Showing papers by "Medical Research Council published in 2003"

LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1.

Abstract: We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as gamma chain (gamma(c)) deficiency] in 9 out of 10 patients by retrovirus-mediated gamma(c) gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with gammadelta+ or alphabeta+ T cell receptors) has occurred in the two youngest patients. Both patients' clones showed retrovirus vector integration in proximity to the LMO2 proto-oncogene promoter, leading to aberrant transcription and expression of LMO2. Thus, retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.

Met, metastasis, motility and more

Abstract: Hepatocyte growth factor/scatter factor and its receptor, the tyrosine kinase Met, arose late in evolution and are unique to vertebrates In spite of this, Met uses molecules such as Gab1 — homologues of which are present in Caenorhabditis elegans and Drosophila melanogaster — for downstream signalling Pivotal roles for Met in development and cancer have been established: Met controls cell migration and growth in embryogenesis; it also controls growth, invasion and metastasis in cancer cells; and activating Met mutations predispose to human cancer

Using Intake Biomarkers to Evaluate the Extent of Dietary Misreporting in a Large Sample of Adults: The OPEN Study

Abstract: This paper describes the Observing Protein and Energy Nutrition (OPEN) Study, conducted from September 1999 to March 2000. The purpose of the study was to assess dietary measurement error using two self-reported dietary instruments-the food frequency questionnaire (FFQ) and the 24-hour dietary recall (24HR)-and unbiased biomarkers of energy and protein intakes: doubly labeled water and urinary nitrogen. Participants were 484 men and women aged 40-69 years from Montgomery County, Maryland. Nine percent of men and 7% of women were defined as underreporters of both energy and protein intake on 24HRs; for FFQs, the comparable values were 35% for men and 23% for women. On average, men underreported energy intake compared with total energy expenditure by 12-14% on 24HRs and 31-36% on FFQs and underreported protein intake compared with a protein biomarker by 11-12% on 24HRs and 30-34% on FFQs. Women underreported energy intake on 24HRs by 16-20% and on FFQs by 34-38% and underreported protein intake by 11-15% on 24HRs and 27-32% on FFQs. There was little underreporting of the percentage of energy from protein for men or women. These findings have important implications for nutritional epidemiology and dietary surveillance.

Depleting Neuronal PrP in Prion Infection Prevents Disease and Reverses Spongiosis

Abstract: The mechanisms involved in prion neurotoxicity are unclear, and therapies preventing accumulation of PrPSc, the disease-associated form of prion protein (PrP), do not significantly prolong survival in mice with central nervous system prion infection. We found that depleting endogenous neuronal PrPc in mice with established neuroinvasive prion infection reversed early spongiform change and prevented neuronal loss and progression to clinical disease. This occurred despite the accumulation of extraneuronal PrPSc to levels seen in terminally ill wild-type animals. Thus, the propagation of nonneuronal PrPSc is not pathogenic, but arresting the continued conversion of PrPc to PrPSc within neurons during scrapie infection prevents prion neurotoxicity.

Antibody Multispecificity Mediated by Conformational Diversity

Abstract: A single antibody was shown to adopt different binding-site conformations and thereby bind unrelated antigens. Analysis by both x-ray crystallography and pre-steady-state kinetics revealed an equilibrium between different preexisting isomers, one of which possessed a promiscuous, low-affinity binding site for aromatic ligands, including the immunizing hapten. A subsequent induced-fit isomerization led to high-affinity complexes with a deep and narrow binding site. A protein antigen identified by repertoire selection made use of an unrelated antibody isomer with a wide, shallow binding site. Conformational diversity, whereby one sequence adopts multiple structures and multiple functions, can increase the effective size of the antibody repertoire but may also lead to autoimmunity and allergy.

Initial burden of disease estimates for South Africa, 2000.

