Recognition of genetic predisposition in pediatric cancer patients: An easy-to-use selection tool

Genetic predisposition for childhood cancer is under diagnosed. Identifying these patients may lead to therapy adjustments in case of syndrome-related increased toxicity or resistant disease and syndrome-specific screening programs may lead to early detection of a further independent malignancy. Cancer surveillance might also be warranted for affected relatives and detection of a genetic mutation can allow for reproductive counseling.Here we present an easy-to-use selection tool, based on a systematic review of pediatric cancer predisposing syndromes, to identify patients who may benefit from genetic counseling. The selection tool involves five questions concerning family history, the type of malignancy, multiple primary malignancies, specific features and excessive toxicity, which results in the selection of those patients that may benefit from referral to a clinical geneticist

Significance of various parameters derived from biological variability of lipoprotein(a), homocysteine, cysteine, and total antioxidant status

Analytical and biological components of variability and various derived indices have been determined for lipoprotein(a) [Lp(a)], homocysteine (Hcy), cysteine (Cys), and total antioxidant status (TAOS) in ostensibly healthy adult Caucasians and in stable outpatients with an increased serum Lp(a). In healthy Caucasians, average intraindividual biological CVs (CVb) were 20.0% for Lp(a), 9.4% for Hcy, 5.9% for Cys, and 2.8% for TAOS, CVbs being similar in men and women. In the outpatient group, CVbs were comparable for Hcy, Cys, and TAOS, but significantly lower for Lp(a) (7.5% vs 20.0%; P <0.0001). Moreover, a significant inverse relation between both biological and analytical CVs (CVa) and serum Lp(a) concentrations was demonstrated. We conclude that average CVa and CVb values, and hence average derived indices, are adequate for Hcy, Cys, and TAOS, whereas individual values should be used for Lp(a)

A highly scalable parallel implementation of H.264

Developing parallel applications that can harness and efficiently use future many-core architectures is the key challenge for scalable computing systems. We contribute to this challenge by presenting a parallel implementation of H.264 that scales to a large number of cores. The algorithm exploits the fact that independent macroblocks (MBs) can be processed in parallel, but whereas a previous approach exploits only intra-frame MB-level parallelism, our algorithm exploits intra-frame as well as inter-frame MB-level parallelism. It is based on the observation that inter-frame dependencies have a limited spatial range. The algorithm has been implemented on a many-core architecture consisting of NXP TriMedia TM3270 embedded processors. This required to develop a subscription mechanism, where MBs are subscribed to the kick-off lists associated with the reference MBs. Extensive simulation results show that the implementation scales very well, achieving a speedup of more than 54 on a 64-core processor, in which case the previous approach achieves a speedup of only 23. Potential drawbacks of the 3D-Wave strategy are that the memory requirements increase since there can be many frames in flight, and that the frame latency might increase. Scheduling policies to address these drawbacks are also presented. The results show that these policies combat memory and latency issues with a negligible effect on the performance scalability. Results analyzing the impact of the memory latency, L1 cache size, and the synchronization and thread management overhead are also presented. Finally, we present performance requirements for entropy (CABAC) decoding. This work was performed while the fourth author was with NXP Semiconductors.Peer ReviewedPostprint (author's final draft

The ubiquitin-conjugating DNA repair enzyme is a maternal factor essential for early embryonic development in mice

The Saccharomyces cerevisiae RAD6 protein is required for a surprising diversity of cellular processes, including sporulation and replicational damage bypass of DNA lesions. In mammals, two RAD6-related genes, HR6A and HR6B, encode highly homologous proteins. Here, we describe the phenotype of cells and mice deficient for the mHR6A gene. Just like mHR6B knockout mouse embryonic fibroblasts, mHR6A-deficient cells appear to have normal DNA damage resistance properties, but mHR6A knockout male and female mice display a small decrease in body weight. The necessity for at least one functional mHR6A (X-chromosomal) or mHR6B (autosomal) allele in all somatic cell types is supported by the fact that neither animals lacking both proteins nor females with only one intact mHR6A allele are viable. In striking contrast to mHR6B knockout males, which show a severe spermatogenic defect, mHR6A knockout males are normally fertile. However, mHR6A knockout females fail to produce offspring despite a normal ovarian histology and ovulation. The absence of mHR6A in oocytes prevents development beyond the embryonic two-cell stage but does not result in an aberrant methylation pattern of histone H

Transcriptional regulation of androgen receptor gene expression in Sertoli cells and other cell types

Cooperative actions of FSH and androgens on initiation, maintenance, and restoration of spermatogenesis have been described. In the present experiments the regulatory effects of FSH on androgen receptor (AR) gene expression in Sertoli cells were studied. In immature rats injection of FSH (1 microgram/g BW, ip) resulted in a rapid down-regulation of testicular AR mRNA expression (4 h), followed by recovery to the control level (10 h). Using cultured immature Sertoli cells, a similar transient effect on AR mRNA expression was observed after the addition of FSH (500 ng/ml) or (Bu)2cAMP (0.5 mM). Cycloheximide treatment of the cells did not prevent the rapid FSH-induced down-regulation of AR mRNA expression, indicating that de novo protein synthesis is not required for this effect. Furthermore, using a transcriptional run-on assay, no marked decrease in the rate of AR gene transcription was found upon treatment of the cultured Sertoli cells with FSH for 2 or 4 h. This demonstrates that the short term effect of FSH or AR mRNA expression reflects a change in mRNA stability. The AR protein level was not markedly affected by the transient decrease in AR mRNA expression. When immature Sertoli cells were incubated with FSH for longer time periods (24-72 h), both AR mRNA and protein expression were increased. In Sertoli cells isolated from 15-day-old rats, this increase was higher (mRNA, 2- to 3-fold; protein, 2-fold) than in Sertoli cell

Loss of HR6B ubiquitin-conjugating activity results in damaged synaptonemal complex structure and increased crossing-over frequency during the male meiotic prophase.

The ubiquitin-conjugating enzymes HR6A and HR6B are the two mammalian homologs of Saccharomyces cerevisiae RAD6. In yeast, RAD6 plays an important role in postreplication DNA repair and in sporulation. HR6B knockout mice are viable, but spermatogenesis is markedly affected during postmeiotic steps, leading to male infertility. In the present study, increased apoptosis of HR6B knockout primary spermatocytes was detected during the first wave of spermatogenesis, indicating that HR6B performs a primary role during the meiotic prophase. Detailed analysis of HR6B knockout pachytene nuclei showed major changes in the synaptonemal complexes. These complexes were found to be longer. In addition, we often found depletion of synaptonemal complex proteins from near telomeric regions in the HR6B knockout pachytene nuclei. Finally, we detected an increased number of foci containing the mismatc

A novel member of the transmembrane serine/threonine kinase receptor family is specifically expressed in the gonads and in mesenchymal cells adjacent to the mullerian duct

The activin and TGF-beta type II receptors are members of a separate subfamily of transmembrane receptors with intrinsic protein kinase activity, wh