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227 Publications visible to you, out of a total of 227
WHO grade-specific comparative genomic hybridization pattern of astrocytoma - a meta-analysis
Genetical Statistics and Systems Biology

Abstract (Expand)

To detect novel genetic alterations, many astrocytomas have been investigated by comparative genomic hybridization (CGH). To identify aberration profiles characteristic of World Health Organization … (WHO) grade I, II, III, and IV astrocytoma, we performed a meta-analysis of detailed genome wide CGH data of all 467 cases published so far. After expansion of all given aberrations to the maximum of 850 GTG-band resolution, the frequencies of genetic imbalances were calculated for each chromosomal band, separately for all four WHO grades. Low-grade astrocytoma has already demonstrated one characteristic of glioblastoma multiforme, gain of chromosome 7 with a hot spot at 7q32, but without loss of chromosome 10. In anaplastic astrocytoma, a more complex aberration pattern emerges from diffuse genetic imbalances. Gains of 7q32-q36 and 7p12 become the most frequent aberrations at chromosome 7. In glioblastoma multiforme, coarse aberrations like +7, -9p, -10, and -13 represent the most frequent aberrations as a characteristic pattern. In contrast to lower tumor grades, glioblastoma multiforme demonstrates +7p12 as the most frequently affected band on chromosome 7. To quantify the gradual transition from WHO grade II-IV astrocytoma, we calculated the relative increase and decrease in frequency for each detected aberration of the tumor genome. The most pronounced and diverse changes of genetic material occur at the virtual transition from low-grade to anaplastic astrocytoma. Further transition to glioblastoma multiforme is characterized by gain of 1p, chromosome 7, and loss of chromosome 10. Summing up, the expansion of the CGH results to the 850 GTG-band resolution enabled a meta-analysis to visualize WHO grade-specific aberration profiles in astrocytoma.

Authors: Heidrun Holland, Thomas Koschny, Peter Ahnert, Jürgen Meixensberger, Ronald Koschny

Date Published: 1st Oct 2010

Publication Type: Journal article

Genetic regulation of serum phytosterol levels and risk of coronary artery disease
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnPhytosterols are plant-derived sterols that are taken up from food and can serve as biomarkers of cholesterol uptake. Serum levels are under tight genetic control. We … used a genomic approach to study the molecular regulation of serum phytosterol levels and potential links to coronary artery disease (CAD).\backslashr\backslashnMETHODS AND RESULTS\backslashr\backslashnA genome-wide association study for serum phytosterols (campesterol, sitosterol, brassicasterol) was conducted in a population-based sample from KORA (Cooperative Research in the Region of Augsburg) (n=1495) with subsequent replication in 2 additional samples (n=1157 and n=1760). Replicated single-nucleotide polymorphisms (SNPs) were tested for association with premature CAD in a metaanalysis of 11 different samples comprising 13 764 CAD cases and 13 630 healthy controls. Genetic variants in the ATP-binding hemitransporter ABCG8 and at the blood group ABO locus were significantly associated with serum phytosterols. Effects in ABCG8 were independently related to SNPs rs4245791 and rs41360247 (combined P=1.6 x 10(-50) and 6.2 x 10(-25), respectively; n=4412). Serum campesterol was elevated 12% for each rs4245791 T-allele. The same allele was associated with 40% decreased hepatic ABCG8 mRNA expression (P=0.009). Effects at the ABO locus were related to SNP rs657152 (combined P=9.4x10(-13)). Alleles of ABCG8 and ABO associated with elevated phytosterol levels displayed significant associations with increased CAD risk (rs4245791 odds ratio, 1.10; 95% CI, 1.06 to 1.14; P=2.2 x 10(-6); rs657152 odds ratio, 1.13; 95% CI, 1.07 to 1.19; P=9.4 x 10(-6)), whereas alleles at ABCG8 associated with reduced phytosterol levels were associated with reduced CAD risk (rs41360247 odds ratio, 0.84; 95% CI, 0.78 to 0.91; P=1.3 x 10(-5)).\backslashr\backslashnCONCLUSION\backslashr\backslashnCommon variants in ABCG8 and ABO are strongly associated with serum phytosterol levels and show concordant and previously unknown associations with CAD.

