Gene expression variation to predict 10-year survival in lymph-node-negative breast cancer

Background  

It is of great significance to find better markers to correctly distinguish between high-risk and low-risk breast cancer patients since the majority of breast cancer cases are at present being overtreated.     

A prospective study of children treated for retinoblastoma: cognitive and visual outcomes in relation to treatment

PURPOSE: : To assess cognitive and visual outcomes in children treated for retinoblastoma. PATIENTS AND METHODS: A population-based group of 22 children treated for retinoblastoma were followed in a longitudinal, prospective study. Eleven children had unilateral tumours, all of which had been enucleated. The remaining 11 had bilateral tumours. Seven of these had undergone unilateral enucleation and local or external beam radiation to the other eye. Four children had been treated with local or external beam radiation only. Cognitive outcome and visual function was assessed at 4 and 6 years of age. RESULTS: We found no general delay in cognitive or motor development at 4 or 6 years of age. Better cognitive capacities were found in the bilateral/irradiated retinoblastoma patients than in unilateral/non-irradiated patients. However, two of the irradiated children, both of whom had been treated at 1 month of age, performed below group mean. None of the children was totally blind. Three children were visually impaired due to tumours affecting the macular area in the remaining eye; another three had subnormal visual acuity but no macular pathology. A total of 14 children had been enucleated and had normal vision in the remaining eye. Visual fields and dark adaptation were adversely affected in a few cases, but colour vision was normal in all. CONCLUSION: Bilateral retinoblastoma seems to be associated with superior cognitive capacities. Few children were visually impaired according to WHO criteria. We speculate that children treated during the first months of life may be at risk of adverse cognitive and visual outcomes. The immature brain may be affected by radiation treatment, causing both cognitive and visual deviations.     

Outcome after treatment of congenital unilateral cataract

PURPOSE: To evaluate long-term functional outcome after treatment of congenital unilateral cataract. METHODS: The records of 30 consecutive children operated on before the age of 12 months at St. Erik's Eye Hospital over a 5-year period (1991-96) were reviewed retrospectively. The patients were followed until 4-9.5 years of age. Linear Snellen visual acuity (VA), occlusion therapy compliance, and the presence of nystagmus, strabismus and other complications are reported. RESULTS: Six children achieved VA of 0.1 or better. They were all operated on before 3 months of age. Of the 12 infants operated on before 6 weeks of age, four have VA between 0.3 and 0.4 and eight have VA of finger counting or less. Four developed severe secondary glaucoma within 6 months of cataract extraction. Two of these had persistent fetal vasculature. Three eyes developing glaucoma became amaurotic. Occlusion therapy was abandoned before the age of 2.5 years in 21 children. CONCLUSION: Good levels of VA were achieved only in children who underwent cataract surgery before 3 months of age and who adhered to the occlusion therapy schedule. Severe secondary glaucoma developed in four out of 12 children operated on within 6 weeks. Full compliance with the occlusion therapy programme was uncommon.     

Functional and morphological effects of styrene on the auditory system of the rat

The effect of inhaled styrene on the structure and function of the auditory organ of the male Wistar rat was studied. The animals were exposed either to 600, 300 or 100 ppm styrene (12 h/day, 5 days/week, for 4 weeks). Auditory sensitivity was tested prior to and after the exposure by auditory brain stem audiometry (ABR) at frequencies of 1.0, 2.0, 4.0 and 8.0 kHz. Inner ear morphological changes were studied by light- and electron-microscopy. Exposure to 600 ppm styrene caused a 3 dB hearing loss only at the highest test frequency (8 kHz). Quantitative morphological analysis of cochlear hair cells (cytocochleograms) showed that 600 ppm styrene caused a severe outer hair cell (OHC) loss particularly in the third OHC row of the upper basal and lower middle coil. The inner hair cells were usually intact. Exposure to lower styrene concentrations (100 and 300 ppm) caused no unequivocal functional deficit or hair cell damage. We conclude that there appears to be a concentration threshold for styrene ototoxicity in rats (between 300 and 600 ppm).     

Composite resin fillings and inlays. An 11-year evaluation

The purpose of this randomized, clinical study was to evaluate the clinical performance of composite resin materials used for fillings and indirect inlays. Twenty-eight sets of five class II restorations (two fillings, three inlays) were placed in 88 premolars and 52 molars in 28 adults. Brilliant Dentin and Estilux Posterior were used for both fillings and inlays, and SR-Isosit for inlays only. After 11 years, 27 sets of restorations (96%) were evaluated clinically using modified United States Public Health Service criteria. Replaced or repaired restorations were observed in 16% of the fillings and 17% of the inlays, and a further 5% of the restorations were replaced for reasons not related to the restoration. The remaining 107 restorations exhibited optimal ratings in 30% of the fillings and 12% of the inlays (P<0.05) and acceptable ratings in 70% and 88%, respectively. The reasons for failure were fracture of restoration (four fillings, five inlays), secondary caries (two fillings, four inlays), fracture of tooth (two inlays), loss of proximal contact (two fillings), and loss of restoration (one inlay). Failures were seen more frequently in molar than premolar restorations (P<0.05), with no significant difference between fillings and inlays or between the five types of restoration (P>0.05).     

