INtegrating the emerging research Potential of the University of Athens Cancer Research Group in the European research area

Final Report Summary - INSPIRE (INtegrating the emerging research Potential of the University of Athens Cancer Research Group in the European research area)

Executive Summary:
The main concept of INsPiRE was the scientific and technological reinforcement of the National & Kapodistrian University of Athens (NKUA) basic and translational Cancer Research Group (NKUA-CRG) towards its integration into the more advanced core of the European cancer research area. Thus, a central objective of the proposal was to gain a full convergence of NKUA-CRG to the European research area of excellence, by facilitating the transformation of an existing multidisciplinary high-quality research, technological and education unit to a research entity unique in Greece and South-Eastern Europe that would be comparable to other outstanding research and/or educational units in Europe. This objective was achieved via a number of concerted actions and a carefully designed work plan. The mobilisation, the increase of visibility and the exposure of the NKUA-CRG human resources to an international scientific environment via two-way secondments, conferences, invited lectures and recruitment of experienced researchers were among the main axes of INsPiRE. Ten strategic partners located in some of the most eminent European research entities, namely, the Universities of Geneva, Oslo and Tuebingen, the Technical University of Munich, the Max Planck Institute of Biochemistry, the Center National de la Recherche Scientifique, the Danish Institute of Cancer Biology and the Imperial College of London, strengthened the existing links and the transfer of know-how. The acquisition of new state-of-the-art instrumentation for laser tissue microdissection/capture; confocal laser scanning microscopy live cell imaging; tissue cryo-sectioning/freeze substitution for advanced immuno-electron microscopy; nucleic acid sequencing; advanced flow cytometry and high throughput isolation and characterization of novel bioactive compounds was (among others) part of a drug screening platform. This platform enabled NKUA-CRG to offer various cost-effective solutions and to facilitate lead-compound identification. Finally, the popularization, the promotion and the dissemination of the research activities to the scientific community and the stakeholders, was a significant part of this project. The anticipated scientific and technological reinforcement of NKUA-CRG enhanced its existing scientific, educational and technological strengths, leading to the establishment of a research entity unique in Greece and South-Eastern Europe, fully integrated to the current European research system.

Project Context and Objectives:
Following the WP breakdown, the context and main objectives during the 36 months of implementation were as follows:
Work Package 1: The successful implementation of the project required significant coordination effort concerning the establishment (Task 1.1) monitoring and control of all distinct committees or boards of the project (Task 1.2) the ethical issues (Task 1.3) as well as the various activities and tasks within different work packages including the two financial audits (Task 1.4) and the dissemination of the results. In this regard, the director of the Department of Histology – Embryology (DHE) Prof. C. Kittas was the coordinator of the INsPiRE Management Team and provided decision-making and consultation for the implementation of each task.
The Project Management Team comprised the Coordinator (who coordinated all administrative bodies) and the deputy Coordinators who assisted the Coordinator in his tasks. The Steering committee consisted of the Project Management Team and ad hoc selected members of the five NKUA-CRG Departments. Scientific and technological consulting was provided by the External Scientific & Research Strategy Advisory Board with representatives from all EU participating organisations, a senior exploitation research manager from the Industry (Mr Foteinos, executive VP for Corporate R&I of LAVIPHARM S.A.) and a senior officer (Ms S. Kolyva) from the Hellenic Secretariat of Research and Technology.
Evaluation of the project development and scientific achievements took place according to the targets of the program. The External Scientific & Research Strategy Advisory Board provided consulting and evaluation of the scientific impact and progress during the entire project and beyond its completion. Moreover, the role of the Advisory Board was to fine-tune and propose sustainable solutions for NKUA-CRG S&T strategy. Three gatherings of all members of this Advisory Board along with the Steering Committee of INsPiRE have been performed during the kick-off, mid-term and the final meetings of the project. Specific indicators to measure the efficiency of the planned secondments included joint participations in congresses and publications, development of common research activities and applications in National and EU research grants, as well as effective transfer of know how that was demonstrated by open lectures or the performance of the instrumentation that was acquired by NKUA-CRG. As an indicator of its successful implementation and increase of research potential, INsPiRE delivered more than 15 publications in prestigious international peer reviewed journals; to these publications only the current proposal is acknowledged. Finally, an indicator of the successful hiring of experienced researchers was the increase of the publication number in prestigious international peer reviewed scientific journals.
The planned research was submitted to the Ethics Committee of the Faculty of Biology. The outcome of the consultation process was in alignment with the national competent body in the field of Research Ethics was documented in the dedicated deliverable and was monitored all over the 36 months duration of the project.
An external auditor was appointed who, along with the personnel of the NKUA Special Account for Research Grants reviewed the accounts and their compliance with the work plan and the EC rules and guides.

RESOURCES:
The activities of this work package were estimated to cost € 104,641.5 (total EC contribution including Overheads). Specifically, in this WP the budget allocation was as follows:
1. € 42,000 to a full time secretary [30 person months (PMs) from the total of the 36 PMs secretarial support].
2. Kick-off and mid-term meetings organization: 11,000 €/event (8,500 € for travelling, accommodation and daily allowances of the EU experts that participate in INsPiRE, plus 2,500 € for lunch and dinner costs (~40-50 participants))
3. Final meeting organization: 24,450 € (16,000 € for travelling, accommodation and daily allowance of the EU experts that participate in INsPiRE, plus 8,450 € for lunch and dinner costs (~60-70 participants))
4. Auditing (two reporting periods) were subcontracted (€ 10,000 cost).
Work Package 2: The second action was focused on the acquisition of new instrumentation for conventional and high-throughput analyses. This WP was fundamental for the success of the project and had been designed to enhance the technological and scientific capacity of NKUA-CRG and to complement the existing facilities of the drug screening platform. Under the control of the Management Team, an internal committee defined the instruments’ specifications and proceeded to market research. An international tender, equipment purchases (Task 2.1) and finally installation and maintenance (Task 2.2) of the equipment followed.
The official procedure for international tenders was followed in collaboration with the NKUA Special Account for Research Grants. The international tender for the acquisition of the equipment was performed according to the specifications defined by the ITC. At the end of the international tender the NKUA-CRG academic members met to score the technical specifications of the offered instruments. On the basis of the best financial quote that meets the necessary technical requirements the best offer was selected.
Two representatives from each of the five NKUA-CRG’s Departments were responsible for the receipt of the new instrumentation, for the supervision of the installation process and for the demonstration of good operation.

RESOURCES:
The activities of this work package following market research for the equipment cost during the negotiation period had been estimated to cost € 994,458 (total EC contribution including overheads).
1. Equipment costed € 920,000 and included state-of-the-art instrumentation for Laser Tissue Microdissection/Capture (€ 180,000); new instrumentation and peripherals for Confocal Laser Scanning Microscope live cell imaging and advanced cryo-immuno Electron Microscopy (€ 230,000); instrumentation for high capacity automatic genetic analyses and nucleic acid sequencing (€ 180,000); state-of-the-art instrumentation for Flow cytometry (FACS) (€ 150,000) and an automated platform for characterization of novel bioactive compounds comprised of a High Performance Liquid Chromatography along with an evaporation system for solvent removal (€ 180,000).
2. Also, ~ 8,000 € referred to consumables needed for the condition and maintenance of the Laser Tissue Microdissection/Capture (~ 6,000 € for the potential replacement of the cap mover which is the arm of the instrument used for the transfer of the sample) and the cryo-ultramicrotome (resharpening or replacement of the diamond knifes used for tissue sectioning ~ 2,000 €).
3. € 1,400 referred to secretarial support in this WP (1 PM from the total of the 36 PMs for secretarial support).
Work Package 3: The procedure of instrumentation upgrading was coupled with know-how transfer from selected European research entities on the three main scientific and technological research axes (see above) of NKUA-CRG. Know-how transfer familiarized NKUA-CRG’s researchers with new scientific concepts and educated them in the usage of novel technological tools. NKUA-CRG acquired know-how by strengthening existing collaborations or by developing new strategic partnerships with top research institutions from Denmark, France, Germany, Norway, Switzerland and the United Kingdom. In this activity the NKUA-CRG Team devoted two-way secondments (Task 3.1) or short visits (Task 3.2) from NKUA-CRG to the collaborating EU institutions and vice versa; several academic members and experienced researchers participated in these activities. The planned mobility program promoted the joint usage of research infrastructures and increased the complementarity among scientists, resulting in the development of joint projects and future participations in EU research grants. Another activity which enforced know-how transfer and sustainability of the added value was the recruitment of engineers and experienced researchers (Task 3.3).
Thirteen experienced researchers and two engineers were hired from the Group for a period of 33 and 34 PMs respectively; particular effort was invested towards their continued employment by NKUA-CRG beyond the end of INsPiRE.

