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Search Results: 1 - 10 of 193016 matches for " Thilo D?rk "
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TOPBP1 missense variant Arg309Cys and breast cancer in a German hospital-based case-control study
Magda A Blaut, Natalia V Bogdanova, Michael Bremer, Johann H Karstens, Peter Hillemanns, Thilo Drk
Journal of Negative Results in BioMedicine , 2010, DOI: 10.1186/1477-5751-9-9
Abstract: Only a small proportion of breast cancer cases can be attributed to mutations in high-penetrance genes such as BRCA1 or BRCA2, and much of the remaining cases are attributed to more common gene variants with lower penetrance [1,2]. As many of the hitherto known susceptibility factors have been implicated in the cellular responses to DNA double-strand breaks and replication stress, there is considerable interest in genetic variants of additional proteins involved in these pathways [2].TOPBP1 encodes a protein that shares homology to BRCA1, is aberrantly expressed in breast carcinomas and has a critical role in DNA damage and replication checkpoint pathways [3-7]. TOPBP1 encodes a 1522 amino acid BRCT domain protein that interacts with DNA topoisomerase IIβ and is involved in ATM/ATR-mediated DNA damage and replication checkpoint pathways [3-6]. Reduced or aberrantly localized TopBP1 expression has been observed in a significant proportion of breast cancer specimens [7]. Functional TOPBP1 variants therefore represent plausible candidate breast cancer susceptibility alleles. A recent sequencing and case-control association study has assessed the role of germ-line variants in Finnish breast and ovarian cancer patients [8]. The novel Arg309Cys substitution was observed at significantly higher frequency in 125 familial breast and/or ovarian cancer patients compared to 697 healthy controls (15.2% versus 7.0%; P = 0.002), and a 2.4-fold increase in risk was suggested [8]. We aimed to corroborate this finding in a hospital-based series of 1064 German breast cancer patients and 1014 population controls.Our German study population consisted of a hospital-based series of 1012 unselected breast cancer patients who were treated at the Department of Radiation Oncology at Hannover Medical School from 1996-1999 and an additional small series of 52 patients with bilateral breast cancer collected later from the same hospital. Median age at onset of breast cancer was 57 years in this p
Mutation analysis of the MDM4 gene in German breast cancer patients
Scarlett Reincke, Lina Govbakh, Bettina Wilhelm, Haiyan Jin, Natalia Bogdanova, Michael Bremer, Johann H Karstens, Thilo Drk
BMC Cancer , 2008, DOI: 10.1186/1471-2407-8-52
Abstract: We sequenced the whole MDM4 coding region and flanking untranslated regions in genomic DNA samples obtained from 40 German patients with familial breast cancer. Selected variants were subsequently screened by RFLP-based assays in an extended set of breast cancer cases and controls.Our resequencing study uncovered two MDM4 coding variants in 4/40 patients. Three patients carried a silent substitution at codon 74 that was linked with another rare variant in the 5'UTR. No association of this allele with breast cancer was found in a subsequent screening of 133 patients with bilateral breast cancer and 136 controls. The fourth patient was heterozygous for the missense substitution D153G which is located in a less conserved region of the MDM4 protein but may affect a predicted phosphorylation site. The D153G substitution only partially segregated with breast cancer in the family and was not identified on additional 680 chromosomes screened.This study did not reveal clearly pathogenic mutations although it uncovered two new unclassified variants at a low frequency. We conclude that there is no evidence for a major role of MDM4 coding variants in the inherited susceptibility towards breast cancer