Abstract: BACKGROUND: This paper describes the first national burden of disease study for South Africa The main focus is the burden due to premature mortality, ie years of life lost (YLLs) In addition, estimates of the burden contributed by morbidity, ie the years lived with disability (YLDs), are obtained to calculate disability-adjusted life years (DALYs); and the impact of AIDS on premature mortality in the year 2010 is assessed METHOD: Owing to the rapid mortality transition and the lack of timely data, a modelling approach has been adopted The total mortality for the year 2000 is estimated using a demographic and AIDS model The non-AIDS cause-of-death profile is estimated using three sources of data: Statistics South Africa, the National Department of Home Affairs, and the National Injury Mortality Surveillance System A ratio method is used to estimate the YLDs from the YLL estimates RESULTS: The top single cause of mortality burden was HIV/AIDS followed by homicide, tuberculosis, road traffic accidents and diarrhoea HIV/AIDS accounted for 38% of total YLLs, which is proportionately higher for females (47%) than for males (33%) Pre-transitional diseases, usually associated with poverty and underdevelopment, accounted for 25%, non-communicable diseases 21% and injuries 16% of YLLs The DALY estimates highlight the fact that mortality alone underestimates the burden of disease, especially with regard to unintentional injuries, respiratory disease, and nervous system, mental and sense organ disorders The impact of HIV/AIDS is expected to more than double the burden of premature mortality by the year 2010 CONCLUSION: This study has drawn together data from a range of sources to develop coherent estimates of premature mortality by cause South Africa is experiencing a quadruple burden of disease comprising the pre-transitional diseases, the emerging chronic diseases, injuries, and HIV/AIDS Unless interventions that reduce morbidity and delay morbidity become widely available, the burden due to HIV/AIDS can be expected to grow very rapidly in the next few years An improved base of information is needed to assess the morbidity impact more accurately

Infectious HIV-1 assembles in late endosomes in primary macrophages.

Abstract: Although human immunodeficiency virus type 1 (HIV-1) is generally thought to assemble at the plasma membrane of infected cells, virions have been observed in intracellular compartments in macrophages Here, we investigated virus assembly in HIV-1–infected primary human monocyte-derived macrophages (MDM) Electron microscopy of cryosections showed virus particles, identified by their morphology and positive labeling with antibodies to the viral p17, p24, and envelope proteins, in intracellular vacuoles Immunolabeling demonstrated that these compartments contained the late endosomal marker CD63, which was enriched on vesicles within these structures and incorporated into the envelope of budding virions The virus-containing vacuoles were also labeled with antibodies against LAMP-1, CD81, and CD82, which were also incorporated into the viral envelope To assess the cellular source of infectious viruses derived from MDM, virus-containing media from infected cells were precipitated with specific antibodies Only antibodies against antigens found in late endosomes precipitated infectious virus, whereas antibodies against proteins located primarily on the cell surface did not Our data indicate that most of the infectious HIV produced by primary macrophages is assembled on late endocytic membranes and acquires antigens characteristic of this compartment This notion has significant implications for understanding the biology of HIV and its cell–cell transmission

Ectopic beta-chain of ATP synthase is an apolipoprotein A-I receptor in hepatic HDL endocytosis.

Abstract: The effect of high-density lipoprotein (HDL) in protecting against atherosclerosis is usually attributed to its role in 'reverse cholesterol transport'. In this process, HDL particles mediate the efflux and the transport of cholesterol from peripheral cells to the liver for further metabolism and bile excretion. Thus, cell-surface receptors for HDL on hepatocytes are chief partners in the regulation of cholesterol homeostasis. A high-affinity HDL receptor for apolipoprotein A-I (apoA-I) was previously identified on the surface of hepatocytes. Here we show that this receptor is identical to the beta-chain of ATP synthase, a principal protein complex of the mitochondrial inner membrane. Different experimental approaches confirm this ectopic localization of components of the ATP synthase complex and the presence of ATP hydrolase activity at the hepatocyte cell surface. Receptor stimulation by apoA-I triggers the endocytosis of holo-HDL particles (protein plus lipid) by a mechanism that depends strictly on the generation of ADP. We confirm this effect on endocytosis in perfused rat liver ex vivo by using a specific inhibitor of ATP synthase. Thus, membrane-bound ATP synthase has a previously unsuspected role in modulating the concentrations of extracellular ADP and is regulated by a principal plasma apolipoprotein.