RESOURCES:
The activities of this work package have been estimated to cost € 1,149,340.5 (total EC contribution including overheads).
1. Travel fees, accommodation expenses and per diem during the secondments and/or short visits (total cost of ~ € 160,450). For the long term secondments of the NKUA-CRG personnel or the experienced researchers that visited the EU labs it was allocated € 1,200/month for accommodation, € 500 for travel cost (airplane tickets, train, etc.) and € 2,100/month for daily allowances. For the senior EU or NKUA-CRG researchers or Academic members that exchanged visits, we allocated a cost of € 105/day for daily allowances, € 500 for travel cost (airplane tickets, train, etc.) and € 150/day for accommodation.
2. For hiring the two engineers (34 PMs each) and the thirteen experienced researchers (33 PMs each), costs summed up to €98,600 and € 815,100 respectively.
Work Package 4: This work package aimed to enhance the NKUA-CRG visibility in the EU & International research area and to increase the exposure of its researchers to the international scientific environment in order to communicate the knowledge produced by the Group to other scientists working in similar fields. This goal was achieved through the organization of conferences/workshops and the participation in international conferences. Two international conferences and three workshops were organized in the thematic areas of “cancer immunology/immunotherapy” (Task 4.1); “tumour biomarkers” (Task 4.2); “molecular links of ageing and cancer” (Task 4.3); “tumour barriers and cancer” (Task 4.4) and the “effects of natural products on cell cycle” (Task 4.5). Some of the world's renowed specialists in the respective fields were invited. Target group included scientists, stakeholders and members of the pharmaceutical industry. NKUA-CRG research staff from its constituent Departments also participated over the three years in more than six international conferences in relevant thematic areas (Task 4.6).

RESOURCES:
The activities of this WP had been estimated to cost € 203,514 (total EC contribution including overheads).
1. € 150,000 referred to the estimated cost for conference/workshop organization (~ € 30,000 each). The anticipated cost/event (mean duration of 2½-3 days) included travel expenses, registration and accommodation cost for ~10-15 invited speakers (~ € 15,000); costs for participants’ (~85-100) lunch, coffee breaks and dinner (~ € 13,000) and ~ € 2,000 for renting the required facilities (e.g. lecture room, audio, etc.).
2. Other expenses (e.g. abstract book/program printings, VAT, website, congress secretariat etc) were covered by sponsorships and registration fees.
3. For six congress participations was foreseen an overall cost of ~ € 36,000 (i.e. two participants per event with an average cost of ~ € 3,000/event/participant). The average anticipated cost of ~ € 3,000 per event/participant for a six days international congress was budgeted as follows: ~ € 900 accomodation, ~ € 700 registration, ~ € 800 travel expenses and ~ € 600 for daily allowances.
4. € 4,200 for secretarial support had been also included in this WP (3 PMs from the total of the 36 PMs for secretarial support).
Work Package 5: To accelerate the convergence of NKUA-CRG at the European level, the need for dissemination of its achievements and technological platforms to the scientific and industrial community, as well as to other EU stakeholders was high. To this end, a NKUA-CRG brochure and informative web-sites have been designed and developed (Task 5.1) along with article publications in peer-reviewed international scientific journals (Task 5.2). Dissemination of the NKUA-CRG activities in a large public audience was achieved via press releases to national and international media. Also, two info days (at months 18 and 36) were performed, to which main national stakeholders (including industrial partners) were invited (Task 5.3); intellectual property management seminars (month 18) trained NKUA-CRG researchers to these issues.

RESOURCES:
The activities of this work package had been estimated to cost € 43,096 (total EC contribution including overheads).
1. Leaflets and brochures for INsPiRE and NKUA-CRG (i.e. artistic design, graphics and printing) along with posters for advertisement of the initiative or scientific data presentation in S&T events where NKUA-CRG members participated was ~ € 5,000.
2. Publication of the > 15 articles in international peer reviewed journals: ~ € 25,000.
3. € 2,800 were allocated for secretarial support in this WP (2 PMs from the total of the 36 PMs for secretarial support).
4. The cost (€ 4,800) for the INsPiRE web site establishment and for upgrading the existing web-sites of the five NKUA-CRG departments was subcontracted.

Project Results:
Work Package 2: Upgrading – Acquiring research equipment
Summary of progress towards objectives:
The objective of WP2 was the acquisition of new state-of-the-art instrumentation for high throughput genomic analyses/sequencing, laser tissue microdissection/capture, advanced flow cytometry and CLSM/TEM advanced imaging and cryo-immunolocalization. Also, the purchase of instrumentation for high throughput discovery and characterization of new natural bioactive compounds was performed.

Significant results:
The following new state-of-the-art instruments were requested within the current project:
1. Laser Tissue Microdissection/Capture System (Department of Histology-Embryology, Medical School)
2. Upgrades and peripherals for Confocal Laser Scanning Microscope for live cell imaging and advanced cryo-immuno Electron Microscopy (Department of Cell Biology & Biophysics, Faculty of Biology)
3. System for High capacity automatic genetic analyses and nucleic acid sequencing (Department of Biochemistry and Molecular Biology, Faculty of Biology)
4. Flow cytometer (FACS) (Department of Animal and Human Physiology, Faculty of Biology)
5. Automated platform for characterization of novel bioactive compounds (comprised of a High Performance Liquid Chromatography along with an evaporation system for solvent removal) (Department of Pharmacy, School of Health Sciences)
According to the workplan, consumables needed for the condition and maintenance of the Laser Tissue Microdissection/Capture and the cryo-ultramicrotome for the resharpening of the diamond knifes used for tissue sectioning were purchased.
Finally, maintenance and service as well as the upgrade of the specific instruments and equipment that were bought at the beginning of the INsPiRE project, were also realized.

Deviations’ explanations:
The instruments for the Confocal Laser Scanning Microscope were expected to be purchased during the 1st period but, due to minor technical issues from the vendors, they were delayed. In addition, because of an underspent amount of approximately 80,000 €, it was requested to spend an additional amount for maintenance and service and for the upgrade of the specific instruments and equipment that were purchased at the beginning of the INsPiRE project.
Corrective actions:
The installation of the Confocal Laser Scanning Microscope and the relevant payment were completed successfully during 2014.

Resources:
The activities of Work Package 2, following market research for the equipment cost during the negotiation period have been estimated to cost 994,458.00 €. Equipment costs estimation 920,000.00 € was not exceeded as relevant equipment costs currently present the following breakdown:
High Performance Liquid Chromatography/evaporation system for solvent removal (93,800.00 €), Instrumentation for high capacity automatic genetic analyses and nucleic acid sequencing (140,000.00 €), Nucleic acid sequencing system (39,900.00 €), Confocal Laser Scanning Microscope/Cryo-immuno Electron Microscopy (229,900.00 €), Laser Tissue Microdissection/Capture system (179,900.00 €), Evaporation system for solvent removal (85,900.00 €), Instrumentation for Flow cytometry (FACS) (150,000.00 €), with a total of 919,400.00 €
An amount of 8,000 € refers to the consumables needed for the condition and maintenance of the Laser Tissue Microdissection/Capture (6,000 € for the replacement of the cap mover which is the arm of the instrument used for the transfer of the sample) and the cryo-ultramicrotome (sharpening of the diamond knifes used for tissue sectioning 2,000 €). Finally, 1,400 € refer to secretarial support in this WP (1 PM from the total of the 36 PMs for secretarial support).

The additional amount spent for the upgrade of the specific instruments and equipment that were purchased at the beginning of the INsPiRE project was 53,000 €:
1. Upgrade of the instrumentation of Cryo-immuno Electron Microscopy: 15,000.00 €
2. Software upgrade for the system of High Performance Liquid Chromatography: 7,000.00 €
3. Upgrade of the instrumentation for Flow cytometry (FACS): 16,000.00 €
4. Upgrade of the instrumentation for high capacity automatic genetic analyses: 10,000.00 €
5. Software upgrade for the system of nucleic acid sequencing: 5,000.00 €

The additional amount spent for the maintenance and service of specific instruments and equipment that were purchased at the beginning of the INsPiRE project was 15,317.07 €:
1. Maintenance of the system of High Performance Liquid Chromatography: 8,000.00 €
2. Maintenance of the Confocal Laser Scanning Microscope: 7,317.07 €
Work Package 3: Transfer of know-how / Recruitment of experienced researchers
Summary of progress towards objectives:

The main objective of the third work package was to transfer the necessary know-how to the personnel of the NKUA-CRG and to develop strategic partnerships and network activities with well-established research Institutions in Denmark, Germany, France, Norway, Switzerland and the United Kingdom. In terms of the total of the 36 months, know-how transfer was achieved by the following activities:
• Two-way secondments of the researchers;
• Short term visits and invited lectures;
• Recruitment of two engineers and thirteen experienced researchers.

