The recurrent translocation t(5;11)(q35;p15.5) associated with a 5q deletion, del(5q), has been reported in childhood acute myeloid leukemia (AML). We report the cloning of the translocation ...breakpoints in de novo childhood AML harboring a cryptic t(5;11)(q35;p15.5). Fluorescence in situ hybridization (FISH) analysis demonstrated that the nucleoporin gene (NUP98) at 11p15.5 was disrupted by this translocation. By using 3′–rapid amplification of complementary DNA ends (3′-RACE) polymerase chain reaction, we identified a chimeric messenger RNA that results in the in-frame fusion of NUP98to a novel gene, NSD1. The NSD1 gene has 2596 amino acid residues and a 85% homology to the murine Nsd1with the domain structure being conserved. The NSD1 gene was localized to 5q35 by FISH and is widely expressed. The reciprocal transcript, NSD1-NUP98, was also detected by reverse transcriptase–polymerase chain reaction. This is the first report in which the novel gene NSD1 has been implicated in human malignancy.
1. The effects on British farmland wildlife of the management of four genetically modified herbicide-tolerant crops are currently being studied in a 5-year trial termed the Farm-Scale Evaluations ...(FSE), the first 4 years of which are completed. The FSE is controversial and extensive. There has been intense scrutiny of the experimental design and proposed analysis, and of the estimated statistical power to detect effects of a given magnitude, should any exist. 2. For each crop, the FSE is a form of on-farm trial with a single composite null hypothesis and a simple randomized block experimental design. This has statistical implications for the imposition of treatments by growers and the need for proper randomization. The choice of a half-field experimental unit was based on field availability, the focus on herbicide management, the need to reduce variability and efficiency gains in sampling effort. Farms and fields were selected to represent the range of variability of geography and intensiveness across Britain for each crop. 3. Results of a power analysis suggested that the planned replication of the FSE of about 60 fields per crop over 3 years would be sufficient to provide useful information, from which valid statistical inferences could be drawn. The achieved replication for spring crops in the FSE exceeded, by more than threefold, that in any of 82 comparable terrestrial manipulative ecological experiments undertaken previously. 4. Here, we exemplify a range of analyses including covariates, interactions between various factors including years and treatments, diagnostic procedures to aid selection of the most efficient statistical model, the estimation of power from coefficients of variation, a novel and apparently robust test statistic and the calculation of overall variance from within- and between-unit variability. Preliminary results indicated that a simple log-normal model appeared adequate for most analyses. 5. Synthesis and applications. Statistical challenges created by the scope of the FSE were resolved from a sound knowledge of good experimental design. There is an urgent need for further statistical studies to develop experimental designs or modelling approaches that allow similar studies of genetically modified (GM) crops, at reduced cost. However, this power analysis has shown that this cannot be achieved at the expense of adequate replication, essential for all risk assessment studies.
Glutathione-S-Transferases (GSTs) comprise a family of isoenzymes that provide protection to mammalian cells against electrophilic metabolites of carcinogens and reactive oxygen species. Previous ...studies have shown that the CpG-rich promoter region of the pi-class gene GSTP1 is methylated at single restriction sites in the majority of prostate cancers. In order to understand the nature of abnormal methylation of the GSTP1 gene in prostate cancer we undertook a detailed analysis of methylation at 131 CpG sites spanning the promoter and body of the gene. Our results show that DNA methylation is not confined to specific CpG sites in the promoter region of the GSTP1 gene but is extensive throughout the CpG island in prostate cancer cells. Furthermore we found that both alleles are abnormally methylated in this region. In normal prostate tissue, the entire CpG island was unmethylated, but extensive methylation was found outside the island in the body of the gene. Loss of GSTP1 expression correlated with DNA methylation of the CpG island in both prostate cancer cell lines and cancer tissues whereas methylation outside the CpG island in normal prostate tissue appeared to have no effect on gene expression.
The aim of this study was to determine whether multiwalled carbon nanotubes (MWNCT) are taken up by and are toxic to human intestinal enterocytes using the Caco-2 cell model. Caco-2 cells were ...exposed to 50 μg/ml MWCNT (oxidized or pristine) for 24 h, and experiments were repeated in the presence of 2.5 mg/L natural organic matter. Cells displayed many of the properties that characterize enterocytes, such as apical microvilli, basolateral basement membrane, and glycogen. The cell monolayers also displayed tight junctions and electrical resistance. Exposure to pristine and oxidized MWCNT, with or without natural organic matter, did not markedly affect viability, which was assessed by measuring activity of released lactate dehydrogenase (LDH) and staining with propidium iodide. Ultrastructural analysis revealed some damage to microvilli colocalized with the MWCNT; however, neither type of MWCNT was taken up by Caco-2 cells. In contrast, pristine and oxidized MWCNT were taken up by the macrophage RAW 264.7 line. Our study suggests that intestinal enterocytes cells do not take up MWCNT.
The retinoblastoma gene (Rb) is one of the best characterized tumor suppressor genes, and its inactivation is associated with a number of cancers. Previous studies have shown, by restriction enzyme ...analysis, that the promoter region of the Rb gene is methylated in a significant proportion of primary retinoblastoma tumors. We now report the first detailed methylation sequence analysis of the CpG island spanning the retinoblastoma promoter from hypermethylated retinoblastoma tumors. Our results show methylation is not confined to a specific CpG site, as detected by restriction enzyme studies, but extends to essentially all 27 CpG dinucleotides spanning the retinoblastoma CpG island, including the core promoter. The methylation pattern from each tumor DNA sample is different, ranging from densely to sparsely methylated profiles. Single CpG sites, in particular the E2F transcription factor binding site, as well as blocks of CpGs, were undermethylated in some tumor samples. Possible interference of methylation could be due to the binding of sequence-specific protein factors at these sites in the tumor cells. This study highlights that the dynamics of DNA methylation in cancer cells are clearly different from normal cells and gives an insight into the mechanism of abnormal methylation of CpG islands in cancer cells.
