Electron Transfer-oxy Radical Mechanism for Anti-cancer Agents: 9-anilinoacridines

A possible mode of action involving electron transfer is advanced for the 9- anilinoacridines. The mechanism entails formation of toxic oxy radicals which destroy the neoplasm. Cyclic voltammetry was performed on iminium type ions derived by protonation of the acridines. Reductions were generally reversible with potentials of about - 0.60 V. Involvement of quinoidal metabolites is also a possibility. The relationship of electrochemical behavior to structure and physiological activity is addressed

Anti-cancer Action of Metal Complexes: Electron Transfer and Oxidative Stress?

Evidence is presented in support of an electron transfer mechanism for various metal complexes possessing anti-neoplastic properties. Cyclic voltammetry was performed on several metallocenes, bis(acetato)bis(imidazole)Cu(II), and coordination compounds (Cu or Fe) of the anti-tumor agents, bipyridine, phenanthroline, hydroxyurea, diethyldithiocarbamate, and α, α1-bis(8-hydroxyquinolin-7-yl)-4-methoxytoluene. The favorable reduction potentials ranged from +0.5 to -0.5 V. Electrochemical behavior is correlated in some cases with structure and physiological activity. Relevant literature data are discussed

Charge Transfer-oxy Radical Mechanism for Anti-cancer Agents

The proposal is advanced that anti-cancer drugs generally function by charge transfer resulting in formation of toxic oxy radicals which destroy the neoplasm. Electrochemical studies were performed with some of the main types of agents: iminium ions (adenine iminium from alkylating species, iminium metabolite of 6-mercaptopurine, nitidine, other polynuclear iminiums) and metal complexes (Pt(II)diaquodiammine-guanosine, copper salicylaldoximes). Reduction potentials ranged from -0.4 to -1.2 V. Literature data for quinones are presented and radiation is discussed. Based on the theoretical framework, a rationale is offered for the carcinogen-anti-cancer paradox and the role of antioxidants

Interactions of asbestos-activated macrophages with an experimental fibrosarcoma

Supernatants from in vivo asbestos-activated macrophages failed to show any cytostatic activity against a syngeneic fibrosarcoma cell line in vitro. UICC chrysotile-induced peritoneal exudate cells also failed to demonstrate any growth inhibitory effect on the same cells in Winn assays of tumor growth. Mixing UICC crocidolite with inoculated tumor cells resulted in a dose-dependent inhibition of tumor growth; this could, however, be explained by a direct cytostatic effect on the tumor cells of high doses of crocidolite, which was observed in vitro

The pirate in the pump: children's views of objects as imaginary friends at the start of school

The main aim of this paper is to use a phenomenological approach (Merleau-Ponty, 1962. Phenomenology of Perception. Evanston: Northwestern University Press; Merleau-Ponty. 1968. The Visible and the Invisible: Followed by Working Notes. Evanston: Northern University Press) to contribute a new theoretical understanding of what imaginary friends mean for children in the context of starting school. The paper addresses the specific area of ‘object-friends’ and draws on examples from an empirical and consultative study of a small sample of five and six-year-old children’s everyday experiences of friendship in school. The paper argues that if practitioners consider embodiment approaches and listen attentively to the knowledge and information that children share about their imaginary friends, this could be used to nurture children’s early learnin

Electrochemistry of omeprazole, active metabolites and a bound enzyme model. Possible involvement of electron transfer in anti-ulcer action

Electrochemical studies were performed with omeprazole, active metabolites and a bound enzyme model. The active metabolites, cyclic sulfenamide and sulfur radical entities, exhibited reduction potentials of -0.3 V and -0.2 V respectively. The value for the bound enzyme model was -0.7 V and that for omeprazole was> -1.4 V. The results lend credence to the hypothesis that electron transfer comprises part of the mode of action in addition to (H+/K+) ATPase inhibition.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29819/1/0000165.pd

Concerted loop motion triggers induced fit of FepA to ferric enterobactin

Spectroscopic analyses of fluorophore-labeled Escherichia coli FepA described dynamic actions of its surface loops during binding and transport of ferric enterobactin (FeEnt). When FeEnt bound to fluoresceinated FepA, in living cells or outer membrane fragments, quenching of fluorophore emissions reflected conformational motion of the external vestibular loops. We reacted Cys sulfhydryls in seven surface loops (L2, L3, L4, L5, L7 L8, and L11) with fluorophore maleimides. The target residues had different accessibilities, and the labeled loops themselves showed variable extents of quenching and rates of motion during ligand binding. The vestibular loops closed around FeEnt in about a second, in the order L3 > L11 > L7 > L2 > L5 > L8 > L4. This sequence suggested that the loops bind the metal complex like the fingers of two hands closing on an object, by individually adsorbing to the iron chelate. Fluorescence from L3 followed a biphasic exponential decay as FeEnt bound, but fluorescence from all the other loops followed single exponential decay processes. After binding, the restoration of fluorescence intensity (from any of the labeled loops) mirrored cellular uptake that depleted FeEnt from solution. Fluorescence microscopic images also showed FeEnt transport, and demonstrated that ferric siderophore uptake uniformly occurs throughout outer membrane, including at the poles of the cells, despite the fact that TonB, its inner membrane transport partner, was not detectable at the poles

