Treating rheumatic patients with a malignancy

Management of patients with inflammatory rheumatic disease and a history of (or even a current) malignant disease poses some particular challenges. As direct evidence of the risk of (recurrent or de novo) malignancy in patients with a history of malignant disease is scarce, such a risk may be estimated indirectly from the principal carcinogenicity of the respective drug to be used or (also indirectly) from cancer reactivation data from the transplant literature. In general, cancer risk is increased in patients receiving combination immunosuppressive treatment, but the risk in patients receiving individual drugs (with the exception of alkylating agents) remains entirely unclear. Indirect evidence supports the intuitive concept that the risk of cancer decreases over time after a successful cancer treatment. The only two studies in rheumatic patients with a cancer history were small and have not been able to show an increase in cancer reactivation. The risk of reactivation also depends on the site and location of the prior malignancy. In conclusion, the decision to treat a patient with a history of cancer immunosuppressively should be shared by the rheumatologist and the oncologist. Once the decision is established, such patients need intensive and close monitoring.     

Glycation of the Muscle-Specific Enolase by Reactive Carbonyls: Effect of Temperature and the Protection Role of Carnosine,Pirydoxamine and Phosphatidylserine

Reactive carbonyls such as 4-hydroxy-2-nonenal (4-HNE), trans-2-nonenal (T2 N), acrolein (ACR) can react readily with nucleophilic protein sites forming of advanced glycation end-products (AGE). In this study, the human and pig muscle-specific enolase was used as a protein model for in vitro modification by 4-HNE, T2 N and ACR. While the human enolase interaction with reactive α-oxoaldehyde methylglyoxal (MOG) was demonstrated previously, the effect of 4-HNE, T2 N and ACR has not been identified yet. Altering in catalytic function were observed after the enzyme incubation with these active compounds for 1–24 h at 25, 37 and 45 °C. The inhibition degree of enolase activity occurred in following order: 4-HNE > ACR > MOG > T2 N and inactivation of pig muscle-specific enolase was more effective relatively to human enzyme. The efficiency of AGE formation depends on time and incubation temperature with glycating agent. More amounts of insoluble AGE were formed at 45 °C. We found that pirydoxamine and natural dipeptide carnosine counteracted AGE formation and protected enolase against the total loss of catalytic activity. Moreover, we demonstrated for the first time that phosphatidylserine may significantly protect enolase against decrease of catalytic activity in spite of AGE production.     

Interactions of 2,6-substituted purines with purine nucleoside phosphorylase from Helicobacter pylori in solution and in the crystal,and the effects of these compounds on cell cultures of this bacterium

Helicobacter pylori represents a global health threat with around 50% of the world population infected. Due to the increasing number of antibiotic-resistant strains, new strategies for eradication of H. pylori are needed. In this study, we suggest purine nucleoside phosphorylase (PNP) as a possible new drug target, by characterising its interactions with 2- and/or 6-substituted purines as well as the effect of these compounds on bacterial growth. Inhibition constants are in the micromolar range, the lowest being that of 6-benzylthio-2-chloropurine. This compound also inhibits H. pylori 26695 growth at the lowest concentration. X-ray structures of the complexes of PNP with the investigated compounds allowed the identification of interactions of inhibitors in the enzyme’s base-binding site and the suggestion of structures that could bind to the enzyme more tightly. Our findings prove the potential of PNP inhibitors in the design of drugs against H. pylori.     

Resonant modes and musical ratios in otoacoustic emissions

The ratios between frequency components of evoked otoacoustic emissions (OAE) were investigated for 100 ears. The signals were decomposed by means of an adaptive approximation method into basic waveforms coming from a very large and redundant dictionary of Gabor functions. The high time-frequency resolution of the method and the parametric representation of the waveforms allowed for an estimation of the frequency ratios of the basic components. A repetitive occurrence of the “fifths”, “fourths” and octaves connected with the Pythagorean temperament was found. The octaves containing “fifths” were identified. This kind of sequences in OAE tend to appear in the same form for tonal stimulations of different frequencies and for broadband stimuli. The significance of the results was confirmed by comparison to Monte Carlo simulations of the null hypothesis of random distribution of frequency modes. These findings support the resonance theory of hearing, which binds musical ratios with the geometrical spacing of outer hair cells in the cochlea.     

