Steric Determinants of Pt/DNA Interactions and Anticancer Activity

Studies directed at establishing the structural features that control Pt/DNA interactions and the anticancer activity of Pt drugs are described. [1H, 15N]-HSQC 2D NMR spectroscopic studies of the reactions of cisplatin with oligonucleotides containing ApG and GpA binding sites reveal dramatic differences in the rates of formation of monofunctional adducts at the two sites. When the reactant is cis-[Pt(NH3)2(OH2)2]2+ no such differences are observed suggesting that outer-sphere interactions between the reactant and the oligonucleotide may play a substantial role in determining the rates. Rates of closure to the bifunctional adducts are similar to those observed for cisplatin. Studies of the adduct profiles formed by sterically bulky and/or optically active complexes reveal that steric interactions play a major role in mediating the binding of Pt(ll) to DNA but that hydrogen bonds play less of a role. In vitro cytotoxic activities for these complexes do not always follow the trends that would be expected on the basis of the adduct profiles

The Leukemia-Specific Fusion Gene ETV6/RUNX1 Perturbs Distinct Key Biological Functions Primarily by Gene Repression

-positive leukemic cell lines.-positive ALL samples underline the relevance of these pathways and molecular functions. We also validated six differentially expressed genes representing the categories “stem cell properties”, “B-cell differentiation”, “immune response”, “cell adhesion” and “DNA damage” with RT-qPCR. fusion gene interferes with key regulatory functions that shape the biology of this leukemia subtype. E/R may thus indeed constitute the essential driving force for the propagation and maintenance of the leukemic process irrespective of potential consequences of associated secondary changes. Finally, these findings may also provide a valuable source of potentially attractive therapeutic targets

Eavesdropping near-field contactless payments: a quantitative analysis

This paper presents an assessment of how successful an eavesdropping attack on a contactless payment transaction can be in terms of bit and frame error rates, using an easily concealable antenna and low-cost electronics. Potential success of an eavesdropping attack largely depends on the correct recovery of the data frames used in the ISO 14443 standard. A near-field communication inductive loop antenna was used to emulate an ISO 14443 transmission. For eavesdropping, an identical inductive loop antenna as well as a shopping trolley modified to act like an antenna were used. The authors present and analyse frame error rates obtained with the authors equipment over a range of distances, up to 100 cm, well above the official maximum operating distance depending on the magnetic field strength

Eavesdropping near-field contactless payments: a quantitative analysis

Abstract: This paper presents an assessment of how successful an eavesdropping attack on a contactless payment transaction can be in terms of bit and frame error rates, using an easily concealable antenna and low-cost electronics. Potential success of an eavesdropping attack largely depends on the correct recovery of the data frames used in the ISO 14443 standard. A near-field communication inductive loop antenna was used to emulate an ISO 14443 transmission. For eavesdropping, an identical inductive loop antenna as well as a shopping trolley modified to act like an antenna were used. The authors present and analyse frame error rates obtained with the authors equipment over a range of distances, up to 100 cm, well above the official maximum operating distance depending on the magnetic field strength

Cancer-related inflammation and treatment effectiveness

Inflammation is a recognised hallmark of cancer that substantially contributes to the development and progression of malignancies. In established cancers, there is increasing evidence for the roles that local immune response and systemic inflammation have in progression of tumours and survival of patients with cancer. This knowledge provides an opportunity to target these inflammatory responses to improve patient outcomes. In this Review, we examine the complex interplay between local immune responses and systemic inflammation, and their influence on clinical outcomes, and propose potential anti-inflammatory interventions for patients with cancer

Can metal complexes serve as hypoxia activated prodrugs? Investigations of a Co(III) complex of the MMP inhibitor marimastat

For many years proof that the hypoxic nature of malignant tumours can be used to selectively target anticancer drugs has been sought. Several classes of potential redox activated anticancer drugs have been developed to take advantage of the reducing environment resulting from the hypoxia. Drug complexes with redox active metal centres as carriers have been investigated, but have largely been employed with cytotoxic drugs that require release of the drug intracellularly, complicating the design of such complexes. MMP inhibitors, a new class of anticancer drug, conversely act in the extracellular environment and we have investigated inhibitor complexes with several redox active transition metals. Marimastat is an MMP inhibitor with potent in-vitro antimetastatic activity and was recently in Phase III clinical trials for a variety of cancer types. We have synthesised a Co(II1) complex of marimastat incorporating the tetradentate ligand tpa (tris(2-methylpyridyl)amine) as a carrier ligand. The complex was structurally characterised in the solid state by single crystal X-ray diffraction, the first example of a crystal structure containing marimastat. 2D COSY and NOESY NMR spectra showed that the complex exists in two isomeric forms in solution, corresponding to the cis and trans isomers yet only crystallises in one of these forms. Biological testing of the complex in mice with 4T1.2 tumours showed interesting and unexpected outcomes. Initial results of the tumour growth inhibition study showed that a significant inhibition of growth was exhibited by the complex over the free inhibitor and the control. However, the metastatic potential of both free marimastat and the complex were higher than the control indicating likely problems with the experimental protocol. Further experiments are needed to determine the potential of such complexes as hypoxia activated prodrugs but there appears at least to be some promise

Direct and Indirect Targets of the E2A-PBX1 Leukemia-Specific Fusion Protein

<div><p><i>E2A-PBX1</i> is expressed as a result of the t(1;19) chromosomal translocation in nearly 5% of cases of childhood acute lymphoblastic leukemia. The E2A-PBX1 chimeric transcription factor contains the N-terminal transactivation domain of E2A (TCF3) fused to the C-terminal DNA-binding homeodomain of PBX1. While there is no doubt of its oncogenic potential, the mechanisms of E2A-PBX1-mediated pre-B cell transformation and the nature of direct E2A-PBX1 target genes and pathways remain largely unknown. Herein we used chromatin immunoprecipitation assays (ChIP-chip) to identify direct targets of E2A-PBX1, and we used gene expression arrays of siRNA E2A-PBX1-silenced cells to evaluate changes in expression induced by the fusion protein. Combined ChIP-chip and expression data analysis gave rise to direct and functional targets of E2A-PBX1. Further we observe that the set of ChIP-chip identified E2A-PBX1 targets show a collective down-regulation trend in the E2A-PBX1 silenced samples compared to controls suggesting an activating role of this fusion transcription factor. Our data suggest that the expression of the E2A-PBX1 fusion gene interferes with key regulatory pathways and functions of hematopoietic biology. Among these are members of the WNT and apoptosis/cell cycle control pathways, and thus may comprise an essential driving force for the propagation and maintenance of the leukemic phenotype. These findings may also provide evidence of potentially attractive therapeutic targets.</p></div