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Samatov T.R.,SRC Bioclinicum | Tonevitskaya S.A.,Moscow State University of Mechanical Engineering
Progress in histochemistry and cytochemistry | Year: 2015

The metastatic cascade comprises the following steps in sequential manner: the future metastatic cell has to leave the primary tumor mass, degrade the surrounding extracellular matrix, extravasate and circulate within in the bloodstream. Thereafter it has to attach to the endothelium of a target organ, intravasate into the connective tissue and has to proliferate to form a clinically detectable metastasis. We overview the in vitro microfluidic platforms modelling the metastatic cascade and the evolution towards systems capable of recapitulating all the steps by a single comprehensive model. Copyright © 2015. Published by Elsevier GmbH.


PubMed | SRC Bioclinicum and RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry
Type: Journal Article | Journal: Biotechnology letters | Year: 2016

Myelin oligodendrocyte glycoprotein (MOG) is one of the major autoantigens in multiple sclerosis (MS), therefore selective depletion of autoreactive lymphocytes exposing MOG-specific B cell receptors (BCRs) would be beneficial in terms of MS treatment.Using E. coli we generated an efficient protocol for the purification of the recombinant immunotoxin DT-MOG composed of the extracellular Ig-like domain of MOG fused in frame with the catalytic and translocation subunits of diphtheria toxin (DT, Corynebacterium diphtheriae) under native conditions with a final yield of 1.5mg per liter of culture medium. Recombinant DT-MOG was recognized in vitro by MOG-reactive antibodies and has catalytic activity comparable with wild-type DT.Enhanced pharmacokinetics (mean residence time in the bloodstream of 61min) and minimized diminished nonspecific toxicity (LD50=1.76mg/kg) of the DT-MOG makes it a potential candidate for the immunotherapy of MS.


Turchinovich A.,German Cancer Research Center | Turchinovich A.,University of Heidelberg | Samatov T.R.,SRC Bioclinicum | Tonevitsky A.G.,Russian Academy of Medical Sciences | And 2 more authors.
Frontiers in Genetics | Year: 2013

Nuclease resistant extracellular miRNAs have been found in all known biological fluids. The biological function of extracellular miRNAs remains questionable; however, strong evidence suggests that these miRNAs can be more than just byproducts of cellular activity. Some extracellular miRNA species might carry cell-cell signaling function during various physiological and pathological processes. In this review, we discuss the state-of-the-art in the field of intercellular miRNA transport and highlight current theories regarding the origin and the biological function of extracellular miRNAs. © 2013 Turchinovich, Samatov, Tonevitsky and Burwinkel.


Oliveira-Ferrer L.,University of Hamburg | Rossler K.,University of Hamburg | Haustein V.,University of Hamburg | Schroder C.,University of Hamburg | And 9 more authors.
British Journal of Cancer | Year: 2014

Background:C-Fos was initially described as oncogene, but was associated with favourable prognosis in ovarian cancer (OvCa) patients. The molecular and functional aspects underlying this effect are still unknown.Methods:Using stable transfectants of SKOV3 and OVCAR8 cells, proliferation, migration, invasion and apoptotic potential of c-FOS-overexpressing clones and controls were compared. Adherence to components of the extracellular matrix was analysed in static assays, and adhesion to E-selectin, endothelial and mesothelial cells in dynamic flow assays. The effect of c-FOS in vivo was studied after intraperitoneal injection of SKOV3 clones into SCID mice, and changes in gene expression were determined by microarray analysis.Results:Tumour growth after injection into SCID mice was strongly delayed by c-FOS overexpression, with reduction of lung metastases and circulating tumour cells. In vitro, c-FOS had only weak influence on proliferation and migration, but was strongly pro-apoptotic. Adhesion to components of the extracellular matrix (collagen I, IV) and to E-selectin, endothelial and mesothelial cells was significantly reduced in c-FOS-overexpressing OvCa cells. This corresponds to deregulation of adhesion proteins and glycosylation enzymes in microarray analysis.Conclusion:In addition to its known pro-apoptotic effect, c-FOS might influence OvCa progression by changing the adhesion of OvCa cells to peritoneal surfaces. © 2014 Cancer Research UK.