Probiotics for treating infectious diarrhoea.

Abstract: Background Probiotics are microbial cell preparations or components of microbial cells that have a beneficial effect on the health and well being of the host. Probiotics may offer a safe intervention in acute infectious diarrhoea to reduce the duration and severity of the illness. Objectives To assess the effects of probiotics in proven or presumed infectious diarrhoea. Search strategy We searched the Cochrane Infectious Diseases Group's trials register (December 2002), the Cochrane Controlled Trials Register (The Cochrane Library Issue 4, 2002), MEDLINE (1966 to 2002), EMBASE (1988 to 2002), and reference lists from studies and reviews. We also contacted organizations and individuals working in the field, and pharmaceutical companies manufacturing probiotic agents. Selection criteria Randomized controlled trials comparing a specified probiotic agent with placebo or no probiotic in people with acute diarrhoea that is proven or presumed to be caused by an infectious agent. Data collection and analysis Two reviewers independently assessed trial methodological quality and extracted data. Main results Twenty-three studies met the inclusion criteria with a total of 1917 participants, mainly in countries with low overall mortality rates. Trials varied in relation to the probiotic(s) tested, dosage, methodological quality, and the diarrhoea definitions and outcomes. Probiotics reduced the risk of diarrhoea at 3 days (relative risk 0.66, 95% confidence interval 0.55 to 0.77, random effects model; 15 studies) and the mean duration of diarrhoea by 30.48 hours (95% confidence interval 18.51 to 42.46 hours, random effects model, 12 studies). Subgroup analysis by probiotic(s) tested, rotavirus diarrhoea, national mortality rates, and age of participants did not fully account for the heterogeneity. Reviewers' conclusions Probiotics appear to be a useful adjunct to rehydration therapy in treating acute, infectious diarrhoea in adults and children. More research is needed to inform the use of particular probiotic regimens in specific patient groups.

International Collaborative Ovarian Neoplasm trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma.

Abstract: Background: Adjuvant chemotherapy has been suggested as a possible strategy to improve survival in women with early-stage ovarian cancer; however, all randomized studies to date have been too small to answer this question reliably Methods: We performed a preplanned combined analysis of two parallel randomized clinical trials (International Collaborative Ovarian Neoplasm 1 [ICON1] and Adjuvant ChemoTherapy In Ovarian Neoplasm [ACTION]) in early-stage ovarian cancer that compared platinum-based adjuvant chemotherapy with observation following surgery Between November 1990 and January 2000, 925 patients (477 in ICON1 and 448 in ACTION) who had surgery for early-stage ovarian cancer were randomly assigned to receive platinum-based adjuvant chemotherapy (n = 465) or observation (n = 460) until chemotherapy was indicated Kaplan-Meier analysis was used to compare overall and recurrence-free survival by treatment allocation In subgroup analyses of pretreatment age, tumor stage, histologic cell type, and differentiation grade, the differences in relative size of effect were tested using a chi-square test for interaction or a chi-square test for trend All tests of statistical significance were two-sided Results: After a median follow-up of over 4 years, 245 patients had died or had a recurrence (ICON1: 133, ACTION: 112) Overall survival at 5 years was 82% in the chemotherapy arm and 74% in the observation arm (difference = 8% [95% confidence interval (CI) = 2% to 12%]; hazard ratio [HR] = 067, 95% CI = 050 to 090; P = 008) Recurrence-free survival at 5 years was also better in the adjuvant chemotherapy arm than it was in the observation arm (76% versus 65%, difference = 11% [95% CI = 5% to 16%]; HR = 064, 95% CI = 050 to 082; P = 001) Subgroup analyses provided no evidence of a difference in the size of effect of chemotherapy on survival in any pretreatment subcategory Conclusions: Platinum-based adjuvant chemotherapy improved overall survival and recurrence-free survival at 5 years in this combined group of patients with early-stage ovarian cancer defined by the inclusion criteria of the ICON1 and ACTION trials

The nature and identification of quantitative trait loci: a community's view.