in German patients.As part of a genome surveillance network, the tumour suppressor protein p53 becomes stabilized after DNA damage and modulates intracellular responses such as cell cycle arrest, DNA repair, senescence or apoptosis [1-3]. Multiple mechanisms regulate the activity of p53 at the posttranscriptional level [4,5]. One important antagonist, MDM2, is essential for ubiquitylation and subsequent degradation of p53 to maintain it at low levels in unstressed cells [6]. An MDM2-related protein, MDM4, has more recently emerged as another p53-interacting protein with a central role in the DNA damage response [7-9].MDM4, also known as MDMX, is a 490 amino acid protein that is structurally related to MDM2 and binds to both, p53 and MDM2 [8]. MDM4 is regarded a negative regulator o
Mutation Analysis of BRCA1, BRCA2, PALB2 and BRD7 in a Hospital-Based Series of German Patients with Triple-Negative Breast Cancer
Franziska Pern, Natalia Bogdanova, Peter Schürmann, Min Lin, Aysun Ay, Florian L?nger, Peter Hillemanns, Hans Christiansen, Tjoung-Won Park-Simon, Thilo Drk
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0047993
Abstract: Triple-negative breast cancer (TNBC) is an aggressive form of breast carcinoma with a poor prognosis. Recent evidence suggests that some patients with TNBC harbour germ-line mutations in DNA repair genes which may render their tumours susceptible to novel therapies such as treatment with PARP inhibitors. In the present study, we have investigated a hospital-based series of 40 German patients with TNBC for the presence of germ-line mutations in BRCA1, BRCA2, PALB2, and BRD7 genes. Microfluidic array PCR and next-generation sequencing was used for BRCA1 and BRCA2 analysis while conventional high-resolution melting and Sanger sequencing was applied to study the coding regions of PALB2 and BRD7, respectively. Truncating mutations in BRCA1 were found in six patients, and truncating mutations in BRCA2 and PALB2 were detected in one patient each, whereas no truncating mutation was identified in BRD7. One patient was a double heterozygote for the PALB2 mutation, c.758insT, and a BRCA1 mutation, c.927delA. Our results confirm in a hospital-based setting that a substantial proportion of German TNBC patients (17.5%) harbour germ-line mutations in genes involved in homology-directed DNA repair, with a preponderance of BRCA1 mutations. Triple-negative breast cancer should be considered as an additional criterion for future genetic counselling and diagnostic sequencing.
Prostate Cancer Risk Is not Altered by TP53AIP1 Germline Mutations in a German Case-Control Series
Manuel Luedeke, Irina Coinac, Carmen M. Linnert, Natalia Bogdanova, Antje E. Rinckleb, Mark Schrader, Walther Vogel, Josef Hoegel, Andreas Meyer, Thilo Drk, Christiane Maier
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034128
Abstract: Prostate cancer susceptibility has previously been associated with truncating germline variants in the gene TP53AIP1 (tumor protein p53 regulated apoptosis inducing protein 1). For two apparently recurrent mutations (p.Q22fs and p.S32X) a remarkable OR of 5.1 was reported for prostate cancer risk. Since these findings have not been validated so far, we genotyped p.Q22fs and p.S32X in two German series with a total of 1,207 prostate cancer cases and 1,495 controls. The truncating variants were not significantly associated with prostate cancer in none of the two cohorts, nor in the combined analysis [odds ratio (OR) = 1.16; 95% confidence interval (CI 95%) = 0.62–2.15; p = 0.66]. Carriers showed no significant differences in family history of prostate cancer, age at diagnosis, Gleason score or PSA at diagnosis when compared to non-carrier prostate cancer cases. The large sample size of the combined cohort rejects a high-risk effect greater than 2.2 and indicates a limited role of TP53AIP1 in prostate cancer predisposition.
