The visit took place over two days, the 12th and 13th January 2012. It started with a general presentation of the previous research unit by its director. Then each group of the future research unit presented its past achievements as well as its project for the next contract 2013-2017. The reasoning leading to the new perimeter of the unit as well as the forthcoming organization of the common facilities (Federation) were subsequently exposed by their respective directors. These speeches were followed by a general discussion with all the staff of the laboratory. The remaining of the first day was dedicated to visits of the laboratories and discussions with the group members in front of posters. After a discussion between the institutional representatives (UDS, CNRS) and the committee members, the second day was dedicated to internal discussions to the committee.

History and geographical location of the unit, and overall description of its field and activities:

The laboratory "Chemistry of complex matter" ("Chimie de la matière complexe") is a 'Unité Mixte de Recherche' CNRS / Université de Strasbourg (UMR 7140). It results from the incorporation of three new teams originating from the UMR 7177, to the former UMR 7140 "Molecular tectonics of solids" ("Tectonique Moléculaire des Solides"). The laboratory aims at addressing complexity of chemical matter envisaged as the next relevant organization level in chemistry after molecules and supramolecules. The activity of the laboratory will cover theory, syntheses, analyses, and physicochemical investigations.

Management team:

Director: Mr Mir Wais HOSSEINI Adjunct-Directors: Mr Jean-Marc PLANEIX together with Ms Petra HELLWIG in the future unit.

 Assessment of the unit

Overall opinion on the unit:

The research unit unifies five complementary teams around the common and promising topic of Chemistry of Complex Matter, which will be practiced along various nationally and internationally-recognized approaches. Although they will be totally independent with respect of the use of their financial resources and their scientific interests, the team members share a common dynamic spirit and the enlarged perimeter of the new UMR could provide interesting opportunities for all its five components. The unit should eventually benefit from the dynamics and the supports from the Labex"Chemistry of Complex Systems" and from the Idex allocated to Strasbourg University. All these elements have convinced the committee of experts of the relevance of the unit contour.

Despite such favorable features, the committee members have been also concerned by several weakening elements. The five constitutive unit teams are presently dispersed geographically, which does not facilitate the emergence of a common culture. Several unit members cumulate local and national responsabilities much beyond the relative significance of the unit size. Although this result probably expresses their concerns for community interests, this engagement is at the same time a risk for securing the future of the unit by addressing the most ambitious and time-demanding scientific projects. The committee members eventually noted that currently non existing or partial technical and instrumental support will need to be implemented to fulfill all the unit projects.

Strengths and opportunities:

Timely relevance of the topic of Chemistry of complex systems.

Expertise and complementarity of the five research groups.

Quality of the scientific production.

Quality of human resources.

The five teams share a common dynamical spirit for organizing and practicing science as well as a consensus about governance principles.

Participation to the Strasbourg University Idex and to the Labex "Chemistry of Complex Systems".

Weaknesses and risks:

No continuity of the unit premises.

Extremely important involvement in training and structuring activities at the regional and at the national level.

Lack of technical support in two groups.

Lack of defined strategy for facilitated access to platform mass spectrometers

Recommendations:

Although approving the pragmatic and science quality-driven approach of the unit, the committee members strongly encourage all the unit members to aim at synergism. In particular, this support could materialize in addressing a few meaningful high-level scientific challenges, which would be also valuable to create a unit spirit. The unit global investment in local and national policies should also be more equally shared among the unit members to reorient more time and energy to the emergence and the developments of new projects.

 Detailed assessments

Assessment of scientific quality and production:

The research unit unifies five teams around a common scientific motto (Chemistry of Complex Matter). Although more restricted than in the context of the Labex "Chemistry of Complex Systems" to which two unit teams participate, the unit interpretation of complexity is relevant and in phase with several recent developments in chemistry.

The gathered multidisciplinary and complementary expertises (organic/inorganic/biological chemistry, material science -crystal engineering, analytical and physical chemistry -bioelectrochemistry, X-ray diffraction, IR-, MS spectroscopy, and theory -chemoinformatics, PACHA) are recognized in their respective fields, both at the national and international levels.

The enlarged perimeter of the new UMR could provide interesting opportunities for all its five components. They have been convincingly evoked by the unit director as well as by the team leaders during the visit. Although approving the pragmatic and science quality-driven approach of the unit director, the committee members strongly encourage all the unit members to aim at synergism. In particular, this support could materialize in addressing a few meaningful high-level scientific challenges.

The quality (documented by numerous publications in previewed international journals with good to high impact factors) and the quantity of publications, communications, and dissertations are globally very good. All the members of the research unit are authors of documents.

