Genetic variation in stromal proteins decorin and lumican with breast cancer: investigations in two case-control studies.

INTRODUCTION: The stroma is the supportive framework of biologic tissue in the breast, consisting of various proteins such as the proteoglycans, decorin and lumican. Altered expression of decorin and lumican is associated with breast tumors. We hypothesized that genetic variation in the decorin (DCN) and lumican (LUM) genes may contribute to breast cancer. METHODS: We investigated associations of 14 common polymorphisms in the DCN and LUM genes with 798 breast cancer cases and 843 controls from Mayo Clinic, MN, USA. One polymorphism per gene with the strongest risk association in the Mayo Clinic sample was genotyped in 4,470 breast cancer cases and 4,560 controls from East Anglia, England (Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH)). RESULTS: In the Mayo Clinic sample, six polymorphisms were associated with breast cancer risk (P trend <or= 0.05). The association with LUM rs2268578, evaluated further in SEARCH, was positive, although the odds ratios (OR) were weaker and not statistically significant. ORs were 1.4 (95% confidence interval [CI], 1.1 to 1.8) for heterozygotes and 2.2 (95% CI, 1.1 to 4.3; P2 df = 0.002) for homozygotes in the Mayo Clinic sample, and were 1.1 (95% CI, 0.9 to 1.2) for heterozygotes and 1.4 (95% CI, 1.0 to 2.1; P2 df = 0.13) for homozygotes in the SEARCH sample. In combined analyses, the ORs were 1.1 (95% CI, 1.0 to 1.2) for heterozygotes and 1.6 (95% CI, 1.2 to 2.3; P2 df = 0.005) for homozygotes. Positive associations for this polymorphism were observed for estrogen receptor-positive tumors in both the Mayo Clinic sample (OR for heterozygotes = 1.5, 1.1 to 1.9 and OR for homozygotes = 2.5, 1.2 to 5.3;P2 df = 0.001) and the SEARCH sample (OR for heterozygotes = 1.0, 0.9 to 1.1 and OR for homozygotes = 1.6, 1.0 to 2.5; P2 df = 0.10). In combined analyses, the ORs were 1.1 (95% CI, 0.9 to 1.2) for heterozygotes and 1.9 (95% CI, 1.3 to 2.8; P2 df = 0.001) for homozygotes. CONCLUSIONS: Although LUM rs2268578 was associated with breast cancer in the Mayo Clinic study, particularly estrogen receptor-positive breast cancer, weaker and modest associations were observed in the SEARCH sample. These modest associations will require larger samples to adequately assess the importance of this polymorphism in breast cancer

Визначення понять «резидент» і «нерезидент»: проблеми теорії і практики

Досліджено практику застосування понять «резидент» та «нерезидент» у як в Україні так і окремих зарубіжних країнах, а також надано авторське бачення щодо визначення даних термінів. Автори статті визначають умови оподаткування операцій з нерезидентами з огляду на існуючі особливості правозастосовної діяльності і вно­сять окремі пропозиції щодо удосконалення процедури адміністрування податків, що стягуються з нерезидентів.Исследована практика применения понятий «резидент» и «нерезидент» как в Украине, так и отдельных зарубежных странах, а также предоставлено авторское виденье относительно определения данных терминов. Авторы статьи определяют условия налогообложения операций с нерезидентами, учитывая существующие особен­ности правоприменительной деятельности, вносят отдельные предложения относи­тельно усовершенствования процедуры администрирования налогов, которые удержи­ваются из нерезидентов.Іn this article practice of application of concepts «resident» and «non­resident» are explored both in Ukraine and some foreign countries, and granted the author’s view on the definition of these terms. The authors of the article determine the term of taxation of operations with non­residents, taking into account the existing features of legal activity and make some suggestions in relation to the improvement of procedure of administration of taxes which are tightened from non­residents

Validation of a fast method for quantification of intra-abdominal and subcutaneous adipose tissue for large-scale human studies

