron K$\alpha$ line is therefore produced in a Compton-thin material, like the BLR, similarly to what found in another Seyfert galaxy, NGC7213, but with the notable difference that MCG+8-11-11 presents spectral signatures from an accretion disc. The very low accretion rate of NGC7213 could explain the lack of relativistic signatures in its spectrum, but the absence of the torus in both sources is more difficult to explain, since their luminosities are comparable, and their accretion rates are completely different., Comment: 8 pages, 6 figure, accepted for publication in Astronomy and Astrophysics

We report on our Chandra Cycle 9 program to observe half of the 60 (unobserved by Chandra) 3C radio sources at z, Comment: 12 pages, 37 figures (the complete version of the paper with all figures is available on line, see appendix for details), ApJ accepted

Oncolytic herpes simplex virus (oHSV) vectors have shown promise in the treatment of patients with recurrent brain tumors although few complete responses have accrued. Impediments to effective therapy include limited vector distribution on delivery, a consequence of injected virion particle trapping in the tumor extracellular matrix (ECM). To enhance virus delivery and spread, we investigated the use of the matrix metalloproteinase-9 (MMP-9) as a means to degrade collagen type IV, a major component of the ECM and basement membranes of gliomas that is absent in normal brain tissue. SK-N-AS neuroblastoma cells were transduced for constitutive, elevated expression of MMP-9, which did not enhance tumor cell migration in vitro or tumor progression in a murine xenograft brain tumor model. MMP-9 expression improved the distribution and infection of oHSV vectors in spheroid model in vitro. Furthermore, MMP9 induced a vector infection over larger areas of brain tumors in vivo. These results suggest that vector delivery and distribution in vivo can be improved by compromising the ECM, potentially enhancing oncolytic efficacy.