Authors: Daniel Teupser, Ronny Baber, Uta Ceglarek, Markus Scholz, Thomas Illig, Christian Gieger, Lesca Miriam Holdt, Alexander Leichtle, Karin H. Greiser, Dominik Huster, Patrick Linsel-Nitschke, Arne Schäfer, Peter S. Braund, Laurence Tiret, Klaus Stark, Dorette Raaz-Schrauder, Georg M. Fiedler, Wolfgang Wilfert, Frank Beutner, Stephan Gielen, Anika Grosshennig, Inke R. König, Peter Lichtner, Iris M. Heid, Alexander Kluttig, Nour E El Mokhtari, Diana Rubin, Arif B. Ekici, André Reis, Christoph D. Garlichs, Alistair S. Hall, Gert Matthes, Christian Wittekind, Christian Hengstenberg, Francois Cambien, Stefan Schreiber, Karl Werdan, Thomas Meitinger, Markus Loeffler, Nilesh J. Samani, Jeanette Erdmann, Heinz-Erich Wichmann, Heribert Schunkert, Joachim Thiery

Date Published: 1st Aug 2010

Publication Type: Journal article

Transapical aortic valve implantation in 100 consecutive patients: comparison to propensity-matched conventional aortic valve replacement
Genetical Statistics and Systems Biology

Abstract (Expand)

AIMS\backslashr\backslashnTo evaluate the outcome of transapical aortic valve implantation (TA-AVI) in comparison to conventional surgery.\backslashr\backslashnMETHODS AND RESULTS\backslashr\backslashnOne … hundred consecutive high-risk patients with symptomatic aortic valve stenosis received TA-AVI using the Edwards SAPIEN pericardial xenograft between February 2006 and January 2008. Patient age was 82.7 +/- 5 years, 77 were females, logistic EuroSCORE predicted risk of mortality was 29.4 +/- 13% and Society Thoracic Surgeons score risk for mortality was 15.2 +/- 8.3%. Propensity score analysis was used to identify a control group of patients that underwent conventional aortic valve replacement (C-AVR). Transapical aortic valve implantation was performed successfully in 97 patients, whereas three patients required early conversion. There were no new onset neurological events in the TA-AVI group and early extubation was performed in 82 patients. Echocardiography revealed good valve function with low transvalvular gradients in all patients. Thirty-day survival was 90 +/- 3 vs. 85 +/- 4% for TA-AVI vs. C-AVR, and 1-year survival was 73 +/- 4 vs. 69 +/- 5% (P = 0.55).\backslashr\backslashnCONCLUSION\backslashr\backslashnTransapical aortic valve implantation is a safe, minimally invasive, and off-pump technique to treat high-risk patients with aortic stenosis. Results of the initial 100 patients are good and compare favourably to conventional surgery.

Authors: Thomas Walther, Gerhard Schuler, Michael Andrew Borger, Joerg Kempfert, Jörg Seeburger, Yvonne Rückert, Joerg Ender, Axel Linke, Markus Scholz, Volkmar Falk, Friedrich Wilhelm Mohr

Date Published: 1st Jun 2010

Publication Type: Journal article

Bortezomib sensitizes primary human esthesioneuroblastoma cells to TRAIL-induced apoptosis
Genetical Statistics and Systems Biology

Abstract (Expand)

