Synthesis and characterisation of a new benzamide-containing nitrobenzoxadiazole as a GSTP1-1 inhibitor endowed with high stability to metabolic hydrolysis

The antitumor agent 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (1) is a potent inhibitor of GSTP1-1, a glutathione S-transferase capable of inhibiting apoptosis by binding to JNK1 and TRAF2. We recently demonstrated that, unlike its parent compound, the benzoyl ester of 1 (compound 3) exhibits negligible reactivity towards GSH, and has a different mode of interaction with GSTP1-1. Unfortunately, 3 is susceptible to rapid metabolic hydrolysis. In an effort to improve the metabolic stability of 3, its ester group has been replaced by an amide, leading to N-(6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexyl)benzamide (4). Unlike 3, compound 4 was stable to human liver microsomal carboxylesterases, but retained the ability to disrupt the interaction between GSTP1-1 and TRAF2 regardless of GSH levels. Moreover, 4 exhibited both a higher stability in the presence of GSH and a greater cytotoxicity towards cultured A375 melanoma cells, in comparison with 1 and its analog 2. These findings suggest that 4 deserves further preclinical testing

Quantifying the unknown: issues in simulation validation and their experimental impact

The assessment of the reliability of Monte Carlo simulations is discussed, with emphasis on uncertainty quantification and the related impact on experimental results. Methods and techniques to account for epistemic uncertainties, i.e. for intrinsic knowledge gaps in physics modeling, are discussed with the support of applications to concrete experimental scenarios. Ongoing projects regarding the investigation of epistemic uncertainties in the Geant4 simulation toolkit are reported.Comment: To be published in the Proceedings of the 13th ICATPP Conference on Astroparticle, Particle, Space Physics and Detectors for Physics Applications, Villa Olmo, Como, 3-7 October 201

Research in Geant4 electromagnetic physics design, and its effects on computational performance and quality assurance

The Geant4 toolkit offers a rich variety of electromagnetic physics models; so far the evaluation of this Geant4 domain has been mostly focused on its physics functionality, while the features of its design and their impact on simulation accuracy, computational performance and facilities for verification and validation have not been the object of comparable attention yet, despite the critical role they play in many experimental applications. A new project is in progress to study the application of new design concepts and software techniques in Geant4 electromagnetic physics, and to evaluate how they can improve on the current simulation capabilities. The application of a policy-based class design is investigated as a means to achieve the objective of granular decomposition of processes; this design technique offers various advantages in terms of flexibility of configuration and computational performance. The current Geant4 physics models have been re-implemented according to the new design as a pilot project. The main features of the new design and first results of performance improvement and testing simplification are presented; they are relevant to many Geant4 applications, where computational speed and the containment of resources invested in simulation production and quality assurance play a critical role.Comment: 4 pages, 4 figures and images, to appear in proceedings of the Nuclear Science Symposium and Medical Imaging Conference 2009, Orland

Geant4-related R&D for new particle transport methods

A R&D project has been launched in 2009 to address fundamental methods in radiation transport simulation and revisit Geant4 kernel design to cope with new experimental requirements. The project focuses on simulation at different scales in the same experimental environment: this set of problems requires new methods across the current boundaries of condensed-random-walk and discrete transport schemes. An exploration is also foreseen about exploiting and extending already existing Geant4 features to apply Monte Carlo and deterministic transport methods in the same simulation environment. An overview of this new R&D associated with Geant4 is presented, together with the first developments in progress.Comment: 4 pages, to appear in proceedings of the Nuclear Science Symposium and Medical Imaging Conference 2009, Orland

Therapeutic effect of interleukin 12 on mouse haemangiosarcomas is not associated with an increased anti-tumour cytotoxic T-lymphocyte activity.

In syngeneic mice, the H5V polyoma middle-T oncogene-transformed endothelioma cell line induces Kaposi's sarcoma-like cavernous haemangiomas that regress transiently, probably because of an anti-tumour immune response, but eventually grow progressively and kill the host. To evaluate the generation of tumour-specific cytotoxic T lymphocytes (CTLs), spleen cells of tumour-bearing mice were restimulated with irradiated H5V cells in mixed leucocyte-tumour cell cultures. Tumour-specific CTLs were demonstrable only when low numbers of H5V stimulator cells were used (<1 H5V cell per 50 splenocytes). We found that H5V cells secrete immunosuppressive mediators because CTL generation was blocked when H5V cells culture supernatants were added to allogeneic mixed leucocyte cultures. As numerous tumour-derived immunosuppressive mediators may interfere with interleukin 12 (IL-12) production, we tested whether IL-12 treatment of the tumour-bearing mice would augment their immune response and thus suppress tumour growth. Indeed, IL-12 inhibited tumour growth and prevented mortality, but did not increase anti-H5V CTL generation either in vitro or in vivo. Moreover, the anti-tumour activity in IL-12-treated mice was abrogated by anti-interferon (IFN)-gamma monoclonal antibody (MAb) co-administration. These results strongly suggest that the anti-tumour effect of IL-12 is principally mediated by IFN-gamma release that in turn blocks H5V cell proliferation and induces the release of factors that suppress angiogenesis

Increasing the bandwidth of resonant gravitational antennas: The case of Explorer

Resonant gravitational wave detectors with an observation bandwidth of tens of hertz are a reality: the antenna Explorer, operated at CERN by the ROG collaboration, has been upgraded with a new read-out. In this new configuration, it exhibits an unprecedented useful bandwidth: in over 55 Hz about its frequency of operation of 919 Hz the spectral sensitivity is better than 10^{-20} /sqrt(Hz) . We describe the detector and its sensitivity and discuss the foreseable upgrades to even larger bandwidths.Comment: 4 pages- 4 figures Acceted for publication on Physical Review Letter

Particle acoustic detection in gravitational wave aluminum resonant antennas

The results on cosmic rays detected by the gravitational antenna NAUTILUS have motivated an experiment (RAP) based on a suspended cylindrical bar, which is made of the same aluminum alloy as NAUTILUS and is exposed to a high energy electron beam. Mechanical vibrations originate from the local thermal expansion caused by warming up due to the energy lost by particles crossing the material. The aim of the experiment is to measure the amplitude of the fundamental longitudinal vibration at different temperatures. We report on the results obtained down to a temperature of about 4 K, which agree at the level of about 10% with the predictions of the model describing the underlying physical process.Comment: RAP experiment, 16 pages, 7 figure