Abstract: This white paper by eighty members of the Complex Trait Consortium presents a community's view on the approaches and statistical analyses that are needed for the identification of genetic loci that determine quantitative traits. Quantitative trait loci (QTLs) can be identified in several ways, but is there a definitive test of whether a candidate locus actually corresponds to a specific QTL?

Statistical approaches for assessing the relative validity of a food-frequency questionnaire: use of correlation coefficients and the kappa statistic

Abstract: Objective To compare different statistical methods for assessing the relative validity of a self-administered, 150-item, semi-quantitative food-frequency questionnaire (FFQ) with 4-day weighed diet records (WR). Design Subjects completed the Scottish Collaborative Group FFQ and carried out a 4-day WR. Relative agreement between the FFQ and WR for energy-adjusted nutrient intakes was assessed by Pearson and Spearman rank correlation coefficients, the percentages of subjects classified into the same and opposite thirds of intake, and Cohen's weighted kappa. Subjects Forty-one men, mean age 36 (range 21-56) years, and 40 women, mean age 33 (range 19-58) years, recruited from different locations in Aberdeen, Scotland. Results Spearman correlation coefficients tended to be lower than Pearson correlation coefficients, and were above 0.5 for 10 of the 27 nutrients in men and 17 of the 27 nutrients in women. For nutrients with Spearman correlation coefficients above 0.5, the percentage of subjects correctly classified into thirds ranged from 39 to 78%, and weighted kappa values ranged from 0.23 to 0.66. Conclusions Both Spearman correlation coefficients and weighted kappa values are useful in assessing the relative validity of estimates of nutrient intake by FFQs. Spearman correlation coefficients above 0.5, more than 50% of subjects correctly classified and less than 10% of subjects grossly misclassified into thirds, and weighted kappa values above 0.4 are recommended for nutrients of interest in epidemiological studies.

SOCS-3 regulates onset and maintenance of TH2-mediated allergic responses

Abstract: Members of the suppressor of cytokine signaling (SOCS) family are involved in the pathogenesis of many inflammatory diseases. SOCS-3 is predominantly expressed in T-helper type 2 (T(H)2) cells, but its role in T(H)2-related allergic diseases remains to be investigated. In this study we provide a strong correlation between SOCS-3 expression and the pathology of asthma and atopic dermatitis, as well as serum IgE levels in allergic human patients. SOCS-3 transgenic mice showed increased T(H)2 responses and multiple pathological features characteristic of asthma in an airway hypersensitivity model system. In contrast, dominant-negative mutant SOCS-3 transgenic mice, as well as mice with a heterozygous deletion of Socs3, had decreased T(H)2 development. These data indicate that SOCS-3 has an important role in regulating the onset and maintenance of T(H)2-mediated allergic immune disease, and suggest that SOCS-3 may be a new therapeutic target for the development of antiallergic drugs.

Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia

Abstract: Background: Mutations of the transforming growth factor β (TGFβ) receptor components ENDOGLIN and ALK-1 cause the autosomal dominant vascular disorder hereditary haemorrhagic telangiectasia (HHT). Heterozygous mutations of the type II receptor BMPR2 underlie familial primary pulmonary hypertension. Objective: To investigate kindreds presenting with both pulmonary hypertension and HHT. Methods: Probands and families were identified by specialist pulmonary hypertension centres in five countries. DNA sequence analysis of ALK-1 , ENDOGLIN , and BMPR2 was undertaken. Cellular localisation was investigated by heterologous overexpression of mutant constructs in both BAEC and HeLa cells. The impact of a novel sequence variant was assessed through comparative analysis and computer modelling. Results: Molecular analysis of 11 probands identified eight missense mutations of ALK-1 , one of which was observed in two families. Mutations were located within exons 5 to 10 of the ALK-1 gene. The majority of ALK-1 mutant constructs appeared to be retained within the cell cytoplasm, in the endoplasmic reticulum. A novel GS domain mutation, when overexpressed, reached the cell surface but is predicted to disrupt conformational changes owing to loss of a critical hydrogen bond. Two novel missense mutations were identified in ENDOGLIN . Conclusions: The association of pulmonary arterial hypertension and HHT identifies an important disease complication and appears most common among subjects with defects in ALK-1 receptor signalling. Future studies should focus on detailed molecular analysis of the common cellular pathways disrupted by mutations of ALK-1 and BMPR2 that cause inherited pulmonary vascular disease.

A quantitative, highly sensitive cell-based infectivity assay for mouse scrapie prions

Abstract: Prions are usually quantified by bioassays based on intracerebral inoculation of mice that are slow, imprecise, and costly. We have isolated neuroblastoma N2a sublines highly susceptible to mouse prions, as evidenced by accumulation of infectivity and the scrapie form of prion protein (PrPSc), and developed quantitative in vitro assays for prion infectivity. In the scrapie cell (SC) assay, susceptible N2a cells are exposed to prion-containing samples for 3 days, grown to confluence, and split 1:10 three times, and the proportion of PrPSc-containing cells is determined with automated counting equipment. In a log/log plot, the dose–response is linear over two logs of prion concentrations. The SC assay is about as sensitive as the mouse bioassay, 10 times faster, >2 orders of magnitude less expensive, and suitable for robotization. SC assays performed in a more time-consuming end point titration format extend the sensitivity and show that infectivity titers measured in tissue culture and in the mouse are similar.

Growth Faltering in Rural Gambian Infants Is Associated with Impaired Small Intestinal Barrier Function, Leading to Endotoxemia and Systemic Inflammation

Abstract: Growth faltering of rural Gambian infants is associated with a chronic inflammatory enteropathy of the mucosa of the small intestine that may impair both digestive/absorptive and barrier functions. The aim of this study was to determine whether the enteropathy was associated with a compromised barrier function that allowed translocation of antigenic macromolecules from the gut lumen into the body, with subsequent systemic immunostimulation, resulting in growth retardation. Rural Gambian infants were studied longitudinally at regular intervals between 8 and 64 wk of age. On each study day, each child was medically examined, anthropometric measurements were made, a blood sample was taken and an intestinal permeability test performed. Evidence of chronic immunostimulation was provided by abnormally elevated white blood cell, lymphocyte and platelet counts, and frequently raised plasma concentration of C-reactive protein. Intestinal permeability was abnormal and associated with impaired growth (r = -0.41, P < 0.001). Plasma concentrations of endotoxin and immunoglobulin (Ig)G-endotoxin core antibody were also elevated and related to both growth (r = -0.30, P < 0.02; r = -0.64, P < 0.0001, respectively) and measures of mucosal enteropathy. Plasma IgG, IgA and IgM levels increased rapidly with age toward adult concentrations. Raised values were related to poor growth but also to measures of mucosal enteropathy and the endotoxin antibody titer. The interrelationships among these variables and growth suggested that they were all part of the same growth-retarding mechanism. These data are consistent with the hypothesis of translocation of immunogenic lumenal macromolecules across a compromised gut mucosa, leading to stimulation of systemic immune/inflammatory processes and subsequent growth impairment.