Central obesity is the hallmark of a number of non-inheritable disorders. The advent of imaging techniques such asMRI has allowed for a fast and accurate assessment of body fat content and distribution. However, image analysis continues to be one of the major obstacles to the use of MRI in large-scale studies. In this study we assess the validity of the recently proposed fat–muscle quantitation system (AMRATM Profiler) for the quantification of intra-abdominal adipose tissue (IAAT) and abdominal subcutaneous adipose tissue (ASAT) from abdominal MR images. Abdominal MR images were acquired from 23 volunteers with a broad range of BMIs and analysed using sliceOmatic, the current gold-standard, and the AMRATM Profiler based on a non-rigid image registration of a library of segmented atlases. The results show that there was a highly significant correlation between the fat volumes generated by the two analysis methods, (Pearson correlation r = 0.97, p < 0.001), with the AMRATM Profiler analysis being significantly faster (~3 min) than the conventional sliceOmatic approach (~40 min). There was also excellent agreement between the methods for the quantification of IAAT (AMRA 4.73 ± 1.99 versus sliceOmatic 4.73 ± 1.75 l, p = 0.97). For the AMRATM Profiler analysis, the intra-observer coefficient of variation was 1.6% for IAAT and 1.1% for ASAT, the inter-observer coefficient of variationwas 1.4%for IAAT and 1.2%for ASAT, the intra-observer correlationwas 0.998 for IAAT and 0.999 for ASAT, and the inter-observer correlation was 0.999 for both IAAT and ASAT. These results indicate that precise and accurate measures of body fat content and distribution can be obtained in a fast and reliable form by the AMRATM Profiler, opening up the possibility of large-scale human phenotypic studies

The rs5743836 polymorphism in TLR9 confers a population-based increased risk of non-Hodgkin lymphoma

We are grateful to Paulo Vieira, Cecília Leão, Manuel T. Silva, Nuno Sousa, Jorge Correia- Pinto, Joana Palha, Margarida Correia-Neves, Margarida Lima and Matthew Berry for all their input throughout these studies and critical reading of the manuscript. We are grateful to the patients who joint this study as well as to all members of the Life and Health Sciences Research Institute and School of Health Sciences, University of Minho, who contributed in any way to the development of this workNon-Hodgkin lymphoma (NHL) has been associated with immunological defects, chronic inflammatory and autoimmune conditions. Given the link between immune dysfunction and NHL, genetic variants in toll-like receptors (TLRs) have been regarded as potential predictive factors of susceptibility to NHL. Adequate anti-tumoral responses are known to depend on TLR9 function, such that the use of its synthetic ligand is being targeted as a therapeutic strategy. We investigated the association between the functional rs5743836 polymorphism in the TLR9 promoter and risk for B-cell NHL and its major subtypes in three independent case-control association studies from Portugal (1160 controls, 797 patients), Italy (468 controls, 494 patients) and the US (972 controls, 868 patients). We found that the rs5743836 polymorphism was significantly overtransmitted in both Portuguese (odds ratio (OR), 1.85; P=7.3E-9) and Italian (OR, 1.84; P=6.0E-5) and not in the US cohort of NHL patients. Moreover, the increased transcriptional activity of TLR9 in mononuclear cells from patients harboring rs5743836 further supports a functional effect of this polymorphism on NHL susceptibility in a population-dependent manner.AC, NSO, MTC, and AJA were financially supported by a fellowship from Fundação para a Ciência e Tecnologia, Portugal. MS is a Ciência 2007 fellow. This study was supported by Fundação para a Ciência e Tecnologia, Portugal (PIC/IC/83313/2007) and by Fundação Calouste Gulbenkian, Serviço de Saúde e Desenvolvimento Humano, Portugal (Grant Number:Proc/60666-MM/734). CFS, PB and LC were supported by National Institutes of Health (NIH) grants CA122663 and CA104682, and PB also by NIH grants CA45614 and CA89745

Body shape and size in 6-year old children: assessment by three-dimensional photonic scanning.