Maltseva D.V.,SRC Bioclinicum | Khaustova N.A.,SRC Bioclinicum | Fedotov N.N.,Moscow State University | Matveeva E.O.,SRC Bioclinicum | And 5 more authors.
Journal of Clinical Bioinformatics | Year: 2013

Background: Quantification and normalization of RT-qPCR data critically depends on the expression of so called reference genes. Our goal was to develop a strategy for the selection of reference genes that utilizes microarray data analysis and combines known approaches for gene stability evaluation and to select a set of appropriate reference genes for research and clinical analysis of breast samples with different receptor and cancer status using this strategy.Methods: A preliminary search of reference genes was based on high-throughput analysis of microarray datasets. The final selection and validation of the candidate genes were based on the RT-qPCR data analysis using several known methods for expression stability evaluation: comparative {increment}Ct method, geNorm, NormFinder and Haller equivalence test.Results: A set of five reference genes was identified: ACTB, RPS23, HUWE1, EEF1A1 and SF3A1. The initial selection was based on the analysis of publically available well-annotated microarray datasets containing different breast cancers and normal breast epithelium from breast cancer patients and epithelium from cancer-free patients. The final selection and validation were performed using RT-qPCR data from 39 breast cancer biopsy samples. Three genes from the final set were identified by the means of microarray analysis and were novel in the context of breast cancer assay. We showed that the selected set of reference genes is more stable in comparison not only with individual genes, but also with a system of reference genes used in commercial OncotypeDX test.Conclusion: A selection of reference genes for RT-qPCR can be efficiently performed by combining a preliminary search based on the high-throughput analysis of microarray datasets and final selection and validation based on the analysis of RT-qPCR data with a simultaneous examination of different expression stability measures. The identified set of reference genes proved to be less variable and thus potentially more efficient for research and clinical analysis of breast samples comparing to individual genes and the set of reference genes used in OncotypeDX assay. © 2013 Maltseva et al.; licensee BioMed Central Ltd.


Tonevitsky A.G.,Russian Academy of Medical Sciences | Maltseva D.V.,SRC Bioclinicum | Abbasi A.,University of Tübingen | Samatov T.R.,SRC Bioclinicum | And 6 more authors.
BMC Physiology | Year: 2013

Background: MiRNAs are essential mediators of many biological processes. The aim of this study was to investigate the dynamics of miRNA-mRNA regulatory networks during exercise and the subsequent recovery period. Results: Here we monitored the transcriptome changes using microarray analysis of the whole blood of eight highly trained athletes before and after 30 min of moderate exercise followed by 30 min and 60 min of recovery period. We combined expression profiling and bioinformatics and analysed metabolic pathways enriched with differentially expressed mRNAs and mRNAs which are known to be validated targets of differentially expressed miRNAs. Finally we revealed four dynamically regulated networks comprising differentially expressed miRNAs and their known target mRNAs with anti-correlated expression profiles over time. The data suggest that hsa-miR-21-5p regulated TGFBR3, PDGFD and PPM1L mRNAs. Hsa-miR-24-2-5p was likely to be responsible for MYC and KCNJ2 genes and hsa-miR-27a-5p for ST3GAL6. The targets of hsa-miR-181a-5p included ROPN1L and SLC37A3. All these mRNAs are involved in processes highly relevant to exercise response, including immune function, apoptosis, membrane traffic of proteins and transcription regulation. Conclusions: We have identified metabolic pathways involved in response to exercise and revealed four miRNA-mRNA networks dynamically regulated following exercise. This work is the first study to monitor miRNAs and mRNAs in parallel into the recovery period. The results provide a novel insight into the regulatory role of miRNAs in stress adaptation. © 2013 Tonevitsky et al.; licensee BioMed Central Ltd.


