Array CGH demonstrates characteristic aberration signatures in human papillary thyroid carcinomas governed by RET/PTC.

The aim of this study is to investigate additional genetic alterations in papillary thyroid carcinomas (PTCs) with known RET/PTC rearrangements. We applied array-based comparative genomic hybridization (array CGH) to 33 PTC (20 PTC from adults, 13 post-Chernobyl PTC from children) with known RET/PTC status. Principal component analysis and hierarchical cluster analysis identified cases with similar aberration patterns. Significant deviations between tumour-groups were obtained by statistical testing (Fisher's exact test in combination with Benjamini-Hochberg FDR-controlling procedure). FISH analysis on FFPE sections was applied to validate the array CGH data. Deletions were found more frequently in RET/PTC-positive and RET/PTC-negative tumours than amplifications. Specific aberration signatures were identified that discriminated between RET/PTC-positive and RET/PTC-negative cases (aberrations on chromosomes 1p, 3q, 4p, 7p, 9p/q, 10q, 12q, 13q and 21q). In addition, childhood and adult RET/PTC-positive cases differ significantly for a deletion on the distal part of chromosome 1p. There are additional alterations in RET/PTC-positive tumours, which may act as modifiers of RET activation. In contrast, alterations in RET/PTC-negative tumours indicate alternative routes of tumour development. The data presented serve as a starting point for further studies on gene expression and function of genes identified in this study.

Instability of microsatellites in radiation-associated thyroid tumours with short latency periods.

PURPOSE: To determine the instability of microsatellite sequences in post-Chernobyl thyroid tumours from children and young adults, and to ascertain whether they correlated with the age of the patient at the time of the accident and the tumour latency period. MATERIALS AND METHODS: The stability of 26 microsatellite markers was investigated in 122 radiation-associated thyroid tumours (96 children, 26 adults) from Belarus and 39 spontaneous thyroid tumours (adults) from Munich without radiation history. RESULTS: A significant correlation between patient age at the time of the accident and the instability of microsatellite sequences was established. Also, a high instability of microsatellite sequences was found in 28 early thyroid tumours from Belarus with latency periods of 6-8 years, in contrast to a low instability of microsatellites in 94 tumours emerging 9-11 years after the accident. Microsatellite instability in the reference group from Munich proved similar to the early thyroid tumours from Belarus. CONCLUSION: Early, fast-growing and aggressive post-Chernobyl thyroid tumours are characterized by an increase in microsatellite instability.

Retention of cadmium in organs of the rat after a single dose of labeled cadmium-3-phytate.

Because of the low safety factor estimated for the normal content of Cd in human foods, it is important to establish the influence of food constituents such as phytate on the bioavailability of this toxic metal. We studied the retention of radioactive(109)Cd administered to rats as a chloride or a phytate in a single dose by stomach tube. The animals were fed either a normal rat chow containing 0.29% of phytate or a low phytate diet containing less than 0.1% phytate. Highly elevated levels of(109)Cd were found only in the animals that were supplied with(109)Cd as a chloride and had been fed the low phytate diet. In the animals supplied with(109)Cd as a phytate, which had also received the low phytate diet, the levels of(109)Cd in the intestine were as high as those in the group mentioned before, but the retentions in all other tissues resembled those of the respective groups fed the normal chow. The findings indicate that phytate is responsible for a considerable decrease in the intestinal absorption of Cd. Furthermore, it appears to exert an influence on the kinetics of Cd retention in the intestine.

The influence of exposure to different levels of cadmium on the secretion and biological halflife of corticosterone in the rat.

The adrenal cortex is one of various tissues where elevated concentrations of cadmium have been found. To determine whether this accumulation would lead to an alteration in the function of the adrenal cortex, corticosterone secretion and its turnover in the blood pool were studied in the rat at various levels of cadmium exposure. Weanling male rats received cadmium with drinking water. Within eight weeks of exposure to cadmium concentrations of 30, 150 and 300 mg/l in the drinking water the biological half-life of corticosterone in blood had decreased. It is not known whether this was due to an increase in degradation of the hormone or an increase in excretion. At exposures up to 150 mg cadmium/l this loss of hormone from the blood was sufficiently compensated, or even over-compensated for by an increased rate of corticosterone secretion by the adrenals. At an exposure of 300 mg cadmium/l, however, the secretion rate had decreased below that of the controls, thus leading to a decrease in the corticosterone level in blood. The lack of ability to compensate for the loss of the hormone from blood signals functional insufficiency of the adrenal cortex. This occurred at a concentration of 5.6 micrograms Cd/g fresh adrenal tissue, which is approximately 5 times the cadmium concentration reported for the adrenals of "unexposed" humans. Whether the secretory inhibition originates in the adrenal cortex itself or in its regulating system could not be conclusively demonstrated by this experiment.

Identification of two products of mitochondrial protein synthesis associated with mitochondrial adenosine triphosphatase from Neurospora crassa.

Soluble mitochondrial ATPase (F1) isolated from Neurospora crassa is resolved by dodecylsulfate-gel electrophoresis into five polypeptide bands with apparent molecular weights of 59000, 55000, 36000, 15000 and 12000. At least nine further polypeptides remain associated with ATPase after disintegration of mitochondria with Triton X-100 as shown by the analysis of an immunoprecipitate obtained with antiserum to F1 ATPase. Two of the associated polypeptides with apparent molecular weights of 19000 and 11000 are translated on mitochondrial ribosomes, as demonstrated by incorporation in vivo of radioactive leucine in the presence of specific inhibitors of mitochondrial (chloramphenicol) and extramitochondrial (cycloheximide) protein synthesis. The appearance of mitochondrial translation products in the immunoprecipitated ATPase complex is inhibited by cycloheximide.. The same applies for some of the extramitochondrial translation products in the presence of chloramphenicol. This suggests that both types of polypeptides are necessary for the assembly of the ATPase complex