Publications by authors named "B Ziems"

8 Publications

Copy Number Alterations with Prognostic Potential in Clear Cell Renal Cell Carcinoma.

Urol Int 2018 18;101(4):417-424. Epub 2018 Sep 18.

Department of Urology, University Hospital Rostock, Rostock, Germany.

Objectives: To detect chromosomal aberrations in a genome-wide manner with potential value for prognosis in groups of patients with different histopathological grading in clear cell renal carcinoma (ccRCC).

Material And Methods: We performed a copy number alteration analysis using the Affymetrix platform and SNP 6.0 mapping arrays with samples from 48 ccRCC-patients. The data analysis was done using 3 different Software Platforms: Affymetrix Genotyping Console (version and 2 open-source packages for validation: PennCNV and PICNIC.

Results: Consistent changes were found to divide the tumors into 4 groups: first group showed typical losses on 3p, second group losses on 3p plus gains on 5q, third group gains on chromosome 7 plus losses on chromosome 8; fourth group did not show any major changes. We selected the affected genes with the highest consistency and identified 13 different genes mapping in the SNP 6.0 results and Kyoto Encyclopedia of Genes and Genomes. Remarkable for further consideration were the phosphatidylinositol 3-kinase pathway, BRAF, MET, EGLN1; growth factors, for example, HGF, PGF and TGFB2.

Conclusion: A multimodal approach with a well-defined workflow for detecting genomic aberrations by using array technologies and comparing the findings with different comprehensive databases may provide insights into functional tumor processes and help to identify potential new targets for more individualized future treatment.
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March 2019

Stratification of clear cell renal cell carcinoma (ccRCC) genomes by gene-directed copy number alteration (CNA) analysis.

PLoS One 2017 9;12(5):e0176659. Epub 2017 May 9.

Department of Urology, University of Rostock, Rostock, Germany.

Tumorigenic processes are understood to be driven by epi-/genetic and genomic alterations from single point mutations to chromosomal alterations such as insertions and deletions of nucleotides up to gains and losses of large chromosomal fragments including products of chromosomal rearrangements e.g. fusion genes and proteins. Overall comparisons of copy number alterations (CNAs) presented in 48 clear cell renal cell carcinoma (ccRCC) genomes resulted in ratios of gene losses versus gene gains between 26 ccRCC Fuhrman malignancy grades G1 (ratio 1.25) and 20 G3 (ratio 0.58). Gene losses and gains of 15762 CNA genes were mapped to 795 chromosomal cytoband loci including 280 KEGG pathways. CNAs were classified according to their contribution to Fuhrman tumour gradings G1 and G3. Gene gains and losses turned out to be highly structured processes in ccRCC genomes enabling the subclassification and stratification of ccRCC tumours in a genome-wide manner. CNAs of ccRCC seem to start with common tumour related gene losses flanked by CNAs specifying Fuhrman grade G1 losses and CNA gains favouring grade G3 tumours. The appearance of recurrent CNA signatures implies the presence of causal mechanisms most likely implicated in the pathogenesis and disease-outcome of ccRCC tumours distinguishing lower from higher malignant tumours. The diagnostic quality of initial 201 genes (108 genes supporting G1 and 93 genes G3 phenotypes) has been successfully validated on published Swiss data (GSE19949) leading to a restricted CNA gene set of 171 CNA genes of which 85 genes favour Fuhrman grade G1 and 86 genes Fuhrman grade G3. Regarding these gene sets overall survival decreased with the number of G3 related gene losses plus G3 related gene gains. CNA gene sets presented define an entry to a gene-directed and pathway-related functional understanding of ongoing copy number alterations within and between individual ccRCC tumours leading to CNA genes of prognostic and predictive value.
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September 2017

A computational method for designing diverse linear epitopes including citrullinated peptides with desired binding affinities to intravenous immunoglobulin.

BMC Bioinformatics 2016 Apr 8;17:155. Epub 2016 Apr 8.

Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA.

Background: Understanding the interactions between antibodies and the linear epitopes that they recognize is an important task in the study of immunological diseases. We present a novel computational method for the design of linear epitopes of specified binding affinity to Intravenous Immunoglobulin (IVIg).

