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

Structural polymorphism of intramolecular quadruplex of human telomeric DNA: effect of cations, quadruplex-binding drugs and flanking sequences

G-quadruplex structures formed in the telomeric DNA are thought to play a role in the telomere function. Drugs that stabilize the G-quadruplexes were shown to have anticancer effects. The structures formed by the basic telomeric quadruplex-forming unit G3(TTAG3)3 were the subject of multiple studies. Here, we employ 125I-radioprobing, a method based on analysis of the distribution of DNA breaks after decay of 125I incorporated into one of the nucleotides, to determine the fold of the telomeric DNA in the presence of TMPyP4 and telomestatin, G-quadruplex-binding ligands and putative anticancer drugs. We show that d[G3(TTAG3)3125I-CT] adopts basket conformation in the presence of NaCl and that addition of either of the drugs does not change this conformation of the quadruplex. In KCl, the d[G3(TTAG3)3125I-CT] is most likely present as a mixture of two or more conformations, but addition of the drugs stabilize the basket conformation. We also show that d[G3(TTAG3)3125I-CT] with a 5′-flanking sequence folds into (3+1) type 2 conformation in KCl, while in NaCl it adopts a novel (3+1) basket conformation with a diagonal central loop. The results demonstrate the structural flexibility of the human telomeric DNA; and show how cations, quadruplex-binding drugs and flanking sequences can affect the conformation of the telomeric quadruplex

Metodologias utilizadas para detectar distúrbios emocionais em clínicas de assistência primária à saúde: revisão de literatura

A series of studies in the field of Epidemiological Psychiatry have been performed over the last two decades, and these have focused on the ability of primary care physicians to detect emotional disorders in the patients that attend their practices. The scientific methodology utilized in these studies is the subject of this review, which contains a discussion concerning: a) interviewer awareness bias; b) accuracy of the instruments and c) medical and psychological concepts involved in defining minor emotional disorders. Suggestions for change in the methodology are made in each of the sections of the review.Na área de epidemiologia psiquiátrica vêm sendo realizados, nos últimos vinte anos, estudos que têm como finalidade medir a habilidade que clínicos gerais possuem em detectar distúrbios emocionais nos pacientes que procuram atendimento na rede básica de saúde. A metodologia utilizada nesses estudos é o tema central da atual revisão, que contém a) viés do entrevistador; b) acuidade dos instrumentos; e c) conceitos médicos e psicológicos envolvidos na definição de distúrbio psiquiátrico menor. São também apresentadas sugestões para mudanças de metodologia