University of Düsseldorf

About: University of Düsseldorf is a education organization based out in Düsseldorf, Germany. It is known for research contribution in the topics: Population & Transplantation. The organization has 25225 authors who have published 49155 publications receiving 1946434 citations.

A prospective study of cumulative job stress in relation to mental health

Abstract: This study tests associations between psychosocial stress at work measured by the effort-reward imbalance model in a dynamic perspective, and multiple indicators of poor mental health, in a prospective design 1986 male and female employees from four Belgian enterprises were followed-up over one year within the framework of the Somstress study Based on two consecutive measurements, an index of cumulative job stress was constructed and its associations with five indicators of mental health were studied, excluding caseness at entry (for depression, anxiety, somatisation, chronic fatigue and psychotropic drug consumption respectively) Taking into account the longitudinal design, four categories of job stress are defined: 1) employees free from stress at both measures, 2) job stress present at first measure but not at the second one, 3) recent onset of job stress as evidenced by second measure 4) workers exposed to stress at both measures Multivariate logistic regression with appropriate adjustments was applied In bivariate analysis, a clear graded association of cumulative job stress with all five mental health indicators is observed, both in men and women In multivariate logistic regression analysis, recent onset of stress is strongly associated with poor mental health among men (odds ratios ranging from 18 to 46), while cumulative stress shows strongest effects on mental health in women (odds ratios ranging from 14 to 71) Cumulative experience and recent onset of job stress in terms of high effort spent and low reward received is associated with elevated risk of all five indicators of poor mental health at follow-up in a large cohort of employees

Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus.

Abstract: High levels of serum IgE are considered markers of parasite and helminth exposure. In addition, they are associated with allergic disorders, play a key role in anti-tumoral defence, and are crucial mediators of autoimmune diseases. Total IgE is a strongly heritable trait. In a genome-wide association study (GWAS), we tested 353,569 SNPs for association with serum IgE levels in 1,530 individuals from the population-based KORA S3/F3 study. Replication was performed in four independent population-based study samples (total n = 9,769 individuals). Functional variants in the gene encoding the alpha chain of the high affinity receptor for IgE (FCER1A) on chromosome 1q23 (rs2251746 and rs2427837) were strongly associated with total IgE levels in all cohorts with P values of 1.85 x 10(-20) and 7.08 x 10(-19) in a combined analysis, and in a post-hoc analysis showed additional associations with allergic sensitization (P = 7.78 x 10(-4) and P = 1.95 x 10(-3)). The "top" SNP significantly influenced the cell surface expression of FCER1A on basophils, and genome-wide expression profiles indicated an interesting novel regulatory mechanism of FCER1A expression via GATA-2. Polymorphisms within the RAD50 gene on chromosome 5q31 were consistently associated with IgE levels (P values 6.28 x 10(-7)-4.46 x 10(-8)) and increased the risk for atopic eczema and asthma. Furthermore, STAT6 was confirmed as susceptibility locus modulating IgE levels. In this first GWAS on total IgE FCER1A was identified and replicated as new susceptibility locus at which common genetic variation influences serum IgE levels. In addition, variants within the RAD50 gene might represent additional factors within cytokine gene cluster on chromosome 5q31, emphasizing the need for further investigations in this intriguing region. Our data furthermore confirm association of STAT6 variation with serum IgE levels.

Vitamins E and C are safe across a broad range of intakes

Abstract: Apoptosis, a fundamental process essential for normal tissue homeostasis and development, is closely associated with the activation of a class of aspartate-specific cysteinedependent proteases, called caspases, that lead to the demise of the cell via limited proteolysis of a multitude of cellular substrates [1, 2]. Caspases are expressed as inactive zymogens that become activated upon cleavage by other caspases in a so-called caspase activation cascade, or by mere oligomerization instigated by the formation of large multi-protein complexes such as the death-inducing signaling complex (DISC) or the apoptosome [3, 4]. Whereas DISC formation occurs via the so-called extrinsic death pathway that is instigated by activation of members of the death receptor family such as CD95, tumor necrosis factor receptor (TNF-R) or the receptors of the TNF-Rrelated apoptosis-inducing ligand (TRAIL), the apoptosome is formed following activation of mitochondria and is hence termed the intrinsic or mitochondrial death pathway. Based on their order in cell death pathways, caspases can be divided into initiator (caspase-2, -8, -9, and -10) and effector (caspase-3, -6, and -7) caspases. Among them, caspase-3, a member of the latter group, is absolutely crucial for apoptosis induction, as this enzyme is not only activated downstream of both the extrinsic and intrinsic death pathway, it is also responsible for the cleavage of the majority of substrates known so far [1, 5]. More importantly, with the proteolysis of discrete substrates, caspase-3 evokes some of the typical morphological and biochemical alterations associated with apoptosis. For instance, whereas the caspase-3-mediated cleavages of a-fodrin, gelsolin, rho-associated kinase-1 (ROCK-1) and p21-activated kinase 2 (PAK2) contribute to membrane blebbing, cleavage of the inhibitor of the caspase-activated DNase (ICAD) leads to the typical DNA fragmentation pattern observed in apoptosis [1]. Furthermore, with the cleavagemediated activation of the calcium-independent phospholipase A2 and subsequent production of the chemotactic phospholipid lysophosphatidylcholine, caspase-3 appears to be also responsible for the generation of so-called ‘‘eatme’’ signals that induce migration of phagocytes to the site of apoptotic cell death [6]. Thus, caspase-3 not only instigates and pursues the demise of a cell, but, in addition, makes sure that the corpse is properly disposed, a function crucial for avoiding inflammatory processes. Hence, determination of the processing and activation of caspase-3 are common means to assess apoptotic signal transduction pathways in numerous cell lines of varying origin. Curiously, several reports still claim the presence of caspase-3 in the breast carcinoma cell line MCF-7 in which this enzyme is supposed to contribute to apoptosis signaling [7–15]. This was not only demonstrated indirectly via fluorometric assay systems measuring caspase-3-like activities—that might be also elicited by the closely related caspase-7—but by Western blotting analyses demonstrating directly the presence of this protease in MCF-7 cells. However, in addition to the lack of caspase-10 [16], an initiator caspase in the extrinsic death pathway, MCF-7 cells do also not express caspase-3 [17]. Ten years ago, we demonstrated unambiguously that the lack of caspase-3 in these cells is caused by a 47-base pair deletion within exon 3 of the CASP3 gene resulting in the skipping of this exon during premRNA splicing and introduction of a premature stop codon at position 42 that completely abrogates translation of the CASP-3 mRNA [17]. Although caspase-3-deficient MCF-7 R. U. Janicke (&) Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, University of Dusseldorf, Universitatsstrasse 1, 40225 Dusseldorf, Germany e-mail: Janicke@uni-duesseldorf.de

