Exploring the Effects of Glycosylation and Etherification of the Side Chains of the Anticancer Drug Mitoxantrone

Herein we report the synthesis and biological evaluation of symmetric and asymmetric analogues of the DNA intercalating drug mitoxantrone (MTX) in which the side chains of the parent drug were modified through glycosylation or methyl etherification. Several analogues with glycosylated side chains exhibited higher DNA affinity than the parent MTX. The most potent in vitro cytotoxicity was observed for MTX analogue 8 (1,4‐dimethoxy‐5,8‐bis[2‐(2‐methoxyethylamino)ethylamino]anthracene‐9,10‐dione) with methoxy ether containing side chains. Treatment of melanoma‐bearing mice with MTX or analogue 8 decreased the intraperitoneal tumor burden relative to untreated mice; the effect of 8 was less pronounced than that of MTX. In vitro metabolism assays of MTX with rabbit liver S9 fraction gave rise to several metabolites; almost no metabolites were detected for MTX analogue 8 . The results presented indicate that derivatization of the MTX side chain primary hydroxy groups may result in a significant improvement in DNA affinity and lower susceptibility to the formation of potentially toxic metabolites.     

Perceived beneficial and detrimental postwar responses of Israeli adults: Are they positively or negatively linked to each other?

This study first compares two theoretical perspectives on the links between beneficial and detrimental posttraumatic responses. One group of studies claims that positive posttraumatic responses tend to be positively related with negative stress-related responses. Others posit that, after a severe stress, these responses are negatively correlated with each other. We argue that these contradictory results represent the different theoretical positions on the nature of favorable postwar outcomes. A second issue investigated is the associations of beneficial and detrimental postwar responses with demographic variables as well as with exposure to the stress of war. An Israeli adult sample (n = 870) was administered two different measures of negative posttraumatic outcomes (resource loss and postwar symptoms) and two different measures of positive posttraumatic outcomes (resource gains and posttraumatic recovery) one year after they were badly affected by a war. Resource gains correlated positively with resource loss, whereas PTR correlated negatively with postwar symptoms. There were also positive associations between the two measures of stress as well as the two beneficial posttraumatic outcomes. Older age, being a woman, lower economic status, and higher exposure to traumatic events tended to correlate positively with both measures of detrimental outcomes. These variables correlated negatively with PTR, and three of them (excluding economic status) were not significantly linked with resource gains. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Effects of monoglyceride content,cooling rate and shear on the rheological properties of olive oil/monoglyceride gel networks

Functionality of conventional fat spreads can be achieved without hydrogenation by the formation of stable network structures upon cooling of mixtures of monoglycerides (MGs) and vegetable oils from the melt. Such mixtures are healthy substitutes for margarine and butter. The effects of MG content, cooling rate and shear on the temperature ramp, mechanical spectra and hardness of olive oil/MG gel networks were investigated. A minimum MG volume fraction was necessary for formation of a gelled network, but this concentration was less than that needed for a space‐filling network structure. Onset of gel network or structure formation was indicated by a sudden divergence in value of the elastic modulus G′. The temperature at onset of structure formation, T_o, final G′ value and network hardness all increased with increase in MG content. High cooling rates led to low final G′ values but harder networks, and vice versa. Maximum gel network development occurred when moderate shear (about 300 s^?1) was applied at incipient gelation. Copyright © 2004 Society of Chemical Industry     

Induction of T cell adhesion to extracellular matrix or endothelial cell ligands by soluble or matrix-bound interleukin-7

The putative effects of interleukin (IL)-7, operating in the context of extracellular matrix (ECM), on the adhesion of human T cells were examined. Recombinant human, IL-7 was found to bind ECM or fibronectin (FN) with IC50 values of 10-100 nM. Nanogram amounts of both soluble and, especially, FN- or ECM-bound IL-7, which differentially affected the morphologies of FN-adherent T cells, induced the adhesion of resting CD4+ and CD8+ T cells in dose-dependent and beta 1 integrin-dependent manners. Under static and flow conditions, soluble IL-7 also induced the binding of unstimulated T cells to vascular cell adhesion molecule-1, suggesting that this cytokine can also modulate integrin binding to endothelial cell ligands. The effects of affinity modulation by IL-7 of FN-specific beta 1 integrins depend on the presence of soluble FN, which inhibited T cell adhesion to FN induced by FN-bound IL-7 or by an integrin-specific affinity-modulating monoclonal antibody, but not by soluble IL-7 or phorbol 12-myristate 13-acetate. These findings provide an example of a major ECM integrin ligand, FN, which is capable of modulating its adhesive interactions with specific immune cells by associating with and presenting a cytokine in a bio-active state.     