Randomized trial of single agent paclitaxel given weekly versus every three weeks and with peroral versus intravenous steroid premedication to patients with ovarian cancer previously treated with platinum

The aim of this study was to evaluate the efficacy and toxicity of paclitaxel given at the same dose intensity and administered weekly (arm A) or every 3 weeks (arm B), and to assess the safety of intravenous steroids versus standard peroral premedication. Two hundred and eight patients with advanced ovarian cancer previously treated with no more than one platinum-containing regimen were randomized to receive either a weekly infusion of paclitaxel or an infusion every 3 weeks. The median delivered dose intensity was 77.6 mg/m 2 /week in the weekly arm, and 72.7 mg/m 2 /week in the every 3 weeks arm. WHO grade 3-4 hematological and non-hematological toxicity occurred more frequently in arm B. No difference in number of severe events of hypersensitivity, response rate, time to progression or survival between arms was observed. Weekly paclitaxel at a dose of 67 mg/m 2 /week was found to have a better safety profile and seemed to be as effective as the equivalently dosed schedule every 3 weeks. Intravenous steroids are a safe alternative to oral steroids.     

SHP-2 is involved in heterodimer specific loss of phosphorylation of Tyr771 in the PDGF beta-receptor

We have previously shown that the binding site for GTPase activating protein of Ras (RasGAP) in the PDGF beta-receptor, Tyr771, is phosphorylated to a much lower extent in the heterodimeric configuration of PDGF alpha- and beta-receptors, compared to the PDGF beta-receptor homodimer. The decreased recruitment of the RasGAP to the receptor leads to prolonged activation of the Ras/MAP kinase pathway, which could explain the increase in mitogenicity seen upon induction of heterodimers. The molecular mechanism underlying these differences was investigated. We could show that the loss of phosphorylation of Tyr771 was dependent on presence of intact binding sites for the protein tyrosine phosphatase SHP-2 on the PDGF beta-receptor. Thus, in PDGF receptor mutants in which binding of SHP-2 was lost, a higher degree of phosphorylation of Tyr771 was seen, while other phosphorylation sites in the receptor remained virtually unaffected. Thus, SHP-2 appears to play an important role in modulating phosphorylation of Y771, thereby controlling RasGAP recruitment and Ras/MAP kinase signaling in the heterodimeric configuration of the PDGF receptors.     

Association of chromosome 19q13.2-3 haplotypes with basal cell carcinoma: tentative delineation of an involved region using data for single nucleotide polymorphisms in two cohorts

We have previously used single nucleotide polymorphisms to detect an association of basal cell carcinoma (BCC) in Caucasian Americans and Danes with the genome region 19q13.2-3, which contains several genes involved in the nucleotide excision repair of DNA. In this exploratory paper we have extended the data and used them in a chromosomal scan. The results indicate the presence of a gene variation modulating the risk of developing BSS in a submegabase region including and surrounding the gene RAI. Specifically, persons that are homozygous for the haplotype RAI intron 1(A) RAI exon 6(A) appear at increased risk for BCC. In addition, we have looked for possible synergisms between all pairs of markers. We find that a marker in GLTSCR1, presumably separated from RAI by several million bases, supplements the most significant marker in RAI in separating cases from controls, which may suggest the presence of an independent, risk-modulating variation in this second gene region.     

Inter-individual variation,seasonal variation and close correlation of OGG1 and ERCC1 mRNA levels in full blood from healthy volunteers

The mRNA levels of the nucleotide excision DNA repair gene ERCC1 and the base excision DNA repair gene OGG1 were quantified in 43 healthy volunteers in a dietary intervention trial as markers for the DNA repair capacity. Nine samples were collected from each subject over a period of 52 days. Sampling took place from January to May. The mRNA levels of OGG1 and ERCC1 correlated closely (r = 0.86, P < 0.0001) after normalization to either 18S ribosomal RNA or to beta-actin mRNA. The levels of OGG1 and ERCC1 mRNA were relatively constant within an individual with intra-individual correlation (R(2) = 0.45-0.46) in a General Linear Model. The amounts of ERCC1 and OGG1 relative to 18S RNA were doubled in May compared with January. This coincided with an increase in the monthly influx of sunlight from 18 MJ/m(2) in January to 242 MJ/m(2) in May. The mRNA levels of both ERCC1 and OGG1 were positively correlated to the average daily influx of sunlight in the previous 30 and 5 days (r = 0.49; r = 0.37, respectively, P < 0.001). There were no significant effects of the dietary interventions. The inter-individual variation was 5-10-fold, which is more than the observed 2-3-fold seasonal variation. Thus, despite seasonal variation of the individual mRNA levels, the inter-person variation is still far larger than the intra-person variation, supporting the use as biomarkers.