In terms of the Deliverable D3.1 Report on experienced researchers and engineers’ recruitment / contract, the recruitment schedule was based on the identification of the required candidates’ qualifications, the announcement of the position at pan-European level, interviewing potential candidates and contract signing with the selected researchers.
With regard to Deliverable D3.2 First report on know-how transfer, within the activities of Task 3.2 Short-term visits / invited lectures, the activities of the 1st reporting period entail 2 short term visits of distinguished EU researchers to NKUA-CRG and 1 short term visit and 2 secondments of NKUA-CRG’s senior and junior researchers to collaborating EU research institutes.
With regard to Deliverable D3.3 Second report on know-how transfer, within the activities of Task 3.2 Short-term visits / invited lectures, the activities of the 2nd reporting period entail 2 short term visits of distinguished EU researchers to NKUA-CRG and 2 secondments of NKUA-CRG’s senior and junior researchers to collaborating EU research institutes.
With regard to Deliverable D3.4 Third report on know-how transfer, within the activities of Task 3.2 Short-term visits / invited lectures, the activities of the 2nd reporting period entail 2 short term visits of distinguished EU researchers to NKUA-CRG, 4 short term visits of research staff from NKUA to EU institutions and 11 secondments of NKUA-CRG’s senior and junior researchers to collaborating EU research institutes.
In terms of the added value and increase of the research capacity / quality of NKUA-CRG due to secondments’ materialization, D3.5 refers to the Report on the added value and increase of research capacity / quality of NKUA-CRG.
In terms of recruiting engineers and experienced researchers in order to perform the INsPiRE research, D3.6 refers to the first Report on the research activities of the hired experienced researchers and the summary of their results, the future perspective of the research and the follow-up.
In terms of recruiting engineers and experienced researchers to perform the INsPiRE research, D3.7 refers to the second Report on the research activities of the hired experienced researchers and the summary of their results, the future perspective of the research and the follow-up.
In terms of recruiting engineers and experienced researchers in order to perform the INsPiRE research purposes, D3.8 refers to the third Report on the research activities of the hired experienced researchers and the summary of their results.

Significant results:
Two engineers (for 34 PMs each) and thirteen experienced researchers (for 33 PMs each) have been recruited. The experienced researchers and the engineers contributed to the development of the research activities of the INsPiRE group and the maintenance and daily on-demand-use of the new instrumentation, respectively. The project received four (4) applications for the positions of Engineers (ENs) and fifty-six (56) applications for the positions of experienced researchers (ERs), most of them from Greece but also from Serbia, France, the Netherlands, USA, UK, Germany, Spain, Poland, Sweden, Italy, Portugal, India, Bangladesh, Ukraine, Ireland and Canada. The selection of applicants was carried out by the Project Steering Committee which took special precautions to address gender issues.

The results of the research performed during months 1-36 by the experienced researchers encompassed the following:
1. Study of the expression of factors of the DNA damage response (DDR) pathway, INK4A gene products locus, p53, p21WAF1/Cip1, Cdc6 and others, mainly in human clinical samples and animal model tissues, in combination with pathology reports. Assessment of the biochemical interaction between the p21WAF1/Cip1 and DDR pathway in tumors and cell cultures as well as between the DDR and the ARF pathway, in cell cultures and their extrapolation in various cell lines and cellular systems. Assessing the role of the E2F1 transcription factor in the digestive system. Guidelines on the Application of the Sudan Black B staining technique for detection of senescent cells. Development and applications of the CRISPR/Cas9 technology. Assessing repair of the I-SceI-induced DSB by BIR employing GFP-based reporters, in cell cultures overexpressing p21WAF1/Cip1.
2. Provision of technical histopathology expertise on the laser-assisted capture microdissection (LCM) instrument currently being installed on the premises of DHE, University of Athens.
3. Study of the expression, status, regulation and (functional) interactions of factors of the DNA damage response (DDR) pathway, INK4A gene products locus, p53, p21WAF1/Cip1, Cdc6 and others, mainly in various cell lines and cellular systems.
4. Discovery of plant bioactive compounds that can be used as anti-cancer agents.
5. Optimization of the extraction process of plants selected as potential anti-cancer agents and chemical profiling of obtained extracts using contemporary means of analytical methods. Additionally, the study of the extraction, analysis and cytotoxic/cytostatic effects of by-products created during olive treatment. Application of the various extraction techniques and analytical methodologies developed to specific plants and extracts and combining the chemical profile with specific biological activities.
6. Development and optimization of natural product lead compounds as anti-cancer agents.
7. Evaluation of natural compounds, derived from different stages of olive processing, that presented significant anticancer activity against the human cancer cell lines FM3 (melanoma), HCT-116 (colon), HeLa (cervix), MCF-7/SKBR-3 (breast), HL-60 and K562 (both leukemic).
8. Computational evaluation and virtual screening of natural compounds that can be used as anti-cancer agents and the rational design of optimized semi-synthetic analogues.
9. HPLC-DAD-MS/MS profiling and chemical classification of generated microfractions. Development of scale up chromatographic methodologies. Microfractionation procedure of promising extracts.
10. Virtual screening of the NCI compound library and the in-house NKUA natural products library for bromodomain binding molecules (~2.5∙105 entries). In vitro evaluation of the 40 top-ranked compounds against 12 bromodomains using DSF. Identification of a hit with high affinity for the fifth bromodomain of PB1 protein. Exploration of the synthetic pathway of new inhibitors of PB1 protein. Synthesis of a hit compound along with 10 analogs. 4 cocrystal structures of the complexes between the lead as well as its 3 analogues and the PB1 protein. ITC results for the interaction of those analogues with PB1 and determination of Kd, DH, -TDS and DG values. Selectivity assessment of those analogues against 12 members of the bromodomain family.
11. Literature survey about promising natural products with anti-ageing activity. Synthesis and biological evaluation of 5-bromoindirubins series (patent filled and deposited). Synthesis and biological evaluation of indirubin hybrids. Deep biological evaluation of Acrovestone analogs: anti-angiogenic agents (CAM assay), 5-LO inhibitors. In vivo evaluation of indirubin analogs (previously developed) as: anti-melanoma agents, acting as JAK/Src inhibitors.
12. Study of the regulation of main cellular proteolytic pathways (ubiquitin-proteasome and autophagy-lysosome system) and of the antioxidant response pathway Nrf2/ keap1 during in vivo ageing and under proteotoxic or oxidative stress.
13. Study of the molecular mechanisms linked to the human cancer cells’ resistance acquisition to chemotherapeutic drugs.
14. Establishment of transgenic mouse strains over-expressing Clusterin (CLU) / Apolipoprotein J. CLU is involved in many age-related diseases (such as atherosclerosis, diabetes, kidney and neuron degeneration, and cancer) but so far its function in vivo has only been studied in CLU KO mice.
15. Backcrosses studies to eliminate the CBA background of the transgenic mouse strains over-expressing CLU and thus obtain congenic strains. Crosses of sibling transgenic CLU heterozygous mice for each strain to obtain transgenic CLU homozygous mice. Tissue screening in transgene homozygous, heterozygous and non-transgenic control mice in order to evaluate CLU expression levels. Analysis of the responses of chemoresistant human osteosarcoma cell lines to agents/drugs triggering the proteostasis network components.
16. Analysis of the proteostasis network functional involvement in carcinogenesis.
17. Study of the molecular cross-talk of proteasome functionality and Nrf2-mediated antioxidant responses towards the maintenance of organismal homeostasis and the moderate pharmacological activation of proteasome induces lifespan extension in Drosophila. Study of dietary AGEs or lipofuscin by (among others) disrupting proteostasis accelerating age-related biomolecules’ damage and therefore contributing to the ageing phenotype.
18. Study of the anti-neoplastic activity of certain plant-derived extracts in cultures of human malignant cells.
19. Study of the clinical value of a number of potential tumor biomarkers, namely kallikrein-related peptidases (KLKs) in colorectal cancer (CRC), as well as BCL2-like 12 (BCL2L12) and L-DOPA decarboxylase (DDC) in head and neck squamous cell carcinoma (HNSCC).
20. Analysis of the mechanism of action of prothymosin alpha as adjuvant, to promote Th1-type immune responses and stimulate anti-cancer reactive lymphocyte responses in vitro and in vivo.
21. Screening of effects induced by the 6-BIO and 6-BIO-PIP compounds on human and mouse normal and tumor cell lines. Metabolomic profiling of U2 OS and KH OS human parental and chemoresistant osteosarcoma cell lines. Monitoring and analyzing the hypothesized cross-talk of PDR and DDR in the human cancer cell lines Saos2, U2 OS, KH OS after silencing ATM gene expression. Studying the impact of p21 and p53 overexpression on PDR in Saos2-p21-Tet ON and Saos2-p53-Tet ON inducible cancer cell lines.
22. The establishment of the idea that carcinogenesis is characterized by increased oxidative damage and proteome instability, while most PN modules examined were found to be induced early during tumourigenesis. Proof that tumor cells are significantly more sensitive to proteotoxic and/or oxidative stress compared to normal cells.
23. Expansion of 12 cell lines (ovarian and breast cancer), development of growth curves by the MTT assay and development of a range of non-toxic concentrations and time-points for the effect of metformin (as a single agent or as an adjuvant) in each of the 12 cell lines
24. Study of ACD3S-activated NK-92 cells demonstrating statistically significant increased cytotoxicity against K562, FM-3 and MCF-7 cells. Study of ACD3S-activation of NK-92 cells for 24 h restoring perforin production to levels comparable to those of standard NK-92 cells. When ACD3S-activated NK-92 cells were administered in SCID mice previously inoculated with FM-3 or MCF-7 cells, tumors grew at a slower rate and mice survived longer.

