AID/APOBEC-network reconstruction identifies pathways associated with survival in ovarian cancer

Background Building up of pathway-/disease-relevant signatures provides a persuasive tool for understanding the functional relevance of gene alterations and gene network associations in multifactorial human diseases. Ovarian cancer is a highly complex heterogeneous malignancy in respect of tumor anatomy, tumor microenvironment including pro-/antitumor immunity and inflammation; still, it is generally treated as single disease. Thus, further approaches to investigate novel aspects of ovarian cancer pathogenesis aiming to provide a personalized strategy to clinical decision making are of high priority. Herein we assessed the contribution of the AID/APOBEC family and their associated genes given the remarkable ability of AID and APOBECs to edit DNA/RNA, and as such, providing tools for genetic and epigenetic alterations potentially leading to reprogramming of tumor cells, stroma and immune cells. Results We structured the study by three consecutive analytical modules, which include the multigene-based expression profiling in a cohort of patients with primary serous ovarian cancer using a self-created AID/APOBEC-associated gene signature, building up of multivariable survival models with high predictive accuracy and nomination of top-ranked candidate/target genes according to their prognostic impact, and systems biology-based reconstruction of the AID /APOBEC-driven disease-relevant mechanisms using transcriptomics data from ovarian cancer samples. We demonstrated that inclusion of the AID/APOBEC signature-based variables significantly improves the clinicopathological variables-based survival prognostication allowing significant patient stratification. Furthermore, several of the profiling-derived variables such as ID3, PTPRC/CD45, AID, APOBEC3G, and ID2 exceed the prognostic impact of some clinicopathological variables. We next extended the signature-/modeling- based knowledge by extracting top genes co-regulated with target molecules in ovarian cancer tissues and dissected potential networks/pathways/regulators contributing to pathomechanisms. We thereby revealed that the AID/APOBEC- related network in ovarian cancer is particularly associated with remodeling/fibrotic pathways, altered immune response, and autoimmune disorders with inflammatory background. Conclusions The herein study is, to our knowledge, the first one linking expression of entire AID/APOBECs and interacting genes with clinical outcome with respect to survival of cancer patients. Overall, data propose a novel AID/APOBEC-derived survival model for patient risk assessment and reconstitute mapping to molecular pathways. The established study algorithm can be applied further for any biologically relevant signature and any type of diseased tissue

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Parenting Stress Index and specific language impairment

Ziel der vorliegenden Studie ist eine differenzierte Erfassung des Stresserlebens bei Müttern von Kindern mit einer Sprachentwicklungsstörung anhand eines standardisierten Fragebogens. 63 Mütter sprachentwicklungsgestörter Kinder im Alter von 3;0 bis 6;5 Jahren wurden an der Klinischen Abteilung Phoniatrie-Logopädie der Wiener Universitätsklinik für Hals-, Nasen- und Ohrenkrankheiten konsekutiv rekrutiert. Das Stresserleben der Mütter wurde anhand des „Parenting Stress Index – PSI“ von Abidin (1995) erfasst und die Ergebnisse wurden mit den Werten jener Mütter einer nach Geschlecht und Alter parallelisierten Kontrollgruppe verglichen. Es zeigen sich signifikante Mittelwertsunterschiede zwischen den Müttern der klinischen Gruppe und jenen der Kontrollgruppe, in fast allen Skalen des PSI erweisen sich die Stress-Scores der Mütter sprachentwicklungsgestörter Kinder höher als jene der Mütter der Kontrollgruppe. 68% der Mütter der klinischen Stichprobe sind einem überdurchschnittlichen Stresserleben ausgesetzt, während nur 1,5% der Mütter sprachlich unauffälliger Kinder eine über dem Normbereich liegende Stressbelastung aufweisen. Es zeigt sich, dass die Erfassung des Ausmaßes der elterlichen Belastung und die Identifizierung einzelner Stressoren bei Müttern sprachentwicklungsgestörter Kinder eine wichtige Aufgabe darstellen. Für eine erfolgreiche Intervention bei Kindern mit einer Sprachentwicklungsstörung sollten auch die Mütter unbedingt vermehrt betreut und unterstützt werden.(DIPF/Orig.)The aim of the present study was to get a differentiated view of stress experience of mothers of children with a specific language impairment with a standardised questionnaire. Our sample consisted of 63 mothers of language impaired children between 3;0 and 6;5 years consecutively recruited at the University-ENT clinic of Vienna. Parenting stress was assessed by the “Parenting Stress Index” of Abidin (1995) and the results were compaired to mothers of a control group matched by sex and age of the children. The results showed significant mean differences between mothers of the clinical and the control group. In nearly all subscales mothers of language impaired children have higher stress scores than mothers of the control group. 68% of mothers of the clinical group are exposed to above-average stress levels whereas only 1,5% of mothers of children with normal language development show above-average parenting stress. For a successful intervention on children with a specific language impairment it seems to be very important to identify parental stressors and to treat and support parents too.(DIPF/Orig.

