Background— A significant number of patients treated with anthracyclines develop cardiotoxicity (anthracycline-induced cardiotoxicity [ACT]), mainly presenting as arrhythmias (acute ACT) or congestive heart failure (chronic ACT). There are no data on pharmacogenomic predictors of ACT. Methods and Results— We genotyped participants of the German non-Hodgkin lymphoma study (NHL-B) who were followed up for the development of heart failure for a median of >3 years. Single-nucleotide polymorphisms (SNPs) were selected from 82 genes with conceivable relevance to ACT. Of 1697 patients, 55 developed acute and 54 developed chronic ACT (cumulative incidence of either form, 3.2%). We detected 5 significant associations with polymorphisms of the NAD(P)H oxidase and doxorubicin efflux transporters. Chronic ACT was associated with a variant of the NAD(P)H oxidase subunit NCF4 (rs1883112, −212A→G; symbols with right-pointing arrows, as edited?‘ odds ratio [OR], 2.5; 95% CI, 1.3 to 5.0). Acute ACT was associated with the His72Tyr polymorphism in the p22phox subunit (rs4673; OR, 2.0; 95% CI, 1.0 to 3.9) and with the variant 7508T→A (rs13058338; OR, 2.6; 95% CI, 1.3 to 5.1) of the RAC2 subunit of the same enzyme. In agreement with these results, mice deficient in NAD(P)H oxidase activity, unlike wild-type mice, were resistant to chronic doxorubicin treatment. In addition, acute ACT was associated with the Gly671Val variant of the doxorubicin efflux transporter multidrug resistance protein 1 (MRP1) (OR, 3.6; 95% CI, 1.6 to 8.4) and with the Val1188Glu-Cys1515Tyr (rs8187694-rs8187710) haplotype of the functionally similar MRP2 (OR, 2.3; 95% CI, 1.0 to 5.4). Polymorphisms in adrenergic receptors previously demonstrated to be predictive of heart failure were not associated with ACT. Conclusions— Genetic variants in doxorubicin transport and free radical metabolism may modulate the individual risk to develop ACT.

Interleukin-10 (IL-10) has a critical role in the regulation of immune responses. The relative contribution of genetic and environmental factors to IL-10 production is under debate. We performed a twin study in 246 monozygotic and dizygotic twins to assess the heritability of IL-10 production after LPS stimulation in whole blood. In addition, the influence of promoter single nucleotide polymorphisms (À1082, À819 and À592) on transcriptional activity and their binding to nuclear factors was studied in luciferase reporter gene and electrophoretic mobility shift assays. IL-10 production showed a genetic determination with a heritability of 0.5. Decreasing body mass index (BMI), smoking and female gender lead to decreased IL-10 production. In monocytes, the À1082A allele showed higher binding affinity to the transcription factor PU.1 resulting in decreased transcriptional activity of À1082A promoter haplotypes. Genetic determination of IL-10 secretion is probably lower than that previously reported. Fifty percent of the observed variability explained by genetic factors. Female individuals produce less IL-10 than male subjects. Environmental factors like smoking and decreasing BMI exert suppressing effects on IL-10 production. Although the À1082A allele shows higher binding affinity to the PU.1 transcription factor and lower transcriptional activity, this polymorphism probably explains only a small fraction of the observed heritability.

Tumor necrosis factor-alpha is considered to be one of the important mediators in the pathogenesis of psoriasis. A strong association of juvenile onset psoriasis with the major histocompatibility complex encoded HLA-Cw6 antigen has been reported but it is unclear whether Cw6 itself or a closely linked gene is involved in the pathogenesis. This study has focused on the association of promoter polymorphisms of the major histocompatibility complex encoded tumor necrosis factor-alpha gene with psoriasis and psoriatic arthritis. Tumor necrosis factor-alpha promoter polymorphisms were sought by sequence-specific oligonucleotide hybridization and by direct sequencing in Caucasian patients with juvenile onset psoriasis and with psoriatic arthritis and in healthy controls. A mutation at position -238 of the tumor necrosis factor-alpha promoter was present in 23 of 60 patients (38%; p < 0.0001; p[corr] < 0.008) with juvenile onset psoriasis and in 20 of 62 patients (32%; p < 0.0003; p[corr] < 0.03) with psoriatic arthritis, compared with seven of 99 (7%) Caucasian controls. There was a marked increase of homozygotes for this mutation in the psoriasis group. Another mutation at position -308 was found in similar proportions of patients and controls. Our study shows a strong association of the tumor necrosis factor-alpha promoter polymorphism at position -238 with psoriasis and psoriatic arthritis. Our findings suggest that this promoter polymorphism itself or a gene in linkage disequilibrium with tumor necrosis factor-alpha predispose to the development of psoriasis.