Results: We show that the method, called Pythia-design can accurately design peptides with both high-binding affinity and low binding affinity to IVIg. To show this, we experimentally constructed and tested the computationally constructed designs. We further show experimentally that these designed peptides are more accurate that those produced by a recent method for the same task. Pythia-design is based on combining random walks with an ensemble of probabilistic support vector machines (SVM) classifiers, and we show that it produces a diverse set of designed peptides, an important property to develop robust sets of candidates for construction. We show that by combining Pythia-design and the method of (PloS ONE 6(8):23616, 2011), we are able to produce an even more accurate collection of designed peptides. Analysis of the experimental validation of Pythia-design peptides indicates that binding of IVIg is favored by epitopes that contain trypthophan and cysteine.

Conclusions: Our method, Pythia-design, is able to generate a diverse set of binding and non-binding peptides, and its designs have been experimentally shown to be accurate.
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April 2016

Oxidatively modified LDL particles in the human placenta in early and late onset intrauterine growth restriction.

Placenta 2013 Dec;34(12):1142-9

Introduction: Reduced serum LDL concentrations have been observed in pregnancies complicated by intrauterine growth restriction (IUGR) as compared to healthy pregnant women. Since increased oxidative stress has been suggested to play a major role in IUGR we now hypothesized that the lower LDL concentrations are accompanied by an accumulation of oxidized LDLs in the placenta.

Methods: Fifteen placentas of near term and preterm born IUGR, and a gestational age matched control group (CTRL n = 15) were analyzed. Placental minimal modified LDL and fully oxidized LDL particles were measured by ELISA, and by immunohistochemistry, and were related to maternal and fetal serum lipid profiles.

Results: We found fully oxidized LDL but not minimal modified LDL being increased in the preterm subgroup of IUGR (n = 10) as compared to preterm CTRL (n = 10; p < 0.05). An increased staining intensity of trophoblasts in preterm IUGR subjects as compared to preterm CTRL has been confirmed by immunohistochemistry (p < 0.05). No difference could be found between the term groups (n = 5 each). Correlation analysis revealed an inverse relationship of maternal LDL (ρ = −0.49, p = 0.03) and fetal HDL cholesterol (ρ = −0.46, p = 0.04) with placental fully oxidized LDL particle concentration within preterms.

Discussion: IUGR is a heterogeneous entity. Different pathomechanisms seem to underlie the disease in preterm and term subjects with oxidation of LDL within the placenta possibly taking place in preterm IUGRs.

Conclusions: We conclude that the reduced maternal LDL cholesterol concentration in IUGR pregnancies is attributed to increased accumulation of oxidized LDL particles within the placenta at least in early onset IUGR
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December 2013

miRNA expression profiles determined in maternal sera of patients with HELLP syndrome.

Hypertens Pregnancy 2014 May 4;33(2):215-35. Epub 2013 Dec 4.

Department of Gynecology and Obstetrics, University of Rostock , Rostock , Germany.

Objective: Syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP) represents a distinct subgroup of severe preeclampsia. The aim of our study was to identify differentially expressed miRNAs in sera of patients with HELLP syndrome in comparison to unaffected controls.

Study Design: Blood samples were obtained from patients with manifest HELLP syndrome and matched unaffected controls. The expression of 754 mature miRNAs was assessed using the TaqMan Array format (n = 12). Results of seven differentially expressed miRNAs were further validated by single quantitative real-time polymerase chain reaction (qPCR) assays.

Results: Serum miRNA analysis allowed detection of maternal and fetal miRNAs. Distinct miRNA expressions were confirmed for miR-122, miR-758 and miR-133a represented by a median up-regulation ≥ two-fold in the HELLP group. The liver specific miR-122 was 11.5-fold increased with an area under curve (AUC) of 0.82 in the receiver operating characteristic (ROC) analysis. Cluster analyses of our data uncovered subgroups of HELLP patients were associated with clinical subtypes and differences in organ manifestation.

Conclusion: In our proof of principle study, we demonstrated that patients with HELLP syndrome showed alterations of serum miRNA expression patterns. Data analysis goes along with the hypothesis that HELLP syndrome is regarded to be a heterogeneous disease.
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May 2014