Combined effects of single nucleotide polymorphisms TP53 R72P and MDM2 SNP309, and p53 expression on survival of breast cancer patients
Marjanka K Schmidt, Johanna Tommiska, Annegien Broeks, Flora E van Leeuwen, Laura J Van't Veer, Paul DP Pharoah, Douglas F Easton, Mitul Shah, Manjeet Humphreys, Thilo Drk, Scarlett A Reincke, Rainer Fagerholm, Carl Blomqvist, Heli Nevanlinna
Breast Cancer Research , 2009, DOI: 10.1186/bcr2460
Abstract: We pooled data from four breast cancer cohorts within the Breast Cancer Association Consortium for which both TP53 R72P and MDM2 SNP309 were genotyped and follow-up was available (n = 3,749). Overall and breast cancer-specific survival analyses were performed using Kaplan-Meier analysis and multivariate Cox's proportional hazards regression models.Survival of patients did not differ by carriership of either germ-line variant, R72P (215G>C) or SNP309 (-410G>T) alone. Immunohistochemical p53 staining of the tumor was available for two cohorts (n = 1,109 patients). Survival was worse in patients with p53-positive tumors (n = 301) compared to patients with p53-negative tumors (n = 808); breast cancer-specific survival: HR 1.6 (95% CI 1.2 to 2.1), P = 0.001. Within the patient group with p53-negative tumors, TP53 rare homozygous (CC) carriers had a worse survival than G-allele (GG/GC) carriers; actuarial breast cancer-specific survival 71% versus 80%, P = 0.07; HR 1.8 (1.1 to 3.1), P = 0.03. We also found a differential effect of combinations of the two germ-line variants on overall survival; homozygous carriers of the G-allele in MDM2 had worse survival only within the group of TP53 C-allele carriers; actuarial overall survival (GG versus TT/TG) 64% versus 75%, P = 0.001; HR (GG versus TT) 1.5 (1.1 to 2.0), P = 0.01. We found no evidence for a differential effect of MDM2 SNP309 by p53 protein expression on survival.The TP53 R72P variant may be an independent predictor for survival of patients with p53-negative tumors. The combined effect of TP53 R72P and MDM2 SNP309 on survival is in line with our a priori biologically-supported hypothesis, that is, the role of enhanced DNA repair function of the TP53 Pro-variant, combined with increased expression of the Mdm2 protein, and thus overall attenuation of the p53 pathway in the tumor cells.Breast cancer outcome may be affected by germ-line variants in genes that play a role in DNA damage control and repair such as TP53 (R72P
Mutation Analysis of the ERCC4/FANCQ Gene in Hereditary Breast Cancer
Sandra Kohlhase, Natalia V. Bogdanova, Peter Schürmann, Marina Bermisheva, Elza Khusnutdinova, Natalia Antonenkova, Tjoung-Won Park-Simon, Peter Hillemanns, Andreas Meyer, Hans Christiansen, Detlev Schindler, Thilo Drk
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0085334
Abstract: The ERCC4 protein forms a structure-specific endonuclease involved in the DNA damage response. Different cancer syndromes such as a subtype of Xeroderma pigmentosum, XPF, and recently a subtype of Fanconi Anemia, FA-Q, have been attributed to biallelic ERCC4 gene mutations. To investigate whether monoallelic ERCC4 gene defects play some role in the inherited component of breast cancer susceptibility, we sequenced the whole ERCC4 coding region and flanking untranslated portions in a series of 101 Byelorussian and German breast cancer patients selected for familial disease (set 1, n = 63) or for the presence of the rs1800067 risk haplotype (set 2, n = 38). This study confirmed six known and one novel exonic variants, including four missense substitutions but no truncating mutation. Missense substitution p.R415Q (rs1800067), a previously postulated breast cancer susceptibility allele, was subsequently screened for in a total of 3,698 breast cancer cases and 2,868 controls from Germany, Belarus or Russia. The Gln415 allele appeared protective against breast cancer in the German series, with the strongest effect for ductal histology (OR 0.67; 95%CI 0.49; 0.92; p = 0.003), but this association was not confirmed in the other two series, with the combined analysis yielding an overall Mantel-Haenszel OR of 0.94 (95% CI 0.81; 1.08). There was no significant effect of p.R415Q on breast cancer survival in the German patient series. The other three detected ERCC4 missense mutations included two known rare variants as well as a novel substitution, p.E17V, that we identified on a p.R415Q haplotype background. The p.E17V mutation is predicted to be probably damaging but was present in just one heterozygous patient. We conclude that the contribution of ERCC4/FANCQ coding mutations to hereditary breast cancer in Central and Eastern Europe is likely to be small.