MCF-7 breast carcinoma cells do not express caspase-3

Abstract: Apoptosis, a fundamental process essential for normal tissue homeostasis and development, is closely associated with the activation of a class of aspartate-specific cysteinedependent proteases, called caspases, that lead to the demise of the cell via limited proteolysis of a multitude of cellular substrates [1, 2]. Caspases are expressed as inactive zymogens that become activated upon cleavage by other caspases in a so-called caspase activation cascade, or by mere oligomerization instigated by the formation of large multi-protein complexes such as the death-inducing signaling complex (DISC) or the apoptosome [3, 4]. Whereas DISC formation occurs via the so-called extrinsic death pathway that is instigated by activation of members of the death receptor family such as CD95, tumor necrosis factor receptor (TNF-R) or the receptors of the TNF-Rrelated apoptosis-inducing ligand (TRAIL), the apoptosome is formed following activation of mitochondria and is hence termed the intrinsic or mitochondrial death pathway. Based on their order in cell death pathways, caspases can be divided into initiator (caspase-2, -8, -9, and -10) and effector (caspase-3, -6, and -7) caspases. Among them, caspase-3, a member of the latter group, is absolutely crucial for apoptosis induction, as this enzyme is not only activated downstream of both the extrinsic and intrinsic death pathway, it is also responsible for the cleavage of the majority of substrates known so far [1, 5]. More importantly, with the proteolysis of discrete substrates, caspase-3 evokes some of the typical morphological and biochemical alterations associated with apoptosis. For instance, whereas the caspase-3-mediated cleavages of a-fodrin, gelsolin, rho-associated kinase-1 (ROCK-1) and p21-activated kinase 2 (PAK2) contribute to membrane blebbing, cleavage of the inhibitor of the caspase-activated DNase (ICAD) leads to the typical DNA fragmentation pattern observed in apoptosis [1]. Furthermore, with the cleavagemediated activation of the calcium-independent phospholipase A2 and subsequent production of the chemotactic phospholipid lysophosphatidylcholine, caspase-3 appears to be also responsible for the generation of so-called ‘‘eatme’’ signals that induce migration of phagocytes to the site of apoptotic cell death [6]. Thus, caspase-3 not only instigates and pursues the demise of a cell, but, in addition, makes sure that the corpse is properly disposed, a function crucial for avoiding inflammatory processes. Hence, determination of the processing and activation of caspase-3 are common means to assess apoptotic signal transduction pathways in numerous cell lines of varying origin. Curiously, several reports still claim the presence of caspase-3 in the breast carcinoma cell line MCF-7 in which this enzyme is supposed to contribute to apoptosis signaling [7–15]. This was not only demonstrated indirectly via fluorometric assay systems measuring caspase-3-like activities—that might be also elicited by the closely related caspase-7—but by Western blotting analyses demonstrating directly the presence of this protease in MCF-7 cells. However, in addition to the lack of caspase-10 [16], an initiator caspase in the extrinsic death pathway, MCF-7 cells do also not express caspase-3 [17]. Ten years ago, we demonstrated unambiguously that the lack of caspase-3 in these cells is caused by a 47-base pair deletion within exon 3 of the CASP3 gene resulting in the skipping of this exon during premRNA splicing and introduction of a premature stop codon at position 42 that completely abrogates translation of the CASP-3 mRNA [17]. Although caspase-3-deficient MCF-7 R. U. Janicke (&) Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, University of Dusseldorf, Universitatsstrasse 1, 40225 Dusseldorf, Germany e-mail: Janicke@uni-duesseldorf.de