Synthesis of hybrid anticancer agents based on kinase and histone deacetylase inhibitors

Fragments based on the VEGFR2i Semaxanib (SU5416, (vascular endothelial growth factor receptor-2 inhibitor) and the HDACi (histone deacetylase inhibitor) SAHA (suberanilohydroxamic acid) have been merged to form a range of low molecular weight dual action hybrids. Vindication of this approach is provided by SAR, docking studies, in vitro cancer cell line and biochemical enzyme inhibition data as well as in vivo Xenopus data for the lead molecule (Z)-N1-(3-((1H-pyrrol-2-yl)methylene)-2-oxoindolin-5-yl)- N8-hydroxyoctanediamide 6

Challenges of the Truth Commissions to Deal with Injustice Against Indigenous Peoples

Truth commissions are still being created around the world in order to redress human rights violations, in accordance to the right of victims to an effective remedy and the right to know the truth to the fullest extent possible. As non-judicial official bodies, which investigate violent historical periods often silenced or denied, truth commissions recognize the dignity of the victims, and propose policies to prevent more violations from happening in the future. Further to that purpose, the recommendations of truth commissions generally seek to identify the causes of the violations, determining patterns of abuse and preventing recurrence.This paper examines some of the challenges that truth commissions face when addressing Indigenous Peoples’ issues, reflecting what measures have to be taken into account in order to establish truth commissions that respect the rights, perspectives and needs of Indigenous Peoples

Beam Test Performance and Simulation of Prototypes for the ALICE Silicon Pixel Detector

The silicon pixel detector (SPD) of the ALICE experiment in preparation at the Large Hadron Collider (LHC) at CERN is designed to provide the precise vertex reconstruction needed for measuring heavy flavor production in heavy ion collisions at very high energies and high multiplicity. The SPD forms the innermost part of the Inner Tracking System (ITS) which also includes silicon drift and silicon strip detectors. Single assembly prototypes of the ALICE SPD have been tested at the CERN SPS using high energy proton/pion beams in 2002 and 2003. We report on the experimental determination of the spatial precision. We also report on the first combined beam test with prototypes of the other ITS silicon detector technologies at the CERN SPS in November 2004. The issue of SPD simulation is briefly discussed.Comment: 4 pages, 5 figures, prepared for proceedings of 7th International Position Sensitive Detectors Conference, Liverpool, Sept. 200

Molecular signatures associated with the treatment of triple-negative MDA-MB231 breast cancer cells with the histone deacetylase inhibitors JAHA and SAHA

Jay Amin Hydroxamic Acid (JAHA; N8-ferrocenylN1-hydroxy-octanediamide) is a ferrocene-containing analogue of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA). JAHA’s cytotoxic activity on MDA-MB231 triple negative breast cancer (TNBC) cells at 72 h has been previously demonstrated with an IC50 of 8.45 M. JAHA’s lethal effect was found linked to perturbations of cell cycle, mitochondrial activity, signal transduction and autophagy mechanisms. In order to glean novel insights on how MDA-MB231 breast cancer cells respond to the cytotoxic effect induced by JAHA, and to compare the biological effect with the related compound SAHA, we have employed a combination of differential display-PCR, proteome analysis and COMET assay techniques and shown some differences in the molecular signature profiles induced by exposure to either HDACis. In particular, in contrast to the more numerous and diversified changes induced by SAHA, JAHA has shown a more selective impact on expression of molecular signatures involved in anti-oxidant activity and DNA repair. Besides expanding the biological knowledge of the effect exerted by the modifications in compound structures on cell phenotype, the molecular elements put in evidence in our study may provide promising targets for therapeutic interventions on TNBCs

Performance of ALICE pixel prototypes in high energy beams

The two innermost layers of the ALICE inner tracking system are instrumented with silicon pixel detectors. Single chip assembly prototypes of the ALICE pixels have been tested in high energy particle beams at the CERN SPS. Detection efficiency and spatial precision have been studied as a function of the threshold and the track incidence angle. The experimental method, data analysis and main results are presented.Comment: 10 pages, 9 figures, contribution to PIX2005 Workshop, Bonn (Germany), 5-8 September 200

Performance of prototypes for the ALICE electromagnetic calorimeter

The performance of prototypes for the ALICE electromagnetic sampling calorimeter has been studied in test beam measurements at FNAL and CERN. A $4\times4$ array of final design modules showed an energy resolution of about 11% /$\sqrt{E(\mathrm{GeV})}$ $\oplus$ 1.7 % with a uniformity of the response to electrons of 1% and a good linearity in the energy range from 10 to 100 GeV. The electromagnetic shower position resolution was found to be described by 1.5 mm $\oplus$ 5.3 mm /$\sqrt{E \mathrm{(GeV)}}$. For an electron identification efficiency of 90% a hadron rejection factor of $>600$ was obtained.Comment: 10 pages, 10 figure