Assessment of the unit's integration into its environment:

The five unit teams have mainly motivated their research by progress at the cutting edge of fundamental knowledge. Transfer of knowledge to the industrial sector has not been put forward as a major motivation of scientific projects. However, one should note that two groups have already very good contacts with major industrial partners. This perspective should be encouraged and extended to other teams to diversify funding resources and enlarge professional employment perspectives for the students and post-docs trained within the unit.

In contrast, several members of the unit are strongly engaged in various and highly significant organizational activities relying on their expertise and dynamism (chairing the Collegium, adjunct director of the Strasbourg Foundation and "Chemistry of Complex Systems" Labex, direction of the Chemistry UFR…).

The five teams globally do not suffer from any major lack of financial support. In particular, they benefited from significant local grants during the last contract, which mainly originated from the Strasbourg Foundation of Chemistry. The recent Strasbourg success to the Idex selection is prone to sustain this trend. Two groups additionnally belong to the recently supported Labex "Chemistry of Complex Systems", which should also contribute to secure the financial support of their scientific activity in the forthcoming years. Despite such opportunities, the committee members strongly encourage the unit teams to apply to external financing sources (in particular national -ANR -and european -ERC, Marie Curie, etc.).

Assessment of the research unit's reputation and drawing power:

The research unit's reputation and attractivity is well documented in a list of prizes and distinguished awards, invitations to international and national events and also by the listed invited professors, postdocs and high-level students of national and international origin.

There exist various collaborations of excellence with national and international laboratories (Frankfurt, Illinois, Pennstate, San Francisco, ANKA Karlsruhe, BESSY Berlin, Freiburg, etc). The unit is also engaged in an active policy of institutional partnership.

Assessment of the unit's governance and life:

The new unit results from the association of the two original teams from the UMR 7140 with three new teams originating from the UMR 7177. Despite this major change, the committee has been convinced that the five teams share a common spirit and organizational rules about science practice so as to build a coherent laboratory.

The unit management relies on the director, two adjunct-directors, a board of principal investigators and the unit council (including all the permanent members + 2 representatives elected among non-permanent members). The task force has been efficient to conceive the unit project, which was discussed within each team. Further effort should be now directed to favor interactions between the permanent members, both to share the unit project and to support the emergence of common scientific projects. From the latter point of view, the unit presently suffers from the lack of premise continuity, which should be remediated in the course of the next contract. In relation to the present geographical dispersion, the committee members have estimated that the unit should benefit from the organization of a real "Conseil de laboratoire" obeying the CNRS rules.

The five research groups will be scientifically independent entities. Further scientific activity and emergence of new common projects will be mainly stimulated by organizing three one-day symposia per year during which the team members will present their results and achievements. Although recognizing the relevance of the pragmatic attitude of the unit director, who will make strong efforts to support excellent emerging projects, the committee recommends the additional organization of prospective seminars devoted to identifying research opportunities within the unit.

The unit members are strongly involved both in educational activities and structuring of regional and national research. Whereas this involvment is to be generally encouraged, the committee members have estimated that it was probably excessive with regards to both the size of the unit and the existence of other human resources on the esplanade site of Strasbourg University.

Assessment of the strategy and 5-year project:

The five constitutive teams have defined a common referential for practicing and supporting scientific activity. This referential has been materialized under the timely motto of complex matter organizations, which covers various interpretations within the unit. In fact, the five research groups will be scientifically and financially independent entities. Recurrent financial supports and fellowships originating from the university or the CNRS will be shared on the basis of the number of permanent staff members.

Assessment of the unit's involvement in training:

The unit members are strongly involved in training at all stages of the university curriculum. They are specifically in charge of numerous pivotal management responsibilities at the Bachelor, Master, and Doctoral School levels.  Detailed assessments

Assessment of scientific quality and production:

The research activity of the Molecular Tectonics group is of considerable quality and original. It has been until now and continues to be of purely fundamental nature (basic curiosity-driven research). It deals with a bottom-up approach to the synthesis of functional molecular materials based on the control of intermolecular associations and self-assembly processes driven by recognition. This approach allows to iteratively assembling various tectons to yield crystalline products (1D-, 2D-, 3D-coordination networks, porous crystals by formation of cavities and channels through H-or coordination bonds). Also crystals of crystals accessible through 3D epitaxial growth were investigated. New developments include surface patterning (collaboration with ISIS, Strasbourg) and the design of luminescent liquid crystals (collaboration with IPCMS, Strasbourg). In addition, two new fields of research have been initiated: the first one deals with molecular motion and the conception of molecular gates and turnstile processes based on functionalized porphyrins. The second deals with molecular photonics systems emitting in the NIR, based on the complexation of lanthanide cations by porphyrin bearing chelating units. Some guiding principles in terms of potential applications exist (see projects below). Citation of the team publications by other groups is moderate (average of 6.97 citations per published article in 2007-2011; 30 % of these are self-citations; due to the small size of the international community in this area), showing a good but not exceptional impact of the research.