Astrocyte- and hepatocyte-specific expression of genes from the distal serpin subcluster at 14q32.1 associates with tissue-specific chromatin structures

The distal serpin subcluster contains genes encoding alpha1-antichymotrypsin (ACT), protein C inhibitor (PCI), kallistatin (KAL) and the KAL-like protein, which are expressed in hepatocytes, but only the act gene is expressed in astrocytes. We show here that the tissue-specific expression of these genes associates with astrocyte- and hepatocyte-specific chromatin structures. In hepatocytes, we identified 12 Dnase I-hypersensitive sites (DHSs) that were distributed throughout the entire subcluster, with the promoters of expressed genes accessible to restriction enzyme digestion. In astrocytes, only six DHSs were located exclusively in the 5' flanking region of the act gene, with its promoter also accessible to restriction enzyme digestion. The acetylation of histone H3 and H4 was found throughout the subcluster in both cell types but this acetylation did not correlate with the expression pattern of these serpin genes. Analysis of histone modifications at the promoters of the act and pci genes revealed that methylation of histone H3 on lysine 4 correlated with their expression pattern in both cell types. In addition, inhibition of methyltransferase activity resulted in suppression of ACT and PCI mRNA expression. We propose that lysine 4 methylation of histone H3 correlates with the tissue-specific expression pattern of these serpin genes.     

Cobalt complexes with cinchonidine and quinidine: effect of C8/C9 stereochemistry and 6'-substitution on intermolecular interactions

The title compounds, (cinchonidinium)trichlorocobalt(II) [(C(19)H(23)ON(2))CoCl(3)] (CoCdn) and (quinidinium)trichlorocobalt(II) [(C(20)H(25)O(2)N(2))CoCl(3)] (CoQd), are zwitterions that differ in absolute configuration and conformation. In both complexes, the sp(3) nitrogen of quinuclidine is protonated, whereas the sp(2) nitrogen of quinoline is linked to the Co(II) atom, which coordinates three chlorine atoms in distorted tetrahedral geometry. The mutual orientations of the quinoline and quinuclidine moieties in CoCdn and CoQd differ significantly because of different hydrogen bonding involving the hydroxyl group. In both complexes, the quinuclidine NH groups and hydroxyl groups are hydrogen-bond donors to the chlorine atoms of Co(II) tetrahedra. In CoQd the hydrogen bonding leads to formation of a nine-membered ring consisting of Co, two chlorines, and a fragment of the quinidine molecule. A comparison of the crystal structures of four Cinchona alkaloid complexes with trichlorocobalt(II) shows that their space groups are determined by the absolute configuration of the alkaloid, whereas the hydrogen-bonding pattern is mainly affected by the substituent in the quinoline ring, i.e., by hydrogen or methoxyl group.     

Novel, flexible, and conformationally defined analogs of gepirone: synthesis and 5-HT1A, 5-HT2A, and D2 receptor activity

Novel, flexible arylpiperazine gepirone analogs (1a-3a) with a mixed 5-HT1A/5-HT2A receptor profile, low D2 receptor affinity, and agonistic (2a) or partial agonistic (1a, 3a) activity toward 5-HT1A receptor sites were synthesized. Their conformationally restricted counterparts (1b-3b) were selective 5-HT1A ligands (over 5-HT2A and D2 receptors), which turned out to be agonists (2b, 3b), or partial agonist (1b) of 5-HT1A receptors.     

Position-specific incorporation of a highly photodurable and blue-laser excitable fluorescent amino acid into proteins for fluorescence sensing

A new fluorescent amino acid, L-2-acridonylalanine, was incorporated into proteins at specific positions using 4-base codon/anticodon strategy. The efficiency of the incorporation was high enough to obtain enough quantities of the mutants. The acridonyl group was highly fluorescent when it was excited at the wavelengths of blue-lasers and was highly photodurable compared with conventional fluorophores often used for biological analyses. The fluorescence intensity was sensitive to small changes in the polarity of the environment. When the nonnatural amino acid was incorporated into specific positions of streptavidin, the mutant protein worked as a fluorescent sensor to biotin. Similarly, when the amino acid was incorporated into camel single-chain antibody, the mutant protein sensitively responded to the antigen molecule. The high incorporation efficiency, the high photodurability, the excitability with blue-lasers, and high sensitivity to the environment make the acridonylalanine as the promising fluorescent amino acid for sensing small molecules when incorporated into specific positions of various antibodies, receptors, and enzymes.