ISSN 1866-8836
Клеточная терапия и трансплантация

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Volume 1, Number 4
03/01/2010
Volume 1, Number 4
Editor-in-Chief
Afanasyev B. V. (St. Petersburg, Russia)
Co-Editors-in-Chief
Wagemaker G. (Rotterdam, Netherlands)
Zander A. R. (Hamburg, Germany)
Deputy Editor
Chukhlovin A. B. (St. Petersburg, Russia)
Fehse B. (Hamburg, Germany)
Novik A. А. (Moscow, Russia)
Managing Editor
Claudia Koltzenburg (Hamburg, Germany)
Editorial Board
Aleynikova O. (Minsk, Belarus)
Alyansky A. (St. Petersburg, Russia)
Anagnostou A. (Boston, USA)
Andreeff M. (Houston, USA)
Bacher U. (Hamburg, Germany)
Baуkov V. (St. Petersburg, Russia)
Baranov V. S. (St. Petersburg, Russia)
Barkhatov I. (St. Petersburg, Russia)
Baum C. (Hannover, Germany)
Bilko N. (Kiev, Ukraine)
Borset M. (Trondheim, Norway)
Buechner Th. (Muenster, Germany)
Bykov V. (St. Petersburg, Russia)
Dini G. (Genoa, Italy)
Drize N. (Moscow, Russia)
Egeland T. (Oslo, Norway)
Elstner E. (Berlin, Germany)
Emanuel V. (St. Petersburg, Russia)
Everaus H. (Tartu, Estonia)
Ferrara J. (Ann Arbor, USA)
Fibbe W. (Leiden, Netherlands)
Galibin O. (St. Petersburg, Russia)
Ganser A. (Hannover, Germany)
Granov D. (St. Petersburg, Russia)
Ivanov R. (Moscow, Russia)
Klimko N. (St. Petersburg, Russia)
Kolb H.-J. (Muenchen, Germany)
Konopleva M. (Houston, USA)
Koza V. (Pilsen, Czech Republic)
Kroeger N. (Hamburg, Germany)
Malikov A. (St. Petersburg, Russia)
Mikhailova N. (St. Petersburg, Russia)
Mentkevich G. (Moscow, Russia)
Nagler A. (Tel Hashomer, Israel)
Nemkov A. (St. Petersburg, Russia)
Neth R. (Hamburg, Germany)
Nevorotin A.J. (St. Petersburg, Russia)
Ostertag W. (Hamburg, Germany)
Palutke M. (Detroit, USA)
Roumiantsev A. G. (Moscow, Russia)
Savchenko V. G. (Moscow, Russia)
Smirnov A. V. (St. Petersburg, Russia)
Stamm C. (Berlin, Germany)
Tetz V. (St. Petersburg, Russia)
To B. (Adelaide, Australia)
Totolian A. A. (St. Petersburg, Russia)
Uss A.L. (Minsk, Belarus)
Vilesov A. (St. Petersburg, Russia)
Westenfelder Ch. (Salt Lake City, USA)
Wisloff F. (Oslo, Norway)
Zubarovskaya L. (St. Petersburg, Russia)
Zvartau E. (St. Petersburg, Russia)
In this Issue

When we were asked to edit a special issue of Cellular Therapy and Transplantation (CTT) on the topic of Gene and Cell Therapy, it was quite clear that this would be a demanding task. As is well known, there are a number of excellent, high-ranked journals representing (or cooperating with) the leading international and national societies established in this research area. For a newcomer journal this means tough competition to get some manuscripts of significant impact.

Despite its relatively short history, CTT has already established a nice tradition which made life much easier. The journal tries to devote some space to historical, ground-breaking work. It wasn’t too difficult to identify a publication cited in multiple gene therapy reviews, but hardly read by any of the younger researchers due to accessibility problems. In fact, the manuscript by Edward Tatum based on a lecture he gave in May 1966 contains a very concrete and elaborate vision of the possibilities offered by a novel technique which he named genetic therapy. The visionary power of Tatum’s article is really astonishing; particularly if one considers that he wrote his article at a time when the techniques of recombinant DNA were still to be invented. As good Science fiction Tatum’s article is still, more than 40 years after its publication, very enjoyable, even if one does not agree with all his ideas. We suggest that going back to the roots will be interesting for everybody working in the field.

We are also happy that Charles Coutelle from Imperial College London, a pioneer in basic and translational gene therapy research, agreed to write a Commentary on Tatum’s article. This commentary is much more than reminiscence; analyzing Tatum’s work from the today’s point of view Charles raises a number of important and critical issues to be resolved in modern genetics and gene therapy.

The present issue contains two very interesting articles on regulatory issues in gene and cell therapy, one by Christine Voelkel and colleagues devoted to retrovirus-mediated gene transfer into hematopoietic stem cells, and the other by Anja Elstner et al. on the regulatory landscape in human ES cell research. We are certain that these contributions will be of interest for many readers active or interested in clinical gene therapy and ES stem cell research.

We are pleased to present the work by Vera V. Sergeevicheva and colleagues on a clinical study with mesenchymal stromal cells in Novosibirsk, Russia. The authors found improved hematopoietic recovery in MSC-treated hemoblastosis (proliferative disorders of blood-forming cells) patients after hematopoietic stem cell transplantation. This publication also underlines the journal’s policy to provide space for important contributions from Eastern countries.

The introduction of novel ways of publishing is another main focus of CTT. In line with this, this issue contains a video publication on the in vitro behavior of MSC. The contribution by Claudia Lange and colleagues clearly illustrates the advantages associated with the novel possibilities of data presentation offered by the internet.

Sooner or later many researchers working with last-generation Becton Dickinson flow cytometers experience that with regard to data presentation and figure export, FACS-Diva software clearly represents a pain point of these high-end devices. In their Method paper, Kristoffer Weber and Boris Fehse introduce their straightforward and easy method to overcome these limitations, step-by-step.

Diagnostics and therapy of Philadelphia chromosome-positive leukemia have been revolutionized in the last decade. This was a stimulus for the journal to devote this issue’s state-of-the art Hematology review to these topics. We are happy that Nikolay N. Mamaev accepted the Editor’s invitation and provided a very comprehensive overview on Ph+ leukemia.

Finally, we use the current issue of CTT to introduce a novel format in the journal, namely a Forum for the discussion of topics of interest for the scientific community. The first contribution to the Forum section comes from Alexey I. Nevorotin who, based on his own extensive experience, provides writing advice for Russian scientists who want to publish their results in English-language journals. We are very grateful that Robert M. Frederickson, one of the most experienced editors in the field, currently Editor of Molecular Therapy, one of the top journals in experimental medicine, agreed to contribute his personal view on this topic in a comprehensive article also published in the Forum section of this issue.

Besides the contributors we have to thank the colleagues who made this issue possible. Firstly, thanks to the managing editor Claudia Koltzenburg and her team (René J. Hornung, Liudmila Lashkouskaya, Melissa Pritchard, and Anna Starikova) who have done a great job.

Following another nice tradition of the journal we are delighted to thank the reviewers of this issue for their invaluable help: Ulrike Bacher, Alexey B. Chukhlovin, Ulrike Köhl, Srinivas Koduru, Claudia Lange, Binghua Li, Vladimir Prassolov, Axel Schambach, Bernd Schiedlmeier, Sonja Schrepfer, Alexander B. Smolyaninov, Anna G. Turkina, and Anke Wahlers. Also, we have to thank The Johns Hopkins University Press for the opportunity to obtain a reprint licence of the Tatum article. Last but not least, we are indebted to the Deutsche Forschungsgemeinschaft for supporting this open access journal project.

Boris Fehse, Christopher Baum

Keynote

Keynote comment

Articles

Ongoing dynamics in the regulatory landscape of human embryonic stem cell research

Anja Elstner*1, Annette Noack*1, Alexander Damaschun1, Glyn Stacey2, Begoňa Arán3, Ilona Gawronska1, Anna Veiga3,4,
Joeri Borstlap1 and Andreas Kurtz1

* Both authors contributed equally

Retrovirus mediated hematopoietic gene therapy: A European regulatory perspective with special focus on the situation in Germany

Christine Voelkel1,2, Anke Lührmann2, Christopher Baum1,3, and Heiko E. von der Leyen2

Autologous mesenchymal stromal cells of hemoblastosis patients efficiently support hematopoietic recovery after stem cell transplantation

Vera V. Sergeevicheva1, Ekaterina Y. Shevela1, Svetlana A. Sizikova1, Alexander D. Kulagin2, Irina V. Kruchkova1,
Andrey V. Gilevich1, Igor A. Lisukov2, Vladimir A. Kozlov1, Alexander A. Ostanin1, Elena R. Chernykh1

The MSCs' in vitro community: where to go?

Sascha Lange, Axel R. Zander, Claudia Lange

Methods

Hematology review

Forum

Keynote

Molecular biology, nucleic acids, and the future of medicine

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E. L. Tatum

Rockefeller University, New York, New York

Reprinted with Permission of The Johns Hopkins University Press.
Originally published in: Perspectives in Biology and Medicine 10:1 (1966), 19-32.

Keynote comment

From mould to man. Edward Lewis Tatum’s vision of the future of medicine.

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Charles Coutelle

Emeritus Professor of Gene Therapy, Imperial College London, Faculty of Medicine, National Heart and Lung Institute, Molecular and Cellular Medicine Section, SW7 2AZ UK

Articles

Ongoing dynamics in the regulatory landscape of human embryonic stem cell research

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Anja Elstner*1, Annette Noack*1, Alexander Damaschun1, Glyn Stacey2, Begoňa Arán3, Ilona Gawronska1, Anna Veiga3,4,
Joeri Borstlap1 and Andreas Kurtz1

* Both authors contributed equally

1Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Germany; 2The UK Stem Cell Bank, National Institute for Biological Standards and Control, South Mimms, UK; 3Banc de Linies Cel.lulars, Center of Regenerative Medicine Barcelona (CMRB); 4Institut Universitari Dexeus, Barcelona, Spain

The international situation regarding the specific nature of regulation on human embryonic stem cell research is still quite complex due to pluralistic historical, cultural and ethical opinions that dominate in respective countries. By establishing the Human European Stem Cell Registry (hESCreg, www.hescreg.eu) in 2007, the EU initiated the first steps towards comparison and science-driven harmonization of hESC legislation. The hESCreg consortium currently includes representatives from 15 countries (including European and non-European countries), who act as National Contacts for hESCreg and regularly update the registry with information on stem cells as well as legislative and ethical discussions in the field of stem cell research. Several of these countries have experienced recent legislative changes; these were implemented in China, Finland, the Netherlands, Norway, the United Kingdom, and the USA. Others expect regulatory changes in the near future, such as in Australia, India, and Turkey. Whilst many countries have introduced legislation to liberalize embryonic stem cell research, others hold to stricter regulations on embryo-derived stem cells (e.g. Turkey, Germany, Hungary, and Italy). In this article we summarize and complete the information on the current status of international hESC regulation provided in our recent report.

Articles

Retrovirus mediated hematopoietic gene therapy: A European regulatory perspective with special focus on the situation in Germany

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Christine Voelkel1,2, Anke Lührmann2, Christopher Baum1,3, and Heiko E. von der Leyen2

1Department of Experimental Hematology, Hannover Medical School, D-30625 Hannover, Germany;
2Hannover Clinical Trial Center GmbH, D-30625 Hannover, Germany;
3Division of Experimental Hematology, Cincinnati Children’s Research Foundation, Cincinnati, Ohio, USA


Correspondence
Prof. Dr. Heiko E. von der Leyen, Hannover Clinical Trial Center GmbH, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany,
Tel.: +49 511 533 333 0, Fax: +49 511 533 333 99, E-mail: vdleyen@spam is badclinical-trial-center.de

Retrovirus mediated gene therapy has already proven to be more than just a theoretical option to treat patients with severe genetic defects. Clinical gene therapy trials of X-linked severe combined immunodeficiency or adenosine deaminase deficiency have demonstrated the success and potential benefit of the therapy. Nevertheless, the complexity of the therapeutic products and their biological origin, as well as virus-related safety concerns require the need of a strict regulatory framework in order to guarantee the quality of the individual products and safety of the patients. The aim of this review is to give an overview of the rapidly evolving regulatory framework of Advanced Therapy Medicinal Products in Europe. We will summarize the most important regulatory documents to be considered before entering the clinical development phase – not only from a German but also from a European perspective.

Articles

Autologous mesenchymal stromal cells of hemoblastosis patients efficiently support hematopoietic recovery after stem cell transplantation

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Vera V. Sergeevicheva1, Ekaterina Y. Shevela1, Svetlana A. Sizikova1, Alexander D. Kulagin2, Irina V. Kruchkova1,
Andrey V. Gilevich1, Igor A. Lisukov2, Vladimir A. Kozlov1, Alexander A. Ostanin1, Elena R. Chernykh1

1Institute of Clinical Immunology SB RAMS, Novosibirsk, Russia;
2Novosibirsk State Medical University, Novosibirsk, Russia

Mesenchymal stromal cells (MSCs) derived from bone marrow possess immunoregulatory activity and are able to support hematopoiesis. Unfortunately, data concerning the biological properties of MSCs in various pathologies is poor and often discrepant. In this study, we demonstrated that MSCs derived from bone marrow of patients with hemoblastoses have fibroblast-like morphology and a typical phenotype. Moreover, the patients' MSCs possess well-defined hematopoietic-supporting activity coupled with decreased immunosuppressive potential. These properties prove the clinical application of co-transplantation of autologous hematopoietic stem cells and MSCs in oncohematology to achieve a rapid hematopoietic recovery. Therefore we investigated the safety and hematopoietic effects of MSCs in patients with hematological malignancies receiving peripheral blood hematopoietic stem cell (PBSC) transplantation. We revealed the decreasing of the period of neutropenia and thrombocytopenia in the patients with hematological tumors after high-dose chemotherapy, when autologous PBSC were co-transplanted with ex vivo expanded autologous MSCs. Our results show that co-transplantation of autologous MSCs with PBSC is feasible and safe. The shortening of hematopoietic recovery time suggests that MSC may have a positive impact on hematopoiesis.

Articles

The MSCs' in vitro community: where to go?

Sascha Lange, Axel R. Zander, Claudia Lange

Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany

Correspondence:
Claudia Lange, Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany, E-mail: cllange@spam is baduke.uni-hamburg.de

Human mesenchymal stromal cells (hMSC) are presently being investigated extensively for their potential use as cellular therapeutics in regenerative medicine. They can be easily isolated, e.g., from bone marrow by plastic adherence, and expanded in vitro. These videos show the proliferation of hMSC, and how they interact with each other and divide. The large distances hMSC can conquer call into question the cloning carried out by low-density seeding.

Methods

Diva-Fit: A step-by-step manual for generating high-resolution graphs and histogram overlays of flow cytometry data obtained with FACSDiva software

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Kristoffer Weber, Boris Fehse

Research Dept. Cell and Gene Therapy, Clinic for Stem Cell Transplantation, UCCH, University Medical Centre Hamburg-Eppendorf, Germany


Correspondence:
Research Dept. Cell and Gene Therapy, Clinic for Stem Cell Transplantation, UCCH, University Medical Centre Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
Phone: +49-40-7410-52705 / +49-40-7410-55518
E-mail: k.weber@spam is baduke.de or fehse@spam is baduke.de

