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  • Wiley Online Library  (24)
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  • 1
    In: Biometrical Journal, March 2014, Vol.56(2), pp.287-306
    Description: Discovery of prognostic and diagnostic biomarker gene signatures for diseases, such as cancer, is seen as a major step toward a better personalized medicine. During the last decade various methods have been proposed for that purpose. However, one important obstacle for making gene signatures a standard tool in clinical diagnosis is the typical low reproducibility of these signatures combined with the difficulty to achieve a clear biological interpretation. For that purpose in the last years there has been a growing interest in approaches that try to integrate information from molecular interaction networks. Most of these methods focus on classification problems, that is learn a model from data that discriminates patients into distinct clinical groups. Far less has been published on approaches that predict a patient's event risk. In this paper, we investigate eight methods that integrate network information into multivariable Cox proportional hazard models for risk prediction in breast cancer. We compare the prediction performance of our tested algorithms via cross‐validation as well as across different datasets. In addition, we highlight the stability and interpretability of obtained gene signatures. In conclusion, we find GeneRank‐based filtering to be a simple, computationally cheap and highly predictive technique to integrate network information into event time prediction models. Signatures derived via this method are highly reproducible.
    Keywords: Biomarker ; Cox Regression ; Gene Signature ; Network Information
    ISSN: 0323-3847
    E-ISSN: 1521-4036
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  • 2
    In: Movement Disorders, November 2015, Vol.30(13), pp.1794-1801
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1002/mds.26319/abstract Byline: Ina Schmitt, Oliver Kaut, Hassan Khazneh, Laura deBoni, Ashar Ahmad, Daniela Berg, Christine Klein, Holger Frohlich, Ullrich Wullner Keywords: Parkinson's disease; [alpha]-synuclein; DNA methylation; blood; l-dopa Abstract Background Increasing gene dosages of [alpha]-synuclein induce familial Parkinson's disease (PD); thus, the hypothesis has been put forward that regulation of gene expression, in particular altered [alpha]-synuclein gene methylation, might be associated with sporadic PD and could be used as a biological marker. Methods We performed a thorough analysis of [alpha]-synuclein methylation in bisulfite-treated DNA from peripheral blood of 490 sporadic PD patients and 485 healthy controls and in addition analyzed the effect of levodopa (l-dopa) on [alpha]-synuclein methylation and expression in cultured mononuclear cells. Results [alpha]-Synuclein was hypomethylated in sporadic PD patients, correlated with sex, age, and a polymorphism in the analyzed sequence stretch (rs3756063). [alpha]-Synuclein methylation separated healthy individuals from sporadic PD with a specificity of 74% (male) and 78% (female), respectively. [alpha]-Synuclein methylation was increased in sporadic PD patients with higher l-dopa dosage, and l-dopa specifically induced methylation of [alpha]-synuclein intron 1 in cultured mononuclear cells. Conclusions [alpha]-Synuclein methylation levels depended on disease status, sex, age, and the genotype of rs3756063. The pharmacological action of l-dopa was not limited to the dopamine precursor function but included epigenetic off-target effects. The hypomethylation of [alpha]-synuclein in sporadic PD patients' blood already observed in previous studies was probably underestimated because of effect of l-dopa, which was not known previously. The analysis of [alpha]-synuclein methylation can help to identify nonparkinsonian individuals with reasonable specificity, which offers a valuable tool for researchers and clinicians. [c] 2015 International Parkinson and Movement Disorder Society Article Note: Funding agencies: This work was supported by the Deutsche Parkinson Vereinigung (dPV); the Hans Tauber Stiftung; the Internationale Parkinson Fonds; and the pure consortium, in particular J. Wiltfang, the German Research Council (DFG: WU 184/9-1) and the Deutsche Zentrum fur neurodegenerative Erkrankungen (DZNE). This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking [Aetionomy [grant number 115568]). Relevant conflicts of interest/financial disclosures: The analysis of the methylation pattern of the [alpha]-synuclein gene for diagnostic purposes is part of the European patent application EP 2668291 A1. Full financial disclosures and author roles may be found in the online version of this article. Supporting information: Additional Supporting Information may be found in the online version of this article Additional Supporting Information may be found in the online version of this article at the publisher's web-site. CAPTION(S): Supplementary Information
    Keywords: Parkinson'S Disease ; Α‐Synuclein ; Dna Methylation ; Blood ; L ‐Dopa
    ISSN: 0885-3185
    E-ISSN: 1531-8257
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  • 3
    Language: English
    In: Chemie Ingenieur Technik, June 2012, Vol.84(6), pp.905-917
    Description: Membrane technology plays more and more a crucial role in the purification of biotechnological products. Integration of membrane based unit operations becomes a trend for ongoing process designs. By this, in addition to the well‐established membrane unit operations like microfiltration, ultrafiltration, nanofiltration and reverse osmosis, new membranes, modules and systems were developed in the last years. Herein, the efforts in the area of membrane chromatography should be mentioned as a major research topic. This paper focuses on the state of the art in membrane technology, especially in the field of biotechnology, and on innovative developments in the field of membrane chromatography as well as on process design methods, which are necessary to fulfill the challenges for competitive technologies for the future. To minimize the risk that is inherent in the design of any new process, it is essential to use unit operation models that describe the process behavior accurately. Modeling efforts, which were originally developed for other membrane unit operations, show a great potential for the adaption to new developed membrane technologies. An important challenge in the integration of membrane unit operations into bioprocesses is the scale‐up into industrial scale. Based on the state of the art, today's membrane systems, scaling techniques and research efforts are described and future trends are shown.
