Behaviour of some indicators of oxidative stress in postmenopausal and fertile women

OBJECTIVE: Unsaturated fatty acids are known to have a crucial role in the pathogenesis of atherosclerosis. They are very sensitive to oxidation caused by excess free oxygen radicals and the consequent oxidative status, and it is well known that lipid and lipoprotein metabolism is markedly altered in postmenopausal women. Oxidative stress is involved in the pathophysiology of atherosclerosis and our study aim was to assess the presence of such stress in postmenopausal women. DESIGN: One hundred and one women were enrolled in the study. Fifty were fertile (32.5+/-1.1 years) with regular menses and fifty-one were postmenopausal women (52.1+/-1.3 years). None of the study cohort had ever used hormone replacement therapy. Malonaldehyde (MDA), 4-hydroxynenal (4-HNE), oxidized lipoproteins (ox LDL) and glutathione peroxidase (GSH-PX) values were determined as we believe they reveal oxidative stress. RESULTS: MDA, 4-HNE and ox LDL concentrations were higher in postmenopausal than fertile women (p<0.001), while GSH-PX concentrations were significantly higher in fertile women than in postmenopausal subjects (p<0.001). CONCLUSIONS: Our data revealed the presence of oxidative stress in postmenopausal women.     

A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups

Inactivation of the tumor suppressor gene, CDKN2A, can occur by deletion, methylation, or mutation. We assessed the principal mode of inactivation in childhood acute lymphoblastic leukemia (ALL) and frequency in biologically relevant subgroups. Mutation or methylation was rare, whereas genomic deletion occurred in 21% of B-cell precursor ALL and 50% of T-ALL patients. Single nucleotide polymorphism arrays revealed copy number neutral (CNN) loss of heterozygosity (LOH) in 8% of patients. Array-based comparative genomic hybridization demonstrated that the mean size of deletions was 14.8 Mb and biallelic deletions composed a large and small deletion (mean sizes, 23.3 Mb and 1.4 Mb). Among 86 patients, only 2 small deletions were below the resolution of detection by fluorescence in situ hybridization. Patients with high hyperdiploidy, ETV6-RUNX1, or 11q23/MLL rearrangements had low rates of deletion (11%, 15%, 13%), whereas patients with t(9;22), t(1;19), TLX3, or TLX1 rearrangements had higher frequencies (61%, 42%, 78%, and 89%). In conclusion, CDKN2A deletion is a significant secondary abnormality in childhood ALL strongly correlated with phenotype and genotype. The variation in the incidence of CDKN2A deletions by cytogenetic subgroup may explain its inconsistent association with outcome. CNN LOH without apparent CDKN2A inactivation suggests the presence of other relevant genes in this region.     

Predictive value of early 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) during salvage chemotherapy in relapsing/refractory Hodgkin lymphoma (HL) treated with high-dose chemotherapy

This retrospective study evaluated whether early 2-[fluorine-18]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) after two cycles of salvage chemotherapy (PET2) could predict survival after high-dose chemotherapy (HDC). Twenty-four Hodgkin lymphoma (HL) patients were included. PET2 was negative in 58% and positive in 42% of patients. Ninety per cent of patients (9/10) with positive PET2 relapsed after HDC while all but one patient with negative PET2 maintained a complete remission. The 2-year progression-free survival was 93% vs. 10% for patients with negative and positive PET2, respectively ( P  < 0.001). This study shows that interim PET can predict the outcome after high-dose chemotherapy in HL patients.     

Inactivation of glutathione peroxidase activity contributes to UV-induced squamous cell carcinoma formation

Cutaneous squamous cell carcinomas (CSCC) are a common malignancy of keratinocytes that arise in sites of the skin exposed to excessive UV radiation. In the present study, we show that human SCC cell lines, preneoplastic solar keratoses (SK), and CSCC are associated with perturbations in glutathione peroxidase (GPX) activity and peroxide levels. Specifically, we found that two of three SKs and four of five CSCCs, in vivo, were associated with decreased GPX activity and all SKs and CSCCs were associated with an elevated peroxide burden. Given the association of decreased GPX activity with CSCC, we examined the basis for the GPX deficiency in the CSCCs. Our data indicated that GPX was inactivated by a post-translational mechanism and that GPX could be inactivated by increases in intracellular peroxide levels. We next tested whether the decreased peroxidase activity coupled with an elevated peroxidative burden might contribute to CSCC formation in vivo. This was tested in Gpx1(-/-) and Gpx2(-/-) mice exposed to solar-simulated UV radiation. These studies showed that Gpx2 deficiency predisposed mice to UV-induced CSCC formation. These results suggest that inactivation of GPX2 in human skin may be an early event in UV-induced SCC formation.     

Denosumab osteonecrosis of the mandible: A new entity?A case report

In the treatment of osteoporosis, M. Kahler and bone metastases from prostate and breast cancer bisphosphonates play a major role. Not all patients respond well to bisphosphonate treatment. Since a few years adverse effects of these drugs have been reported. A new drug, denosumab, a fully human monoclonal antibody to RANKL, has recently been developed. This case reports a 74-year-old male patient with a medical history of diabetes mellitus, angina pectoris, coronary bypasses, hypertension, and prostate cancer with multiple metastases to lymph nodes, bone and lungs. The prostate cancer was treated according to the protocol. But he was never treated with bisphosphonates. Instead he was included in a phase III randomized double blind multicenter trial, testing the efficacy of denosumab compared to zoledronic acid in the treatment of bone metastases of hormone resistant prostate cancer. Only 7 months after start of denosumab infectious symptoms developed, followed by infestation of the mandible. Despite surgical treatment fistula and exposed bone remained. This case illustrates that use of denosumab can lead to a type of osteonecrosis resembling bisphosphonate related osteonecrosis of the jaws.     