TNF-related apoptosis-inducing ligand (TRAIL), a promising novel anti-cancer cytokine of the TNF superfamily, and Bortezomib, the first-in-class clinically used proteasome inhibitor, alone or in … combination have been shown to efficiently kill numerous tumor cell lines. However, data concerning primary human tumor cells are very rare. Using primary esthesioneuroblastoma cells we analyzed the anti-tumor potential and the mechanism employed by Bortezomib in combination with TRAIL for the treatment of this rare but aggressive tumor. Expression of components of the TRAIL pathway was analyzed in tumor specimens and isolated primary tumor cells at the protein level. Cells were treated with TRAIL, Bortezomib, and a combination thereof, and apoptosis induction was quantified. Clonogenicity assays were performed to elucidate the long-term effect of this treatment. Despite expressing all components of the TRAIL pathway, freshly isolated primary esthesioneuroblastoma cells were completely resistant to TRAIL-induced apoptosis. They could, however, be very efficiently sensitized by subtoxic doses of Bortezomib. The influence of Bortezomib on the TRAIL pathway was analyzed and showed upregulation of TRAIL death receptor expression, enhancement of the TRAIL death-inducing signaling complex (DISC), and downregulation of anti-apoptotic proteins of the TRAIL pathway. Of clinical relevance, TRAIL-resistant primary tumor cells could be repeatedly sensitized by Bortezomib, providing the basis for repeated clinical application schedules. This is the first report on the highly synergistic induction of apoptosis in primary esthesioneuroblastoma cells by Bortezomib and TRAIL. This combination, therefore, represents a promising novel therapeutic option for esthesioneuroblastoma.

Authors: Ronald Koschny, Heidrun Holland, Jaromir Sykora, Hande Erdal, Wolfgang Krupp, Manfred Bauer, Ulrike Bockmuehl, Peter Ahnert, Jürgen Meixensberger, Wolfgang Stremmel, Henning Walczak, Tom M. Ganten

Date Published: 1st Apr 2010

Publication Type: Journal article

ANRIL expression is associated with atherosclerosis risk at chromosome 9p21
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVE\backslashr\backslashnWe tested the hypothesis that expression of transcripts adjacent to the chromosome 9p21 (Chr9p21) locus of coronary artery disease was affected by the genotype at this … locus and associated with atherosclerosis risk.\backslashr\backslashnMETHODS AND RESULTS\backslashr\backslashnWe replicated the locus for coronary artery disease (P=0.007; OR=1.28) and other manifestations of atherosclerosis such as carotid plaque (P=0.003; OR=1.31) in the Leipzig Heart Study, a cohort of 1134 patients with varying degree of angiographically assessed coronary artery disease. Expression analysis in peripheral blood mononuclear cells (n=1098) revealed that transcripts EU741058 and NR_003529 of antisense noncoding RNA in the INK4 locus (ANRIL) were significantly increased in carriers of the risk haplotype (P=2.1x10(-12) and P=1.6x10(-5), respectively). In contrast, transcript DQ485454 remained unaffected, suggesting differential expression of ANRIL transcripts at Chr9p21. Results were replicated in whole blood (n=769) and atherosclerotic plaque tissue (n=41). Moreover, expression of ANRIL transcripts was directly correlated with severity of atherosclerosis (EU741058 and NR_003529; P=0.02 and P=0.001, respectively). No consistent association of Chr9p21 or atherosclerosis was found with expression of other genes such as CDKN2A, CDKN2B, C9orf53, and MTAP.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnOur data provide robust evidence for an association of ANRIL but not CDKN2A, CDKN2B, C9orf53, and MTAP, with atherosclerosis and Chr9p21 genotype in a large cohort.

Authors: Lesca Miriam Holdt, Frank Beutner, Markus Scholz, Stephan Gielen, Gábor Gäbel, Hendrik Bergert, Gerhard Schuler, Joachim Thiery, Daniel Teupser

Date Published: 1st Mar 2010

Publication Type: Journal article

Transplantation of placenta-derived mesenchymal stromal cells upon experimental stroke in rats
Genetical Statistics and Systems Biology

Abstract (Expand)

The beneficial effects of bone marrow-derived mesenchymal stromal cell (MSC) administration following experimental stroke have already been described. Despite several promising characteristics, … placenta-derived MSC have not been used in models of focal ischemia. The aim of the current study is to investigate the impact of intravenously transplanted placenta-derived MSC on post-stroke recovery. Permanent occlusion of the middle cerebral artery was induced in spontaneously hypertensive rats. MSC were obtained from the human maternal or fetal placenta and intravenously administered after 24 h (single transplantation) or after 8 h and 24 h (dual transplantation). Sensorimotor deficits were quantified for 60 days using the beam walk test and the modified Neurological Severity Score system. Infarct volume was determined in vivo by means of magnetic resonance imaging on days 1, 8, 29 and 60. Astroglial reactivity was semiquantitatively ascertained within a small and a broad region adjacent to the lesion border. The double infusion of placental MSC was superior to single transplantation in the functional tests. However, a significant difference to the control group in all outcome parameters was observed only for maternally derived MSC. These findings suggest that placental tissue constitutes a promising source for experimental stroke therapies. The beneficial effects of bone marrow-derived mesenchymal stromal cell (MSC) administration following experimental stroke have already been described. Despite several promising characteristics, placenta-derived MSC have not been used in models of focal ischemia. The aim of the current study is to investigate the impact of intravenously transplanted placenta-derived MSC on post-stroke recovery. Permanent occlusion of the middle cerebral artery was induced in spontaneously hypertensive rats. MSC were obtained from the human maternal or fetal placenta and intravenously administered after 24 h (single transplantation) or after 8 h and 24 h (dual transplantation). Sensorimotor deficits were quantified for 60 days using the beam walk test and the modified Neurological Severity Score system. Infarct volume was determined in vivo by means of magnetic resonance imaging on days 1, 8, 29 and 60. Astroglial reactivity was semiquantitatively ascertained within a small and a broad region adjacent to the lesion border. The double infusion of placental MSC was superior to single transplantation in the functional tests. However, a significant difference to the control group in all outcome parameters was observed only for maternally derived MSC. These findings suggest that placental tissue constitutes a promising source for experimental stroke therapies.

Authors: Alexander Kranz, Daniel-Christoph Wagner, Manja Kamprad, Markus Scholz, Uwe Richard Schmidt, Franziska Nitzsche, Zami Aberman, Frank Emmrich, Ute-Maria Riegelsberger, Johannes Boltze

Date Published: 1st Feb 2010

Publication Type: Journal article

Comparison of estimators for measures of linkage disequilibrium
Genetical Statistics and Systems Biology

Abstract (Expand)

The measurement of biallelic pair-wise association called linkage disequilibrium (LD) is an important issue in order to understand the genomic architecture. A plethora of measures of association in two … by two tables have been proposed in the literature. Beside the problem of choosing an appropriate measure, the problem of their estimation has been neglected in the literature. It needs to be emphasized that the definition of a measure and the choice of an estimator function for it are conceptually unrelated tasks. In this paper, we compare the performance of various estimators for the three popular LD measures D’, r and Y in a simulation study for small to moderate samples sizes (N\textless=500). The usual frequency-plug-in estimators can lead to unreliable or undefined estimates. Estimators based on the computationally expensive volume measures have been proposed recently as a remedy to this well-known problem. We confirm that volume estimators have better expected mean square error than the naive plug-in estimators. But they are outperformed by estimators plugging-in easy to calculate non-informative Bayesian probability estimates into the theoretical formulae for the measures. Fully Bayesian estimators with non-informative Dirichlet priors have comparable accuracy but are computationally more expensive. We recommend the use of non-informative Bayesian plug-in estimators based on Jeffreys’ prior, in particular when dealing with SNP array data where the occurrence of small table entries and table margins is likely.

Authors: Markus Scholz, Dirk Hasenclever

Date Published: 2010

Publication Type: Journal article

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