Thyroid cancer following nuclear tests in French Polynesia

BACKGROUND: Between 1966 and 1974, France conducted 41 atmospheric nuclear tests in Polynesia, but their potential health effects have not previously been investigated. METHODS: In a case-control study, we compared the radiation exposure of almost all the French Polynesians diagnosed with differentiated thyroid carcinoma between 1981 and 2003 (n = 229) to the exposure of 373 French Polynesian control individuals without cancer from the general population. Radiation exposures were estimated using measurements after the nuclear tests, age at time of each test, residential and dietary information. RESULTS: The average thyroid dose before 15 years of age was about 1.8 mGy, and 5% of the cases and 3% of the controls received a dose above 10 mGy. Despite this low level of dose, and after adjusting for ethnic group, level of education, body surface area, family history of thyroid cancer and number of pregnancies for women, we observed an increasing risk (P = 0.04) of thyroid cancer with increasing thyroid dose received before age of 15 years, which remained after excluding non-aggressive differentiated thyroid micro-carcinomas. This increase of risk per unit of thyroid radiation dose was higher (P = 0.03) in women who later experienced four or more pregnancies than among other women. CONCLUSION: The risk estimate is low, but is based on limited exposure data. The release of information on exposure, currently classified, would greatly improve the reliability of the risk estimation. British Journal of Cancer (2010) 103, 1115-1121. doi: 10.1038/sj.bjc.6605862 www.bjcancer.com Published online 31 August 2010 (c) 2010 Cancer Research U

A critical role for Gly25 in the B chain of human thrombin

We have recently identified (Akhavan S et al., Thromb Haemost 2000; 84: 989-97) a patient with a mild bleeding diathesis associated to an homozygous mutation in the thrombin B chain (Gly25Ser, chymotrypsinogen numbering, i.e. position 330 in human prothrombin numbering). Transient transfection of wild-type prothrombin (FII-WT) and mutant prothrombin (designated FII-G25((330))S) cDNA in COS-7 cells showed a mild reduction (50%) in FII-G25((330))S production. Recombinant proteins, stably expressed in Chinese hamster ovary cells, were isolated and activated by TaYpan snake or Echis carinatus venoms. We show that the G25((330))S mutation results in a decrease in the rate of prothrombin proteolytic activation. The mutation also significantly decreases (i) the catalytic activity of thrombin with a 9-fold reduction in catalytic efficiency of the mutant toward S-2238; (ii) the interaction with benzamidine; (iii) the rate of inhibition by TLCK and antithrombin; and (iv) the rate of hydrolysis of macromolecular substrates (fibrinogen, protein C). In contrast, exosite I does not appear to be affected by the molecular defect. These results, together with molecular modeling and dynamics, indicate that Gly25((330)) is important for proper expression and probably proper folding of prothrombin, and also plays a critical role in both the alignment of the catalytic triad and the flexibility of one of the activation segments of prothrombi

Quantitative gene expression in Budd-Chiari syndrome: a molecular approach to the pathogenesis of the disease

Background: Budd-Chiari syndrome (BCS) is associated with parenchymal changes leading to major architecture remodelling. In order to gain further insight into the pathogenesis of BCS, we investigated expression of a set of genes involved in the course of chronic liver diseases. Methods: Quantitative expression of 35 selected genes involved in extracellular matrix regulation, growth factors, and angiogenesis was investigated in 13 cases of BCS and compared with 10 normal livers and 13 cirrhosis cases by real time reverse transcription-polymerase chain reaction. Differential gene expression was considered significant for genes showing at least a twofold variation, with p<0.05. Results: Expression of 14 genes was significantly increased in BCS versus normal liver, with the highest increase in superior cervical ganglion 10 (SCG10) gene. BCS cases were classified according to their evolution and morphological pattern as either acute or chronic in six and seven cases, respectively. Unsupervised hierarchical clustering of acute and chronic BCS cases on the basis of similarity in gene expression pattern led to distinction between the two groups. Expression of three genes was significantly different in acute versus chronic BCS (increase in matrix metalloproteinase 7 and SCG10, decrease in thrombospondin-1 for chronic BCS). Seventeen and 10 genes, mainly involved in extracellular matrix and vascular remodelling, were significantly deregulated in acute BCS versus normal liver and cirrhosis, respectively. Conclusion: These results show that BCS cases display a specific gene expression profile that is different from that of normal liver and cirrhosis; the molecular configuration of BCS can be readily distinguished by its evolution and morphological pattern