Cartilage-Specific Matrix and Integrin Expression in Three-Dimensional Articular Chondrocyte Cultures Overexpressing Human Interleukin-10
Riccarda D. Müller,Thilo John,Benjamin Kohl,Anja Feldner
Clinical Medicine : Arthritis and Musculoskeletal Disorders , 2008,
Abstract: Interleukin (IL)-10 overexpression inhibits joint inflammation, however the effect of high local concentrations of IL-10 on chondrocyte homeostasis remains unclear. The aim of this study was to determine the effects of IL-10 overexpression on cartilage matrix production in three-dimensional (3D) chondrocyte cultures. Human articular chondrocytes were transduced with adenoviral vectors alone (adv/empty) or by vectors either overexpressing enhanced green fluorescence protein (adv/EGFP) or human IL-10 (adv/hIL-10) before their transfer to a 3D culture system. Non-transduced chondrocytes were used as controls. The expression of IL-10 or EGFP was confirmed using ELISA or flow cytometry. Chondrocytes synthesis of collagen types II and I, aggrecan, fibronectin and β1-integrin was determined over a period of 14 days post transduction using flow cytometry or immunohistochemistry. adv/EGFP or adv/IL-10 transduced chondrocytes expressed EGFP or secreted IL-10 detectable over the 2 weeks culture period. No suppression of collagen type II, aggrecan or β1-integrin synthesis by IL-10 overexpression was found and the deposition of collagen type I and bronectin remained unaffected compared to the controls. IL-10 overexpression does not impair key features of chondrocytes differentiated phenotype (e.g. collagen type II and aggrecan expression) suggesting the potential use of IL-10 for gene therapeutic approaches in the joint.
Epidemic dynamics on an adaptive network
Thilo Gross,Carlos Dommar D'Lima,Bernd Blasius
Physics , 2005, DOI: 10.1103/PhysRevLett.96.208701
Abstract: Many real world networks are characterized by adaptive changes in their topology depending on the dynamic state of their nodes. Here we study epidemic dynamics in an adaptive network, where susceptibles are able to avoid contact with infected by rewiring their network connections. We demonstrate that adaptive rewiring has profound consequences for the emerging network structure, giving rise to assortative degree correlation and a separation into two loosely connected sub-compartments. This leads to dynamics such as oscillations, hysteresis and 1st order transitions. We describe the system in terms of a simple model using a pair-approximation and present a full local bifurcation analysis. Our results indicate that the interplay between dynamics and topology can have important consequences for the spreading of infectious diseases and related applications.
How to predict community responses to perturbations in the face of imperfect knowledge and network complexity
Helge Aufderheide,Lars Rudolf,Thilo Gross,Kevin D. Lafferty
Quantitative Biology , 2013, DOI: 10.1098/rspb.2013.2355
Abstract: It is a challenge to predict the response of a large, complex system to a perturbation. Recent attempts to predict the behaviour of food webs have revealed that the effort needed to understand a system grows quickly with its complexity, because increasingly precise information on the elements of the system is required. Here, we show that not all elements of the system need to be measured equally well. This suggests that a more efficient allocation of effort to understand a complex systems is possible. We develop an iterative technique for determining an efficient measurement strategy. Finally, in our assessment of model food webs, we find that it is most important to precisely measure the mortality and predation rates of long-lived, generalist, top predators. Prioritizing the study of such species will make it easier to understand the response of complex food webs to perturbations.
Generalized modeling of ecological population dynamics
Justin D. Yeakel,Dirk Stiefs,Mark Novak,Thilo Gross
Quantitative Biology , 2010, DOI: 10.1007/s12080-011-0112-6
Abstract: Over the past years several authors have used the approach of generalized modeling to study the dynamics of food chains and food webs. Generalized models come close to the efficiency of random matrix models, while being as directly interpretable as conventional differential-equation-based models. Here we present a pedagogical introduction to the approach of generalized modeling. This introduction places more emphasis on the underlying concepts of generalized modeling than previous publications. Moreover, we propose a shortcut that can significantly accelerate the formulation of generalized models and introduce an iterative procedure that can be used to refine existing generalized models by integrating new biological insights.
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