Ontogeny of nitric oxide in the pulmonary vasculature

The vasodilator molecule nitric oxide is critically involved in the successful cardiopulmonary transition from fetal to postnatal life. It is produced in the pulmonary endothelium by the endothelial isoform of the enzyme nitric oxide synthase. The expression of endothelial nitric oxide synthase in the lung increases dramatically during late gestation, optimizing the capacity for nitric oxide production at the time of birth. Studies in cultured cell models indicate that the developmental upregulation may be mediated by estrogen, and that the expression of the enzyme is also upregulated by oxygen. Pulmonary endothelial nitric oxide synthase expression is diminished in models of congenital diaphragmatic hernia and neonatal pulmonary hypertension induced by fetal ductal ligation. Thus, there is normally a marked developmental upregulation in endothelial nitric oxide synthase expression in the lung during late fetal life, and attenuated expression of the enzyme may contribute to the pathophysiology of a variety of forms of neonatal pulmonary vascular disease.     

Analysis of the Ac promoter: structure and regulation

BACKGROUND: Aberrant expression of CD23 (low affinity IgE receptor) on cells of the monocyte/macrophage series in peripheral blood and lesional skin of patients with atopic eczema has been demonstrated. It is not known whether this abnormality results from a fundamental systemic problem of the monocytes of these patients or reflects local changes to cell populations within the skin tissues. OBJECTIVES: This study was designed to determine whether this aberrant expression was caused by local cutaneous influences on mature cells or fundamental changes in monocyte differentiation. The possible relationship between these aberrations and clinical severity was also investigated by repeating these immunopathological studies after a course of efficacious treatment with Chinese herbal therapy (CHT). METHODS: Peripheral blood mononuclear cells were obtained from patients with atopic eczema before, and after 8 weeks of treatment. Efficacy of CHT was quantified on clinical grounds. Monocytes were isolated by adherence to plastic and cultured for up to 7 days. Samples were harvested at 2, 5 and 7 days of culture and cytospins prepared. Immunocytochemical staining to identify phenotypic subsets was performed on the monocytes at time 0 and on maturing cells from culture. This immunocytology was quantified using computerized image analysis equipment to determine the emergence of macrophage subsets and their level of CD23 expression. Biopsies were taken from lesional skin before and after treatment and immunohistology was performed on cryostat sections to determine the number of antigen presenting cells expressing CD23 as well as the level of expression of these molecules. RESULTS: The results showed that increased numbers of monocytes from patients with atopic eczema express CD23 at day 0 and that cultured monocytes from these patients differentiate faster during the 7 day culture period as compared to normal controls. Efficacious treatment did not affect the number of peripheral blood monocytes expressing CD23. However, treatment did lead to a significant decrease in the number of CD23+ mature macrophages in the skin as well as a reduction in the level of expression of this moiety. These results demonstrate that changes in clinical severity are more closely related to the expression of CD23 on mature antigen presenting cells in lesional skin rather than to differentiating peripheral blood monocyte CD23 expression. CONCLUSIONS: These results suggests that local factors within lesional skin govern the accumulation and the expression of CD23 on mature macrophages and that these factors may be more relevant to the pathogenesis of the disease than aberrations in CD23 expression that may occur systemically.     

The solubility parameters of aromatic polyamides

The degrees of swelling of rigid aromatic polyamide networks in various solvents, nonsolvents, and solvent mixtures were used to determine their solubility parameters. This was made possible because of the amorphous nature of the rigid networks and the low levels of intersegmental H-bonding. The solubility parameters are: δ = 23.0 (MPa)^1/2, δ_d = 18.0 (MPa)^1/2, δ_p = 11.9 (MPa)^1/2, and δ_H = 7.9 (MPa)^1/2. The determined values are believed to be good approximations of the solubility parameters of stiff linear aromatic polyamides, because of the essential identity of their structure and the stiff segments in the networks.     

Selective Sampling for Nearest Neighbor Classifiers

Most existing inductive learning algorithms work under the assumption that their training examples are already tagged. There are domains, however, where the tagging procedure requires significant computation resources or manual labor. In such cases, it may be beneficial for the learner to be active, intelligently selecting the examples for labeling with the goal of reducing the labeling cost. In this paper we present LSS—a lookahead algorithm for selective sampling of examples for nearest neighbor classifiers. The algorithm is looking for the example with the highest utility, taking its effect on the resulting classifier into account. Computing the expected utility of an example requires estimating the probability of its possible labels. We propose to use the random field model for this estimation. The LSS algorithm was evaluated empirically on seven real and artificial data sets, and its performance was compared to other selective sampling algorithms. The experiments show that the proposed algorithm outperforms other methods in terms of average error rate and stability.     

Quantum correlations at negative absolute temperatures

We study behavior of quantum discord, a kind of quantum correlation, in systems of dipole–dipole interacting spins in an external magnetic field in the whole temperature range ( \(-\infty ). It was shown that negative temperatures, which are introduced to describe inversions in the population in a finite level system, provide more favorable conditions for emergence of quantum correlations including entanglement. We show that at negative temperature, the correlations become more intense and discord exists between remote spins being in separated states.