BACKGROUND: Body shape and size are typically described using measures such as body mass index (BMI) and waist circumference, which predict disease risks in adults. However, this approach may underestimate the true variability in childhood body shape and size. OBJECTIVE: To use a comprehensive three-dimensional photonic scan approach to describe variation in childhood body shape and size. SUBJECTS/METHODS: At age 6 years, 3350 children from the population-based 2004 Pelotas birth cohort study were assessed by three-dimensional photonic scanner, traditional anthropometry and dual X-ray absorptiometry. Principal component analysis (PCA) was performed on height and 24 photonic scan variables (circumferences, lengths/widths, volumes and surface areas). RESULTS: PCA identified four independent components of children's body shape and size, which we termed: Corpulence, Central:peripheral ratio, Height and arm lengths, and Shoulder diameter. Corpulence showed strong correlations with traditional anthropometric and body composition measures (r>0.90 with weight, BMI, waist circumference and fat mass; r>0.70 with height, lean mass and bone mass); in contrast, the other three components showed weak or moderate correlations with those measures (all r<0.45). There was no sex difference in Corpulence, but boys had higher Central:peripheral ratio, Height and arm lengths and Shoulder diameter values than girls. Furthermore, children with low birth weight had lower Corpulence and Height and arm lengths but higher Central:peripheral ratio and Shoulder diameter than other children. Children from high socio-economic position (SEP) families had higher Corpulence and Height and arm lengths than other children. Finally, white children had higher Corpulence and Central:peripheral ratio than mixed or black children. CONCLUSIONS: Comprehensive assessment by three-dimensional photonic scanning identified components of childhood body shape and size not captured by traditional anthropometry or body composition measures. Differences in these novel components by sex, birth weight, SEP and skin colour may indicate their potential relevance to disease risks.This article is based on data from the study ‘Pelotas Birth Cohort, 2004’ conducted by the Postgraduate Program in Epidemiology at Federal University of Pelotas, in collaboration with Brazilian Public Health Association (ABRASCO). The 2004 birth cohort study is supported by the Wellcome Trust through the scheme called ‘Major Awards for Latin America on Health Consequences of Population Change’. The World Health Organization, Brazilian National research Council (CNPq) and Brazilian Ministry of Health have supported previous phase of the study. LPS is supported by ‘Science without Borders’ Brazilian scheme under protocol number 201801/2014-0.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ijo.2016.3

Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10−13), 1q42.13 (rs41271473, P=1.06 × 10−10), 4q24 (rs71597109, P=1.37 × 10−10), 4q35.1 (rs57214277, P=3.69 × 10−8), 6p21.31 (rs3800461, P=1.97 × 10−8), 11q23.2 (rs61904987, P=2.64 × 10−11), 18q21.1 (rs1036935, P=3.27 × 10−8), 19p13.3 (rs7254272, P=4.67 × 10−8) and 22q13.33 (rs140522, P=2.70 × 10−9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response

Bilirubin is a specific marker for the diagnosis of acute appendicitis

Total serum bilirubin and other biochemical parameters have been associated with acute appendicitis, mainly in complicated cases. The present study aimed to evaluate the role of biochemical parameters in the diagnosis of acute appendicitis, and to further investigate the role of bilirubin as a diagnostic marker irrespective of the severity of the pathology. All recorded cases of appendicectomies in a 1-year period in a single institution were reviewed. The median values of white cell count, C-reactive protein and total serum bilirubin on admission were associated with final histology, and their respective rates of abnormal and normal values were compared between patients who were proven to have negative histology and patients who were proven to have acute appendicitis. A total of 300 patients were studied. Median total serum bilirubin, white cell count and C-reactive protein on admission were significantly associated with acute appendicitis (P<0.001). Respective rates of normal and abnormal values were significantly associated with final histology (P<0.001). Total serum bilirubin demonstrated higher specificity (0.88) but lower sensitivity (0.26) and diagnostic accuracy (0.40) for acute appendicitis. In conclusion, total serum bilirubin on admission should be considered in the diagnostic workup to confirm rather than exclude appendicitis, without focusing on subgroups of specific severity of the disease. White cell count and C-reactive protein may also contribute to the diagnostic work-up, although with limited accuracy

A genome-wide association study of marginal zone lymphoma shows association to the HLA region

Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10−15) and HLA-B (rs2922994, P=2.43 × 10−9) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility