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CENTRE FOR PRE-CLINICAL TESTING OF ACTIVE SUBSTANCES

Final Report Summary - CPCTAS (Centre for pre-clinical testing of active substances)

Project context and objectives:

CPCTAS is a project financed under the Seventh Framework Programme (FP7) within Regions of knowledge Work Programme through the Coordination and Support Actions funding scheme. The project coordinator was Faculty of Science University of Kragujevac, Serbia (FSUKG). Other project beneficiaries were: Faculty of Medicine University of Kragujevac (FMUKG), Institute Curie Paris (ICSR), School of Medicine, Aristotle University Thessalonica (SMT) and Faculty of Natural Sciences and Mathematics Skopje (FNSMS). Realisation of the CPCTAS project started on 1 May 2008.

The broad objective of this project was to establish regional centre for pre-clinical testing of active substances that will cooperate with both hospitals and pharmaceutical industries from many countries of Western Balkan.

The first project objective was to bring together the existing laboratories at the University of Kragujevac currently working on some of the aspects of drug testing and to establish formal centralised research Centre for pre-clinical testing of active substances. The second project objective was to reinforce research potential of the CPCTAS through the networking and international cooperation of existing laboratories in Serbia with the members of the European Research Area (ERA). It was planned to reinforce existing CPCTAS capacities during 36 months project period through training and re-training of the researchers, upgrade and renewal of equipment, and exchange of know-how and experience. The third project objective was to provide international reliability of the future research results. Standardisation of the testing methodology and accreditation of laboratory according to ISO 17025 standard and appropriate European Union (EU) legislative were chosen as the main tools in accomplishing this objective. Finally, disseminative activities were foreseen in order to assure realisation of the fourth project objective - recognition of the centre as a respectable and reliable partner in the field of testing of active substances.

The main activities, recognised as necessary for the realisation of this project, were international cooperation through networking, exchange of know-how and experience and upgrading of the CPCTAS research capacities to the highest quality.

At the beginning of the project CPCTAS was registered as a formal centre in FSUKG Statute according to the internal regulations and with approval of the University of Kragujevac. Organisational structure of the centre was established and six young researchers and one technician were employed.

Upgrading of the centre's research potentials started with scientific training of young researchers and purchase of equipment. It was continued with organisation of workshops for exchanging of experience and know-how between project beneficiaries. Re-training of already employed researchers in form of one-month visits to EU partners was started as a part of upgrade of the Centre's research potentials.

All newly employed young researchers realised two-month and one-month visits for research trainings to EU laboratories as planned. Re-training of seven professional researchers from FSUKG, FMUKG and FNSMS at ICSR and SMT was realised. Five workshops for exchange of know-how and research experience were organised during project period with participation of experts from all beneficiaries. Scientific conference 'Preclinical testing of active substances and cancer research' was held at the end of project period as final, crucial activity for upgrading CPCTAS research potentials.

Dissemination of project results was realised through the project web site with daily updated information about all project activities. Project results were disseminated both internally (workshop organisation) and externally (television, newspapers, WIRE2010).

During CPCTAS project, long lasting network of research institutions from EU and Western Balkan countries (WBC) interested in the development and testing of active substances established. International cooperation, that was promoted through this project, is a positive example not only for spreading ERA to WBC, but also for increasing the competitiveness of WBC centres of excellence and research institutions inside of ERA. Laboratories at University of Kragujevac already had significant research results in pre-clinical testing of active substances. Reinforcing them into centralised CPCTAS, renewing equipment and re-educating researchers boosted their capacities and give CPCTAS the opportunity to become a leading institution in WBC region. The environment that created at the CPCTAS will give chance to carry out high quality research in the cooperation with EU institutions. Upgrading research on active substances for human usage through the exchange of experience and research results, potential development of new testing methodologies and the cooperation and networking that established between EU and WBC partners is the main benefit from this project.

The final result of the project is established Centre for pre-clinical testing of active substances with significant research potential that cooperate with both hospitals and pharmaceutical industries. The international cooperation between EU and Western Balkan partner institutions that was established through this project is a strong foundation for current and future mutual research activities. This cooperation accelerate the setting up of sustainable partnership between the most competitive research centres of EU and WBC with the research interests in the investigation of active substances. Twining of testing methodologies is realised in the laboratories in EU and in Western Balkan towards the improvement of research capacities of Western Balkan centres. Scientific and technological reintegration of Serbian society into the ERA, reinforcement of scientific and technical human resources and infrastructures and upgrading of research programmes are the main benefits of this project.

Better and more integrated Western Balkan countries in the FP7 networks and RTD projects as well as in the Member State's national cooperation programmes as a prerequisite of these countries successful integration into ERA are achieved.

Project results:

The complexity and the quantity of the proposed work demand collaborative efforts of many laboratories possessing different expertise. The CPCTAS was assembled by fusing three laboratories that currently work in the scope of FSUKG (for bioinorganic chemistry, microbiology and physiology) and two laboratories from the FMUKG (for immunology and pharmacology) with the central laboratory organised at the FSUKG - Laboratory for Cell and Molecular Biology. The mentioned laboratories have already recognised a common interest for integration, cooperation and development of the CPCTAS. The organisational scheme of the CPCTAS (administration, management and research) was made according to the available models and positive experience of EU partner's institutions. The laboratory for bioinorganic chemistry produces chemical substances as potential medicaments. Those substances are further tested in the other laboratories using currently available assays such as microbiological, biochemical, immunological, immunohistochemical and pharmacological. In order to complete the basic research phase of the pre-clinical drug discovery process, molecular-based assays that were unavailable at the start of the project, was developed in the central laboratory. Active substances that pass this first phase of testing, being characterised as potentially beneficial to human could be further tested on animal models. Animal aspect of pre-clinical drug screening was not part of the current project. However, it could be developed in the future guided by EU partners, especially ICSR which has long successful experience in the use of animal models for drug testing.

The possible risk that could prevent the development of the CPCTAS, as potentially unstable economic and political situation in Republic of Serbia, were not influenced CPCTAS project realisation. Moreover, strong support and full recognition of CPCTAS development benefit by the respectable national institutions and ministry of science is achieved. High-quality work of the project manager, CPCTAS management team and respectable project officer, their skilful communication with the respectable organisations and officials significantly lowered all risk for project progress.

The proper development of the CPCTAS and its accreditation according to ISO/IEC 17025 standard required international cooperation of professional staff from FSUKG and FMUKG with EU partners. The experience and research potential of the two respectable EU partner institutions, such as ICSR and SMT, was assisted development of the CPCTAS and its positioning as a leading research centre in WBC region. The engagement of another WBC partner from FYR Macedonia was of crucial importance for reintegration of WBC region and restoration of trans-national cooperation in Western Balkan.

Assistance of EU partner institutions in the development of the CPCTAS included reinforcement of technical potentials, re-training and training of the CPCTAS researchers and exchange of scientific know-how. At the begging of the project, existing equipment in CPCTAS laboratories was functional for standard haematological, biochemical, microbiological, physiological, immunological, histological and pharmacological analysis. However, in general this equipment was old, in some cases even more than a several decades. Therefore, the reinforcement of equipment was necessary precondition for successful functioning of the CPCTAS. The new equipment was purchased at the beginning of the first project year. An employment of qualified technicians and researchers, in total number of seven persons, was necessary to insure that equipment will be adequately used. The recruitment of the personnel was made in the first trimester and they were started working once CPCTAS is formally recognised. Short stays, in duration of two months, in EU partner institutions were organised for newly employed researchers for either basic training in molecular biology, biochemistry and cell biology techniques or for specialised training for specific techniques, such as RT-PCR. Possible risk for project implementation - the low interest of researchers for the education and training abroad, was not actualised during project period. In addition, we were aware of need for re-training of our permanent professional staff. In order to be re-trained for use of the modern equipment and techniques, permanent researches currently working at the laboratories at the FSUKG and FMUKG as well as at the FNSMS were performed an internship in duration of one month at the EU partner institution. The total number of senior researchers that was included in this activity is seven.

Workshops for the exchange of know-how and experience between EU partners and WBC partners were organised at the CPCTAS. Short stays of EU partners at the CPCTAS were a chance to establish the collaborations with colleagues from WBC region regarding specific research activities. Finally, scientific conference 'Preclinical testing of active substances and cancer research' was held at the end of project period, and considered as final, crucial activity for upgrading CPCTAS research potentials. These activities were continued during the whole project lifetime.

The dissemination of the CPCTAS development and project results was realised through the website, connections with institutions of interest (pharmaceutical companies, hospitals, ministry of science) and through the workshops. The purpose of these dissemination workshops was to spread the awareness of importance of active substances investigation for human use with special attention to the CPCTAS' role in this process. The Website was created in first two project months. Seven dissemination workshops were organised during project period. The sustainability of the CPCTAS was assured by implementation of standardised testing procedures necessary for the international recognition of research results, and by accreditation of the CPCTAS according to the ISO/IEC 17025 standards issued by competent standardisation bodies in Serbia. All necessary procedures were internally adopted and implemented in the CPCTAS before the end of the project. Successful dissemination of project results was further insured the sustainability of the CPCTAS through the financial support by Serbian Ministry of Education and Science within research projects.

Full development of the complex and multidisciplinary centre, such as CPCTAS at University of Kragujevac, was required the period of three years. Long period is due to the time necessary for the adequate re-education of permanent staff, employment and education of new staff, update and purchase of the equipment, upgrade and standardisation of existing and new methodologies according to EU standards as well as for establishment of the international cooperation that would lead CPCTAS to the integration in ERA.

During project period, all planed milestones - implemented website, formal adoption of CPCTAS with organisational scheme, employment of new professional staff, equipment purchasing, information system software, retrained professional staff, adoption of management system of quality according to ISO 17025 standards, accreditation - were achieved with small correction in timing of the last one (ISO 17025 accreditation is under process). All deliverables were also correctly submitted during project period. The all planed project activities were realised with 92.64 % of granted EU budget.

Project objectives and achieved results

1. One of the main project objectives was to bring together the existing laboratories at the University of Kragujevac that have been working on some of the aspects of drug testing and to establish formal centralised research centre for pre-clinical testing of active substances. It was planned to achieve this objective through creation of the institutional regulatory acts at the FSUKG and with its approval at the University of Kragujevac.

The official adoption of CPCTAS by the respectable institutions in Serbia. The official adoption of the CPCTAS was performed by FSUKG in the period before project started, finished in March 2008. The CPCTAS was registered as a formal centre in FSUKG Statute according to the internal regulations and with approval of the University of Kragujevac (see http://cpctas.pmf.kg.ac.rs online).

The visit of the Serbian CPCTAS management team to the EU partner institutions was realised in the beginning and at the end of the project. The important aspect of these visits was the introduction to the management, administration and research organisation of the EU and WBC partner institutions. This experience helped to organise the management structure and work in CPCTAS.

2. The second project objective was upgrade of research potentials of established centre. It was planned to achieve this through upgrade and renewal of both personal and technical capacities of the centre. Employment of six new young researchers and one technician in centre was planned. It is planned to upgrade CPCTAS research potential through two-month trainings of newly employed young researchers, as well as one-month trainings of senior researchers in EU partner institutions. Upgrade and renewal of the research equipment required for the functioning of the CPCTAS was planned according to the model laboratories in EU partner's institutions. Organisation of workshops and seminars / conference was planned as another important activity for upgrading CPCTAS research potentials.

The employment of the new professional staff. Young researchers, six researchers and one technician, employed by the contract for the work on the project, and their engagement were last during the whole project period.

New employed researchers (see http://cpctas.pmf.kg.ac.rs online): Ivana D. Radojevic, MSc of Biology, PhD student, FSUKG; Jovana B. Zizic, graduated molecular biologist and physiologist, PhD student, FSUKG; Dragana S. Djacic, graduated biologist, PhD student, FSUKG; Marija Milovanovic, MD, PhD student, FMUKG; Vladislav Volarevic, MD, PhD student, FMUKG; Milorad Milosev, MSc of Biochemistry, PhD student, FMUKG. Technician staff: Ana Obradovic, graduated biologist, FSUKG.