With regard to Task 3.2 in terms of short-term visits and invited lectures exploiting invited lecturing and scientific consulting in the field of the researchers’ expertise, the most significant outcomes are the following:
1. The short term visit of Toby J. Athersuch, PhD MRC-HPA Centre for Environment & Health, Imperial College London, succeeded in providing a forum for knowledge transfer, primarily through one-to-one consultation relating to specific study design and data analysis issues. Furthermore, opportunities for advancing research collaborations were identified, specifically in relation to NMR and UPLC-MS method development and data analysis.
2. The short term visit realized by Prof. Luca Scorrano, Department of Cell Physiology and Metabolism, University of Geneva, succeeded in providing a forum for knowledge transfer, invited lecturing and scientific consulting in the field of Prof. Scorrano and NKUA-CRG academic members’ expertise. Also, discussions for future collaborations, networking and further exchange of know-how were successful as the groups of Professors Scorrano and Trougakos have launched a collaborative research project. Furthermore, opportunities for participating in joint grant applications were identified. Finally, an MSc graduate student from the DHE was recruited by Prof. Scorrano as a new PhD member for his new lab in the University of Padova, Italy.
3. The short term visit of Prof. A. Skorilas to the Technical University of Munich (10/2/13 – 15/2/13) provided Prof. Scorilas with the opportunity to learn the collaboration possibilities in terms of tissue banks and scientific equipment of the Department of Obstetrics and Gynecology. He also met many principal researchers of the aforementioned Department and further discussed about several ongoing projects coordinated by Prof. Schmitt and his colleagues. Moreover, Prof. Scorilas and Prof. Schmitt scheduled and discussed about the visit of the latter in the Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens. Additionally, Prof. Scorilas and Prof. Schmitt discussed and initiated the research project (including reagents, specific KLK antibodies and protocols) which was carried out by a member of the NKUA-CRG during the summer 2013 secondment in Prof. Schmitt’s laboratory.
4. The long term secondment of Assistant Professor N. Fokialakis to the Centre National de la Recherche Scientifique (CNRS) and more specifically to the Institut de Chimie des Substances Naturelles (ICSN) in Gif sur Yvette in France, was successfully implemented. There was a significant know-how transfer on the automated procedures for the bioassay guided isolation and structural determination of natural products. More specifically, Dr. N. Fokialakis was trained in cultivating microorganisms and optimizing the production of secondary metabolites, the isolation of bioactive compounds and the application of NMR and MS for structural determination of the isolated compounds.
5. The secondment of Kyriaki Ioannou, PhD Student, to the Department of Animal and Human Physiology, Faculty of Biology, University of Athens to the University of Tuebingen at the laboratory of Prof. G. Pawelec’s referred to the following research elements:
• in vitro study of the ability of prothymosin α (proTα) and proTα (100-109) to stimulate anti-tumor immune responses from naïve T lymphocytes, isolated from the peripheral blood of healthy individuals and;
• in vitro assessment of the effect of various adjuvants (LPS, MALP-2, αGalCerMPEG, c-di-AMP, Advax) on human dendritic cell subsets present in the peripheral blood of healthy individuals.
6. The short term visit realized by Prof. Manfred Schmitt was also a success. Transfer of know-how was realized concerning current state-of-the art on ovarian and breast cancer biomarkers and novel methods for assessing gene expression at multiple levels (DNA/RNA/protein) in human malignancies. A novel collaboration was established on the identification and clinical evaluation of novel biomarkers for the differential diagnosis, prognosis and treatment monitoring of ovarian cancer patients.
7. The long term secondment of Dr Konstantinos Mavridis to the Department of Obstetrics and Gynecology, Technical University of Munich was successfully implemented. There was a significant know-how transfer in making use of a unique tissue bank of ovarian tumors supervised by Professor Manfred Schmitt. Dr Mavridis was also trained in the organization and maintenance of tumor banks, tissue homogenization methods, tissue microarrays and immunohistochemistry techniques for KLK expression, from members of the hosting laboratory and provided the relevant protocols to his research unit.
8. The short term visit of Assist. Prof. Ioannis Trougakos to the Department of Molecular Biosciences, Programme of Cell Biology, Faculty of Mathematics and Natural Sciences in Oslo was a great opportunity to discuss with Prof. Griffiths and his research group on scientific issues concerning their field of expertise and also to plan future joint research projects. Moreover, Prof. Trougakos delivered a lecture on his field of expertise.
9. The long term secondment of Dr Fabiola Sesti to the Department of Molecular Biosciences, Programme of Cell Biology, Faculty of Mathematics and Natural Sciences in Oslo was also realized. Dr. Sesti worked on electron microscopy techniques applied to cell biology.
10. The short term visit of Assist. Prof. Ioannis Trougakos to the Department of Biology at the University of Padova consisted of scientific meetings with the group of Prof. Scorrano. Prof. Trougakos also had the opportunity to evaluate the progress of his student, Eleni Tsakiri, who was at the time in a secondment under the frame of the project, at Prof. Scorrano’s lab. The two Professors discussed on novel state-of-the-art technologies concerning the study of cell death, on the role of mitochondrial proteins in regulating apoptosis and on cell death pathways that are being compromised in senescent normal human cells or chemoresistant human cancer cells.
11. The long term secondment of MSc Eleni Tsakiri to the Department of Biology at the University of Padova was a success. Miss Tsakiri studied the bioenergetic status and the morphology of mitochondria in proteasome knockdown or proteasome activation transgenic Drosophila melanogaster strains. The transfer of know-how and a solid collaboration was achieved between the University of Athens and the Department of Biology, University of Padova on the investigation of effects of proteasome dysfunction on mitochondria and was translated into common publications in international scientific journals, and also is the beginning for new collaborative research plans and application of joint research proposals.
12. The short term visit of Prof. Emmanouil Fragoulis to the Department of Molecular Biology, Max Planck Institute of Biochemistry, Germany was a transfer of knowledge about novel cancer biomarkers in the NKUA-CRG. Prof. Fragoulis presented the program’s data to the Director. He also met many principal researchers of this Department and discussed about several projects coordinated by Prof. Ullrich and his colleagues.
13. The second short term visit realized by Prof. Manfred Schmitt was an opportunity to discuss the future collaboration between the University of Athens and the Technical University of Munich, on breast cancer and triple-negative breast cancer biomarkers. Prof. Schmitt also delivered a seminar presentation. Prof. Schmitt met with Prof. Scorilas in order to discuss on the opportunities of the use of next generation sequencing for the identification of cancer biomarkers, focusing on quality control issues and clinical applicability.
14. The long term secondment of PhD student Kleita Michaelidou to the Technical University of Munich was also realized. Miss Michaelidou was able to work in Prof. Schmitt’s lab on the practice of different DNA/RNA/protein extraction techniques and immunohistochemistry protocols using the envision/polymer method. In addition, she had the opportunity to exchange ideas and to discuss about different laboratory techniques with other PhD students. She also attended a seminar regarding emerging biomarkers in breast cancer care. Finally, she prepared a number of ovarian tissue cDNAs from mRNA analyses in the University of Athens in order to continue a current research project with an increased number of clinical specimens.
15. The short term visit realized by Prof. Graham Pawelec consisted of extensive meetings on the implementation of a joint project most recently granted in the frame of the Bilateral German – Greek cooperation funded by DAAD (Bonn) and the GSRT (Athens). As an expert, Prof. Pawelec gave a total of two lectures, regarding prognostic and predictive markers in cancer and the means for publishing papers.
16. The short term visit realized by Prof. Stefan Stevanovic succeeded in providing a forum of knowledge transfer, invited lecturing and scientific consulting in the fields of expertise and interest of Prof. Stevanovic and Dr. Tsitsilonis, as well as other NKUA-CRG academic members. Discussions for future collaborations, networking and further exchange of know-how were successfully implemented. Finally, a graduate student from the DAHP was agreed to perform a short term (1 month) visit to Prof. Stevanovic’s lab, to continue the collaboration and receive training in new state-of-the-art technologies, such as multi-color flow cytometry.
17. The short term visit realized by Assist. Prof. Ourania Tsitsilonis to the University of Tuebingen consisted of discussions on the recent results that she and her research group had on the determination of the sepsis biomarker prothymosin alpha (100-109) in mouse and human samples. Prof. Tsitsilonis also discussed the possibility of purchasing knock-out mice for TLR-4 and generating transgenic mice for prothymosin alpha. Finally, she had the opportunity to visit the laboratory of Prof. M. Pasparakis at the University of Koeln, where she extensively presented their findings.
18. The short term visit realized by Dr Ioannis Voutsas to the University of Tuebingen succeeded in providing a forum for knowledge transfer, lecturing and scientific consulting. Dr Voutsas presented the most recent results on the determination of the novel biomarker prothymosin alpha (100-109) in human samples, deriving from patients admitted to Intensive Care Units and children with autoinflammatory and infectious diseases. He also discussed about the planning of experiments that are going to be eventually performed for the identification of the decapeptide in human serum samples.
19. The short term visit realized by Prof. Emmanuel Mikros to the MRC-HPA Centre for Environment & Health, Imperial College London aimed at transferring knowledge concerning procedures, applications and trends of state-of-the-art NMR metabolomics techniques. Prof. Mikros followed a 6-day meeting agenda where he had the opportunity to meet Dr. E.Keun as well as several of the PhD and postdoctoral researchers of his group in MRC-HPA/ICL. Finally, Prof. Mikros had the chance to give a talk, presenting the current interests of his own group in CRG-NKUA.
20. The long term secondment realized by Dr Dimitra Benaki to the MRC-HPA Centre for Environment & Health, Imperial College London, aimed at establishing collaborations and expanding the existing knowledge on recent developments in the field of metabolomics, and more precisely in the isotopomer analysis, a very powerful technique for determining site enrichment with stable isotopes. During the visit, she worked on the establishment of NMR detection methods for isotopomer analysis of human prostate cancer cell lines grown in the presence of uniformly 13C-labeled glucose.
21. The long term secondment realized by PhD student Eirini Kouloura to the Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, was a successful transfer of know-how. Mrs Kouloura worked on several projects currently running at the laboratory of Dr Hector Keun. More specifically, she worked on the establishment of an LC-MS assay concerning retinoids in biological samples, on the annotation of the metabolomic profile data from prospective studies of cancer risk, and on the multivariate modeling of metabolomics data from plant extracts to identify novel inhibitors of LOX. She also explored the assessment of synergy in mixtures using multivariate regression techniques.
22. The long term secondment realized by Dr Maria Chalampalaki to the Department of Surgery and Cancer, Faculty of Medicine, Imperial College London was a successful transfer of know-how. Dr Chalampalaki worked on several projects currently running at the laboratory of Dr Hector Keun. More specifically, she worked on the annotation of the metabolomic profile data from prospective studies of cancer risk, on the multivariate modeling of metabolomics data from plant extracts to identify novel inhibitors of LOX and she also drafted initial plants for future collaborations within Horizon 2020 consortia.
23. The short term visit realized by Prof. Jamal Ouazzani succeeded in providing a forum of knowledge transfer, invited lecturing and scientific consulting in the fields of expertise and interest of Prof. Ouazzani. More specifically, Dr. Ouazzani gave a lecture on the isolation of bioactive secondary metabolites of microbial origin. He also spent time to evaluate the facility of the department concerning the growth of the microorganisms, the extraction using CO2 or microwave technology. Moreover, he gave some advice on improvements that can be done and ideas on how to improve further the equipment that was purchased from INsPiRE.
24. The short term visit realized by Prof. Alexios-Leandros Skaltsounis to the National Center for Scientific Research (ISCN), Natural Product Chemistry Institute (CNRS) aimed at continuing the work that Prof. Skaltsounis’ lab had started in CNRS-ISCN. Prof. Skaltsounis has evaluated the results from compounds of Greek plants with anticancer activity. He also discussed in detail the new project MICROSMETICS that had been submitted together with Prof. Jamal Ouazzani in the last call of FP7 and the development of a new proposal in order to submit it under the Horizon 2020 calls.
25. The second long term secondment realized by Assist. Prof. Nikolas Fokialakis to the National Center for Scientific Research (ISCN), Natural Product Chemistry Institute (CNRS) aimed at continuing the work that he had previously started in CNRS-ISCN. Dr. Fokialakis worked on the isolation of compounds that present anticancer activity from microorganisms. He also performed the structural identification of compounds using state-of-the-art techniques like LC-MS and NMR.
26. The long term secondment realized by Dr Aikaterini Termentzi to the National Center for Scientific Research (ISCN), Natural Product Chemistry Institute (CNRS) aimed at transferring knowledge on scientific fields. Dr Termentzi has developed analytical protocols for fingerprinting bioactive extracts using the systems LC-DAD, LC-ELCD and LC-MS. She has also developed analytical protocols for isolating bioactive compounds from complex mixtures. Besides this, she has analyzed bioactive extracts and isolated bioactive compounds.
27. The short-term visit of Prof. V. Gorgoulis and Assist. Prof. A. Kotsinas to the Department of Molecular Biology in Geneva consisted of meetings with Professor Halazonetis, Professor Robbbie Loewith and Professor Ueli Schibler, in order to discuss on current and future joint projects in the field of each Professor. The two Professors also attended internal seminars at the University of Geneva. Moreover, Prof. Gorgoulis gave a seminar presentation. Finally, Prof. Gorgoulis and Assist. Prof. Kotsinas had the opportunity to meet with members of Prof. Halazonetis’ research group, and discussions regarding the CRISPR technology were carried out.
28. The long term secondment realized by Dr Maria Sideridou to the Department of Molecular Biology in Geneva has successfully transferred knowledge on new internationally technological platforms: i) the CRISPR/Cas9 technology and ii) the use of reporter plasmids to assess DNA double strand breaks (DSBs) repair. In parallel, Dr Sideridou gained access and received for transfer to the DHE genetic technology to assess I-SceI-induced DSB by BIR employing GFP-based reporters.
29. The short term visit realized by Prof. Vassilis Gorgoulis and by Assist. Prof. Athanassios Kotsinas to the Department of Cell Cycle and Cancer, Institute of Cancer Biology, Denmark aimed at discussing current trends in cancer biology, promoting and enhancing further collaboration, including planning for future research grants and at presenting in lectures the key-advancements in the field of cancer biology and DNA damage responses. Prof. Gorgoulis and Assist. Prof. Kotsinas attended to an internal seminar at the Institute of Cancer Biology and a few more lectures delivered by several Professors.
30. The long term secondment realized by PhD student Eirini-Stavroula Komseli to the Department of Cell Cycle and Cancer, Institute of Cancer Biology, Denmark resulted in the establishment of a fruitful and long standing collaboration with Profs Bartek and Sorensen. Mrs Komseli investigated the impact of Cdc6, a 60 KDa protein that belongs to the AAA+ family of ATPases and has a pivotal role in replication origin licensing, on normal and cancer cells.
31. The long term secondment realized by PhD student Marilena Papaioannou to the Department of Cell Cycle and Cancer, Institute of Cancer Biology, Denmark resulted in the establishment of a fruitful and long standing collaboration with Profs Bartek and Sorensen. Mrs Papaioannou performed experiments for two different projects. The first project was to investigate the cytotoxic effect of several chemical compounds that have been proposed from in silico models as potential inhibitors of the replication licensing factor CDC6. The second project involved Western Blot analysis of protein extracts received from tissues excised from colon cancer patients.

Deviations and corrective actions:
Few deviations that arose during the 1st period of the project, were covered during the 2nd period.
A few bottleneck cases encountered, but were efficiently resolved. Namely, two engineers (laboratory headed by Assist. Prof. I. Trougakos, laboratory headed by Prof. C. Kittas and Prof. V. Gorgoulis) and 3 experienced researchers (laboratory headed by Prof. L. Skaltsounis, laboratory headed by Assist. Prof. O. Tsitsilonis and laboratory headed by Assoc. Prof. A. Scorilas) formally quit due to personal reasons and were substituted, without significant delay, following the initial procedure of advertising the position, examining CVs and realizing extensive personal interviews.

Resources:
The activities of this work package had initially been estimated to cost 1,149,340.50 €. Resources referring to months 1-36 of the project lifetime cover the following expenses:
• Personnel Costs (98,600.00 € for Technical Support referring to 68 PM, 815,100.00 € for Experienced Researchers referring to 429 PM)
• Luca Scorrano travelling to Athens (2/9/12-6/9/12) (Venice – Athens –Rome – Venice) for meeting with members of the INsPiRE UoA Cancer Research Group; Athersuch Toby travelling to Athens, Greece (3/11-9/11/2012 ) (Heathrow - Athens – Heathrow) , Kyriaki Ioannou visit to the Center for Medical Research, Medical School of the University of Tubingen (1/10-20/12/2012) and Andreas Skorilas’ travel expenses for his visit to the Technical University of Munich (10/2/13-15/2/13); Nikolas Fokialakis to the National Center for Scientific Research (ISCN) (01/01/2013-31/03/2013) (Athens-Paris-Athens); Manfred Schmitt travelling to Athens (26/6/13-30/6/13) (Munich – Athens – Munich) for meeting with members of the INsPiRE UoA Cancer Research Group; Konstantinos Mavridis visit to the Department of Obstetrics and Gynecology, Technical University of Munich (27/07/2013-07/09/2013) (Athens-Munchen-Athens); Ioannis Trougakos to the Department of Molecular Biosciences (29/05/2014-01/06/2014) (Athens – Oslo – Athens); Fabiola Sesti to the Department of Molecular Biosciences (02/05/2014-31/05/2014) (Athens – Munich – Oslo – Athens); Ioannis Trougakos to the Department of Biology at the University of Padova (11/05/2014-14/05/2014) (Athens – Milan – Padova - Milan – Athens); Eleni Tsakiri to the Department of Biology at the University of Padova (01/05/2014-30/06/2014) (Athens – Milan – Padova – Milan – Athens); Emmanouil Fragoulis to the Department of Molecular Biology (07/03/2013-14/03/2013) (Athens - Munich - Athens); Manfred Schmitt travelling to Athens (11/06/14-18/06/14) (Munich – Athens – Munich) for meeting with members of the INsPiRE UoA Cancer Research Group; Kleita Michaelidou to the Technical University of Munich (17/08/2014-28/08/2014) (Athens-Munich-Athens); Graham Pawlec travelling to Athens (13/12/13-18/12/13) (Tuebingen – Athens – Tuebingen) for meeting with members of the INsPiRE UoA Cancer Research Group; Stefan Stevanovic travelling to Athens (22/07/14-25/07/14) (Stuttgart – Thessaloniki – Athens – Stuttgart) for meeting with members of the INsPiRE UoA Cancer Research Group; Ourania Tsitsilonis to the University of Tuebingen (03/07/2014-08/07/2014) (Athens – Stuttgart – Tuebingen – Stuttgart - Athens); Ioannis Voutsas to the University of Tuebingen (21/03/2014-24/03/2014) (Athens – Stuttgart – Athens); Emmanouil Mikros to the MRC-HPA Centre for Environment & Health, Imperial College London (24/09/2013-01/10/2013) (Athens-London-Athens); Dimitra Benaki to the MRC-HPA Centre for Environment & Health, Imperial College London (24/09/2013-23/11/2013) (Athens-London-Athens); Eirini Kouloura to the Department of Surgery and Cancer, Faculty of Medicine, Imperial College London (03/06/2014-03/08/2014) (Athens-London-Athens); Maria Chalampalaki to the Department of Surgery and Cancer, Faculty of Medicine, Imperial College London (06/07/2014-02/08/2014) (Athens-London-Athens); Jamal Ouazzani travelling to Athens (05/3/13-09/3/13) (Paris – Athens – Paris) for meeting with members of the INsPiRE UoA Cancer Research Group; Alexios-Leandros Skaltsounis to the National Center for Scientific Research (ISCN) (09/07/2014-17/07/2014) (Athens-Paris-Athens); Nikolas Fokialakis to the National Center for Scientific Research (ISCN) (26/04/2014-30/05/2014) (Athens-Paris-Athens); Aikaterini Termentzi to the National Center for Scientific Research (ISCN) (26/04/2014-30/05/2014) (Athens-Paris-Athens); Vassilis Gorgoulis and. Athanassios Kotsinas to the Department of Molecular Biology in Geneva (12/12/2013-16/12/2013) (Athens-Geneva-Athens); Maria Sideridou to the Department of Molecular Biology in Geneva (24/08/2014-29/08/2014) (Athens-Patras-Venice-Geneva-Patras-Athens); Vassilis Gorgoulis and Athanassios Kotsinas to the Department of Cell Cycle and Cancer, Institute of Cancer Biology (26/03/2014-28/03/2014) (Athens-Copenhagen-Athens); Eirini-Stavroula Komseli to the Department of Cell Cycle and Cancer, Institute of Cancer Biology (12/07/2014-09/08/2014) (Athens-Copenhagen-Athens); Marilena Papaioannou to the Department of Cell Cycle and Cancer, Institute of Cancer Biology (12/07/2014-09/08/2014) (Athens-Copenhagen-Athens), referring to a total amount of 103,260.61 €.
Work Package 4: Increasing NKUA-CRG visibility in the EU & International Research Area

Summary of progress towards objectives:
The aim of WP4 was to significantly increase the international visibility and exposure of NKUA-CRG research members. This objective was to be achieved at a European and International level via the organization of international scientific events (e.g. conferences, workshops) as well as via the participation of the INsPiRE research staff in international conferences, workshops, symposia, etc.
In terms of the total of 36 months, the INsPiRE research team organized and held two conferences and three workshops, as described within Tasks 4.1 – 4.5 of the project description of work.
With regard to Deliverable D4.1 Conference 1 report / agenda, conclusions, proceedings, list of participants, the Conference 1: “Progress in combination therapy of cancer using novel immunomodulators” was organized and held on 01-03/11/2012.
With regard to Deliverable D4.2 Conference 2 report / agenda, conclusions, proceedings, list of participants, the Conference 2: “Tumour Biomarkers: From Discovery to Clinical Applications” was organized and held on 14-16/06/2014.
With regard to Deliverable D4.3 Workshop 1 report / agenda, conclusions, proceedings, list of participants, the Workshop 1: “Ageing and Cancer cell biology: Convergent and divergent molecular mechanisms” was organized and held on 27-29/06/2013.
With regard to Deliverable D4.4 Workshop 2 report / agenda, conclusions, proceedings, list of participants, the Workshop 2: “Oncogenic Pathways and Anti-Tumor Responses” was organized and held on 23-25/04/2014.
With regard to Deliverable D4.5 Workshop 3 report / agenda, conclusions, proceedings, list of participants, the Workshop 3: “Cell Cycle & Natural Products” was organized and held on 08-09/05/2014.
With regard to Deliverables D4.6 Report on the participation in the S&T events (first report), D4.7 Report on the participation in the S&T events (second report) and D4.8 Report on the participation in the S&T events (third report), members of the NKUA-CRG presented their latest achievements and obtained awards for the quality of their work.

Significant results:
1. Conference 1 brought together several of the leading researchers in Europe and the USA, to report on recent advances made in cancer vaccination, emphasizing on novel strategies, adjuvants and immunomodulators, combinatorial treatments, means to enhance the potency of cancer vaccines and recent results from clinical trials. The Conference had duration of 3 days and numbered 205 participants deriving from the scientific community, pharmaceutical companies and stakeholders from EU and overseas. The Conference was held in Athens, Greece and highlighted the latest developments in the field of cancer immunotherapy and the use of new molecules that have recently entered or are in the process of entering clinical trials. Young researchers and students were encouraged to submit an abstract and present their work in the poster sessions. Invited plenary lectures from distinguished invited speakers were also delivered.
2. Conference 2 covered a wide range of aspects regarding the state-of-the-art in cancer biomarker research. More specifically, the 8 sessions of the conference covered issues such as circulating tumor cells, biological tumor markers, miRNAs as emerging cancer biomarkers, translating molecular pathways into novel cancer biomarkers and novel technological advances and approaches for urologic, leukemia and lymphoma tumor biomarker discovery. The Conference had duration of 3 days and numbered 87 participants deriving from the scientific community, pharmaceutical companies and stakeholders from EU and overseas. The Conference was held in Athens, Greece. Young researchers and students were encouraged to submit an abstract and present their work in the poster sessions. Invited plenary lectures from distinguished invited speakers were also delivered.
3. Workshop 1 provided the venue for researchers in Europe and the USA to establish contact and new collaborations were born. Eminent investigators working in the same area exchanged ideas, reporting recent advances in ageing and cancer cell biology emphasizing their tight connection as well as therapeutic approaches. The Workshop had duration of 3 days and numbered 121 participants deriving from the scientific community, pharmaceutical companies and stakeholders from EU and overseas. The Conference was held in Athens, Greece. Young researchers and students were encouraged to submit an abstract and present their work in the poster sessions. Invited plenary lectures from distinguished invited speakers were also delivered.
4. Workshop 2 provided the venue for researchers in Europe and the USA to establish contact and new collaborations were born. Eminent investigators working in the same area exchanged ideas, reporting recent advances in antitumor responses and oncogenic signaling in cancer. The Workshop had duration of 3 days and numbered 116 participants deriving from the scientific community, pharmaceutical companies and stakeholders from EU and overseas. The Conference was held in Athens, Greece. Young researchers and students were encouraged to submit an abstract and present their work in the poster sessions. Invited plenary lectures from distinguished invited speakers were also delivered.
5. Workshop 3 covered a wide range of aspects regarding the molecular basis of the effects of several previously known or newly discovered natural compounds on cell cycle regulation and its corresponding checkpoints, as well as novel experimental findings that relate natural products with the regulation of cell cycle. Special focus was directed to kinase inhibitors since the implication of those enzymes in the control of cell proliferation and reproduction and thus to the cycle of cell life, is of major importance. Additionally, all processes of natural product production, isolation, characterization and exploitation up to the level of biochemical, biological and clinical trials were addressed. The Workshop had duration of 2 days and numbered 123 participants deriving from the scientific community, pharmaceutical companies and stakeholders from EU and overseas. The Conference was held in Athens, Greece. Young researchers and students were encouraged to submit an abstract and present their work in the poster sessions. Invited plenary lectures from distinguished invited speakers were also delivered.

Because of an underspent amount, it was requested to spend an additional amount of ~5,000 € for participation in S&T events, apart from the 6 events that were initially foreseen:
1. The 2012 EACR Annual Meeting (EACR-22) was held in Barcelona, 7 -10 July. It provided a forum for discussion between scientists working in all fields of cancer research and focused on the latest developments in basic and discovery-driven translational research, through to personalized cancer treatment. Dr. Marinos Tsiatas and Dr. Ioannis Voutsas who attended this annual meeting, presented two posters.
2. The 2012 AACC Annual Meeting was held in Los Angeles, July 15–19. Prof. Emmanuel G. Fragoulis and Assoc. Prof. Andreas Scorilas, who attended this annual meeting, presented two posters, which were distinguished for their scientific excellence. Therefore, both of them received a “2012 Distinguished Abstracts Award”. In more detail, a total of 32 abstracts were selected by a group of National Academy of Clinical Biochemistry (NACB) Fellows for their scientific excellence from a pool of 888 abstracts accepted for the AACC Annual Meeting.
3. The 60th International Congress (Joint Meeting with ASP, AFERP, PSE and SIF) and Annual Meeting of GA, was held on July 28th-August 1st, 2012, in New York, USA. In the course of the congress, one poster presentation by Dr. Argyropoulou, two poster presentations by Dr. Gaboriaud-Kolar and an invited lecture given by professor A.-L. Skaltsounis were presented on INsPiRE-related research results.
4. The 2013 Cold Spring Meeting was held in Cold Spring Harbor Laboratory, 09 -13 September. It provided a forum for discussion between leading scientists over the world working in the fields of Eukaryotic DNA Replication & Genome Maintenance. Assistant Professor Athanasios Kotsinas, who attended this meeting, presented key invited lecture and also chaired a special session devoted to development of the cell cycle and cancer. Professor Vassilis Gorgoulis who was as invited speaker, was not able to participate because a health problem had occurred these days.
5. The International Meeting on Clusterin was held in University of Versailles, 11-13 June 2014. The aim of the Meeting was to bring together clinicians and scientists who work on Clusterin from gene to disease, in the hope of initiating fruitful discussions and successful collaborations. Moreover, the Meeting offered junior scientists a chance to present their work to a local, national and international community. Assist. Professor Ioannis Trougakos, who attended the Meeting, was part of the Scientific Committee and a chairman during Session 1. He also delivered a lecture. PhD student Aimilia Sklirou, who also attended the Meeting, presented a poster.
6. The EMBO Conference was held at the hotel Grecotel Cape Sounio, 7-11 October 2013. The aim of the Conference was to cover topics including the DNA damage detection and signaling, pathways of DNA repair, DNA replication, as well as chromatin structure, ubiquitylation and related processes, ageing, disease and therapeutic applications. Assist. Professor Athanassios Kotsinas, who attended the Meeting, presented a poster.
7. The 23rd Biennial Congress of the European Association for Cancer Research was held at the International Congress Center of Munich (ICM), 5-8 July 2014. The EACR Congress set out to be highly topical and relevant and to meet the needs of researchers at all stages of their careers. It also aimed at providing particular support and encouragement to students and junior researchers. The theme of the 23rd EACR Congress was ‘From Basic Research to Personalised Cancer Treatment’. The programme offered exceptional Plenary Lectures, Plenary Symposia with ample time for discussions, Scientific Symposia, Workshops and Oral and Poster presentations. Professor Vassilis Gorgoulis, who attended the Congress, was an invited lecturer.
8. The 50th ASCO Meeting was held on May 30th – June 3rd 2014 at Chicago, Illinois, USA. The ASCO Meeting is considered to be the premier educational and scientific event in the oncology community. The aim of the Meeting was to allow interactions face-to-face with oncology professionals from all over the world, to introduce new products and services as well as to conduct in-depth one-on-one product demonstrations. Assistant Professor Ourania Tsitsilonis and Dr Pinelopi Samara, who attended the Meeting, presented two posters.
9. The 9th ISCN symposium was held on May 26th – May 29th 2014 at the Lublin Science and Technology Park. The aim of the Conference was to discuss trends, present latest results and exchange ideas relevant to all chromatographic and related techniques, as well as hyphenated methods used in phytochemical analysis, sample preparation and isolation of biologically active metabolites from medicinal plants, food crops and other natural sources. Professor Alexios-Leandros Skaltsounis attended the Conference, as he was invited to participate as a chairman in Session II. Assistant Professor Nektarios Aligiannis attended the Conference and he presented a poster. Finally, Dr Maria Chalampalaki attended the Conference and she delivered a short lecture in Session IV.
10. The Analytical Tools for Cutting-edge Metabolomics Meeting was held on April 30th 2014 at the Science Suite of the Chemistry Center in Piccadilly, London. The conference brought together exceptional scientists for a program consisting of plenary and invited talks, posters, as well as an oral session devoted to early career researchers. It was an excellent opportunity for analytical chemists to learn more about metabolomics and its application, and for metabolomics scientists to improve their knowledge of cutting-edge bioanalytical tools. Dr Maria Chalampalaki attended the Meeting and she presented a poster.
11. The EMBO Workshop on Magnetic Resonance for Cellular Structural Biology was held on June 1st – June 6th, 2014 in Grossetto, Italy. The topics covered in the programme included the most recent and innovative developments in magnetic resonance and other high resolution techniques, their synergistic combination to describe the structural and dynamic properties of the biomolecules involved in specific cellular pathways, as well as the exploration of potential approaches that hold promise for addressing some of the major fundamental questions in mechanistic systems biology. Dr Dimitra Benaki attended the Workshop.

Resources:
The activities of this WP have been estimated to cost 203,514.00 €. The overall costs realized refer to the following activities and total 186,241.43 €:
• 4,208.00 € Travel Costs and registration fee for the team's participation to the “22nd Biennial European Association for Cancer Research Congress” 6/7/2012-12/7/2012 (Athens-Barcelona-Athens)
• 9,140.00 € Travel Costs and registration fee for the team's participation to the “2012 Annual Meeting of the AACC & Clinical Lab Expo”, 14/7/2012-19/7/2012 (Athens-Los Angeles-Athens)
• 5,427.37 € Travel Costs and registration fee for the team's participation in the “8th International Congress on Natural Products Research”, 28/7/2012-1/8/2012 (Athens-New York-Athens)
• 2,767.94 € Travel Costs, accommodation, registration fee and daily allowance for the team's participation to the “2013 Cold Spring Meeting” 9/9/2013-13/9/2013 (Athens-London-New York-London-Athens)
• 2,470.15 € Travel Costs, accommodation, registration fee and daily allowance for the team's participation to the “International Meeting on Clusterin”, 11/06/2014-13/06/2014 (Athens-Paris-Athens)
• 972.85 € Travel Costs, registration fee and daily allowance for the team's participation in the “EMBO Conference”, 7/10/2013-11/10/2013 (Athens-Cape Sounio-Athens)
• 5,700.00 € Travel Costs, accommodation, registration fee and daily allowance for the team's participation in the “23rd Biennial Congress of the European Association for Cancer Research”, 5/07/2014-8/07/2014 (Athens-Munich-Athens)
• 5,515.31 € Travel Costs, accommodation, registration fee and daily allowance for the team's participation in the “50th ASCO Meeting”, 30/05/2014– 03/06/2014 (Athens-London-Chicago-London-Athens)
• 3,537.76 € Travel Costs, accommodation, registration fee and daily allowance for the team's participation in the “9th ISCN symposium”, 26/05/2014-29/05/2014 (Athens-Warsaw-Athens)
• 987.05 € Travel Costs, accommodation, registration fee and daily allowance for the team's participation in the “Analytical Tools for Cutting-edge Metabolomics Meeting”, 30/04/2014 (Athens-London-Athens)
• 1,719.65 € Travel Costs, accommodation, registration fee and daily allowance for the team's participation in the “EMBO Workshop on Magnetic Resonance for Cellular Structural Biology”, 01/06/2014-06/06/2014 (Athens-Rome-Athens)
• 1.563,00 € Other Costs for Renting of the required facilities expenditures in terms of the Conference “Progress in Combination therapy of cancer using novel immunomodulators”, held in Athens 1-3/11/2012
• 12.732,00 €, Travel costs, accommodation and daily allowance in terms of the Conference “Progress in Combination therapy of cancer using novel immunomodulators”, held in Athens 1-3/11/2012
• 13.100,00 €, Other Costs referring to the provision of lunch and dinner costs, in terms of the Conference “Progress in Combination therapy of cancer using novel immunomodulators”, Athens 1-3/11/2012
• 1,000.00 € Other Costs for Renting of the required facilities expenditures in terms of the Conference “Tumour Biomarkers: From Discovery to Clinical Application”, held in Athens 14-16/06/2014
• 11,650.00 €, Travel costs, accommodation and daily allowance in terms of the Conference “Tumour Biomarkers: From Discovery to Clinical Application”, held in Athens 14-16/06/2014
• 16,930.00 €, Other Costs referring to the provision of lunch and dinner costs, in terms of the Conference “Tumour Biomarkers: From Discovery to Clinical Application”, Athens 14-16/06/2014
• 14,697.13 €, Travel costs and accommodation in terms of the Workshop “Ageing and Cancer cell biology: Convergent and divergent molecular mechanisms”, held in Athens 27-28/06/2013
• 12,110.00 €, Other Costs referring to the provision of lunch and dinner costs, in terms of the Workshop “Ageing and Cancer cell biology: Convergent and divergent molecular mechanisms”, Athens 27-28/06/2013
• 13,200.00 €, Travel costs, and accommodation in terms of the Workshop “Oncogenic Pathways and Anti-Tumor Responses”, held in Athens 23-25/04/2014.
• 14,750.00 €, Other Costs referring to the provision of lunch and dinner costs, in terms of the Workshop “Oncogenic Pathways and Anti-Tumor Responses”, Athens 23-25/04/2014.
• 17,663.22 €, Travel costs and accommodation in terms of the Workshop “Cell Cycle & Natural Products”, held in Athens 08-09/05/2014.
• 10,200.00 €, Other Costs referring to the renting of the required facilities expenditures and the provision of lunch and dinner costs, in terms of the Workshop “Cell Cycle & Natural Products”, Athens 08-09/05/2014.
• 4,200.00 € refer to secretarial support in this WP (3 PMs from the total of the 36 PMs for secretarial support)
Work Package 5: Dissemination and promotional activities

Summary of progress towards objectives:
The main objective of this Work package was the dissemination and the promotion of the NKUA-CRG’s research activities, conventional state-of-the-art facilities and high-throughput platforms in the scientific community, health professionals and other stakeholders in Greece and Europe.
Relevant activities performed during the months 1-36 of the project implementation refer to Tasks 5.1 Brochure publication and Web Site establishment/upgrade, 5.2 Publications in internationally quoted peer reviewed scientific journals and 5.3 Dissemination to other stakeholders – organization of Information Days.
With regard to Deliverable D5.1 INsPiRE / NKUA-CRG, brochure publication and Deliverable D5.2 Report on Web sites creation and/or upgrading, the development and distribution of the project’s brochure as well as the project’s website creation were realized.
With regard to Deliverable D5.3 Report on publications in scientific journals (first report), Deliverable D5.4 Report on publications in scientific journals (second report) and Deliverable D5.5 Report on publications in scientific journals (third report), a large amount of papers were published in international peer reviewed journals, exceeding the initially estimated amount of 15 publications.
With regard to Deliverable D5.6 Report on dissemination activities to stakeholders, a list of 19 dissemination activities (including posters, presentations, conference organization, etc.) has been setup.
With regard to Deliverable D5.7 Report on info days and intellectual property management seminars, including list of participants, the first Information Day was organized and held in Athens, Greece, on 25/01/2013, while the second Information Day was organized and held in the island of Spetses, Greece, on 12-13/07/2014. Moreover, the Intellectual Property Management and Protection Seminar was also realized in Athens, on November 26th, 2013.

Significant results:
1. The commencement of the project was published in newspapers and electronic media articles while the development and distribution of the project brochure further assisted to acknowledging and communicating the project and EU funding, during meetings and scientific workshops. The project website served as the main communication tool for the dissemination of the major aspects and outcomes of INsPiRE, hosting information about the project itself, the research updates, the concept and objectives of INsPiRE, the relevant working groups, the EU partners involved, the project events and job listings, the scientific publications and achievements. The website also hosted a specific private area for users with advanced access rights.
2. The results of the research were largely communicated within the research community via publications in peer reviewed journals. The project numbered more than 60 scientific publications.
3. The 1st Information Day was held on January 25th, 2013, at the Library of Health Sciences, in Goudi, Athens. A number of >80 Principal Investigators, University staff, postdoctoral researchers and PhD or MSc students attended this INsPiRE Info‐Day. INsPiRE researchers presented their work and future planning. These presentations were accompanied by extensive discussions and brain-storming.
4. The 2nd Information Day was held on July 12th – 13th, 2014, at the Island of Spetses, near Athens. Researchers presented their work and future planning. These presentations were accompanied by extensive discussions and brain-storming. This event was satellite to the final meeting of INsPiRE. The event had duration of 2 days and numbered 42 participants deriving from the scientific community, pharmaceutical companies and stakeholders from EU.
5. The Intellectual Property Management and Protection Seminar was held on November 26th, 2013, in Athens, Greece. The event was entitled: “Issues related to Intellectual Property in Greece and internationally” and was organized in the School of Pharmacy of NKUA. The speaker was Dr. Dimitrios Roukounas, who has worked in the field of patents. The event numbered 32 participants deriving from the scientific community and pharmaceutical companies.
Because of an underspent amount, it was requested to spend an additional amount of ~5,000 € for publication in scientific journals and of ~4,000 € for printing dissemination material for the project.

Resources:
The activities of this WP have been estimated to cost 43,096.00 €. The overall costs realized refer to the following activities and total 41,567.33 €:
• 3,239.00 € Other Costs terms of Publications for procurement of durable equipment
• 320.00 € Other Costs in terms of Publications for procurement of conference / workshop / meeting organization
• 22,608.33 € Other Costs for Publications in internationally quoted peer reviewed scientific journals
• 4,800.00 € in terms of subcontracting, for the development of the INsPiRE web site
• 7,800.00 € Other Costs for the development of advertising, Posters
• 2,800.00 € refer to secretarial support for WP5 (2 PM from the total of the 36 PMs for secretarial support).

Potential Impact:
The aim of INsPiRE was to increase the NKUA-CRG current technological capacity, to promote future partnerships and scientific networking and finally converge to the established top European research institutions. NKUA-CRG, after INsPiRE completion, is capable of producing high level new knowledge and the team will attract the interest of the industry and other stakeholders resulting in a positive impact on the socio-economic status of the country and its integration in the EU research area. The implementation of INsPiRE enables NKUA-CRG to enlarge existing alliances with academia, government and the biotech/pharmaceutical industries in order to integrate research, development, and commercialization of potentially useful biomedical products.
In terms of scientific impact, the NKUA-CRG members and external collaborators have produced a large body of highly impacted publications in international peer reviewed journals, as a result of the research conducted within INsPiRE. This body of publications is continuously growing and, as expected, it overpassed the initially set goal of 15 publications.
The NKUA-CRG search for new agents with anti-cancer activity focused on (although not limited to) compounds isolated from the plants of the Mediterranean basin. This region of the world is a unique source of novel natural compounds as it is characterized by extended biodiversity and a specific beneficial nutritional pattern, the so called Mediterranean diet. Taken all those data into consideration, it is reasonable to anticipate that the aforementioned activities contributed significantly to the regional economic and social development.
The envisioned economic impact refers to the following aspects. Since a significant part of the research carried out was fundamental/basic research, the advancement of knowledge on cancer and drug discovery will give rise concomitantly to commercial exploitation in a sense that new compounds and/or diagnostic kits or preventive measures can be developed and turned into products that will benefit the patient (commercial exploitation of the work in NKUA-CRG). In the near future, these efforts are expected to produce patentable results and high economic and social benefits. Furthermore, previous experience in collaborating with regional private sectors suggests that promoting scientific excellence in academia augments the willingness for collaboration and know-how transfer. It is considered that through the implementation of INsPiRE the participation of the industry is strengthened.
The potential impact on the socio-economic environment of Greece for better understanding the molecular basis of cancer and putting the basis for new drug design is (as everywhere in the world) immense. Such effects make the region a more attractive, innovative and competitive place to live and work in. Moreover the cross-border, transnational and interregional cooperation is expected to increase regional cooperation in Europe, making EU regions more open to the global market.
The dissemination of the NKUA-CRG scientific expertise and the technological platforms was facilitated through workshops and participation in European and international conferences during months 1-36. The team shared the impact of the project to external research, governmental (or non-governmental) and industrial entities. These actions promoted the leading position of NKUA-CRG in the South-Eastern European area. The significant scientific, technological and economical magnitude of INsPiRE required a European, rather than a national or regional approach. NKUA-CRG exploited the opportunities provided from the project to create sustainable strategic partnerships with eminent EU research Institutions, enabling its integration to more advanced EU research systems and processes. These goals could not be achieved on a national scale.

The main dissemination activities were the following:
1. During the first year of the project, a project brochure was created and was made available to each of the partner organizations and on the website for printing and distribution. The brochure provided information on the project’s aims and objectives. More specifically, the brochure was referring to the instrumentation acquisition, the transfer of know-how which was expected to be accomplished via secondments between the ten European partner Institutes and, also, the dissemination of the project’s research activities. A large number of Brochures was also printed close to the completion of the project to be used to further disseminate the existence, achievements and technical capabilities of NKUA-CRG.
2. The official web address of the INsPiRE Project is http://inspire.uoa.gr and was launched right after the initiation of the project. Moreover, each one of the five WP leaders upgraded and updated his/her personal websites, in order for them to keep up with the latest news of the INsPiRE project.
3. On March 2012, the INsPiRE project was further disseminated via two websites. The articles that were uploaded were introducing the project to the public, describing INsPiRE’s basic axis and planned efforts or technological upgrades.
4. The INsPiRE project was also disseminated in the press. More specifically, an article was published in the University of Athens Press on March 2012, informing the public and the community of the University on the project’s main objectives and aims and on the collaborations between the five different departments of UoA. Another article was published in the scientific magazine “Farmakeftiki” in the 26th Issue (January – March 2014). The article informed on the currently implemented actions of INsPiRE, such as the increase of visibility and exposure of the NKUA-CRG human resources to an international scientific environment, as well as on the new high-tech instrumentation that was acquired during the project. Also, a major dissemination and Press release action referred to a publication of the INsPiRE activities along with interviews from the Coordinator and participating scientists in the Good News website and e-newspaper.
5. There was also effort put for further dissemination to international websites. The following text entitled ““INsPiRE-ing” the technological and scientific development of the University of Athens (Greece) Cancer Research Group” was therefore submitted (publication is pending; if the articles are accepted they will be paid by our own resources) at the Research EU magazine (http://cordis.europa.eu/research-eu/magazine_en.html) and at the European Parliament’s website (https://www.theparliamentmagazine.eu/).
6. CORDIS is the European Commission’s primary repository and portal to disseminate information on all EU-funded research projects and their results in the broadest sense. After the invitation of the EU officer who is responsible for the project, a template was released, containing all necessary information on the INsPiRE project.

List of Websites:

website address: http://inspire.uoa.gr

Contact details:
Prof. Christos Kittas NATIONAL AND KAPODISTRIAN UNIVERSITY OF ATHENS
Tel.: +30 210 746 2303
Fax: +30 210 746 2340
e-mail: ckittas@med.uoa.gr

Final Report Summary - INSPIRE (INtegrating the emerging research Potential of the University of Athens Cancer Research Group in the European research area)

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