Immunotherapeutic efficacy of retargeted ohsvs designed for propagation in an ad hoc cell line

Our laboratory has pursued the generation of cancer‐specific oncolytic herpes simplex viruses (oHSVs) which ensure high efficacy while maintaining a high safety profile. Their blueprint included retargeting to a Tumor‐Associated Antigen, e.g., HER2, coupled to detargeting from natural receptors to avoid off‐target and off‐tumor infections and preservation of the full complement of unmodified viral genes. These oHSVs are “fully virulent in their target cancer cells”. The 3rd generation retargeted oHSVs carry two distinct retargeting moieties, which enable infection of a producer cell line and of the target cancer cells, respectively. They can be propagated in an ad hoc Vero cell derivative at about tenfold higher yields than 1st generation recombinants, and more effectively replicate in human cancer cell lines. The R‐335 and R‐337 prototypes were armed with murine IL‐12. Intratumorally‐administered R‐337 conferred almost complete protection from LLC‐ 1‐HER2 primary tumors, unleashed the tumor microenvironment immunosuppression, synergized with the checkpoint blockade and conferred long‐term vaccination against distant challenge tumors. In summary, the problem intrinsic to the propagation of retargeted oHSVs—which strictly require cells positive for targeted receptors—was solved in 3rd generation viruses. They are effective as immunotherapeutic agents against primary tumors and as antigen‐agnostic vaccines

VST - VLT Survey Telescope Integration Status

The VLT Survey Telescope (VST) is a 2.6m aperture, wide field, UV to I facility, to be installed at the European Southern Observatory (ESO) on the Cerro Paranal Chile. VST was primarily intended to complement the observing capabilities of VLT with wide-angle imaging for detecting and pre-characterising sources for further observations with the VLT.Comment: 2 pages, 2 figures, conferenc

Completing the puzzle of the 2004-2005 outburst in V0332+53: the brightening phase included

Analysis of the data obtained with the RXTE observatory during a powerful outburst of the X-ray pulsar V0332+53 in 2004-2005 is presented. Observational data covering the outburst brightening phase are analysed in detail for the first time. A comparison of source parameters and their evolution during the brightening and fading phases shows no evidence for any hysteresis behaviour. It is found that the dependences of the energy of the cyclotron absorption line on the luminosity during the brightening and fading phases are almost identical. The complete data sequence including the outburst brightening and fading phases makes it possible to impose the more stringent constraints on the magnetic field in the source. The pulse profile and pulsed fraction are studied as functions of the luminosity and photon energy.Comment: 9 pages, 10 figures, accepted for publication in MNRA

Genotype of Immunologically Hot or Cold Tumors Determines the Antitumor Immune Response and Efficacy by Fully Virulent Retargeted oHSV

We report on the efficacy of the non-attenuated HER2-retargeted oHSV named R-337 against the immunologically hot CT26-HER2 tumor, and an insight into the basis of the immune protection. Preliminarily, we conducted an RNA immune profiling and immune cell content characterization of CT26-HER2 tumor in comparison to the immunologically cold LLC1-HER2 tumor. CT26-HER2 tumor was implanted into HER2-transgenic BALB/c mice. Hallmarks of R-337 effects were the protection from primary tumor, long-term adaptive vaccination directed to both HER2 and CT26-wt cell neoantigens. The latter effect differentiated R-337 from OncoVEXGM-CSF. As to the basis of the immune protection, R-337 orchestrated several changes to the tumor immune profile, which cumulatively reversed the immunosuppression typical of this tumor (graphical abstract). Thus, Ido1 (inhibitor of T cell anticancer immunity) levels and T regulatory cell infiltration were decreased; Cd40 and Cd27 co-immunostimulatory markers were increased; the IFNγ cascade was activated. Of note was the dampening of IFN-I response, which we attribute to the fact that R-337 is fully equipped with genes that contrast the host innate response. The IFN-I shut-down likely favored viral replication and the expression of the mIL-12 payload, which, in turn, boosted the antitumor response. The results call for a characterization of tumor immune markers to employ oncolytic herpesviruses more precisely

On the accretion flow geometry in A0535+26

The geometry of accretion flow in the Be/X-ray transient A0535+26 is explored. It is shown that neither moderate nor giant X-ray flaring events observed in the system can be interpreted within the spherically symmetrical accretion model and hence the formation of an accretion disk around the neutron star magnetosphere during the both types of flares is required. The accretion disk can be formed at the periastron if (i) the expansion velocity of the Be star envelope in the equatorial plane is V_wr < 150 km/s and (ii) the parameter accounting for the accretion flow inhomogeneities, xi, satisfies the following condition: xi > 0.16 (Mdot_17)^-1/7, where (Mdot_17)^-1/7 is the rate of mass capture by the neutron star expressed in units of 1017 g/s. We suggest that the `missing' outburst phenomenon can be associated with the spherically symmetrical accretion onto the interchange-stable magnetosphere of the neutron star. The average spin up rate of the neutron star during moderate flares < 3.5 x 10^-12 Hz/s is predicted.Comment: 6 pages, published in A&A 372, 227 (2001

