Mortality is low for young patients (younger than 21 years) with papillary thyroid cancer (PTC), and different mutations might contribute to this. Previous studies detected ret/PTC rearrangements more frequently in PTC from children than adults, and recent reports describe a high incidence of BRAF T1796A transversion in adult PTC. However, BRAF mutations have not been adequately studied in PTC from young patients. We amplified and sequenced segments of the BRAF gene spanning the T1796A transversion site in 14 PTC from patients 10-21 years of age (mean, 17.5 +/- 3.5 years). The PTC (7 = class 1; 5 = class 2; 1 = class 3) ranged from 0.7-2.9 cm in diameter (mean, 1.4 +/- 0.75 cm). None of them (0/14) contained BRAF T1796A and none recurred (mean follow-up, 66 +/- 40 months). This incidence of BRAF T1796A is significantly less than that reported for adult PTC (270/699, 38.6%, p = 0.0015) in several series. None of our PTC (0/10) contained ras mutations, but 7/12 (58%) contained ret/PTC rearrangements. We conclude that BRAF mutations are less common in PTC from young patients, and ret/PTC rearrangements were the most common mutation found in these childhood PTC.

Methionine aminopeptidase 2 (MetAP2) is responsible for the hydrolysis of the initiator methionine molecule from the majority of newly synthesized proteins. We have cloned the MetAP2 gene from the malaria parasite Plasmodium falciparum (PfMetAP2; GenBank accession number AF348320). The cloned PfMetAP2 has no intron, consists of 1,544 bp and encodes a protein of 354 amino acids with a molecular mass of 40,537 D and an overall base composition of 72.54% A + T. PfMetAP2 has 40% sequence identity with human MetAP2 and 45% identity with yeast MetAP2, and is located in chromosome 14 of P. falciparum. The three-dimensional structure of Pf MetAP2 has been modeled based on the crystal structure of human MetAP2, and several amino acid side chains protruding into the binding pocket that differ between the plasmodial and human enzyme have been identified. The specific MetAP2 inhibitors, fumagillin and TNP-470, potently blocked in vitro growth of P. falciparum and Leishmania donavani, with IC(50) values similar to the prototype drugs. Furthermore, in the case of P. falciparum, the chloroquine-resistant strains are equally susceptible to these two compounds.

No abstract

Previous animal studies have demonstrated that following systemic administration phosphorothioate oligodeoxynucleotides (S-ODNs) are primarily excreted by the kidneys and that renal tissue levels of S-ODNs exceed that of other organs. Thus, the kidney may be an ideal target organ for application of antisense S-ODNs in vivo. We examined which cells within the rat kidney have uptake of radiolabeled S-ODNs following intravenous infusion. A 20-base ³⁵S-ODN was infused into 6 adult male Wistar rats. Three animals each were sacrificed 30 min and 4 h after infusion. The kidneys were then removed, fixed, and tissue autoradiography was performed. Similar results were obtained in both groups. The highest level of radioactivity was seen within the proximal tubules. Lower levels of activity were seen within the glomerulus, the parietal epithelial cells of Bowman’s space, and distal tubular cells. Very weak activity was also detected within the cells of the loop of Henle and the medullary collecting ducts. These results demonstrated that within the kidney S-ODNs were taken up primarily by proximal tubular cells, with much lower uptake by cells in other segments of the nephron.

Methionine aminopeptidase 2 (MetAP2) is responsible for the hydrolysis of the initiator methionine molecule from the majority of newly synthesized proteins. We have cloned the MetAP2 gene from the malaria parasite Plasmodium falciparum (PfMetAP2; GenBank accession number AF348320). The cloned PfMetAP2 has no intron, consists of 1,544 bp and encodes a protein of 354 amino acids with a molecular mass of 40,537 D and an overall base composition of 72.54% A + T. PfMetAP2 has 40% sequence identity with human MetAP2 and 45% identity with yeast MetAP2, and is located in chromosome 14 of P. falciparum. The three-dimensional structure of Pf MetAP2 has been modeled based on the crystal structure of human MetAP2, and several amino acid side chains protruding into the binding pocket that differ between the plasmodial and human enzyme have been identified. The specific MetAP2 inhibitors, fumagillin and TNP-470, potently blocked in vitro growth of P. falciparum and Leishmania donavani, with IC₅₀ values similar to the prototype drugs. Furthermore, in the case of P. falciparum, the chloroquine-resistant strains are equally susceptible to these two compounds.