The team has published 62 articles in international refereed journals of high average impact factor (4.56 based on the journal IF of 2010) for the period 2007-2011. For a group of 7 "publishing permanent members", this translates into 1.77 publications per permanent member per year. 13 theses have been defended in the 2007-2011 period. Considering that a large fraction of these publications are communications, the productivity of the team can be considered as quantitatively moderate, although qualitatively excellent. The scientific quality of the contributions has been recognized in the participation in the Labex Chemistry of Complex Systems, which will be directed by M. W. Hosseini. All permanent researchers and research faculty are "publishing". It is worth to note the strong contribution of Research Engineers.

• Assessment of the research team's integration into its environment:

The research carried out by this team is of purely fundamental nature. No industrial partnership or socioeconomic relation has been sought. Most of the researchers of Teams 1 and 2 are involved in the dissemination of scientific knowledge in schools or to the general public, for example as regional coordinator of the 2011 International year of Chemistry.

The unit (UMR) has been successful in attracting financial support from institutional and local sources (UdS, CNRS and especially RTRA-CPER) but not so much from external sources. The scientific report of the team and selfevaluation of the UMR are poorly organized, because external funding from ANR (projects FERROMOL and PMOEAH) and international (project FUMASSEC) sources are shown in Table 3.1 (AERES financial resources table) but nowhere else in the document these contracts are mentioned. In summary, small participation in 2 ANR projects but no project held by the group.

The group, on the other hand, is extremely well integrated into its local environment at the teaching and administrative levels, with some members having served or still serving the University on important roles (Doctoral School, Collegium, RTRA-icFRC, UFR, Scientific Council, …) and thus providing an essential contribution to the organisation and development of chemistry at the University of Strasbourg.

• Assessment of the research team's reputation and drawing power:

The group leader enjoys a very strong international profile. He has received a Prize from (and has been elected honorary member of) the Romanian Chemical Society, and a binational (franco-italian) prize of the Italian Chemical Society. He acted as editor and as member of the editorial board of Chem. Commun. 2000-08; he is co-editor in chief of New J. Chem., and since 2010 member of the advisory board of Crystal Engineering and member of the editorial board of Crystal Engineering Communications. He also had numerous invitations to deliver lectures at international conferences and in other research institutions (48 and 52, respectively) both in France and abroad. He is an elected member of CNU (section 32). At the national level, he has received the silver medal of CNRS in 2011 and is a senior member of IUF since 2004. A younger Professor in the group has also been recognized by the election as junior IUF member. Almost all of the research leaders have given invited talks in international congresses. One other team member participates to the CNRS National committee (section 14). Several group members are heavily involved in pedagogical and organizational tasks. A total of 8 symposia have been organized during the period. With these premises, the group has an attractive profile. It has hosted 5 post-doctoral fellows (3 from abroad), 10 defended PhD (5 from abroad) and trained 7 PhD students (3 from abroad) in the reference period 2008-2011.

The group entertains a few collaborations with French and foreign institutions (New York University, Marie Curie Training Program), but none of these appears to be part of a structured (funded) programme. The majority of the scientific production is proper to the team.

• Assessment of the strategy and 5-year project:

The project part is the best part of the report concerning this team. It is imaginative, broad in scope, and opening to a multitude of potential applications. Even though most of the proposed research remains of purely fundamental nature, specific applications are taken as guide to orient much of it (separation of enantiomers of gaseous inhalation anaesthetics, asymmetric catalysis, luminescent properties,...).

The synthetic strategy for the iterative construction of complex matter from various tectons is based on selfcomplementary building blocks (complex as ligand and complex as metal strategy introduced by Balzani) or complementary couples containing in their backbone recognition sites and a construction algorithm. Relying on the expertise gathered in the tailor made construction of complex periodical architectures, the presented project aims at bridging the gap between structural and functional networks. The first two projects (P1 and P2) thus put forward the valorization of previous results obtained on porous networks and the possibility to design chiral cavities. The first one is based on the ability of ZnSiF 6 to form inorganic pillars to be connected by four flexible enantiomerically pure helical organic tectons and to be tested in chiral separation of anaesthetics enantiomers. The second one proposes decoration by chiral substituents of the hexagonal channels obtained through the assembly of functionalized porphyrins, for the separation of chiral alcohols and enantioselective transformations. Efforts directed towards the elaboration of heterometallic multifunctional networks (porous and luminescent, P3 project) will be pursued, while surface patterning (directional 1D or 2D) will be tackled through the organization of porphyrins bearing mono and tridentate coordination sites (P5 project). Porphyrins, which constitute the stator backbone of molecular turnstiles developed in this group, will be further poly-derivatized and investigated for pH triggered directional movement in the P6 project. Furthermore, the P4 project will make use of new protonated cationic tectons based on bisimidazolium, potentially fluorescent and photoisomerizable, for the elaboration of crystals of crystals and reticulation of (bio)polymers bearing carboxylate or sulfonate groups.