In recent years, flow cytometry has been revolutionized via the introduction of digital data acquisition and analysis tools that facilitate simultaneous investigation of ten or more parameters. At the same time, some data presentation tools offered by commercial suppliers have remained surprisingly “antiquated”. This leads to the ironic fact that high-quality data is often represented by poor-quality illustrations: namely pixelated plots. In particular, data obtained using FACSDiva software is frequently exported into figures as low-resolution pixel graphics resulting in low-quality images. Additionally, even the newest version, Diva_6.1.2, is still unable to generate histogram overlays, a popular and convincing tool for direct data comparison. We hereby present an easy and down-to-earth Diva-Figure-improvement toolbox (Diva-Fit), which facilitates the generation of high-resolution graphs based on data acquired with FACSDiva software. Moreover, Diva-Fit allows the easy removal of unwanted quadrant labels without impairing the quality of FACS plots. Finally, we show that Diva-Fit supports straightforward composition of histogram overlays. All software tools necessary are freely available. We believe that the proposed toolbox may be very useful for many researchers working with flow cytometry.

Methods

Diva-Fit: A step-by-step manual for generating high-resolution graphs and histogram overlays of flow cytometry data obtained with FACSDiva software – Supplementary material

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Kristoffer Weber, Boris Fehse

Research Dept. Cell and Gene Therapy, Clinic for Stem Cell Transplantation, UCCH, University Medical Centre Hamburg-Eppendorf, Germany


Correspondence:
Research Dept. Cell and Gene Therapy, Clinic for Stem Cell Transplantation, UCCH, University Medical Centre Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
Phone: +49-40-7410-52705 / +49-40-7410-55518
E-mail: k.weber@spam is baduke.de or fehse@spam is baduke.de

Here we describe all procedures depicted in the named article in more detail.

Part 1: How to extract high-resolution dot plots and histograms from FACSDiva
Part 2: How to generate histogram overlays (based upon Part 1)
Part 3: How to delete quadrant labels (Q1–Q4) within dot plots (based upon Part 1)

Hematology review

Ph-positive leukemias in the era of modern cytogenetics, molecular biology, tyrosine kinase inhibitors and hematopoietic stem cell transplantation

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Nikolay N. Mamaev

St. Petersburg Pavlov State Medical University, St. Petersburg, Russia


Correspondence:
Nikolay N. Mamaev, Clinical-laboratory Diagnostics Chair, Cytogenetic Lab, St. Petersburg Pavlov State Medical University, 6/8, Tolstoy str., St. Petersburg, 198022, Russia
Phone: +7 (812) 233-12-43 (office) or +7 (812) 726-53-25 (home)
E-mail: nikmamaev@spam is badrambler.ru

The review is devoted to the complex problems of modern cytogenetic and molecular diagnostics of Ph-positive leukemias, their treatment in era tyrosine kinase inhibitors and hematopoietic stem cell transplantation at the condition of cytogenetic and molecular monitoring.

Forum

Research articles in English: what should be considered before submitting a manuscript

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Alexey Nevorotin

I. P. Pavlov Medical University, St. Petersburg, Russia

The author of this compact essay and also of a book on the same topic [1] has always realized that the successful submission of manuscripts to English–language journals invariably requires not only good English but also a high level of research and – in my compatriots’ view – a very special style in which the results should be presented. These prerequisites for successful submission are indispensable, because an editorial board will flatly reject as unreliable even the most interesting results if they are vague, poorly substantiated, and/or the manuscript is incomprehensible. In this study, these three pre-requisites – the level of the results, style of content presentation, and language – will be considered in relation to research articles (RA) intended for submission to English–language journals. Special attention will be paid to the clear differences – despite globalization – in mentalities between Russian scientists and those originating from English-speaking environments, which will both facilitate success and alleviate the sense of bitterness amongst Russian scientists in the case of refusal by encouraging the researcher to adopt the appropriate method in subsequent efforts. Regardless of nationality, the potential contributor to a given journal should clearly understand that when submitting an RA manuscript, the author must either adhere to the journal’s standards or not waste his/her efforts. As the Russian proverb states: “Nobody goes to another monastery with one's own charter.” For convenience, the term author will be used hereafter to denote either a single person, tandem authors, or a team of researchers united by the aim of submitting an RA manuscript – this one included – to an English–language journal.

Forum

Scientific writing navigation: jump in and take a few hits

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Robert M. Frederickson

Editor Molecular Therapy, www.nature.com/mt