Employees' Participation in Enterprises and Satisfaction with Work 2005

The main aim of this survey was to gather further information on the fact that employee-involvement positively influences the working-satisfaction of the employees, which not at least increases the productivity. Employee-involvement means that employees are freer in their actions which gives them certain control over their own work and the feeling that they contribute to the success of the enterprise. The goal is to investigate the interrelation of the dimensions of workers participation in the enterprise and working-satisfaction. From the different kinds of employee-involvement the workers participation in the enterprise was specifically chosen. The analysis was led by the question on the aspects of the elected works council which effect the dimension of the employees satisfaction with work

Genomic imprinting and genetic effects on muscle traits in mice

BACKGROUND: Genomic imprinting refers to parent-of-origin dependent gene expression caused by differential DNA methylation of the paternally and maternally derived alleles. Imprinting is increasingly recognized as an important source of variation in complex traits, however, its role in explaining variation in muscle and physiological traits, especially those of commercial value, is largely unknown compared with genetic effects. RESULTS: We investigated both genetic and genomic imprinting effects on key muscle traits in mice from the Berlin Muscle Mouse population, a key model system to study muscle traits. Using a genome scan, we first identified loci with either imprinting or genetic effects on phenotypic variation. Next, we established the proportion of phenotypic variation explained by additive, dominance and imprinted QTL and characterized the patterns of effects. In total, we identified nine QTL, two of which show large imprinting effects on glycogen content and potential, and body weight. Surprisingly, all imprinting patterns were of the bipolar type, in which the two heterozygotes are different from each other but the homozygotes are not. Most QTL had pleiotropic effects and explained up to 40% of phenotypic variance, with individual imprinted loci accounting for 4-5% of variation alone. CONCLUSION: Surprisingly, variation in glycogen content and potential was only modulated by imprinting effects. Further, in contrast to general assumptions, our results show that genomic imprinting can impact physiological traits measured at adult stages and that the expression does not have to follow the patterns of paternal or maternal expression commonly ascribed to imprinting effects

Genomic imprinting and genetic effects on muscle traits in mice

Abstract Background Genomic imprinting refers to parent-of-origin dependent gene expression caused by differential DNA methylation of the paternally and maternally derived alleles. Imprinting is increasingly recognized as an important source of variation in complex traits, however, its role in explaining variation in muscle and physiological traits, especially those of commercial value, is largely unknown compared with genetic effects. Results We investigated both genetic and genomic imprinting effects on key muscle traits in mice from the Berlin Muscle Mouse population, a key model system to study muscle traits. Using a genome scan, we first identified loci with either imprinting or genetic effects on phenotypic variation. Next, we established the proportion of phenotypic variation explained by additive, dominance and imprinted QTL and characterized the patterns of effects. In total, we identified nine QTL, two of which show large imprinting effects on glycogen content and potential, and body weight. Surprisingly, all imprinting patterns were of the bipolar type, in which the two heterozygotes are different from each other but the homozygotes are not. Most QTL had pleiotropic effects and explained up to 40% of phenotypic variance, with individual imprinted loci accounting for 4-5% of variation alone. Conclusion Surprisingly, variation in glycogen content and potential was only modulated by imprinting effects. Further, in contrast to general assumptions, our results show that genomic imprinting can impact physiological traits measured at adult stages and that the expression does not have to follow the patterns of paternal or maternal expression commonly ascribed to imprinting effects.</p