The projects will certainly benefit from the skills of the various research groups brought together in the new research structure. Some of them are sketched: understanding of energetics in the solid state following a previous collaboration with already published results; monitoring of the early stage of crystal formation by mass spectrometry, which is an emerging and challenging topics in cluster chemistry; constitution of a data base of tectons and of already characterized molecular architectures to be exploited for the design of new relevant combinations ; tackling of molecular motion directionality taking advantage of the expertise in 2D IR techniques, although this idea is not really detailed.

Conclusion:

The research group will be embedded in a research unit composed of five teams focused on a common scientific topic "Chemistry of Complex Matter". Although all the team members will be totally independent with respect of the use of their financial resources and their scientific interests, the Committee strongly encourages all the unit members to aim at synergism. The research proposal convincingly demonstrates that the recognition of similarities in the synthesis of complex matter allows prediction of potential results in related cases. It is clear that this approach sometimes will lead to serendipitous results, which after elucidation provide new insights useful for advanced studies.

All the projects proposed are very challenging and of high scientific quality with significant potential for possible future applications. This is especially true for P1 "Chiral separation of racemic anaesthetics by porous crystals with homochiral space". Especially for this issue the presentation of preliminary results would have been relevant.

Finally, the highly interdisciplinary character of the research of the group and the concentrated use and interplay of the broad spectrum of spectroscopic facilities and expertise (inorganic/organic chemistry, material science, crystal engineering, bioelectrochemistry, X-ray diffraction, IR-, MS spectroscopy, theory) of the unit besides the successful development of the "Chemistry of Complex Matter" on the basis of tectons, guarantee an excellent broad training for young chemists and present a nice example of fundamental "curiosity-driven research". The team consists in three permanent members [1 professor and 2 assistant professors -MDC] with three PhD students and no post-doctoral fellows over the 2007-2011 period. The activity of the team is mostly recognized for the long-term development of the PACHA software package (since 1993) that allows assessment of the thermodynamic stability of self-assembled solids. The strength of this approach is its ability to consider extended systems for which the application of DFT based approaches still remain difficult or impossible. This is especially the case of supramolecular assemblies involving heavy metals and/or numerous water molecules with applications to the Ti based alkoxides, aryloxides or polyoxometalates including giant POMs like the [Mo 132 O 372 (CH 3 COO) 30 (H 2 O) 72 ] 42-(Mo 132 ) nanocapsule. The organization of the water molecules and their dynamics inside the capsule was studied by neutron diffusion techniques and spin echo NMR in collaboration with the CEA Saclay, while the mechanism of its self-assembly was tackled by DFT calculations in collaboration with the Laboratory of Quantum Chemistry in Strasbourg. These investigations have underlined the role of water during self-assembly and have proposed a path for the formation of the pentagonal units and the dimeric linkers essential to the capsule self-assembly. Although interesting, the development of the chemistry of Ti-based alkoxide and aryloxide complexes and their subsequent study by 1H DOSY NMR spectroscopy with discussion of the diffusivity in terms of the shape of the solvated objects are less original and less visible with a clear lack of identified perspective of applications.

Although of good or even very good quality [Angewandte Chemie] the scientific production of the team remained rather modest in the 2007-2008 period with a remarkable increase in 2009-2011 [11 out of 16 publications]. Most of these articles correspond to collaborations at national and international level. Only one out of the 3 PhD theses has currently given rise to a publication. This can be considered as a poor outcome that obviously could largely be improved. It should be noted that one member of the group published 7 articles considered as not being part of the UMR activity.

Concerning the PhD students, none seems to have received financial fellowship support.

• Assessment of the research team's integration into its environment:

No industrial partnership or socioeconomic relation is reported in the document and no mention is given of any ANR or contract providing financial support for the group's activity. There exists an ongoing collaboration project with EMPA for the incorporation of POMs in membranes.

One assistant professor of the group is Director of studies for L1 and involved in numerous education related charges. She supervises the elaboration of short movies for educational purposes and was a key person for the local organization of the Year of Chemistry. This activity includes a record of "grand public" conferences on water.

