Use of antifuse-FPGAs in the Track-Sorter-Master of the CMS Drift Tube Chambers

The front-end system of the Silicon Drift Detectors (SDDs) of the ALICE experiment is made of two ASICs. The first chip performs the preamplification, temporary analogue storage and analogue-to-digital conversion of the detector signals. The second chip is a digital buffer that allows for a significant reduction of the connection from the front-end module to the outside world. In this paper, the results achieved on the first complete prototype of the front-end system for the SDDs of ALICE are presented

DT Sector Collector electronics design and construction

The CMS detector at LHC is equipped with Drift Tubes (DT) chambers for muon detection and triggering in the barrel region. The Sector Collector (SC) modules collect the track segments reconstructed by on-chamber trigger electronics. Data from different chambers are aligned in time and sent to the subsequent reconstruction processors via optical links. Several FPGA devices performing the processing of the data were designed in VHDL, including spy features to monitor the trigger data flow. A test jig was set up with custom hardware and software in order to fully validate final production boards. Installation and commissioning in CMS provided first experience with the synchronization and monitoring tools

The Garisenda Tower in Bologna: Effects of degradation of selenite basement on its static behaviour

The Garisenda tower in Bologna, a 48 m tall structure with a square base of 7.45 meters per side, is characterized by an overall out of plumb of 3.32m in the South-East direction. Its construction dates back to the XI century and, due to its impressive leaning, in 1350–1353 the original height of 60m was reduced to the 48m of the present day (Cavani 1903; Giordano 2000). The tower can be seen as partitioned in a lower portion, with walls composed by two external leaves of selenite stones filled with rubble conglomerate, and an upper portion where the external leaves are made of masonry bricks. Recent investigations have proved that selenite blocks of the basement have been altered as a result of (a) exposition to high temperatures during important fires, that took place at the end of XIV and XVII centuries, and possibly because of the presence of forges (that were demolished at the end of the XIX centuries) and (b) high level of humidity in the inner lower part of the tower. This process has produced a gradual local disintegration of the selenite stones, leading in some case to a reduction of the original 50 to 60 cm thickness by an amount of about 20 cm. The contribution submitted to this conference is aimed at clarifying this important aspect, linked to the ageing and damage of structural stones and the related consequences in terms of stress distribution and concentrations that could induce fracture propagation and sudden collapse of the tower basement

Growth inhibition of human ovarian carcinoma by a novel AvidinOX-anchored biotinylated camptothecin derivative

Oxidized form of avidin, named AvidinOX, provides stable fixation of biotinylated molecules in tissues thus representing a breakthrough in topical treatment of cancer. AvidinOX proved to be a stable receptor for radiolabeled biotin, biotinylated antibodies and cells. In order to expand applicability of the AvidinOX-based delivery platform, in the present study we investigated the possibility to hold biotinylated chemotherapeutics in AvidinOX-treated sites. A novel biotinylated gimatecan-derived camptothecin, coded ST8161AA1, was injected at suboptimal doses into human tumors xenografted in mice alone or pre-complexed to AvidinOX. Significantly higher growth inhibition was observed when the drug was anchored to AvidinOX suggesting the potential utility of this delivery modality for the local treatment of inoperable tumors

Design and Test of the Off-Detector Electronics for the CMS Barrel Muon Trigger

Drift Tubes chambers are used in the CMS barrel for tagging the passage of high Pt muons generated in a LHC event and for triggering the CMS data read out. The Sector Collector (SC) system synchronizes the track segments built by trigger modules on the chambers and deliver them to reconstruction processors (Track Finder, TF) that assemble full muon tracks. Then, the Muon Sorter (MS) has to select the best four candidates in the barrel and to filter fake muons generated by the TF system redundancy. The hardware implementations of the Sector Collector and Muon Sorter systems satisfy radiation, I/O and fast timing constraints using several FPGA technologies. The hardware was tested with custom facilities, integrated with other trigger subsystems, and operated in a beam test. A test beam on a 40 MHz bunched beam validated the local trigger electronics and off-detector prototype cards and the synchronization tools. The CMS Magnet Test and Cosmic challenge in 2006 proved stable and reliable operation of the Drift Tubes trigger and its integration with other trigger systems and with the readout system. Constraints, design, test and operation of the modules are presented

Camptothecin-psammaplin A hybrids as topoisomerase I and HDAC dual-action inhibitors

Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of camptothecin derivatives and HDAC inhibitors. To exploit this synergy in a single active compound, we designed new dual-acting multivalent molecules simultaneously targeting topoisomerase I and HDAC. In particular, a selected compound containing a camptothecin and the psammaplin A scaffold showed a broad spectrum of antiproliferative activity, with IC50values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted in CD-1 nude mice and very high tolerability

Influence of the adamantyl moiety on the activity of biphenylacrylohydroxamic acid-based HDAC inhibitors