Tumor necrosis factor alpha (TNF-alpha) is involved in the pathogenesis of chronic hepatitis C virus infection. The gene for TNF-alpha is encoded in the major histocompatibility locus (MHC). Two polymorphisms at positions -308 and -238 in the TNF-alpha promoter region might influence TNF-alpha expression. These promoter polymorphisms have been linked previously to a number of infectious diseases. TNF-alpha promoter polymorphisms at positions -238 and -308 were studied by DNA sequencing and sequence-specific oligonucleotide hybridization in 82 individuals with chronic hepatitis C and 99 control subjects. Subjects had been HLA class I and class II typed in a previous study. The frequency of the TNF238.2 promoter allele was significantly higher in the hepatitis C group (18.7%) compared to the controls (3.5%; P< 0.0001; pcorr < 0.009). No significant differences in the frequency of the TNF308.2 allele were observed between patients and controls. The increased frequency of the TNF238.2 allele could not be explained by linkage disequilibrium to HLA-B or -DR genes. These findings show an association between the TNF238.2 promoter variant and chronic active hepatitis C. They suggest that this polymorphism or a linked gene may be a host factor contributing to the development of chronic active hepatitis C.

The thermal cycloisomerization of both parent and benzannelated hexa-1,3-dien-5-yne, as well as of carbocyclic 1,3-dien-5-ynes (ring size 7-14), was investigated by using pure density functional theory (DFT) of Becke, Lee, Yang, and Parr (BLYP) in connection with the 6-31G* basis set and the Brueckner doubles coupled-cluster approach [BCCD(T)] with the cc-pVDZ basis set for the parent system. The initial cyclization product is the allenic cyclohexa-1,2,4-triene (isobenzene), while the respective biradical is the transition structure for the enantiomerization of the two allenes. Two consecutive [1,2]-H shifts further transform isobenzene to benzene. For the benzannelated system, the energetics are quite similar and the reaction path is the same with one exception: the intermediate biradical is not a transition state but a minimum which is energetically below isonaphthalene. The cyclization of the carbocyclic 1,3-dien-5-ynes, which follows the same reaction path as the parent system, clearly depends on the ring size. Like the cyclic enediynes, the dienynes were found to cyclize to products with reduced ring strain. This is not possible for the 7- and 8-membered dienynes, as their cyclization products are also highly strained. For 9- to 11-membered carbocycles, all intermediates, transition states, and products lie energetically below the parent system; this indicates a reduced cyclization temperature. All other rings (12- to 14-membered) have higher barriers. Exploratory kinetic experiments on the recently prepared 10- to 14-membered 1,3-dien-5-ynes rings show this tendency, and 10- and 11-membered rings indeed cyclize at lower temperatures.

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Technetium /TBP extraction IPwex process SummaiyThe influence of HNO, concentration on the extraction of Tc^n by 30% TBP in dodecane is investigated. The distribution coefficient of Tc^ increases up to « 0.6 M HNO, and decreases at higher HNO 3 concentrations. The formulae derived for the extraction of HTc04(H,0)n(TBP);" show that the dissociation constant of HTcO, is responsible for this behaviour and that m 4. Other components were added to the system in concentrations encountered in the PUREX process. 10"' to 10"' M NaNO, has only a negligible influence on the extraction of Tc^n, whereas the addition of 1 to 4 M NH, NO3 has a salting-out effect on the concentration of TBP in the aqueous phase and therefore causes lower distribution coefficients for Tc^'. After addition of 1 M uranyl nitrate another extraction mechanism is valid leading to a continuous decrease of the distribution coefficient of TcVD with increasing HNO, concentration. Formulae are also derived for discussion of the extraction of UOjNOjTcO^ (TBP)j. The Observation that TcVn extraction in the presence of uranyl nitrate practically does not depend on temperature in the ränge from 20 to 60 °C is explained by compensation of positive and negative effects of temperature. It was proved that hydrolysis of TBP at higher temperatures does not influence the results.

Cyclo-1,3-dien-5-ynes with ring sizes from 10 to 14 (6 a ± e) have been prepared for the first time by using a five-step synthesis starting from the alkynols 7 a ± e. The final ring-closure was achieved by McMurry coupling of the a,wdialdehydes 12 a ± e with the complex TiCl 3 (DME) 1.5 . Thermal isomerization of the cyclodienynes leads to the corresponding benzocycloalkenes, and it has been shown that the ring size has a considerable influence on the temperature necessary for thermocylization.