• Assessment of the research team's reputation and drawing power:

The group appears to have a rather limited international visibility. Only 4 invited conference talks and 7 oral presentations were given in the reference period. Only two of the invited presentations and one of the oral presentations were genuine scientific talks in an international context. The report only mentions 3 poster presentations with a single international event leading to a limited visibility of the results of the team. The group leader is member of the editorial board of Inter. J. Mol. Science since 2002 and of Water since 2008. No other particular distinction is mentioned in the report. No post-doctoral associate was recruited in the reference period. Even though the group entertains a wide and fruitful network of collaborations based on the use of the PACHA software with several well-known international groups, none of these appears to be part of a structured (funded) program.

• Assessment of the strategy and 5-year project:

The project is presented in four sub-projects, two of them appearing to be the continuation of on-going research. The main project (P4) is in-line with the already recognized expertise of the team; it consists of the upgrading of the PACHA software to include apolar molecular tectons and entropic contributions so as to address dynamic aspects of self-assembly. The adaptation of the code to existing molecular dynamics codes can possibly establish a collaboration with the team 5. The project P3 on 1 H DOSY NMR of POMs (M = Ti, Mo) focusses on the investigation of reliable correlations between diffusion coefficients and their molecular weights; it will likely benefit from complementary data provided by mass spectrometry (Team 4). Two other projects propose to extend the chemistry of oligophenylenes in several directions: self-assembling of 2,2' biphenol containing oligophenylenes to lead to porous and flexible purely organic frameworks (P1); elaboration of photo-sensitive Ti(IV) porous hybrid materials based on multitopic resorcinol ligands separated by oligophenylenes (P2).

Most of the expected potential of the project is based on the recognised expertise of the PACHA software development and its possible evolutions.

Conclusion:

The project announced by this team is not fully convincing and even the realisation of part of it would require a profound change. Even with a globally good quality of publications for its permanent members, this small research team suffers from a lack of visibility exemplified by the too limited number of oral and poster presentations at the international level. The development of the proposed project has to take benefit of possible synergies with the research groups joining the new UMR structure but will certainly require financial support, at least through local or national funding. • Assessment of scientific quality and production:

This team is constituted by one professor and one assistant professor. It investigates the role of proteins in central chemical processes of energy transduction in biological cells (field of molecular bioenergetics), via advanced spectroscopic techniques (IR, Raman), combined with electrochemistry and photochemistry tools. The topic is highly interesting and timely, addressing numerous fundamental knowledge issues and practical applications.

The team has published an important number of papers ( 40), corresponding to an excellent average of 4.7 papers per permanent team member and per year. The targeted journals are the main titles in the domains of biochemistry and physical-chemistry. The team leader has also participated to 5 books on electrochemistry, spectroscopy and biological processes. 4 invited conferences during the evaluation period can be considered as a good achievement, taking into account the size and the recent constitution of the team, while 29 oral communications and 28 posters represent an excellent score.

The group leader has also participated to the organisation of 5 symposia, at the international and local scale.

• Assessment of the research team's integration into its environment:

The team is involved in several industrial and collaborative contracts, evidencing the interest generated by its research in a broader audience than the mere academic partnership. In addition to local support, the group has been particularly successful with respect to its application to numerous calls (Chaire d'excellence ANR, FRM,…). Beyond the comfortable budget generated by its projects, the team benefits from an excellent network of collaborations in France and Germany.

• Assessment of the research team's reputation and drawing power:

The team leader has obtained a "chair of excellence" from ANR and is a young member of the IUF. The group has attracted an important number of researchers and students, many of them from abroad.

Several collaborations with laboratories in France and abroad seem well-established.

• Assessment of the strategy and 5-year project:

The main project of the team is to study enzymes at the molecular level (in particular their reaction mechanisms), upon developing new and challenging spectroscopic tools. For example, using the far IR region to investigate biological molecules is unusual but could provide interesting information on metal-ligand vibration and on the conformational state of the molecules. This latter aspect could constitute an important crosslink with the research activities developed by Team 1. The team will continue studies in electrochemistry as well, to monitor electrochemical properties of proteins, eventually coupling the technique with infrared spectroscopy.

The research strategy and the choice of the subjects are interesting and relevant.

• Conclusion:

The Team 3 is a small but excellent team, which has developed a specific position in the foreground of the research. Its activities and notoriety are expected to grow and to assess the leadership of its principal investigator. Additional permanent staff hiring should be programmed, both for research and technical support, in particular to interact with the other teams of the research unit. The collaborations and contract activities should be maintained and implemented, to ensure a stable financial support to the research and a strong network of relationships. The group composed by 3 permanent staff (2 CNRS researchers, 1DR2, and 1CR1; 1 assistant professor), 6 PhDs and 1 engineer (employed on contract), was created in January 2008. An emeritus researcher (DRCE CNRS), joined this small unit in January 2011.