A Structural Basis for Immunodominant Human T Cell Receptor Recognition

Abstract: The anti-influenza CD8+ T cell response in HLA-A2–positive adults is almost exclusively directed at residues 58–66 of the virus matrix protein (MP(58–66)). Vβ17Vα10.2 T cell receptors (TCRs) containing a conserved arginine-serine-serine sequence in complementarity determining region 3 (CDR3) of the Vβ segment dominate this response. To investigate the molecular basis of immunodominant selection in an outbred population, we have determined the crystal structure of Vβ17Vα10.2 in complex with MP(58–66)–HLA-A2 at a resolution of 1.4 A. We show that, whereas the TCR typically fits over an exposed side chain of the peptide, in this structure MP(58–66) exposes only main chain atoms. This distinctive orientation of Vβ17Vα10.2, which is almost orthogonal to the peptide-binding groove of HLA-A2, facilitates insertion of the conserved arginine in Vβ CDR3 into a notch in the surface of MP(58–66)–HLA-A2. This previously unknown binding mode underlies the immunodominant T cell response.

Multistate Markov models for disease progression with classification error

Abstract: Summary. Many chronic diseases have a natural interpretation in terms of staged progression. Multistate models based on Markov processes are a well-established method of estimating rates of transition between stages of disease. However, diagnoses of disease stages are sometimes subject to error. The paper presents a general hidden Markov model for simultaneously estimating transition rates and probabilities of stage misclassification. Covariates can be fitted to both the transition rates and the misclassification probabilities. For example, in the study of abdominal aortic aneurysms by ultrasonography, the disease is staged by severity, according to successive ranges of aortic diameter. The model is illustrated on data from a trial of aortic aneurysm screening, in which the screening measurements are subject to error. General purpose software for model implementation has been developed in the form of an R package and is made freely available.

Steroid receptor expression in uterine natural killer cells.

Abstract: The endometrium contains a unique subset of uterine-specific natural killer (uNK) cells, the proposed functions of which include a role in decidualization, menstruation, and implantation. These cells increase in number during the mid-late secretory phase of the menstrual cycle and are also present in large numbers in early pregnancy. The cyclical nature of uNK cell appearance suggests hormonal regulation of these cells. To date, it has not been possible to localize either estrogen receptors (ERs) or progesterone receptors (PRs) to uNK cells. In the present study, we have investigated the steroid receptor expression of uNK cells, including not only ER alpha and PR but also wild-type ER beta 1, its variant form ER beta cx/beta 2, and glucocorticoid receptor (GR) using specific monoclonal antibodies and real-time quantitative RT-PCR. mRNA encoding ER alpha, PR, ER beta cx/beta 2, ER beta 1, and GR were identified in extracts of human endometrium across the menstrual cycle and in decidua. Quantitative real-time RT-PCR demonstrated an absence of ER alpha and PR mRNA in purified uNK cells. In contrast, mRNA for ER beta cx/beta 2, ER beta 1, and GR was present in uNK cells. ER alpha, PR, ER beta cx/beta 2, ER beta 1, and GR proteins were identified in endometrial and decidual biopsies. Colocalization using specific monoclonal antibodies confirmed that uNK cells were immunonegative for ER alpha and PR protein. These cells were also immunonegative for ER beta cx/beta 2 but did express ER beta 1 and GR proteins. These results raise the possibility that estrogens and glucocorticoids could be acting directly on uNK cells through ER beta and GR, respectively, to influence gene transcription in the endometrium and decidua.

The Neuroscience of Language: On Brain Circuits of Words and Serial Order

Abstract: How is language organized in the human brain? The Neuroscience of Language, published in 2003, puts forth a systematic model of language to bridge the gap between linguistics and neuroscience. Neuronal models of word and serial order processing are presented in the form of a computational, connectionist neural network. The linguistic emphasis is on words and elementary syntactic rules. Introductory chapters focus on neuronal structure and function, cognitive brain processes, the basics of classical aphasia research and modern neuroimaging of language, neural network approaches to language, and the basics of syntactic theories. The essence of the work is contained in chapters on neural algorithms and networks, basic syntax, serial order mechanisms, and neuronal grammar. Throughout, excursuses illustrate the functioning of brain models of language, some of which are accessible as animations on the book's accompanying web site. It will appeal to graduate students and researchers in neuroscience, psychology, linguistics, and computational modeling.

