Salarin C inhibits the maintenance of chronic myeloid leukemia progenitor cells

We previously showed that incubation of chronic myeloid leukemia (CML) cells in very low oxygen selects a cell subset where the oncogenetic BCR/Abl protein is suppressed and which is thereby refractory to tyrosine kinase inhibitors used for CML therapy. In this study, salarin C, an anticancer macrolide extracted from the Fascaplysinopsis sponge, was tested as for its activity on CML cells, especially after their incubation in atmosphere at 0.1% oxygen. Salarin C induced mitotic cycle arrest, apoptosis and DNA damage. Salarin C also concentration-dependently inhibited the maintenance of stem cell potential in cultures in low oxygen of either CML cell lines or primary cells. Surprisingly, the drug also concentration-dependently enforced the maintenance of BCR/Abl signaling in low oxygen, an effect which was paralleled by the rescue of sensitivity of stem cell potential to IM. These results suggest a potential use of salarin C for the suppression of CML cells refractory to tyrosine kinase inhibitors     

The effects of acute acetaminophen toxicity on hepatic mRNA expression of SOD,CAT, GSH-Px,and levels of peroxynitrite,nitric oxide,reduced glutathione,and malondialdehyde in rabbit

Molecular and Cellular Biochemistry -     

Unusual acrofacial dysostosis with severe limb defects: a new syndrome

The acrofacial dysostoses are a heterogeneous group of disorders characterised by defects in craniofacial and limb development. The hallmarks include downward slanting palpebral fissures, malar hypoplasia, and retrognathia combined with variable limb malformations. We report the patient, a 5-day-old-boy with craniofacial dysmorphic features and upper and lower limb defects respectively.     

A telemedicine instrument for remote evaluation of tremor: design and initial applications in fatigue and patients with Parkinson's Disease

Introduction  

A novel system that combines a compact mobile instrument and Internet communications is presented in this paper for remote evaluation of tremors. The system presents a high potential application in Parkinson's disease and connects to the Internet through a TCP/IP protocol. Tremor transduction is carried out by accelerometers, and the data processing, presentation and storage were obtained by a virtual instrument. The system supplies the peak frequency (fp), the amplitude (Afp) and power in this frequency (Pfp), the total power (Ptot), and the power in low (1-4 Hz) and high (4-7 Hz) frequencies (Plf and Phf, respectively).     

Computer-assisted design for atenolol prodrugs for the use in aqueous formulations

Based on stability studies on the drugs atenolol and propranolol and some of their derivatives it is believed that increasing the lipophilicity of the drug will lead to an increase in the stability of its aqueous solutions and will provide a prodrug system with the potential for releasing atenolol in a controlled manner. Using DFT theoretical calculations we have calculated an intramolecular acid catalyzed hydrolysis in nine maleamic (4-amino-4-oxo-2butenoic) acids (Kirby’s N-alkylmaleamic acids), 1–9. The DFT calculations confirmed that the acid-catalyzed hydrolysis mechanism in these systems involves: (1) a proton transfer from the hydroxyl of the carboxyl group to the adjacent amide carbonyl carbon, (2) an approach of the carboxylate anion toward the protonated amide carbonyl carbon to form a tetrahedral intermediate; and (3) a collapse of the tetrahedral intermediate into products. Furthermore, DFT calculations in different media revealed that the reaction rate-limiting step depends on the reaction medium. In aqueous medium the rate-limiting step is the collapse of the tetrahedral intermediate whereas in the gas phase the formation of the tetrahedral intermediate is the rate-limiting step. Furthermore, the calculations establish that the acid-catalyzed hydrolysis efficiency is largely sensitive to the pattern of substitution on the carbon-carbon double bond. Based on the experimental t_1/2 (the time needed for the conversion of 50% of the reactants to products) and EM (effective molarity) values for processes 1–9 we have calculated the t_1/2 values for the conversion of the two prodrugs to the parental drug, atenolol. The calculated t_1/2 values for ProD 1–2 are predicted to be 65.3 hours and 11.8 minutes, respectively. Thus, the rate by which atenolol prodrug undergoes cleavage to release atenolol can be determined according to the nature of the linker of the prodrug (Kirby’s N-alkylmaleamic acids 1–9).     

Comparisons of substitution, insertion and deletion probes for resequencing and mutational analysis using oligonucleotide microarrays

Although oligonucleotide probes complementary to single nucleotide substitutions are commonly used in microarray-based screens for genetic variation, little is known about the hybridization properties of probes complementary to small insertions and deletions. It is necessary to define the hybridization properties of these latter probes in order to improve the specificity and sensitivity of oligonucleotide microarray-based mutational analysis of disease-related genes. Here, we compare and contrast the hybridization properties of oligonucleotide microarrays consisting of 25mer probes complementary to all possible single nucleotide substitutions and insertions, and one and two base deletions in the 9168 bp coding region of the ATM (ataxia telangiectasia mutated) gene. Over 68 different dye-labeled single-stranded nucleic acid targets representing all ATM coding exons were applied to these microarrays. We assess hybridization specificity by comparing the relative hybridization signals from probes perfectly matched to ATM sequences to those containing mismatches. Probes complementary to two base substitutions displayed the highest average specificity followed by those complementary to single base substitutions, single base deletions and single base insertions. In all the cases, hybridization specificity was strongly influenced by sequence context and possible intra- and intermolecular probe and/or target structure. Furthermore, single nucleotide substitution probes displayed the most consistent hybridization specificity data followed by single base deletions, two base deletions and single nucleotide insertions. Overall, these studies provide valuable empirical data that can be used to more accurately model the hybridization properties of insertion and deletion probes and improve the design and interpretation of oligonucleotide microarray-based resequencing and mutational analysis.