Research fields of investigation were axed to:

-the development of mass spectrometry methodologies using ESI-MS (Electrospray Ionisation Mass Spectrometry) and MALDI-MS (Maldi Assisted Laser Desorption Ionization Mass Spectrometry) for the study of supramolecular systems in chemistry and in biology (protein complexes) with the aim of determining the weight, the stoichiometry, and the stability of such complex structures; -the study of membrane proteins using CE-MS-MS coupling using on-line CE/ESI-Q-TOF and off-line CE/MALDI-TOF-TOF sources and including proteomics approaches (gel multi-enzymatic digestions with different proteases or mixtures ofthem).

Developed by only few laboratories in France, these couplings are especially demanding. The group is notably the European referent of two industrial partners (Bruker Daltonique and Beckman-Coulter) for such instrumental development.

Both goals are great challenges. Through several national and international collaborations involving chemists, biologists and instrument constructors, this group has developped a high level research including a significant risk factor.

The scientific production over 2007-2011 amounts in 19 papers in peer-reviewed journals, 8 invited talks and 17 oral and poster communications, with one PhD defended. All the members are producers and publish in diversified journals with various impact factors. The past and current work more specifically related to the development of the couplings would deserve to be published in journals more connected to the mass spectrometry community and with stronger impact.

Assessment of the research team's integration into its environment:

The team skills are well appreciated by the partners and collaborators of the "Esplanade" site of UDS within the platform of the UMR 7177 (and to a lesser part those of the IBMC). This group has strongly contributed to obtain funds to equip this platform on the basis of (i) successful applications to calls (yielding acquisition of two mass spectrometers -MALDI TOF-TOF and ESI-Q-TOF -part of the maintenance and of the management of which is insured by group members, or (ii) own credits (ANR contracts and development contracts with companies; to acquire several devices -nanoLC chromatography, capillary electrophoresis, purification and desalting systems, ….). This platform is "vital" for the research activities of the team. Access and modalities of use will have to be well defined to maintain the group activity. The corresponding agreement will allow the group to stabilize and enlarge its network of academic and industrial collaborations, making possible to finance research in terms of non permanent staff (post-docs, IE under contract) and equipments (570 000 € over 4 years).

Assessment of the research team's reputation and drawing power:

Due to their status, the researchers have a weak participation in the teaching programs of the University but are involved, since 2005, in an International Research Training Group (GRK 53), which makes it possible to recruit PhDs, post-docs and researchers within German and French laboratories with which they collaborate.

Assessment of the strategy and 5-year project:

The project is centered mainly on four lines linked to mass spectrometric techniques: (i) Development of methods to analyze the nucleation processes of non-covalent complexes; (ii) Development of methodologies to characterise membrane protein complexes (cross-linking strategies and analysis by proteomics); (iii) Development of a rapid and complete high resolution characterisation method of intact isoform proteins with capillary electrophoresis-MS interface; (iv) Study of proteins extracted from archaeo-materials (involving a new incoming assistant professor). These themes of research will be addressed in the continuity of the current work but more in connection with internal collaborations in the new unit.

The feasibility of this project depends on two main points: (i) the methodology of analysis of complex or even very complex systems (membrane proteins); (ii) the CE-MS-MS couplings, of technological order. This project is not really original (numerous groups work on such analytical challenges) but presents a real risk-taking. The success will depend mainly on the availability of equipment (machine time of the analytical platform) and even of new purchases considering that the new CESI interface (200 k€) is loaned during 18 months by Beckman-Coulter.

Conclusion:

This team has demonstrated its strong expertise and its skills to approach analytical challenges by mass spectrometric techniques and capillary electrophoresis, and its capacity to look for financing. Within the new unit, it will be definitively able to develop interactions with other groups by using complementary approaches. It benefits from (i) a specific partnership with the proteomic platform of IBMC, Strasbourg; (ii) strong collaborations with industrial partners (Bruker Daltonique and Beckman-Coulter) which can provide an important support for new technological developments; (iii) several national and international collaborations. In contrast, it has limited autonomy since it heavily relies on platform equipments. From the latter point of view, some specific agreement must be established in relation to the equipments of the scientific platform of the federative structure presently managed by the UMR 7177. Moreover the team projects are ambitious and difficult with respect to the number of permanent staff. Efforts should be concentrated without multiplying applications (at the risk of appearing as just a service provider). Assessment of scientific quality and production:

Team 5 is constituted by one professor, one "directeur de recherche" CNRS and one assistant professor. The central activity of this group is to develop new theoretical descriptions of molecular systems in order to propose new ways to analyze their properties. To this end, the team refines some theories and their domain of applicability but also produces new software.