Marx U.,TU Berlin | Walles H.,University of Würzburg | Hoffmann S.,TU Berlin | Lindner G.,TU Berlin | And 6 more authors.
ATLA Alternatives to Laboratory Animals | Year: 2012

Various factors, including the phylogenetic distance between laboratory animals and humans, the discrepancy between current in vitro systems and the human body, and the restrictions of in silico modelling, have generated the need for new solutions to the ever-increasing worldwide dilemma of substance testing. This review provides a historical sketch on the accentuation of this dilemma, and highlights fundamental limitations to the countermeasures taken so far. It describes the potential of recently-introduced microsystems to emulate human organs in 'organ-on-a-chip' devices. Finally, it focuses on an in-depth analysis of the first devices that aimed to mimic human systemic organ interactions in 'human-on-a-chip' systems. Their potential to replace acute systemic toxicity testing in animals, and their inability to provide alternatives to repeated dose long-term testing, are discussed. Inspired by the latest discoveries in human biology, tissue engineering and microsystems technology, this review proposes a paradigm shift to overcome the apparent challenges. A roadmap is outlined to create a new homeostatic level of biology in 'human-on-a-chip' systems in order to, in the long run, replace systemic repeated dose safety evaluation and disease modelling in animals.


Davydov I.I.,SRC Bioclinicum | Wohlgemuth I.,Max Planck Institute for Biophysical Chemistry | Artamonova I.I.,Russian Academy of Sciences | Urlaub H.,Max Planck Institute for Biophysical Chemistry | And 3 more authors.
Nature Communications | Year: 2013

The emergence of ribosomes and translation factors is central for understanding the origin of life. Recruitment of translation factors to bacterial ribosomes is mediated by the L12 stalk composed of protein L10 and several copies of protein L12, the only multi-copy protein of the ribosome. Here we predict stoichiometries of L12 stalk for >1,200 bacteria, mitochondria and chloroplasts by a computational analysis, and validate the predictions by quantitative mass spectrometry. The majority of bacteria have L12 stalks allowing for binding of four or six copies of L12, largely independent of the taxonomic group or living conditions of the bacteria, whereas some cyanobacteria have eight copies. Mitochondrial and chloroplast ribosomes can accommodate six copies of L12. The last universal common ancestor probably had six molecules of L12 molecules bound to L10. Changes of the stalk composition provide a unique possibility to trace the evolution of protein components of the ribosome. © 2013 Macmillan Publishers Limited. All rights reserved.


Lange T.,University of Hamburg | Samatov T.R.,SRC Bioclinicum | Tonevitsky A.G.,Russian Academy of Medical Sciences | Schumacher U.,University of Hamburg
Carbohydrate Research | Year: 2014

Aberrant glycosylation of cell surface glycoproteins acquired during malignant progression is a common characteristic of human cancer cells. Several biological processes and molecular mechanisms relevant for tumour progression are accompanied by altered mRNA expression levels of certain glycosyltransferases resulting in unusual ratios of common glycoconjugates present in a cancer cell's glycocalyx or even in the development of unusual, cancer-characterizing carbohydrates. This mini-review aims to give a concise overview on the current knowledge of the functional relevance of altered O- and N-glycans during two critical steps of tumour progression: (I) epithelial-to-mesenchymal transition of primary tumour cells during intravasation and (II) adhesion of circulating tumour cells towards the vascular wall during extravasation at a distant metastatic site. Characteristic lectin binding patterns reflecting these glycosylation changes and the resulting prognostic impact of certain lectin binding sites in different neoplasias are reviewed as well. © 2014 Elsevier Ltd. All rights reserved.


Samatov T.R.,SRC Bioclinicum | Tonevitsky A.G.,Russian Academy of Medical Sciences | Schumacher U.,University of Hamburg
Molecular Cancer | Year: 2013

Epithelial-mesenchymal transition (EMT) is a key process in embryonic development and metastases formation during malignant progression. This review focuses on transcriptional regulation, non-coding RNAs, alternative splicing events and cell adhesion molecules regulation during EMT. Additionally, we summarize the knowledge with regard to the small potentially druggable molecules capable of modulating EMT for cancer therapy. © 2013 Samatov et al.; licensee BioMed Central Ltd.

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