Newly employed researchers were engaged in introduction of the adequate use and exploitation of the new equipment, for standardisation of the existing and adoption of the new methodologies for testing of the active substances. The full use of the purchased equipment, as well as the standardisation of the old and new methods for testing of active substances according to the ISO standards was realised during project period.

All new employed researchers (CPCTAS contract) were continuing engagement in home laboratories, financed by research projects of Serbian Ministry of Education and Science. Central part of these new research projects is interdisciplinary project 'Preclinical testing of bioactive substances' (PIBAS), Reg. No 41010, started from 1 January 2011. Research activities in central CPCTAS laboratory (Laboratory for Cell and Molecular Biology) are part of the main subproject within PIBAS project. Within this new project three young researchers (Jovana Zizic, Dragana Djacic and Ivana Radojevic) and one technician (Ana Obradovic) from FSUKG (previously contracted within CPCTAS project) were successfully employed for next four years. Additionally five more new young researchers were employed in CPCTAS laboratories (at FSUKG and FMUKG) within this new project for next four years.
The technical equipping of the CPCTAS. Upgrade and renewal of the research equipment required for the functioning of the CPCTAS was planned according to the model laboratories in EU partner's institutions. All planned equipment was purchased, installed and in use. This activity was resulted by established and technically equipped common central laboratory for cell and molecular biology, which can complete process of cell and molecular testing of active substances. The purchase of the Apparatus for registration of isometric forces and intraluminal pressure in isolated hollow organs and RT thermocycler for the Laboratory for Pharmacology and Laboratory for Immunology, FMUKG, respectively are additionally upgrade of CPCTAS work.

The main results of this task are:

(i) all new equipments are in use;
(ii) new methodologies standardised according to EU and ISO standards are in use;
(iii) over 15 official reports about tested active substances were deliver from central laboratory; and
(iv) more than 20 references (per-review), regarding preclinical testing of active substances, resulted during project period.

Realised equipment purchase:

1. real time PCR system 7500
2. thermo scientific Sorvall WX 80 ultra centrifuge series
3. Systec autoclave VX 55
4. inverted research microscope Nikon ECLIPSE Ti-E
5. vertical laminar flow cabinet BH-EN 2003-S
6. CO2 incubator MD 151 UV Medline
7. liquid nitrogen container
8. microscope Nikon TS 100
9. RT thermocycler Mastercycler ep relplex2 S, Eppendorf
10. apparatus for registration of isometric forces and intraluminal pressure in isolated hollow organs.

All procedures and documentation for purchased equipment were finished in accordance with the Serbian low and legislative.

Mobility (research training and re-training of the professional staff) from WBC partners to EU partner institutions

Re-trained professional staff from FSUKG, FMUKG and FNSMS at ICSR and SMT laboratories. The one-month re-training of the permanently employed professional staff (five persons) from FSUKG and FMUKG, and two persons from FNSMS in the EU partner institutions performed during the project period. Important aspect of these visits was introducing to the research and lab management organisation, as well as mastering of the techniques, methodology and equipment used in EU laboratories. Re-trained permanently employed researchers with working experience in scientific research area had very important role in CPCTAS development due to following reasons:

(i) for adequate organisation of research work and coordination of new employed staff;
(ii) for adequate categorisation, purchasing and work with new equipment;
(iii) transfer of scientific experience from ICSR and SMT laboratories to CPCTAS.

Assistant Natasa Djordjevic, PhD student (field of investigation is physiology) and assistant Olgica Stefanovic, PhD student (field of investigation is microbiology) from FSUKG spent one month per person at ICSR Laboratories in August 2008 (1 August 2008 - 31 August 2008; month 4). Host laboratory: Daniel Louvard (team Danijela Vignjevic). Supervisor: Danijela Vignjevic. Training for following techniques: genotyping; PCR; DNA electrophoresis; cell cultures techniques; dissection of mice.

Milan Novakovic, researcher from Laboratory for pharmacology, FMUKG spent one month at SMT Laboratories in February 2010 (1 February 2010 - 1 March 2010; month 22). Host laboratory: Prof. Dr Dimitrios Kouvelas, Laboratory for Pharmacology. Supervisor: Prof. Dr Dimitrios Kouvelas. Training for following techniques was realised: methods and techniques for design experiment, cell culture, DNA and RNA extraction, real-time PCR, gene expression analysis and gene polymorphism analysis.

Suzana Popovic, senior researcher from Laboratory for Microbiology and Immunology, FMUKG spent one month at SMT Laboratories in July and August 2010 (19 July 2010 - 15 August 2010; months 27 and 28). Host laboratory: Laboratory for Pharmacology. Supervisor: Prof. Dr Dimitrios Kouvelas. Training for following basic techniques in molecular biology was realised: RT PCR and qRT-PCRI, designing primers and determination of primer specificity and optimal concentration for qRT-PCR, RNA isolation, determination of RNA concentration, and evaluation of RNA quality.

Snezana Zivancevic-Simonovic, senior researcher from FMUKG spent one month at SMT Laboratories in April 2011 (1 April 2011 - 30 April 2011; month 36). Host laboratory: Laboratory for Pharmacology. Supervisor: Prof. Dr Dimitrios Kouvelas. Training for following techniques was realised: methods and techniques for design experiment, cell culture, DNA and RNA extraction, real-time PCR, gene expression analysis and gene polymorphism analysis, RT PCR and qRT-PCRI.

Ivan Kungulovski, researcher from Laboratory of Microbiology at the Institute of Biology, FNSMS spent three weeks at Curie Institute, Centre de Recherche, in December 2010 (1 to 24 December 2010; month 32). Host laboratory: Dr Philippe Chavrier, Laboratory of cell biology, Supervisor: Guillaume Montagnac Research scientist at INSERM Institut Curie. Training for following techniques was realised: methods and techniques for design experiments, cell culture, DNA and RNA extraction, PCR, and molecular biology focused on cloning.

Oliver Tusevski, young researcher from Laboratory of Plant Cell and Tissue Culture, FNSMS spent two weeks at SMT Laboratories in April 2011 (3 to 18 April 2011; month 36). Host laboratory: Laboratory for Pharmacology. Supervisor: Prof. Dr Dimitrios Kouvelas. Training for following techniques was realised: methods and techniques for design experiments, development of cell cultures, DNA and RNA extraction, primer design, real-time PCR, gene expression analysis and gene polymorphism analysis.

Trained newly employed researchers from CPCTAS at EU partner laboratories. Two-months (five persons) and one-month (two persons) trainings of new employed young researchers from FSUKG and FMUKG in the network partner institutions were performed during the project period. Important aspect of these visits was the introducing to the research and lab management organisation, as well as mastering of the techniques, methodology and equipment used in EU laboratories. New employed researchers mastered of techniques, methodology and equipment used at ICSR and SMT laboratories in accordance with requirements of the CPCTAS. The students were also introduced to the positive lab routine, such as the organisation of the experiments, presentation and the discussion of the obtained data etc. Additional two-week scientific trainings (seven persons) realised in April 2011 represent significant added value in improving research potentials of CPCTAS and in strengthening networking. During two-week visits new young researchers were introduced with examples of good practice in prominent European labs and young researchers previously contracted to CPCTAS project were extended their research experience. More information about realised visits during this reporting period are available at the web address: http://cpctas.pmf.kg.ac.rs

Dragana Djacic, PhD student from FSUKG was spending two months at ICSR Laboratories in November and December 2008 (2 November 2008 - 24 December 2008; months 7 and 8). Host laboratory: Daniel Louvard (team Danijela Vignjevic). Supervisor: Marie Schoumacher, Nadia Elkhatib, Danijela Vignjevic. Training for following techniques: cell cultures techniques; microscopy; DNA and protein electrophoresis; western blot.

Jovana Zizic, PhD student from FSUKG was spending two months at ICSR Laboratories in November and December 2008 (2 November 2008 - 24 December 2008; months 7 and 8). Host laboratory: François Radvanyi. Supervisors: Celine Vallot, Sandra Rebouissou, Johannes Aubertin, Fatima El Marjou, Danijela Vignjevic. Training for following techniques: isolation of RNA; RT-PCR; qRT-PCR; PCR; DNA sequencing and sequence analysis; genotyping of mice; DNA electrophoresis; theoretical molecular cloning.

Gordana Vasic, researcher from FSUKG spent two months at SMT Laboratories in April, May and June 2009 (27 April 2009 - 26 June 2009.; months 12 to 14). Host laboratory: Prof. Dr Helen Tsoukali, Laboratory for Forensic Medicine and Toxicology. Supervisors: Prof. Dr Nikos Raikos, Prof. Dr Constantinos Zacharis. Training for following techniques was realised: methods and techniques for identification of active substances and toxicology, gas chromatography-mass spectroscopy (GC-MS) technique and high pressure liquid chromatography (HPLC) technique.

Milorad Milosev, young researcher from FMUKG spent one month at SMT Laboratories in June 2009 (1 June 2009 - 1 July 2009; month 14). Host laboratory: Prof. Dr Dimitrios Kouvelas, Laboratory for Pharmacology. Supervisor: Prof. Dr Dimitrios Kouvelas. Training for following techniques was realised: additional methods of testing antimicrobial activity, especially for substances with modulate activity on antibiotics, possible use as pharmaceutical adjuvant.

Vladislav Volarevic, young researcher from FMUKG spent two months at ICSR Laboratories in June and July 2009 (1 June 2009 - 20 July 2009; months 14 and 15). Host laboratory: Prof. Dr Sebastian Amigorena, Immunology Laboratory. Supervisor: Rhys Allen. Training for following techniques was realised: sterile work with cell cultures, isolation of mesenchymal stem cells from mice bone marrow, isolation of lymphocytes from mice lymph nodes and spleens, in vitro activation of CD8+T cells, Western blot (preparation of reagents, probes, membrane striping, and film developing), basic principles of FACS analysis and real-time PCR.

Marija Milovanovic, young researcher from FMUKG spent two months at ICSR Laboratories in June and July 2009 (1 June 2009 - 20 July 2009; months 14 and 15). Host laboratory: Philippe Chavrier. Supervisor: Guillaume Montagnac. Training for following techniques was realised: western blot, FACS analysis, plasmide and siRNA cell transfections; and principles of PCR muthagenesis, DNA sequencing and sequence analysis and microscopy (epifluorescence, TIRF, spinning and electron microscopy).

Ivana Radojevic, young researcher from FSUKG spent one month at FNSMS Laboratories in April and May 2010 (27 April 2010 - 31 May 2010; months 24 and 25). Host laboratory: Laboratory for Microbiology. Supervisor: Prof. Dr Dzoko Kungulovski. Training for following techniques was realised: basic techniques for microbiological quality control of pharmaceutical products, adaptation, selection, growth and control of aerobic granulated bacteria, and routine techniques in molecular microbiology.

Ana Obradovic young researcher from FSUKG spent two weeks at FNSMS Laboratories in April 2011 (4 to 15 April 2011; month 36). Host laboratory: Laboratory for Molecular Biology. Supervisor: Prof. Dr Sasho Panov. Training for following techniques was realised: getting up to date with advanced techniques in molecular biology and clinical diagnosis of human Papilloma virus (HPV).

Dragana Djacic and Milena Curcic, young researchers from FSUKG spent two weeks at FNSMS Laboratories in April 2011 (1 to 16 April 2011; month 36). Host laboratory: Department of Experimental Physiology and Biochemistry, Faculty of Science and Mathematics, FYROM. Supervisor: Assistant Professor Jasmina Dimitrova-Shumkovska. Training for following techniques was realised: biochemical assay - Bradford, TBARS, AOPP, DNPH, determination antioxidant activity of plant and fungi (DPPH assay), activities of different enzymes (catalase, peroxidase) in plant extracts and work with laboratory rat and mice.

Ivana Radojevic and Sava Vasic, young researchers from FSUKG spent two weeks at SMT Laboratories in April 2011 (3 to 18 April 2011; month 36). Host laboratory: Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki. Supervisor: Prof. Dr Dimitrios Kouvelas. Training for following techniques was realised: molecular biology techniques, being able to design the experiment, cell cultures, DNA, RNA extraction, RT-PCR, gene expression analysis.

Jovana Zizic and Danijela Cvetkovic, young researchers from FSUKG spent two weeks at ICSR Laboratories in April 2011 (10 to 21 April 2011; month 36). Host laboratory: Département de Recherche Translationnelle Equipe Biologie du Cancer du Sein Hôpital Saint-Louis Quadrilatère historique. Supervisor: Prof. Dr Thierry Dubois. Training for following techniques was realised: getting up to date with advanced techniques in molecular biology and platforms for automated processing of DNA and protein arrays.

Workshops and seminars organisation. In order to develop CPCTAS with significant research potential in Serbia, it was necessary to organise five know-how workshops and one scientific conference during project period. All workshops were attend by EU experts and they transferred their own organisational and research experience through presentations, discussions and work sessions to professional staff from FSUKG, FMUKG and FNSMS. These activities resulted in the international cooperation between EU and Western Balkan partner institutions, and it is a strong foundation for current and future mutual research activities. This cooperation accelerate the setting up of sustainable partnership between the most competitive research centres of EU and WBC with the research interests in the investigation of active substances. Twining of testing methodologies is realised in the laboratories in EU and in Western Balkan towards the improvement of research capacities of Western Balkan centres. Scientific and technological reintegration of Serbian society into the ERA, reinforcement of scientific and technical human resources and infrastructures and upgrading of research programmes are the main benefits of this project.

The first workshop - Place: CPCTAS, Kragujevac; Date: 16 - 20February 2009

At this workshop, the ICSR experts delivered formal lectures, transferred know-how and their own experiences from the work organisation in their laboratories. During working sessions, the ICSR experts helped to organise work in the newly equipped CPCTAS and also helped to young educated staff to master the methodologies. In the separate session, young researchers from FMUKG presented projects that have been realised in laboratories for experimental immunology and molecular oncology since 2008.

The second CPCTAS workshop - Place: CPCTAS, Kragujevac; Date: 16 - 17 October 2009

The second CPCTAS workshop was realised under the title Pre-clinical testing of active substances on cancer and various model systems. Representatives of all project partners were present at this workshop. Presentation of realised activities of the CPCTAS project was made by project coordinator and CPCTAS team. During the lecture sessions experts from ICSR, SMT and FNSMS presented their research experience and transferred know-how to CPCTAS members. Very opened discussions between participants gave opportunity to CPCTAS members to gain new knowledge and to clarify all dilemmas for future research work.

The third CPCTAS workshop - Place: CPCTAS, Kragujevac; Date: 8-9 March 2010

The third CPCTAS workshop was realised under the title Pre-clinical pharmacological and toxicological testing of active substances with presence of experts from SMT. Working sessions and lectures directed to transfer of know-how and experience to CPCTAS team members on current topics in pharmacological testing of active substances, central nervous system, sample size calculation for experimental studies, natural products and drug food interactions and reproductive toxicity studies were organised at FSUKG and FMUKG. Very useful discussions on several practical issues were made in CPCTAS central laboratory.

The forth workshop - Place: CPCTAS, Kragujevac; Date: 13-15 December 2010

The forth workshop was realised under the title 'Antimicrobial activity of active substances', with presence of colleagues from FNSMS and research team from FSUKG. During this workshop, the representative of local management team were discuss with Prof. Dr Kungulovski about CPCTAS results, plans for third project year, organisation of education of senior researchers from FNSMS, organisation of conference in March, 2011, and financial plan for the last five months of project. Research part of this workshop was realised at the Laboratory for Microbiology, regarding to antimicrobial activity of natural occurring compounds (plant extracts, essential oils) and synthesised compounds (the metal-based compounds).

The fifth workshop - Place: CPCTAS, Kragujevac; Date: 27-29 December 2010

The fifth workshop was realised under the title 'Cytotoxic aspects of active substances. Development of cancer research in CPCTAS', with presence of Dr Danijela Vignjevic-Matic from ICSR and research team from FSUKG. During this workshop, the representative of local management team were discuss with Dr Vignjevic-Matic about CPCTAS results, plans for third project year, organisation of education of senior researchers from FNSMS at ICSR, organisation of conference in March, 2011, and financial plan for the last five months of project. Know-how transfer and research part of this workshop was realised at the Laboratory for Cell and Molecular Biology regarding to the next tasks:

(i) discussion of realised investigation and plan of testing in the next six-month, considering methodologies and techniques of cancer research and testing of active substances;
(ii) current and future research in CPCTAS laboratory;
(iii) analysing the microscopic images (apoptosis, necrosis) and discussion about new approaches in microscopy investigation.

International scientific conference 'Preclinical testing of active substances and cancer research' - Place: Hotel Sumarice, Kragujevac; Date: 16-18 March 2011

Scientific conference entitled 'Preclinical testing of active substances in cancer research' with an internationally recognised symposium on 'Anti-cancer agents, cardiotoxicity and neurotoxicity' was held in Kragujevac, Serbia from 16-18 March 2011. This conference was, beside all other activities, organised as final activity of three year work in frame of FP7 CPCTAS project. The main goal of the conference - to animate many researchers from country and European Union to cooperate on mutual task - multidisciplinary examination of problems in testing active substances in scope of discovery of more efficient drugs, as well as, studying new possibilities in treating cancer patients and problems regarding it, was fully accomplished. The second goal - transfer of new ideas between eminent researchers from country and EU and region was also achieved. Because of the scientific importance, it is expected that the conference with same subject matter would be held periodically.

Conference was divided and completed throughout three topic segments:

1. Scientific conference with international participation 'Preclinical testing of active substances and cancer research'. Within two oral and one poster session, the results of testing of active substances in reputable laboratories and institutions abroad and in our country, were presented. Presented results showed remarkable potential of our laboratories and researchers in field of chemical synthesis of new active substances with improved antimicrobial and antiproliferative properties compared to standard micostatics and cytostatics. It was also clearly showed the inexhaustible source of bioactive substances isolated from natural materials (plants, lichen, fungi), as well as, their good anitmicotic and cytostatic activity. Wide spectrum of preclinical testing of new active substances (chemicals and isolated from plant material) on prokaryotic, eukaryotic and animal model systems, as well as, the efficiency of these analysis, represents important part of the results presented on this conference.

Within three oral and one poster session, results of most recent studies in examination of cancer problems, were presented by Institute Curie from Paris which is one of the most respectable institutions in world in that field of research. There were, in the same place, all leading laboratories and institutions from our country that are dealing with etiology, mechanisms and cancer therapy. Presented results have shown the utmost importance of examination of cancer in molecular level in scope of efficient prevention and therapy of this disease. It was also shown the significance of novel active substances and its cytostatic and proapoptotic effects, as well as, the importance of preclinical testing of these substances on cancer model systems (cell lines, animal models).

2. International symposium on 'Anti-cancer agents, cardiotoxicity and neurotoxicity'. Within international symposium, the importance of anticancer drugs was presented and their effects on cardiovascular and nervous system. Results from this field of study were presented by the most eminent experts and world institutions (Canada, Russia, Belorussia, Slovakia). Presented results showed also major contribution of our eminent experts in therapeutic aspect of cancer research.

3. FP7 Info day - Disseminative session

Scientific conference in figures: number of registered participants was 115 (over 30 more nonregistered viewers in 3 days), 31 researcher from abroad participated (11 from France, 9 from FYROM, 5 from Greece, 2 from Canada, 2 from Russia, 1 from Belarus, 1 from Slovakia), 2 review lectures were given, 44 oral presentations were made, 35 posters presentations were given, 81 abstract was printed in the Conference Abstract book (ISBN 978-86-7760-064-8).

In order to follow progress in CPCTAS development and adequate realisation of project activities, an internal quality and monitoring control was made by EU partner experts. The first and second quality control and monitoring reports were delivered by the ICSR and SMT experts. Dr Thierry Dubois (ICSR) and Prof. Dr Dimitrios Kouvelas (SMT) made quality control and monitoring reports on project activities progress. In these reports, special attention was given to research training of young researchers and to workshops organisation. The both reports were positive with recommendations for future work.

3. The third project objective was to provide international reliability of the future research results. That is provided through standardisation of the testing methodology and the implementation of the quality management system according to the ISO/IEC 17025 standard, performed by the responsible institutions in Serbia. Implementation of the information system together with purchase of computer equipment was planned as a core supporting activity for this objective.

Standardisation of CPCTAS methodologies according to ISO standards

Activities on standardisation started with organisational scheme creation process. Mission and vision of the CPCTAS defined together with basic rules for centre day-to-day work. Analysis of methodologies and techniques from aspects of methodology standardisation started from November 2008 with full engagement of all employed professionals at the CPCTAS. Preparation of the procedures and routines requested for ISO/IEC 17025 standard accreditation was done respecting analysis results. Quality management system according to ISO/IEC 17025 standard for central Laboratory for Cell and Molecular Biology was adopted in March 2011. All necessary documents were made. Certification procedure from the national certification authority (Accreditation Body of Serbia) for the ISO/IEC 17025 standard was started in April 2011 and it is expected that it will be finished until the December 2011.

Accreditation of research laboratory means international acceptance of results of testing, as well as, certified independence and technical competence of laboratory, by which laboratory is able to increase its size of work and participate in different aspects of interlaboratory cooperation such as proficiency testing, interlaboratory comparisons and agreements. Regarding research laboratories, accreditation guarantees competence of provided service, as well as, ongoing raise of organising levels and technical capacities. EU area that is founded on common rules and same conditions of international competition based on standard definition on evaluation of compliance presents one of the leading world markets. Recognition and comparison the accredited laboratories' results of testing, independently of the country they come from, represents one of the main advantages in gaining confidence and rights to placement. Taking into account all above said, laboratories that wish to put quality in the first place and to be competitive on market, perceive advantages in implementation of ISO standard and by that they minimise the level of documentation needed to confirm validation of applied methods.

The key of accredited laboratories competence is their technical competence for research that is based on valid equipment (with allowed measurement uncertainty), certified methods of testing and using of referent materials. Relevant documents, such as standards, protocols for equipment and material using that are published by expert organisations and in science papers, are being used in laboratories for defining research procedures and their application.

What can the experience of Laboratory for Cell and Molecular Biology show?

Defined research procedures are implemented. Adequate research in all phases of laboratory work is being accomplished. The existing capacities and working conditions are optimally being used. High efficiency in work is achieved. Required emergency in completing results is achieved. There is good communication between users and Laboratory. Good cooperation with services of Clinical Centre in Kragujevac is established. After acquired certificate of accreditation the Laboratory is working on constant maintenance and improvement of quality management system by education of employees, regular and emergency work control, by evaluation of achieved work, by application of corrective and preventive measures, etc. Laboratory is aware that development and application of standards for accreditation is dynamic process, which means that documentation has to be re-evaluated and supplemented all the time particularly in case of application for medical laboratory work, and afterwards accreditation on ISO 15189 standard, regarding medical laboratories, would be reconsidered.

Integration with information system

Implementation of the information system was started in second project year and it was realised through three phases: data preparation, software design and software development. Information system implemented and started with testing work in February 2010. Assistant professor Vladimir Cvjetkovic from Department for Physics, Faculty of Science in Kragujevac, was the leading person for this activity. During the third project year, information system was updated and extended in order to support process of ISO accreditation. Information system is available at the web address http://cpctasis.pmf.kg.ac.rs

Information system is the program for general information support of some real system offering many benefits that result in the better management and insight of the real system. CPCTAS CPCTASIS is designed and developed with the aim to cover the most important aspects of the CPCTAS and to offer the information support for the CPCTAS centre where it is needed the most. CPCTASIS is based on the data base with structure that closely resembles the CPCTAS centre structure and includes all important entities and their relationships.

CPCTASIS model that resulted from the analysis included institutions, laboratories, human resources, equipment, experiments, research and publication as the most important entity types that build up the CPCTAS system. Each of the mentioned entity types needed further analysis that resulted in decomposition and detailed structure. Previous integration of web site with information system was kept and further developed, so the web user interface is the main mean for user interaction with CPCTAS Information System, both for data input, and for obtaining data in the form of various required dynamic reports. Special attention was paid to requirements of various data forms and reports necessary for the implementation of the 17025 standard. Further development of the CPCTASIS will closely follow the further development of the centre, and centre activities, requiring the information support.

Project management

Management organisation:

The management structure of the CPCTAS project consists of:

- the project manager (initially Prof. Radoslav Zikic; after his sudden death he was replaced by Prof. Snezana Markovic) - coordinator of project was responsible for management of the project, planning and coordinating all the activities of consortium;
- the technical coordinator (Prof. Snezana Markovic) was nominated by the project coordinator and she was the member of NMT and LCT in the same time;
- the network management team (NMT) was consist of six members: one representative from each partner institution, FSUKG (Prof. Snezana Markovic), FMUKG (Prof. Dejan Baskic), ICSR (Dr Danijela Vignjevic-Matic), SMT (Prof. Dimitrios Kouvelas), FNSMS (Prof. Dzoko Kungulovski), and project secretary (Vladimir Dimitrijevic);
- the local coordinating team (LCT) was consist of three members from coordinating faculty (FSUKG - Prof. Srecko Trifunovic, Prof. Ljiljana Comic, Prof. Snezana Markovic) and three members from associated regional faculty (FMUKG - Prof. Slobodan Jankovic, Prof. Nebojsa Arsenijevic, Prof. Dejan Baskic) from Serbia that makes 6 members of the LCT;
- the project secretary was in charge for administrative work required by the project, such as correspondence between the CPCTAS and network partners.

The project manager was the formal contact person between the responsible EU officials and the participating partners. The project management was centralised and followed hierarchy from the project manager downwards to the NMT and the LCT, and all professional staff members included in the project realisation. The decisions within the consortium were made via communication between the project manager and the NMT and LCT. At first, the LCT considered the matter and solved the problem. If unable to do so, the NMT was contacted and informed of important matters. If the differences in the opinion arise concerning important issues, those was discussed between the partners and resolved collectively. If disagreement persists, decisions were made by formal majority vote. All formal decisions were approved by project officer from EC. As a part of formal agreement, partners were abide to the decisions made by the consortium and were take all responsible steps to implement such decisions. In addition, there was regular communication between the project manager, the NMT, the LCT and all project professional staff.

Management procedures

At kick-up meeting (ICSR, June 2008) the project management structure was established. The NMT and the LCT were responsible for initiating the project, giving overall guidance and concluding the program while proposing potential follow-up cooperation. The project manager, the NMT and LCT were met during the various seminars and conferences to implement the project. Meetings and contacts of the NMT members were realised in order to discuss all aspects of ongoing project activities, to monitor and evaluate the progress of the project, to suggest eventual corrective measures, to coordinate the work of the LCT and own professional staff. Meetings of the NMT were timed in the accordance with dates of important project activities. Meetings of the LCT members were aimed to coordinate the project activities on development of the CPCTAS, organise the work, re-education, employment and education of own professional staff, organise the purchase of equipment and necessary material for project, organise the workshops and conference, coordinate the dissemination activities and provide sustainability of the project.

Communication and reporting

The members of the NMT and LCT were sent written reports to the project manager every six months. These reports suggested the work to be performed in the following six-months period. The project manager, together with members of the NMT and LCT, summarised the overall project status and plan of the future work. The project manager directed the reports to the EC (three annual and final reports). Those annual activity reports contained reports of all activities performed in the giving period including: reports of the main conclusions of the workshops and seminars, evaluation of the success of the training and education of each CPCTAS' staff in the EU partner institution, short manuals for the utilisation of the newly bought equipment, standardised protocols of old and newly introduced methodologies, description of the newly developed information system software and documentation concerning its structure and use. The project manager in three financial reports summarised the actual budgetary situation and received payments, in order to insure the final equilibrium of the expenses in agreement with the EC contract. Two quality control reports (midterm and final) were delivered by the ICSR and SMT expert teams. They evaluated progress of the project and also proposed the guidelines for the future work.

Money transfer

The all participants (consortium) are institutions, which have functional accounting system that work according to the domestic legislative. The money for the CPCTAS funding was transferred from EC to the account of the coordinator institution (FSUKG). The project manager and coordinator institution, in six-month period, transferred the money to the accounts of FMUKG and network partner institutions that are responsible for the distribution and monitoring of the money transfer. Accordingly, the coordinator purchased the equipment itself with respect to Serbian law. The project manager collected and processed cost statements, monitor finances and enforce the EU financial guidelines.

Consortium management tasks and achievements

The consortium management, structured from the project manager - coordinator of the project, network management team (NMT) and the local coordinating team (LCT) set the following tasks for the project period:

1. proper establishing of the consortium management team;
2. proper establishing of CPCTAS, official adoption of this centre and structuring of the adequate organisational scheme for CPCTAS functioning;
3. realisation of employment of the new researchers and technical staff in CPCTAS;
4. organisation of adequate education of the new employed and permanently employed professional staff of the CPCTAS and FNSMS at the EU partner institutions;
5. organisation and realisation of purchase and installation of new equipment for CPCTAS;
6. organisation of introducing and use of new methodologies regarding active substances testing and cancer research;
7. organisation of everyday work of the new researchers and technical staff in CPCTAS in order to the fulfilment of all activities proposed by the project and to achieve fully functional CPCTAS. Coordination of the process preparation of all relevant documents for the accreditation of the CPCTAS and the implementation of the management system of quality according to the ISO and EU standards by the responsible institutions in Serbia;
8. workshops organisation with thematic of know-how exchange with EU partner experts;
9. organisation scientific conference as crucial activity of CPCTAS project;
10. organisation of disseminative activities and disseminative workshops;
11. organisation of audit for FSUKG;
12. adequate distribution and money spending in accordance with proposed activities and domestic legislatives;
13. preparation of the first and second periodic and financial reports, as well as final report to EC.

Project manager with consortium management team and other professional staff included in CPCTAS development achieved all set tasks for project period. There are some corrections in timing of certain activities, which were successfully resolved by CPCTAS management team in consultation with responsible project officer.