    Keywords: Biotechnology ; Membrane ; Process Design ; Process Development ; Separation Technology
    ISSN: 0009-286X
    E-ISSN: 1522-2640
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  • 4
    Language: English
    In: Chemie Ingenieur Technik, June 2012, Vol.84(6), pp.892-904
    Description: For years, microtechnology is being considered as an emerging technique for chemical engineering tasks to overcome safety issues corresponding to high volumes and gaining higher selectivities and yields in reaction technology. Whereas in reaction technology a broad variety of microstructured equipment is available, in product purification/separation adequate equipment is missing. Research is focused on modular fast and flexible smaller production plants being operated continuously instead of batchwise in order to reduce engineering efforts and time‐to‐process. To cope with these demands, an appropriate definition of modules, which could be easily chosen and combined, is inevitable. In addition, these modules have to be well characterized concerning fluid dynamics and separation performance. This paper focuses on the characterization of available modules/devices. A standard method and analysis of the results concerning manufacturing accuracy and operation range is proposed. Miniplant technology is described as an efficient tool to validate process concepts proposed by process simulation studies. Necessary model parameters are determined for industrial complex mixtures in miniaturized laboratory equipment. Parameters are calculated model based to gain maximal accuracy. State of the art of miniplant technology is described and basic characteristic data are presented. For an efficient design of micromodules, an improved fluid dynamic comprehension is essential. A methodically approach is demonstrated that allows a systematically characterization and the definition of an optimal fluid dynamical operation range. Furthermore, the miniplant as a tool for process validation is described.
    Keywords: Microtechnology ; Miniplant ; Process Design ; Process Modeling ; Separation Technology
    ISSN: 0009-286X
    E-ISSN: 1522-2640
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  • 5
    Language: English
    In: Chemical Engineering & Technology, November 2015, Vol.38(11), pp.2035-2044
    Description: Omega‐3 fatty acids are well‐known for health‐preserving effects like blood pressure reduction. Main source of fatty acids is fish oil which has recorded a significant price increase. This has stimulated research on recovering omega‐3 fatty acids from other sources, like the microalgae sp. These stems have in common that the fatty acids are built as storage lipids in the cell interior. Due to the cell wall stability of the cell systems, high disruption energies need to be applied which leads to formation of stable emulsions. Innovative downstream concepts are developed which in contrast to conventional processes are operated free from organic solvents. Several approaches are discussed and compared in terms of cost to common process concepts. Isolation of essential fatty acids from microalgae offers decisive advantages. A method for integration of the required cell disrupture and product purification is developed, aiming at the recovery of polyunsaturated fatty acids. Solvent‐free product purification without organic solvents can be performed which is economically superior to conventional reference processes.
    Keywords: Algae ; Downstream Processing ; Polyunsaturated Fatty Acid ; Solvent‐Free Extraction
    ISSN: 0930-7516
    E-ISSN: 1521-4125
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  • 6
    Language: English
    In: Chemie Ingenieur Technik, June 2012, Vol.84(6), pp.885-891
    Description: The development of efficient engineering methods is an objective of many current research activities. One of the main areas of focus in this context is modularization and standardization in order to reduce project execution time. The intellectual key issue of this approach is the definition of modules that can be reused in a multitude of plant designs, thereby gaining efficiency in comparison to individually created designs. The paper describes an approach to configure any plant design for vendor offers based on customer requests concerning varying capacities, product specifications, plant locations and individual modifications. The novel idea is to assemble a set of tools that allows for a direct connection of 3D plant layouts and the corresponding cost calculations. Ultimately, it is aiming to be able to calculate the equipment size by using a process simulation tool in accordance with defined capacities and the local boundaries of the construction site. As a first proof of principle for the concept HPLC technical plants in a scale of 150 to 1000 mm ID are presented and discussed. Modularization and standardization are intensively studied in order to enhance project development. An approach to configure any plant design for vendor offers based on predefined modules is described. A first proof of principle of this new approach starting with 3D models for cost predictions is presented and discussed using HPLC as an example.