Machine learning in systematic reviews: comparing automated text clustering with Lingo3G and human researcher categorization in a rapid review

Systematic reviews are resource-intensive. The machine learning tools beingdeveloped mostly focus on the study identification process, but tools to assistin analysis and categorization are also needed. One possibility is to useunsupervised automatic text clustering, in which each study is automaticallyassigned to one or more meaningful clusters. Our main aim was to assess theusefulness of an automated clustering method, Lingo3G, in categorizing stud-ies in a simplified rapid review, then compare performance (precision andrecall) of this method compared to manual categorization. We randomlyassigned all 128 studies in a review to be coded by a human researcher blindedto cluster assignment (mimicking two independent researchers) or by a humanresearcher non-blinded to cluster assignment (mimicking one researcherchecking another's work). We compared time use, precision and recall of man-ual categorization versus automated clustering. Automated clustering andmanual categorization organized studies by population and intervention/con-text. Automated clustering failed to identify two manually identified categoriesbut identified one additional category not identified by the human researcher.We estimate that automated clustering has similar precision to both blindedand non-blinded researchers (e.g., 88% vs. 89%), but higher recall (e.g., 89%vs. 84%). Manual categorization required 49% more time than automated clus-tering. Using a specific clustering algorithm, automated clustering can be help-ful with categorization of and identifying patterns across studies in simplersystematic reviews. We found that the clustering was sensitive enough togroup studies according to linguistic differences that often corresponded to themanual categoriesacceptedVersio

Oxidised guanidinohydantoin (Ghox) and spiroiminodihydantoin (Sp) are major products of iron- and copper-mediated 8-oxo-7,8-dihydroguanine and 8-oxo-7,8-dihydro-2-deoxyguanosine oxidation

8-Oxo-7,8-dihydroguanine (8-oxoGua), an important biomarker of DNA damage in oxidatively generated stress, is highly reactive towards further oxidation. Much work has been carried out to investigate the oxidation products of 8-oxoGua by one-electron oxidants, singlet oxygen, and peroxynitrite. This report details for the first time, the iron- and copper-mediated Fenton oxidation of 8-oxoGua and 8-oxo-7,8-dihydro-29-deoxyguanosine (8-oxodGuo). Oxidised guanidinohydantoin (Ghox) was detected as the major product of oxidation of 8-oxoGua with iron or copper and hydrogen peroxide, both at pH 7 and pH 11. Oxaluric acid was identified as a final product of 8-oxoGua oxidation. 8-oxodGuo was subjected to oxidation under the same conditions as 8-oxoGua. However, dGhox was not generated. Instead, spiroiminodihydantoin (Sp) was detected as the major product for both iron and copper mediated oxidation at pH 7. It was proposed that the oxidation of 8-oxoGua was initiated by its one-electron oxidation by the metal species, which leads to the reactive intermediate 8-oxoGua?+, which readily undergoes further oxidation. The product of 8-oxoGua and 8-oxodGuo oxidation was determined by the 29-deoxyribose moiety of the 8-oxodGuo, not whether copper or iron was the metal involved in the oxidation

Different paths to the modern state in Europe: the interaction between domestic political economy and interstate competition

Theoretical work on state formation and capacity has focused mostly on early modern Europe and on the experience of western European states during this period. While a number of European states monopolized domestic tax collection and achieved gains in state capacity during the early modern era, for others revenues stagnated or even declined, and these variations motivated alternative hypotheses for determinants of fiscal and state capacity. In this study we test the basic hypotheses in the existing literature making use of the large date set we have compiled for all of the leading states across the continent. We find strong empirical support for two prevailing threads in the literature, arguing respectively that interstate wars and changes in economic structure towards an urbanized economy had positive fiscal impact. Regarding the main point of contention in the theoretical literature, whether it was representative or authoritarian political regimes that facilitated the gains in fiscal capacity, we do not find conclusive evidence that one performed better than the other. Instead, the empirical evidence we have gathered lends supports to the hypothesis that when under pressure of war, the fiscal performance of representative regimes was better in the more urbanized-commercial economies and the fiscal performance of authoritarian regimes was better in rural-agrarian economie