To investigate the influence of the adamantyl group on the biological properties of known HDAC inhibitors with a 4-phenylcinnamic skeleton, a series of compounds having the adamantyl moiety in the cap structure were synthesized and compared to the corresponding hydroxamic acids lacking this group. An unexpected finding was the substantial reduction of inhibitory activity toward the tested enzymes, in particular HDAC6, following the introduction of the adamantyl group. In spite of the reduced ability to function as HDAC inhibitors, the compounds containing the adamantyl moiety still retained a good efficacy as antiproliferative and proapoptotic agents. A selected compound (2c; ST3056) of this series exhibited an appreciable antitumor activity against the colon carcinoma xenograft HCT116

Design, modeling, synthesis and biological activity evaluation of camptothecin linked platinum anticancer agents

The design, modeling, synthesis and biological activity evaluation of two hybrid agents formed by 7-oxyiminomethylcamptothecin derivatives and diaminedichloro-platinum (II) complex are reported. The compounds showed growth inhibitory activity against a panel of human tumor cell lines, including sublines resistant to topotecan and platinum compounds. The derivatives were active in all the tested cell lines, and compound 1b, the most active one, was able to overcome cisplatin resistance in the osteosarcoma U2OS/Pt cell line. Platinum-containing camptothecins produced platinum-DNA adducts and topoisomerase I-mediated DNA damage with cleavage pattern and persistence similar to SN38, the active principle of irinotecan. Compound 1b exhibited an appreciable antitumor activity in vivo against human H460 tumor xenograft, comparable to that of irinotecan at lower well-tolerated dose levels and superior to cisplatin. The results support the interpretation that the diaminedichloro-platinum (II) complex conjugated via an oxyiminomethyl linker at the 7-position of the camptothecin resulted in a new class of effective antitumor compounds

Improvement of conventional anti-cancer drugs as new tools against multidrug resistant tumors

Multidrug resistance (MDR) is the dominant cause of the failure of cancer chemotherapy. The design of antitumor drugs that are able to evade MDR is rapidly evolving, showing that this area of biomedical research attracts great interest in the scientific community. The current review explores promising recent approaches that have been developed with the aim of circumventing or overcoming MDR. Encouraging results have been obtained in the investigation of the MDR-modulating properties of various classes of natural compounds and their analogues. Inhibition of P-gp or downregulation of its expression have proven to be the main mechanisms by which MDR can be surmounted. The use of hybrid molecules that are able to simultaneously interact with two or more cancer cell targets is currently being explored as a means to circumvent drug resistance. This strategy is based on the design of hybrid compounds that are obtained either by merging the structural features of separate drugs, or by conjugating two drugs or pharmacophores via cleavable/non-cleavable linkers. The approach is highly promising due to the pharmacokinetic and pharmacodynamic advantages that can be achieved over the independent administration of the two individual components. However, it should be stressed that the task of obtaining successful multivalent drugs is a very challenging one. The conjugation of anticancer agents with nitric oxide (NO) donors has recently been developed, creating a particular class of hybrid that can combat tumor drug resistance. Appropriate NO donors have been shown to reverse drug resistance via nitration of ABC transporters and by interfering with a number of metabolic enzymes and signaling pathways. In fact, hybrid compounds that are produced by covalently attaching NO-donors and antitumor drugs have been shown to elicit a synergistic cytotoxic effect in a variety of drug resistant cancer cell lines. Another strategy to circumvent MDR is based on nanocarrier-mediated transport and the controlled release of chemotherapeutic drugs and P-gp inhibitors. Their pharmacokinetics are governed by the nanoparticle or polymer carrier and make use of the enhanced permeation and retention (EPR) effect, which can increase selective delivery to cancer cells. These systems are usually internalized by cancer cells via endocytosis and accumulate in endosomes and lysosomes, thus preventing rapid efflux. Other modalities to combat MDR are described in this review, including the pharmaco-modulation of acridine, which is a well-known scaffold in the development of bioactive compounds, the use of natural compounds as means to reverse MDR, and the conjugation of anticancer drugs with carriers that target specific tumor-cell components. Finally, the outstanding potential of in silico structure-based methods as a means to evaluate the ability of antitumor drugs to interact with drug transporters is also highlighted in this review. Structure-based design methods, which utilize 3D structural data of proteins and their complexes with ligands, are the most effective of the in silico methods available, as they provide a prediction regarding the interaction between transport proteins and their substrates and inhibitors. The recently resolved X-ray structure of human P-gp can help predict the interaction sites of designed compounds, providing insight into their binding mode and directing possible rational modifications to prevent them from becoming P-gp drug substrates. In summary, although major efforts were invested in the search for new tools to combat drug resistant tumors, they all require further implementation and methodological development. Further investigation and progress in the abovementioned strategies will provide significant advances in the rational combat against cancer MDR