Smoking and the risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Abstract: Smoking has recently been recognised as causally associated with the development of gastric cancer (GC). However, evidence on the effect by sex, duration and intensity of smoking, anatomic subsite and cessation of smoking is limited. Our objective was to assess the relation between tobacco use and GC incidence in the European Prospective Investigation into Cancer and Nutrition (EPIC). We studied data from 521,468 individuals recruited from 10 European countries taking part in the EPIC study. Participants completed lifestyle questionnaires that included questions on lifetime consumption of tobacco and diet in 1991-1998. Participants were followed until September 2002, and during that period 305 cases of stomach cancer were identified. After exclusions, 274 were eligible for the analysis, using the Cox proportional hazard model. After adjustment for educational level, consumption of fresh fruit, vegetables and preserved meat, alcohol intake and body mass index (BMI), there was a significant association between cigarette smoking and gastric cancer risk: the hazard ratio (HR) for ever smokers was 1.45 (95% confidence interval [CI] = 1.08-1.94). The HR of current cigarette smoking was 1.73 (95% CI = 1.06-2.83) in males and 1.87 (95% CI = 1.12-3.12) in females. Hazard ratios increased with intensity and duration of cigarette smoked. A significant decrease of risk was observed after 10 years of quitting smoking. A preliminary analysis of 121 cases with identified anatomic site showed that current cigarette smokers had a higher HR of GC in the cardia (HR = 4.10) than in the distal part of the stomach (HR = 1.94). In this cohort, 17.6 % (95% CI = 10.5-29.5 %) of GC cases may be attributable to smoking. Findings from this large study support the causal relation between smoking and gastric cancer in this European population. Stomach cancer should be added to the burden of diseases caused by smoking.

Urine Nitrogen as a Biomarker for the Validation of Dietary Protein Intake

Abstract: When validated for completeness, 24-h urine nitrogen obtained from repeated 24-h urine collections has provided useful insights into the validity of dietary assessments, underreporting behaviors and the structure of measurement errors that are associated with different methods. This is particularly so when nitrogen is combined with another marker in 24-h urine samples, potassium. Although the collection of 24-h urine is a tedious procedure, the method is readily accessible and comparatively inexpensive. Other markers of dietary intake and intermediate risk markers may also be measured in the 24-h urine that is obtained.

FUS/ERG gene fusions in Ewing's tumors.

Abstract: Ewing's tumors are rare pediatric neoplasms that are characterized by specific chromosomal translocations and gene rearrangements. All of the fusion genes reported to date in Ewing's tumors juxtapose the EWS gene at 22q12 to an ETS-related gene, the most common of which are FLI1 at 11q24 and ERG at 21q22. We present here four cases of Ewing's tumor, which showed no evidence of a EWS gene rearrangement, but instead contained translocations involving 16p11 and 21q22. A rearrangement involving the same chromosome bands, t(16;21)(p11;q22), is found in rare cases of acute myeloid leukemia and fuses the FUS gene at 16p11 to the ERG gene at 21q22. In two of our Ewing's tumor cases, we were able to show at the sequence level that the translocation between chromosomes 16 and 21 similarly results in a FUS/ERG fusion. In one case, exons 1-5 and most of exon 6 of FUS were fused in-frame to exon 9 of ERG; in the other case, FUS exons 1-7 were fused in-frame to ERG exons 8-9. The functional fusion transcript is expected to be expressed from the der(21)t(16;21) derivative. In the two other t(16;21)-positive Ewing's cases, we performed bacterial artificial chromosome fluorescence in situ hybridization analysis on metaphases and interphase nuclei to demonstrate colocalization of bacterial artificial chromosomes containing FUS and ERG genes, also highly suggestive of fusion gene formation. These represent the first four cases where FUS, rather than EWS, is rearranged with an ETS-family transcription factor in Ewing's tumors. Our data provide additional evidence that the transactivation domains of the TET family of RNA-binding proteins (such as EWS and FUS) are interchangeable, and suggests a novel mechanism of oncogenesis in Ewing's tumors.