Efficacy of N-acetylcysteine and all-trans retinoic acid in restoring in vitro effective hemopoiesis in myelodysplastic syndromes

We evaluated the in vitro effect on clonogenic potential (CFU-GM) and apoptosis in myelodysplastic syndromes (MDS) progenitors of an anti-oxidant (N-acetylcysteine, NAC) and/or a differentiating (all-trans retinoic acid, ATRA) agent. NAC significantly reduced apoptosis, both NAC and ATRA induced an increase in CFU-GM, but NAC seemed to be particularly effective in the high risk (HR) MDS. NAC + ATRA conferred a significant advantage in terms of CFU-GM with respect to NAC and ATRA alone. Tumor Necrosis Factor-alpha (TNF-alpha) levels decreased after incubation with NAC in the MDS samples. This study shows that ineffective hemopoiesis in MDS could benefit from both NAC and ATRA, suggesting that anti-oxidant treatment may play a role in guaranteeing MDS cell survival, predisposing them towards differentiation.     

Presence of telomerase activity with undetectable p16 gene mutation in Malaysian patients with brain tumor

Recent study has shown that activation of the telomerase and p16 gene mutation are both necessary for tumorigenesis. Our objectives were to detect telomerase activity and investigate the possibility of p16 gene mutations in various types of brain tumor. We analyzed 23 tumor tissues collected in 2000 to 2002. Telomerase activity was detected by a TRAP assay using a TRAPEZE Telomerase Detection Kit (Intergen, Co). PCR-SSCP (Single Strand Conformation Polymorphism) analysis was performed to screen for p16 gene mutation at exon 1 and 2. The activity was detected in 26.1% of the brain tumor samples and mostly present in high-grade tumors. There was a significant association between telomerase activity status and tumor grade but not with patient criteria. Telomerase activity was detected in the analyzed tumors, supporting the fact that activation of telomerase is an important feature for tumorigenesis. There was no mobility shift of p16 gene using SSCP and suggested no mutation at exon 1 and 2 occurred in all samples. These results suggest that another mechanism of p16 gene alterations could be involved and associated with detectable telomerase activity in the progression of tumors.     

The use of the QNST-II as a measure for the identification of children with perceptual-motor deficits

This study aimed to examine the ability of the Quick Neurological Screening Test QNST II) (Mutti et al., 1998) to discriminate between children with and without perceptual-motor deficits and to further clarify its psychometric characteristics. Ninety-four children aged six to seven years were tested on the QNST-II. Out of this pool of subjects, 63 children had perceptual-motor deficits and 31 were typical controls. The children with perceptual-motor deficits scored significantly lower than the control children on the total score and on each of the subtest' s scores of the QNST II. Inter-rater reliability indicated a high degree of correlation between both evaluators' total scores of the QNST II. In terms of the test' s sensitivity and specificity, QNST II scores correctly classified 97% of the children with perceptual-motor deficits and 84% of the children from the control group. The findings of this study support the capability of the QNST II to discriminate between children with perceptual-motor deficits and typical children; thereby suggesting its usefulness as a screening measure to identify children at risk for difficulties in school performance.     

Infant photometry: are mean adult isoluminance values a sufficient approximation to individual infant values?

Individual differences in isoluminance values were studied in infants and adults using a motion nulling paradigm. Two luminance-modulated sinusoidal grating components (spatial frequency=0.25 cpd, temporal frequency=5.6 Hz, speed=22.4 deg/s) were superimposed and moved in opposite directions across a color video screen. The contrasts of the two components were traded off to determine motion nulls. Two conditions were used: red/black vs. green/black, and red/black vs. blue/black grating components. An eye movement based response measure was used for infant subjects, and an average of 308 trials per infant were obtained. As observed in earlier studies, the mean motion null values for infants and adults were highly similar in each condition. The standard errors of motion null values for individual subjects were very small. Individual differences among infants were also small, and were clearly measurable only in the red/black vs. blue/black condition. The close similarity of mean null values, combined with the small individual differences among infants, supports the idea that under the right circumstances mean adult isoluminance values can be used as a sufficient approximation to individual infant isoluminance values in studies of infant color vision. These circumstances are discussed and evaluated in detail.     

Low plasma stem cell factor levels correlate with in vitro leukemic growth in myelodysplastic syndromes

We evaluated the effect of SCF on myeloid differentiation by correlating clonogenic potential (as CFU-GM), bone marrow (BM) plasma SCF levels and CD34/c-kit expression in 57 MDS samples. There was a significant correlation between low SCF levels and 'leukemic' in vitro growth, the number of clusters and the colony/cluster ratio. No correlation was found between BM plasma SCF levels, the pattern of growth and CD34+ c-kit+ expression. These data seem to exclude any direct effect of SCF on leukemogenesis, but suggest that low plasma SCF levels may be at least partially responsible for leukemic growth in MDS.