    Keywords: Downstream Processing ; Engineering ; Modularization ; Package Units ; Separation Technology
    ISSN: 0009-286X
    E-ISSN: 1522-2640
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  • 7
    In: International Journal of Cancer, 15 March 2015, Vol.136(6), pp.E578-E589
    Description: To uncover novel causative genes in patients with unexplained adenomatous polyposis, a model disease for colorectal cancer, we performed a genome‐wide analysis of germline copy number variants (CNV) in a large, well characterized and mutation negative patient cohort followed by a targeted next generation sequencing (NGS) approach. Genomic DNA from 221 unrelated German patients was genotyped on high‐resolution SNP arrays. Putative CNVs were filtered according to stringent criteria, compared with those of 531 population‐based German controls, and validated by qPCR. Candidate genes were prioritized using , expression, and segregation analyses, data mining and enrichment analyses of genes and pathways. In 27% of the 221 unrelated patients, a total of 77 protein coding genes displayed rare, nonrecurrent, germline CNVs. The set included 26 candidates with molecular and cellular functions related to tumorigenesis. Targeted high‐throughput sequencing found truncating point mutations in 12% (10/77) of the prioritized genes. No clear evidence was found for autosomal recessive subtypes. Six patients had potentially causative mutations in more than one of the 26 genes. Combined with data from recent studies of early‐onset colorectal and breast cancer, recurrent potential loss‐of‐function alterations were detected in ), , and in three genes from the family. In the canonical Wnt pathway oncogene (β‐catenin), two potential gain‐of‐function mutations were found. In conclusion, the present study identified a group of rarely affected genes which are likely to predispose to colorectal adenoma formation and confirmed previously published candidates for tumor predisposition as etiologically relevant. What's new? So far, two genes have been implicated in the inheritance of adenomatous polyposis, a condition that leads to colorectal cancer: and . But disturbances in these genes only account for about half of the disease cases. In this study, the authors sought that genetic basis by performing for the first time a genome‐wide investigation into copy number variations among colorectal adenomatous polyposis patients. They identified a group of candidate genes that boost the risk of hereditary colorectal tumors; several patients had disruptions in multiple genes, suggesting that a simple lab test to evaluate risk might not be forthcoming.
    Keywords: Hereditary Colorectal Cancer ; Gastrointestinal Polyposis ; Copy Number Variation ; Candidate Genes ; Unexplained Polyposis ; Genetic Cause ; Next Generation Sequencing
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 8
    Language: English
    In: Chemie Ingenieur Technik, May 2014, Vol.86(5), pp.687-694
    Description: Manufacturing of chemical‐pharmaceutical products is moving increasingly fast on a global scale. Therefore, developing and starting up production facilities fast, with high quality, and at reasonable costs has become extremely challenging. Engineering concepts like modularization, standardization and simultaneous/parallel engineering are discussed as methods for speeding up process design and filing for regulatory approval. Transfer from batch to continuous operation mode of production is pointed out as the key‐issue in such strategies. To cope with the need for higher flexibility in customer driven supply to chemical and pharmaceutical markets, different existing engineering approaches are discussed. Additionally, a new approach based on improvement and standardization of methods for data acquisition in product and process development is presented.
    Keywords: Engineering ; Modularization ; Package Units ; Process Design ; Standardization
    ISSN: 0009-286X
    E-ISSN: 1522-2640
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  • 9
    Language: English
    In: Chemical Engineering & Technology, November 2015, Vol.38(11), pp.2025-2034
    Description: Developing efficient methods for the production of biotechnologically generated products is the goal of various current research approaches. One issue related is the extraction of biomass from aqueous fermentation broths for the isolation of respective products. Based on the high cell wall stability of available microorganisms and the corresponding high energy for cell disruption, extremely stable emulsions result after the indispensable cell disruption in aqueous environment. Therefore, the cell material is often dried and the product is extracted by means of organic solvents from the biomass, which makes these processes difficult both from the economic and toxicological sides. Based on the example of an extraction of polyunsaturated fatty acids from microalgae, a systematic approach is presented for the characterization of emulsion stability and development of process concepts for the subsequent solvent‐free product recovery. The significant price increase of the main source of fatty acids, fish oil, has stimulated research on recovering omega‐3 fatty acids from other sources like microalgae. Due to the cell wall stability, high disruption is necessary, which leads to formation of stable emulsions. A systematic method for the downstream processing of omega‐3 fatty acids from microalgae is presented.
    Keywords: Algae ; Chromatography ; Emulsion Stability ; Polyunsaturated Fatty Acids
    ISSN: 0930-7516
    E-ISSN: 1521-4125
    Source: John Wiley & Sons, Inc.
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  • 10
    Language: English
    In: Biometrical Journal, April 2009, Vol.51(2), pp.304-323
    Description: Targeted gene perturbations have become a major tool to gain insight into complex cellular processes. In combination with the measurement of downstream effects DNA microarrays, this approach can be used to gain insight into signaling pathways. were first introduced by Markowetz . as a probabilistic method to reverse engineer signaling cascades based on the nested structure of downstream perturbation effects. The basic framework was substantially extended later on by Fröhlich ., Markowetz ., and Tresch and Markowetz. In this paper, we present a review of the complete methodology with a detailed comparison of so far proposed algorithms on a qualitative and quantitative level. As an application, we present results on estimating the signaling network between 13 genes in the ER‐α pathway of human MCF‐7 breast cancer cells. Comparison with the literature shows a substantial overlap.
    Keywords: Nested Effects Models ; Perturbation Data ; Signaling Pathway Inference
    ISSN: 0323-3847
    E-ISSN: 1521-4036
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