Subgroups of Paediatric Acute Lymphoblastic Leukaemia Might Differ Significantly in Genetic Predisposition to Asparaginase Hypersensitivity

L-asparaginase (ASP) is a key element in the treatment of paediatric acute lymphoblastic leukaemia (ALL). However, hypersensitivity reactions (HSRs) to ASP are major challenges in paediatric patients. Our aim was to investigate genetic variants that may influence the risk to Escherichia coli-derived ASP hypersensitivity. Sample and clinical data collection was carried out from 576 paediatric ALL patients who were treated according to protocols from the Berlin—Frankfurt—Münster Study Group. A total of 20 single nucleotide polymorphisms (SNPs) in GRIA1 and GALNT10 genes were genotyped. Patients with GRIA1 rs4958351 AA/AG genotype showed significantly reduced risk to ASP hypersensitivity compared to patients with GG genotype in the T-cell ALL subgroup (OR = 0.05 (0.01–0.26); p = 4.70E-04), while no such association was found in pre-B-cell ALL. In the medium risk group two SNPs of GRIA1 (rs2055083 and rs707176) were associated significantly with the occurrence of ASP hypersensitivity (OR = 0.21 (0.09–0.53); p = 8.48E-04 and OR = 3.02 (1.36–6.73); p = 6.76E-03, respectively). Evaluating the genders separately, however, the association of rs707176 with ASP HSRs was confined only to females. Our results suggest that genetic variants of GRIA1 might influence the risk to ASP hypersensitivity, but subgroups of patients can differ significantly in this respect.     

Role of Guanine Nucleotide Exchange Factor-H1 in Complement-mediated RhoA Activation in Glomerular Epithelial Cells

Visceral glomerular epithelial cells (GEC), also known as podocytes, are vital for the structural and functional integrity of the glomerulus. The actin cytoskeleton plays a central role in maintaining GEC morphology. In a rat model of experimental membranous nephropathy (passive Heymann nephritis (PHN)), complement C5b-9-induced proteinuria was associated with the activation of the actin regulator small GTPase, RhoA. The mechanisms of RhoA activation, however, remained unknown. In this study, we explored the role of the epithelial guanine nucleotide exchange factor, GEF-H1, in complement-induced RhoA activation. Using affinity precipitation to monitor GEF activity, we found that GEF-H1 was activated in glomeruli isolated from rats with PHN. Complement C5b-9 also induced parallel activation of GEF-H1 and RhoA in cultured GEC. In GEC in which GEF-H1 was knocked down, both basal and complement-induced RhoA activity was reduced. On the other hand, GEF-H1 knockdown augmented complement-mediated cytolysis, suggesting a role for GEF-H1 and RhoA in protecting GEC from cell death. The MEK1/2 inhibitor, U0126, and mutation of the ERK-dependent phosphorylation site (T678A) prevented complement-induced GEF-H1 activation, indicating a role for the ERK pathway. Further, complement induced GEF-H1 and microtubule accumulation in the perinuclear region. However, both the perinuclear accumulation and the activation of GEF-H1 were independent of microtubules and myosin-mediated contractility, as shown using drugs that interfere with microtubule dynamics and myosin II activity. In summary, we have identified complement-induced ERK-dependent GEF-H1 activation as the upstream mechanism of RhoA stimulation, and this pathway has a protective role against cell death.     

Deuterium-depleted water stimulates GLUT4 translocation in the presence of insulin,which leads to decreased blood glucose concentration

Molecular and Cellular Biochemistry - Deuterium (D) is a stable isotope of hydrogen (H) with a mass number of 2. It is present in natural waters in the form of HDO, at a concentration of...     

Genetic control of the quantitative variation of erythrocytic glyoxalase-1 (GLO-1) in mice

Quantitative genetic variation in the glyoxalase-1 content (QGlo-1) of red cells of mice is described. Its genetic control is shown to be exerted by either the Glo-1 locus or a closely linked gene to the left of H-2K. At least six alleles, designated QGlo-1 ^a through QGlo-1 ^f, can be found in different inbred strains of mice.This work was supported in part by Grants HL 0911 and AI 15413 of the National Institutes of Health and by a grant from the Sally and Alma Solomon Foundation.     

The effect of microhabitats on the leaf litter decomposition and on the distribution of soil animals

Earthworm burrows as microhabitats for other soil fauna were studied in a hornbeam-oak mixed forest in Hungary. Comparative chemical analysis and feeding experiments were carried out to find out whether the leaves in the burrows of large-bodied earthworms are more decomposed than those from the surrounding areas. The total organic matter content, the C/N ratio, the stability coefficient and the percentage of tannins and lipids indicate that the chemical breakdown of the litter material is more advanced in the burrows than on the other parts of the forest floor especially in autumn. No consistent differences were observed in the amounts of other organic components. Feeding experiments showed that three species of the fauna preferred the leaves pulled into the burrows to those from the surrounding areas and the preference was greater in autumn than in spring.
It is suggested that the high density of some soil animals in the burrows in autumn is due to the more palatable food there; in summer the microclimate of the burrows is favoured, whereas spring can be considered as a transition period.