Corrective actions

The main corrective actions were regarding to:

(i) change of the project manager and the representative person from FSUKG;
(ii) change of part of equipment purchase; and
(iii) reallocation of financial source for salaries of three young researchers and one technician from FSUKG for the four month of the last project period (January - April 2011). Project manager, NMT and LCT by strict decision procedure already described, and in consultation with project officer were find the most adequate solutions for these problems.

The kick-off meeting with project officer was realised in June 2008 at ICSR and the project management structure was established. During project period the NMT meetings / consultations were realised in October 2008, May 2009, October 2009, March 2010, December 2010 (two meetings), March 2011 and April 2011, and they were realised within the workshops and conference organised at CPCTAS, and during the LCT visit to EU partner institutions. Generally, during these events, the NMT members discussed and give consensus about organisation of all project activities and, most important, about responsibility for coordination and realisation of activities at its own institution. Some points of the correspondence were organisation of the researcher's education at the EU institutions, organisation of the workshop, consultation about new equipment installation and use of the new methodologies, coordination of disseminative actions, and financial basis of CPCTAS project. Progress of the project activities and achieved results were analysed in details and given recommendations and new plans for the next project period. All NMT meetings / consultations were timing on important and milestone points and activities of CPCTAS project.

During project period, 20 LCT meetings / consultations were realised at CPCTAS laboratories. Generally, LCT meetings were aimed to coordinate the project activities on: development of the CPCTAS, official adoption of CPCTAS, employment of new staff, organisation of the project activities and CPCTAS work, re-training and training of own professional staff, organisation of the workshops and Conference, coordination of the dissemination activities, ISO accreditation, implementation of IS and providing the sustainability of the project.

The project manager together with all NMT and LCT members give the conclusion that management team was successfully realised all set tasks, achieved crucial milestones and delivered significant results during project period. Also, management team in very correct communication with project officer successfully dissolved all problems and provided evident progress for CPCTAS project. Finally and probably most important, CPCTAS management team provided sustainability of CPCTAS research activities through further finance by research projects of Ministry of Education and Science, Republic of Serbia.

Potential impact:

The international cooperation between EU and Western Balkan partner institutions that was established through this project is a strong foundation for the future mutual research activities. This cooperation accelerate the setting up of sustainable partnership between the most competitive research centres of EU and WBC with the research interests in the investigation of active substances. Twining of testing methodologies was realised in the laboratories in EU and in Western Balkan towards the improvement of research capacities of Western Balkan centres. Scientific and technological reintegration of Serbian society into the ERA, reinforcement of scientific and technical human resources and infrastructures and upgrading of research programmes are the main benefits of this project.

Better and more integrated Western Balkan countries in the FP7 networks and RTD projects as well as in the Member State's national cooperation programmes as a prerequisite of these countries successful integration into ERA were achieved.

Impacts expected in this project could be classified in following categories based on their level of importance: national, regional and EU impact.

National impact

The general interest to form CPCTAS is to get the socially and economically stable system that provides financing from the commercial application of the obtained results and permanent education of interested structures. Through the realisation of this project local area get one unique centre for the analysis of active substances, which is in accordance with the concept of sustainable development.

Spreading positive awareness on European integration processes is one of the important national impacts of this project. Promotion of international cooperation on equal base of the CPCTAS with respectable EU institutions have strong positive impact on Serbian academic and research institutions. Reinforcement of human potentials, their research training and re-training stimulate further cooperation through networking and research activities.

The strong national impact lies in the fact that laboratories and institutions from Serbia and other WBC could cooperate with respectable EU institutions on regular and equal base. The equality of work, applied standard procedures and obtained quality of research results help that wider public become aware of respectable position that could be made for Serbian research institutions in the Europe and ERA.

Regional impact

After years of conflicts and divisions Western Balkan countries today finally starts to rebuild confidence and mutual cooperation. Science, sports and other non-political fields become instruments for those reconnections. In this scope, regional impact of this project is obvious. Networking and cooperation of WBC research institutions in this project improve and enlarge the research capacities of Western Balkan centres of competence in terms of S&T policy and research programmes, scientific and technical human resources and S&T infrastructures. Better and more integrated Western Balkan countries in the FP7 networks and in RTD projects is another impact that this project achieved.

The CPCTAS enable reinforcement and updating of the relationships between Serbia and FYROM in scientific and in socio-economical signification. Trans-national cooperation and exchange of experience created positive collaborative atmosphere for further WBC sustainable development.

EU impact

This project helped not only to WBC partners, but it has strong EU impact too. The consortium of respectable institutions helped reinforcement of the EU research centres through international cooperation networking integrating exchange of scientific know-how, mobilisation of human potential and exploitation of RTD results. The project impact to EU partners and to ERA in all was in creating of new methodologies and in further integration of WBC partners in EU national cooperation and research programmes. Further networking cooperation including other interested institutions can result with new investigations of active substances and registered medicaments with important research results.

Besides these socio-economic impacts, very important impact was made in scientific sphere through investigations of active substances on all mentioned levels. Research capacities of CPCTAS and of created network of institutions can be used for further high-quality investigations of active substances benefits for human use. Strong impulse is made for innovative approach both in research and technological development of new active substances. Standardisation of methodologies and the use of sophisticated modern equipment are promoted CPCTAS as reliable and respectable centre of excellence in investigation of active substances.

The next steps were needed for those impacts:

- technical reinforcing of the CPCTAS;
- professional re-training;
- updating of the old and introduction of the new methodologies;
- spreading excellence, exploiting and disseminating results;
- ISO accreditation of CPCTAS.

Above-mentioned steps helped CPCTAS to become strong regional centre with the recognisable position in investigation of active substances and to make all mentioned socio-economic and scientific impacts. Professionally and technically updated CPCTAS is capable of providing services according to EU standards not only for pre-clinical examination of chemical compounds, but also services of wide spectrum of testing, health care, environment protection, etc.

Spreading excellence, exploiting results, disseminating knowledge

The consortium of the project was based on the cooperation between the partner institutions from EU and WBC in order to provide base for integration of the Balkan region into ERA and therefore the European RTD activities and networks. Dissemination measures were core activities of the realised work and they were relevant from the beginning of the project.
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