Influence of tumor microenvironment and fibroblast population plasticity on melanoma growth, therapy resistance and immunoescape

Cutaneous melanoma (CM) tissue represents a network constituted by cancer cells and tumor microenvironment (TME). A key feature of CM is the high structural and cellular plasticity of TME, allowing its evolution with disease and adaptation to cancer cell and environmental alter-ations. In particular, during melanoma development and progression each component of TME by interacting with each other and with cancer cells is subjected to dramatic structural and cellular modifications. These alterations affect extracellular matrix (ECM) remodelling, phenotypic profile of stromal cells, cancer growth and therapeutic response. The stromal fibroblast populations of the TME include normal fibroblasts and melanoma‐associated fibroblasts (MAFs) that are highly abun-dant and flexible cell types interacting with melanoma and stromal cells and differently influencing CM outcomes. The shift from the normal microenvironment to TME and from normal fibroblasts to MAFs deeply sustains CM growth. Hence, in this article we review the features of the normal mi-croenvironment and TME and describe the phenotypic plasticity of normal dermal fibroblasts and MAFs, highlighting their roles in normal skin homeostasis and TME regulation. Moreover, we dis-cuss the influence of MAFs and their secretory profiles on TME remodelling, melanoma progres-sion, targeted therapy resistance and immunosurveillance, highlighting the cellular interactions, the signalling pathways and molecules involved in these processes

BeppoSAX Observations of GRB980425: Detection of the Prompt Event and Monitoring of the Error Box

We present BeppoSAX follow-up observations of GRB980425 obtained with the Narrow Field Instruments (NFI) in April, May, and November 1998. The first NFI observation has detected within the 8' radius error box of the GRB an X-ray source positionally consistent with the supernova 1998bw, which exploded within a day of GRB980425, and a fainter X-ray source, not consistent with the position of the supernova. The former source is detected in the following NFI pointings and exhibits a decline of a factor of two in six months. If it is associated with SN 1998bw, this is the first detection of X-ray emission from a Type I supernova above 2 keV. The latter source exhibits only marginally significant variability. The X-ray spectra and variability of the supernova are compared with thermal and non-thermal models of supernova high energy emission. Based on the BeppoSAX data, it is not possible to firmly establish which of the two detected sources is the GRB X-ray counterpart, although probability considerations favor the supernova.Comment: 16 pages, Latex, 6 PostScript figures and 1 GIF figure, 2 tables, submitted to The Astrophysical Journa

Hard X-ray emission from the galaxy cluster A3667

We report the results of a long BeppoSAX observation of Abell 3667, one of the most spectacular galaxy cluster in the southern sky. A clear detection of hard X-ray radiation up to ~ 35 keV is reported, while a hard excess above the thermal gas emission is present at a marginal level that should be considered as an upper limit to the presence of nonthermal radiation. The strong hard excesses reported by BeppoSAX in Coma and A2256 and the only marginal detection of nonthermal emission in A3667 can be explained in the framework of the inverse Compton model. We argue that the nonthermal X-ray detections in the PDS energy range are related to the radio index structure of halos and relics present in the observed clusters of galaxie.Comment: 15 pages, 1 figure, ApJL in pres

Insights into Thymus Development and Viral Thymic Infections

T-cell development in the thymus is a complex and highly regulated process, involving a wide variety of cells and molecules which orchestrate thymocyte maturation into either CD4+ or CD8+ single-positive (SP) T cells. Here, we briefly review the process regulating T-cell differentiation, which includes the latest advances in this field. In particular, we highlight how, starting from a pool of hematopoietic stem cells in the bone marrow, the sequential action of transcriptional factors and cytokines dictates the proliferation, restriction of lineage potential, T-cell antigen receptors (TCR) gene rearrangements, and selection events on the T-cell progenitors, ultimately leading to the generation of mature T cells. Moreover, this review discusses paradigmatic examples of viral infections affecting the thymus that, by inducing functional changes within this lymphoid gland, consequently influence the behavior of peripheral mature T-lymphocytes

BeppoSAX Detection and Follow-up of GRB980425

We present BeppoSAX GRBM and WFC light curves of GRB980425 and NFI follow-up data taken in 1998 April, May, and November. The first NFI observation has detected within the 8' radius error box of the GRB an X-ray source positionally consistent with the supernova SN 1998bw, exploded within a day of GRB980425, and a fainter X-ray source, not consistent with the position of the supernova. The former source is detected in the following NFI pointings and exhibits a decline of a factor of two in six months. If it is associated with SN 1998bw, this is the first detection of hard X-ray emission from a Type I supernova. The latter source exhibits only marginally significant variability. Based on these data, it is not possible to select either source as a firm candidate for the GRB counterpart.Comment: 2 pages, 1 PostScript figure, submitted to A&AS, Proc. of the Conference "Gamma-Ray Bursts in the Afterglow Era", held in Rome, 1998 November 3-6. Results concerning 'Source 2' have been update