No contribution of GSTM1 and GSTT1 null genotypes to the risk of neutropenia due to benzene exposure in Southeastern Brazil

Exposure to benzene has been associated with haematological diseases such as neutropenia (NEB) and acute myeloid leukaemia (AML). We tested whether the null genotypes of the GSTM1 and GSTT1 genes, involved in benzene inactivation, altered the risk for NEB in southeastern Brazil. Genomic DNA from 55 NEB patients and 330 controls was analysed by multiplex-polymerase chain reaction. The frequency of the GSTM1, GSTT1 and combined null genotypes was similar in patients and controls (GSTM1, 27.3% vs. 38.8%, p = 0.16; GSTT1, 25.5% vs. 19.7%, p = 0.24; GSTM1/GSTT1, 12.7% vs. 6.7%, p = 0.26; respectively). The distribution of genotype classes in NEB patients was similar to normal controls, suggesting that GSTM1 and GSTT1 null genotypes make no specific contribution to the risk of NEB. As the GSTM1 and GSTT1 null genotypes were previously associated with increased risk for AML in Brazil and elsewhere, we hypothesise that different thresholds of chemical exposure relative to distinct GSTM1 and GSTT1 genotypes may determine whether AML or NEB manifests in benzene exposed individuals from southeastern Brazil. Although indicative, our results still require support by prospective and large scale epidemiological studies, with rigorous assessment of daily chemical exposures and control of the possible contribution of other polymorphic genes involved in benzene metabolism

Cytosolic Guanine Nucledotide Binding Deficient Form of Transglutaminase 2 (R580a) Potentiates Cell Death in Oxygen Glucose Deprivation

Transglutaminase 2 (TG2) is a hypoxia-responsive protein that is a calcium-activated transamidating enzyme, a GTPase and a scaffolding/linker protein. Upon activation TG2 undergoes a large conformational change, which likely affects not only its enzymatic activities but its non-catalytic functions as well. The focus of this study was on the role of transamidating activity, conformation and localization of TG2 in ischemic cell death. Cells expressing a GTP binding deficient form of TG2 (TG2-R580A) with high basal transamidation activity and a more extended conformation showed significantly increased cell death in response to oxygen-glucose deprivation; however, targeting TG2-R580A to the nucleus abrogated its detrimental role in oxygen-glucose deprivation. Treatment of cells expressing wild type TG2, TG2-C277S (a transamidating inactive mutant) and TG2-R580A with Cp4d, a reversible TG2 inhibitor, did not affect cell death in response to oxygen-glucose deprivation. These findings indicate that the pro-cell death effects of TG2 are dependent on its localization to the cytosol and independent of its transamidation activity. Further, the conformational state of TG2 is likely an important determinant in cell survival and the prominent function of TG2 in ischemic cell death is as a scaffold to modulate cellular processes

The Brazilian pediatric myelodysplastic cooperative group strategies: are they relevant to improve educational approach and correct diagnosis?

Brazil is a wide country with huge contrasts. Its peculiarities can highlight environmental factors that could influence the frequencies of different cancers. The standard treatment and results achieved from several different areas of the country may not be found in others. The establishment of a national cooperative group has the potential to improve outcomes. The The Brazilian Cooperative Group on Pediatric Patients with Myelodysplastic Syndrome (BCG-MDS-PED) was first organized in January 1997 as a working group of hematologists, pediatric oncologists, pediatric-hematologists, molecular biologists and other professionals in order to study pediatric (age < 18 years) MDS. Six distinct subcommittees constituted with members from several universities: cytology, histopathology, clinical, cytogenetics, molecular biology and epidemiology. The goals of the BCG-MDS-PED were: (i) to offer support for diagnosis and orientation for treatment; (ii) educational Support for the colleagues all over the country and (iii) research on pathogenesis and new approaches for pediatric MDS patients. There are socio-economical differences among the five regions of the country. The BCG-MDS-PED believes that it is absolutely necessary to Study the clinical, cellular, molecular and epidemiological aspects of MDS, taking in account these peculiar differences among populations and regions. Since 1997, 114 pediatric cases were referred to the BCG-MDS-PED from 21 centres. Seven Brazilian states have sent cases to the group, 31 patients were referred from universities, 73 patients from pediatric oncology units (foundations) and 10 patients came from private clinics. Some of these patients have been followed up and/or treated by the physician who referred them to the BCG-MDS-PED for confirmation of the initial diagnosis. The majority of these physicians have required orientation on diagnostic and treatment issues, as well as to complete cytogenetic and molecular studies. From these 114 patients, 64 patients were confirmed as MDS. We believe that, the more numerous the MDS-studied cases, the more experienced will be the referee group on clinical and laboratory features on childhood MDS in Brazil. (C) 2002 Published by Elsevier Science Ltd.26763764