For the period of reference, the team has produced an important number of papers (41). This corresponds to an average of 3.2 papers per permanent and per year. These articles have been published beyond the framework of the team and articles written in collaboration have led to publication in multidisciplinary journals. Members of the team have also participated to 5 books on Chemoinformatics, have given more than 50 conferences and have also taken part to the organization of 14 international symposia, workshops and summer schools.

The scientific production and the dynamism of this team make it a national and international reference in the field of Chemoinformatics.

• Assessment of the research team's integration into its environment:

Overall, the team has proved its capability to obtain funding from various sources. The group has been successful with respect to applications to local and national calls (Region, CNRS, MAE, ANR) but has also received funds from the EU. Moreover, it has established several contracts with private companies quite exclusively through collaborative researches. This aspect of valorization is also attested by the realisation of numerous programs derived from their research that can be now used by any researcher interested by this field. The team is also notably involved in training at the Master level, both at national and international level.

Assessment of the research team's reputation and drawing power:

During the period of reference, the team has received an important number of invited researchers (13; including 5 for periods longer than three months), all of them from abroad, and has hired 4 post-doctoral associates. The group leader is also the coordinator of two "Groupement de Recherche", one national in Chemoinformatics, one international in supramolecular chemistry. These points underline the existence of well-established and long-lasting collaborations with several laboratories in France and abroad.

Assessment of the strategy and 5-year project:

The team has proposed a relevant project, both as a continuity of the existing research but also as an innovative evolution of the axes developed nowadays. Two main directions concern new aspects of the theoretical descriptions of molecular compounds and chemical reactions as well as investigations of 2D and 3D interactions between molecular systems. For each aspect of this project, a detailed overview of the needs (both technical and human) but also of the engaged collaborations is presented, attesting the feasibility of the project on a medium-and long-term. In agreement with the "Directoire" of the new UMR, the team exposed its policy in term of development. This team stressed its wish to create new collaborations within the new laboratory.

In summary, the strategy of this team concerning its project and development seems very relevant.

Conclusion:

This team has become a national and international reference in the field of Chemoinformatics and the projects should strengthen its excellent positioning. The contract activities should be maintained in order to obtain enough funds to allow a technical development as well as to guarantee continuity in the collaborations with foreign groups. Additional permanent staff hiring should be programmed, mainly for technical support that could first stabilize and then enhance the development of new softwares. Establishment of strong collaborations with members of the other teams of the new unit is a good opportunity to access to multidisciplinary and high-impact publications. La disparité et l'inhomogénéité des critères d'analyse et d'appréciations, perceptibles à la lecture du rapport, donne une image brouillée de la complémentarité et de la dynamique de l'unité. Ainsi les critères comme le nombre de publication normalisé par rapport au nombre de publiants, les citations sur la période considérée, les conférences t séminaires, les modes de financement etc, ne sont ni considérés ni analysés de la e même façon pour les différents groupes de recherche.

Le comité d'évaluation met en exergue de façon ostentatoire une faiblesse estimée des aspects applicatifs des recherches menées ce qui semble une conséquence inévitable du caractère fondamental et original de telles recherches. Même si nous considérons que le transfert vers l'appliqué est indéniablement intéressant et un plus, mener des recherches à caractère fondamental est certainement l'une des missions de la recherche ublique et universitaire. Cet aspect ne devrait sans doute pas être considéré dans p l'absolu de façon négative mais évalué au regard du type ou du domaine de recherche.

Concernant la participation à la vie collective et au bon fonctionnement des institutions, au cours d'une réunion organisée par l'Université de Strasbourg, les responsables de l'AERES au plus haut niveau ont très clairement exprimé l'importance donnée à ces taches et l'intérêt à les préciser pour la clarté de d'évaluation. Or dans le rapport, cet aspect est systématiquement présenté de façon négative (faiblesse). Il est à remarquer que les responsabilités assumées par les membres de l'unité relèvent de nominations nationales ou d'élections ouvertes à tous, ce qui dans les deux cas, témoigne d'une reconnaissance nationale ou locale forte. Enfin, les personnes assumant ces responsabilités n'ont abandonné ni l'enseignement ni la recherche et ont publié des manuscrits dans des journaux de très haut niveau. Cette remarque, injustifiée à notre n avis, est décourageante et ous apparaît comme un signe très négatif vis-à-vis de l'implication au service de la communauté scientifique. A l'heure où le ministre de l'enseignement supérieur, à l'occasion de la signature de l'IDEX à Strasbourg, a souligné l'investissement collectif, félicité et remercié ceux qui se ont fortement impliqués pour la réussite de l'ensemble des projets, ces remarques énérales paraissent assez curieuses… s g

