The pattern of gene expression and gene dose profiles of 6-Mercaptopurine- and 6-Thioguanine-resistant human leukemia cells

Exposure of MOLT4 human T-cell leukemia cells to 6-Mercaptopurine (6-MP) and 6-Thioguanine (6-TG) resulted in acquired resistance associated with attenuated expression of the genes encoding concentrative nucleoside transporter 3 (CNT3) and equilibrative nucleoside transporter 2 (ENT2). To identify other alterations at the RNA and DNA levels associated with 6-MP- and 6-TG resistance, we compared here the patterns of gene expression and DNA copy number profiles of resistant sublines to those of the parental wild-type cells. The mRNA levels for two nucleoside transporters were down-regulated in both of the thiopurine-resistant sublines. Moreover, both of these cell lines expressed genes encoding the enzymes of purine nucleotide composition and synthesis, including adenylate kinase 3-like 1 and guanosine monophosphate synthetase at significantly lower levels than wild-type cells. In addition, expression of the mRNA for a specialized DNA polymerase, human terminal transferase encoded by the terminal deoxynucleotidyl transferase (DNTT) gene, was 122- and 93-fold higher in 6-TG- and 6-MP-resistant cells, respectively. The varying responses to 6-MP- and 6-TG observed here may help identify novel cellular targets and modalities of resistance to thiopurines, as well as indicating new potential approaches to individualization therapy with these drugs.     

Changes in the fatty acid profiles of red blood cell membrane phospholipids in human neonates during the first month of life

We have studied the changes in the fatty acid profiles of red blood cell membrane phospholipids in 47 infants who were exclusively fed human milk from birth to 1 month of life. Twenty blood samples were obtained from cord, 15 at 7 days and 12 at 30 days after birth. Membrane phospholipids were obtained from erythrocyte ghosts by thin-layer chromatography and fatty acid composition was determined by gas liquid chromatography. Phosphatidylcholine showed the most important changes during early life; stearic, w6 eicosatrienoic and arachidonic acids decreased whereas oleic and linoleic acids increased. In phosphatidylethanolamine, palmitic and stearic acid declined and oleic, linoleic and docosahexenoic acids increased with advancing age. Small changes were noted for individual fatty acids in phosphatidylserine. In sphingomyelin stearic acid increased from birth to 1 month and linoleic, arachidonic and nervonic acids decreased. Total polyunsaturated fatty acids of the w6 series greater than 18 carbon atoms increased with advancing age in phosphatidylethanolamine and decreased in choline and serine phosphoglycerides and in sphingomyelin. Long chain fatty acids derived from linoleic acid decreased in phosphatidylcholine but increased in ethanolamine and serine phosphoglycerides. The different behavior in the changes observed in fatty acid patterns for each erythrocyte membrane phospholipid may be a consequence of its different location in the cell membrane bilayer and specific exchange with plasma lipid fractions.     

Bone fractures as indicators of intentional violence in the eastern adriatic from the antique to the late medieval period (2nd-16th century AD)

To test the historically documented hypothesis of a general increase in deliberate violence in the eastern Adriatic from the antique (AN; 2nd–6th c.) through the early medieval (EM; 7th–11th c.) to the late‐medieval period (LM; 12th–16th c.), an analysis of the frequency and patterning of bone trauma was conducted in three skeletal series from these time periods. A total of 1,125 adult skeletons—346 from the AN, 313 from the EM, and 466 from the LM series—were analyzed. To differentiate between intentional violence and accidental injuries, data for trauma frequencies were collected for the complete skeleton, individual long bones, and the craniofacial region as well as by type of injury (perimortem vs. antemortem). The results of our analyses show a significant temporal increase in total fracture frequencies when calculated by skeleton as well as of individuals exhibiting one skeletal indicator of deliberate violence (sharp force lesions, craniofacial injuries, “parry” fractures, or perimortem trauma). No significant temporal increases were, however, noted in the frequencies of craniofacial trauma, “parry” fractures, perimortem injuries, or of individuals exhibiting multiple skeletal indicators of intentional violence. Cumulatively, these data suggest that the temporal increase in total fracture frequencies recorded in the eastern Adriatic was caused by a combination of factors that included not only an increase of intentional violence but also a significant change in lifestyle that accompanied the transition from a relatively affluent AN urban lifestyle to a more primitive rural medieval way of life. Am J Phys Anthropol 2012. © 2012 Wiley Periodicals, Inc.     

4H-Chromene-based anticancer agents towards multi-drug resistant HL60/MX2 human leukemia: SAR at the 4th and 6th positions

4H-Chromene-based compounds, for example, CXL017, CXL035, and CXL055, have a unique anticancer potential that they selectively kill multi-drug resistant cancer cells. Reported herein is the extended structure–activity relationship (SAR) study, focusing on the ester functional group at the 4th position and the conformation at the 6th position. Sharp SARs were observed at both positions with respect to cellular cytotoxic potency and selectivity between the parental HL60 and the multi-drug resistant HL60/MX2 cells. These results provide critical guidance for future medicinal optimization.     

Dimensions of human lumbar vertebrae in the sagittal plane

Geometrical dimensions of the lumbar segments were determined from a series of lateral radiographs. A two-dimensional model of the lumbar vertebra in the sagittal plane is used. The model is based on five landmarks, which enable the determination of twelve geometrical parameters. The sample includes 157 healthy young males, 20-38 years old. Two-dimensional analysis of vertebral body height, depth and intervertebral spacing was performed. In all subjects disc height increases from L1 to L5, while anterior height is always bigger than posterior height, which emphasizes the lordotic shape of the lumbar region. Anthropometrical values are presented and geometrical relations between the lumbar segments are discussed.