TRAIL-receptor expression is an independent prognostic factor for survival in patients with a primary glioblastoma multiforme

SummaryPurpose In order to improve the survival of patients with a glioblastoma multiforme tumor (GBM), new therapeutic strategies must be developed. The use of a death inducing ligand such as TRAIL (TNF Related Apoptosis Inducing Ligand) seems a promising innovative therapy. The aim of this study was to quantify the expression of the death regulating receptors TRAIL-R1, TRAIL-R2 and TRAIL on primary GBM specimens and to correlate this expression with survival.Experimental design Expression of TRAIL and TRAIL-receptors was assessed by immunohistochemistry, both quantitatively (% of positive tumor cells) and semi-quantitatively (staining intensity) within both the perinecrotic and intermediate tumor zones of primary GBM specimens. RT-PCR of GBM tissue was performed to show expression of TRAIL receptor mRNA.Results Immunohistochemistry showed a slight diffuse intracytoplasmic and a stronger membranous staining for TRAIL and TRAIL receptors in tumor cells. Semi-quantitative expression of TRAIL showed a significantly higher expression of TRAIL in the perinecrotic zone than in the intermediate zone of the tumor (P=0.0001). TRAIL-R2 expression was significantly higher expressed than TRAIL-R1 (P=0.005). The antigenic load of TRAIL-R2 was positively correlated with survival (P=0.02). Multivariate analysis of TRAIL-R1 within the study group (n=62) showed that age, gender, staining intensity, antigenic load, % of TRAIL-R1 expression, were not statistically correlated with survival however radiotherapy was significantly correlated (multivariate analysis: age: P=0.15; gender: P=0.64; staining intensity: P=0.17; antigenic load: P=0.056; % of TRAIL-R1 expression: P=0.058; radiotherapy: P=0.0001). Subgroup analysis of patients who had received radiotherapy (n=47) showed a significant association of % of TRAIL-R1 expression and the antigenic load of TRAIL-R1 with survival (multivariate analysis: P=0.036, respectively, P=0.023).Multivariate analysis of TRAIL-R2 staining intensity and antigenic load, within the study group (P=0.004, respectively, P=0.03) and the subgroup (P=0.002, respectively, P=0.004), showed a significant association with survival. RT-PCR analysis detected a negative relation between the amount of TRAIL-R1 mRNA and the WHO grade of astrocytic tumors (P=0.03).Conclusions TRAIL-R1 and TRAIL-R2 expression on tumor cells are independent prognostic factors for survival in patients with a glioblastoma multiforme. Both receptors could be targets for TRAIL therapy. As TRAIL-R2 is more expressed, in comparison with TRAIL-R1, on GBM tumor cells, TRAIL-R2 seems to be of more importance as a target for future TRAIL therapy than TRAIL-R1.     

Myelinated and nonmyelinated nerves: comparison of proton MR properties

The magnetic resonance (MR) relaxation rates of protons were compared in the myelinated and nonmyelinated nerves of the garfish. The long, large olfactory nerve of the garfish, as an easily accessible source of nonmyelinated axons, is uniquely suited for such a comparison. The T1 and T2 measurements revealed distinct and consistent differences between nonmyelinated olfactory nerves and myelinated optic and oculomotor nerves. Comparisons between water content, lipid content, and relaxation rates indicated that the differences in MR properties represent complex differences in the distribution and physical environment of the constituent lipid and water protons.     

The human premotor oculomotor brainstem system – can it help to understand oculomotor symptoms in Huntington's disease?

Recent progress in oculomotor research has enabled new insights into the functional neuroanatomy of the human premotor oculomotor brainstem network. In the present review, we provide an overview of its functional neuroanatomy and summarize the broad range of oculomotor dysfunctions that may occur in Huntington's disease (HD) patients. Although some of these oculomotor symptoms point to an involvement of the premotor oculomotor brainstem network in HD, no systematic analysis of this functional system has yet been performed in brains of HD patients. Therefore, its exact contribution to oculomotor symptoms in HD remains unclear. A possible strategy to clarify this issue is the use of unconventional 100-µm-thick serial tissue sections stained for Nissl substance and lipofuscin pigment (Nissl-pigment stain according to Braak). This technique makes it possible to identify the known nuclei of the premotor oculomotor brainstem network and to study their possible involvement in the neurodegenerative process. Studies applying this morphological approach and using the current knowledge regarding the functional neuroanatomy of this human premotor oculomotor brainstem network will help to elucidate the anatomical basis of the large spectrum of oculomotor dysfunctions that are observed in HD patients. This knowledge may aid clinicians in the diagnosis and monitoring of the disease.     

WASP gene mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia

The WASP gene has been recently cloned from Xp11.23 and shownto be mutated in three patients with the Wiskott-Aldrich syndrome(WAS). We have developed a screening protocol for identifyingWASP gene alterations in genomic DNA and have identified a spectrumof novel mutations In 12 additional unrelated families. Thesemissense, nonsense and frameshift mutations involve eight ofthe 12 exons of the gene. Two mutations creating premature terminationcodons were associated with lack of detectable mRNA on Northernblots. Four amino acid substitutions, Leu27Phe, Thr48lle, Val75Metand Arg477Lys, were found In patients with congenital thrombocytopeniaand no clinically evident immune defect indicating that theWASP gene is the site for mutations in X-linked thrombocytopeniaas well as in WAS. A T-cell line from a WAS patient containedtwo independent DNA alterations, a constitutional frameshiftmutation, also present in peripheral blood leukocytes from thepatient, and a compensatory splice site mutation unique to thecell line. The distribution of eight missense mutations providesvaluable information on amino acids which are essential fornormal protein function, and suggests that sites in the firsttwo exons are hot-spots for mutation.     

Xeromammographic automatic exposure termination

A method of automatic exposure termination (AET) for xeromammography has been devised, significantly reducing the rate of repeat exposures due to poor choice of manual exposure factors. AET images are of good quality and are reliably produced. The concept of AET is based on the existence of an optimal transmitted exposure to the selenium plate, which is easily determined experimentally. In routine clinical xeromammography, a repeat rate of 20% was eliminated by the use of AET.