Design of Allosteric Stimulators of the Hsp90 ATPase as New Anticancer Leads

Allosteric compounds that stimulate Hsp90 adenosine triphosphatase (ATPase) activity were rationally designed, showing anticancer potencies in the low micromolar to nanomolar range. In parallel, the mode of action of these compounds was clarified and a quantitative model that links the dynamic ligand-protein cross-talk to observed cellular and in vitro activities was developed. The results support the potential of using dynamics-based approaches to develop original mechanism-based cancer therapeutics

High level of telomerase RNA gene expression is associated with chromatin modification, the ALT phenotype and poor prognosis in liposarcoma

Telomere length is maintained by two known mechanisms, activation of telomerase or alternative lengthening of telomeres (ALT). The ALT pathway is more commonly activated in tumours of mesenchymal origin, although the mechanisms involved in the decision of a cell to activate either telomerase or ALT are unknown at present and no molecular markers exist to define the ALT phenotype. We have previously shown an association between chromatin remodelling, telomerase gene expression and ALT in cell line models. Here, we evaluate these findings and investigate their prognostic significance in a panel of liposarcoma tissue samples to understand the biology underlying the ALT phenotype. Liposarcoma samples were split into three groups: telomerase positive (Tel+); ALT positive; ALT−/Tel−. Differences in telomerase gene expression were evident between the groups with increased expression of hTR in ALT and Tel+ compared to ALT−/Tel− samples and increased hTERT in Tel+ samples only. Investigation of a small panel of chromatin modifications revealed significantly increased binding of acetyl H3 in association with hTR expression. We confirm that the presence of the ALT phenotype is associated with poor prognosis and in addition, for the first time, we show a direct association between hTR expression and poor prognosis in liposarcoma patients

Time series aggregation, disaggregation and long memory

We study the aggregation/disaggregation problem of random parameter AR(1) processes and its relation to the long memory phenomenon. We give a characterization of a subclass of aggregated processes which can be obtained from simpler, "elementary", cases. In particular cases of the mixture densities, the structure (moving average representation) of the aggregated process is investigated

PP-wave and Non-supersymmetric Gauge Theory

We extend the pp-wave correspondence to a non supersymmetric example. The model is the type 0B string theory on the pp-wave R-R background. We explicitly solve the model and give the spectrum of physical states. The field theory counterpart is given by a sector of the large N SU(N) x SU(N) CFT living on a stack of N electric and N magnetic D3-branes. The relevant effective coupling constant is g_{eff}=g_sN/J^2. The string theory has a tachyon in the spectrum, whose light-cone energy can be exactly computed as a function of g_{eff}. We argue that the perturbative analysis in g_{eff} in the dual gauge theory is reliable, with corrections of non perturbative type. We find a precise state/operator map, showing that the first perturbative corrections to the anomalous dimensions of the operators have the behavior expected from the string analysis.Comment: 19 pages. Revised versio

On the Geometry of Matrix Models for N=1*

We investigate the geometry of the matrix model associated with an N=1 super Yang-Mills theory with three adjoint fields, which is a massive deformation of N=4. We study in particular the Riemann surface underlying solutions with arbitrary number of cuts. We show that an interesting geometrical structure emerges where the Riemann surface is related on-shell to the Donagi-Witten spectral curve. We explicitly identify the quantum field theory resolvents in terms of geometrical data on the surface.Comment: 17 pages, 2 figures. v2: reference adde

Activity of a trinuclear platinum complex in human ovarian cancer cell lines sensitive and resistant to cisplatin: cytotoxicity and induction and gene-specific repair of DNA lesions

A collateral sensitivity or a very modest cross-resistance to BBR 3464 was found in 2 ovarian cancer cell lines with experimentally induced resistance to cisplatin. Loss of mismatch repair proteins (hMLH1, hPMS2) or overexpression of nucleotide excision repair proteins (ERCC1) was not detrimental for the cellular sensitivity to BBR 3464. Moreover, interesting differences in the kinetics of formation and removal of DNA lesions at the single-gene (N- ras) level were observed between BBR 3464 and CDDP. © 2001 Cancer Research Campaign www.bjcancer.co

Structural requirements of benzofuran derivatives dehydro-δ-and dehydro-ε-viniferin for antimicrobial activity against the foodborne pathogen listeria monocytogenes

In a recent study, we investigated the antimicrobial activity of a collection of resveratrol-derived monomers and dimers against a series of foodborne pathogens. Out of the tested molecules, dehydro-\u3b4-viniferin and dehydro-\u3b5-viniferin emerged as the most promising derivatives. To define the structural elements essential to the antimicrobial activity against the foodborne pathogen L. monocytogenes Scott A as a model Gram-positive microorganism, the synthesis of a series of simplified benzofuran-containing derivatives was carried out. The systematic removal of the aromatic moieties of the parent molecules allowed a deeper insight into the most relevant structural features affecting the activity. While the overall structure of compound 1 could not be altered without a substantial loss of antimicrobial activity, the structural simplification of compound 2 (minimal inhibitory concentration (MIC) 16 \u3bc\ub5g/mL, minimal bactericidal concentration (MBC) >512 \u3bc\ub5g/mL) led to the analogue 7 with increased activity (MIC 8 \u3bc\ub5g/mL, MBC 64 \u3bc\ub5g/mL)