Ever-increasing interest in oceanography and marine biology and their relevance to global environmental issues create a demand for authoritative reviews summarizing the results of recent research. ...Oceanography and Marine Biology: An Annual Review has catered to this demand since its founding by the late Harold Barnes more than 50 years ago. Its objectives are to consider, annually, the basic areas of marine research, returning to them when appropriate in future volumes; to deal with subjects of special and topical importance; and to add new subjects as they arise.
The favourable reception and complimentary reviews accorded to all the volumes shows that the series is fulfilling a very real need. Volume 55 follows closely the objectives and style of the earlier volumes, continuing to regard the marine sciences—with all their various aspects—as a unity. Physical, chemical, and biological aspects of marine science are dealt with by experts actively engaged in these fields, and every chapter is peer-reviewed by other experts working actively in the specific areas of interest.
Summary Background Thrombolysis is of net benefit in patients with acute ischaemic stroke, who are younger than 80 years of age and are treated within 4·5 h of onset. The third International Stroke ...Trial (IST-3) sought to determine whether a wider range of patients might benefit up to 6 h from stroke onset. Methods In this international, multicentre, randomised, open-treatment trial, patients were allocated to 0·9 mg/kg intravenous recombinant tissue plasminogen activator (rt-PA) or to control. The primary analysis was of the proportion of patients alive and independent, as defined by an Oxford Handicap Score (OHS) of 0–2 at 6 months. The study is registered, ISRCTN25765518. Findings 3035 patients were enrolled by 156 hospitals in 12 countries. All of these patients were included in the analyses (1515 in the rt-PA group vs 1520 in the control group), of whom 1617 (53%) were older than 80 years of age. At 6 months, 554 (37%) patients in the rt-PA group versus 534 (35%) in the control group were alive and independent (OHS 0–2; adjusted odds ratio OR 1·13, 95% CI 0·95–1·35, p=0·181; a non-significant absolute increase of 14/1000, 95% CI −20 to 48). An ordinal analysis showed a significant shift in OHS scores; common OR 1·27 (95% CI 1·10–1·47, p=0·001). Fatal or non-fatal symptomatic intracranial haemorrhage within 7 days occurred in 104 (7%) patients in the rt-PA group versus 16 (1%) in the control group (adjusted OR 6·94, 95% CI 4·07–11·8; absolute excess 58/1000, 95% CI 44–72). More deaths occurred within 7 days in the rt-PA group (163 11%) than in the control group (107 7%, adjusted OR 1·60, 95% CI 1·22–2·08, p=0·001; absolute increase 37/1000, 95% CI 17–57), but between 7 days and 6 months there were fewer deaths in the rt-PA group than in the control group, so that by 6 months, similar numbers, in total, had died (408 27% in the rt-PA group vs 407 27% in the control group). Interpretation For the types of patient recruited in IST-3, despite the early hazards, thrombolysis within 6 h improved functional outcome. Benefit did not seem to be diminished in elderly patients. Funding UK Medical Research Council, Health Foundation UK, Stroke Association UK, Research Council of Norway, Arbetsmarknadens Partners Forsakringsbolag (AFA) Insurances Sweden, Swedish Heart Lung Fund, The Foundation of Marianne and Marcus Wallenberg, Polish Ministry of Science and Education, the Australian Heart Foundation, Australian National Health and Medical Research Council (NHMRC), Swiss National Research Foundation, Swiss Heart Foundation, Assessorato alla Sanita, Regione dell'Umbria, Italy, and Danube University.
The Society of Radiologists in Ultrasound convened a panel of specialists from a variety of medical disciplines to come to a consensus on the management of thyroid nodules identified with thyroid ...ultrasonography (US), with particular focus on which nodules should be subjected to US-guided fine needle aspiration and which thyroid nodules need not be subjected to fine-needle aspiration. The panel met in Washington, DC, October 26-27, 2004, and created this consensus statement. The recommendations in this consensus statement, which are based on analysis of the current literature and common practice strategies, are thought to represent a reasonable approach to thyroid nodular disease.
The mechanisms that underlie thermal tolerance in aquatic ectotherms remain unresolved. Triploid fish have been reported to exhibit lower thermal tolerance than diploids, offering a potential model ...organism to better understand the physiological drivers of thermal tolerance. Here, we compared triploid and diploid juvenile Atlantic salmon (
) in freshwater to investigate the proposed link between aerobic capacity and thermal tolerance. We measured specific growth rates (SGR) and resting (aerobic) metabolic rates (RMR) in freshwater at 3, 7 and 9 weeks of acclimation to 10, 14 and 18°C. Additionally, maximum metabolic rates (MMR) were measured at 3 and 7 weeks of acclimation, and critical thermal maxima (CT
) were measured at 9 weeks. Mass, SGR and RMR differed between ploidies across all temperatures at the beginning of the acclimation period, but all three metrics were similar across ploidies by week 7. Aerobic scope (MMR-RMR) remained consistent across ploidies, acclimation temperatures and time. At 9 weeks, CT
was independent of ploidy, but correlated positively with acclimation temperature despite the similar aerobic scope between acclimation groups. Our findings suggest that acute thermal tolerance is not modulated by aerobic scope, and the altered genome of triploid Atlantic salmon does not translate to reduced thermal tolerance of juvenile fish in freshwater.
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