  Representatives present during the visitScientific Delegate representing AERES: Ms Gilberte CHAMBAUD Representative(s) of the unit's supervising institutions and bodies: Mr Daniel GUILLON, UDS Mr Claude POUCHAN, INC-CNRS Report 1  Introduction Date and conduct of visit: 12-13 th January, 2012

N6:N7

  Other professors and researchers 0 N4: Engineers, technicians and administrative staff *on a permanent position 4 N5: Engineers, technicians and administrative staff * on a non-permanent position 0 Postdoctoral students having spent at least 12 months in the unit 14 Number of producers in the 2008-2011 period who will be present in 2013-2017.

N6:N7N10:

  Engineers, technicians and administrative staff * on a non-permanent position 0 Postdoctoral students having spent at least 12 months in the unit 5 Number of Habilitations to Direct Research (HDR) defended 1 People habilitated to direct research or similar 7 Number of producers in the 2008-2011 period who will be present in 2013-2017.

N6:N7*

  Other professors and researchers 0 N4: Engineers, technicians and administrative staff * on a permanent position 0.2 0,2 N5: Engineers, technicians and administrative staff * on a non-permanent position 0 Postdoctoral students having spent at least 12 months in the unit 0 If different, indicate corresponding FTEs in brackets. ** Number of producers in the 2008-2011 period who will be present in 2013-2017.   Detailed assessments • Assessment of scientific quality and production:

N6:N7N10:TOTAL*

  Other professors and researchers 0 N4: Engineers, technicians and administrative staff * on a permanent position 0 N5: Engineers, technicians and administrative staff * on a non-permanent position 0 Postdoctoral students having spent at least 12 months in the unit 4 Number of Habilitations to Direct Research (HDR) defended 0 People habilitated to direct research or similar 1 If different, indicate corresponding FTEs in brackets. ** Number of producers in the 2008-2011 period who will be present in 2013-2017.

N6:N7*

  Engineers, technicians and administrative staff * on a permanent position 0,3 1 N5: Engineers, technicians and administrative staff * on a non-permanent position 1 Postdoctoral students having spent at least 12 months in the unit 1 If different, indicate corresponding FTEs in brackets. ** Number of producers in the 2008-2011 period who will be present in 2013-2017.   Detailed assessments Assessment of scientific quality and production:

N6:N7N10:TOTAL*

  Other professors and researchers 0 N4: Engineers, technicians and administrative staff * on a permanent position 0 N5: Engineers, technicians and administrative staff * on a non-permanent position 0 Postdoctoral students having spent at least 12 months in the unit 4 Number of Habilitations to Direct Research (HDR) defended 1 People habilitated to direct research or similar 2 If different, indicate corresponding FTEs in brackets. ** Number of producers in the 2008-2011 period who will be present in 2013-2017.

  Supervising bodies' general commentsCommentaires sur le compte rendu d'évaluation de l'UMR 7140

6

   Statistics per field : ST au 10/05/2012

	Notes
		C1	C2	C3	C4
	Critères	Scientific quality and production	Reputation and drawing power, integration into the environment	Laboratory life and governance	Strategy and scientific project
	A+	13	14	18	9
	A	31	26	24	28
	B	9	12	9	15
	C	-	1	-	1
	Non noté	-	-	2	-
	Pourcentages
		C1	C2	C3	C4
	Critères	Scientific quality and production	Reputation and drawing power, integration into the environment	Laboratory life and governance	Strategy and scientific project
	A+	25%	26%	34%	17%
	A	58%	49%	45%	53%
	B	17%	23%	17%	28%
	C	-	2%	-	2%
	Non noté	-	-	4%	-

 Grading

Once the visits for the 2011-2012 evaluation campaign had been completed, the chairpersons of the expert committees, who met per disciplinary group, proceeded to attribute a score to the research units in their group (and, when necessary, for these units' in-house teams).

This score (A+, A, B, C) concerned each of the four criteria defined by the AERES and was given along with an overall assessment.

With respect to this score, the research unit concerned by this report (and, when necessary, its in-house teams) received the overall assessment and the following grades:

Overall assessment of the unit : Chimie de la matière complexe -CMC Unité dont la production, le rayonnement, l'organisation, l'animation et le projet sont très bons.

Grading table:

C1

Scientific quality and production.

C2

Reputation and drawing power, integration into the environment.

C3

Laboratory life and governance.

C4

Strategy and scientific project.

A A A A

Overall assessment of the team : Tectonique Moléculaire Équipe dont la production est excellente, le rayonnement et le projet sont très bons.

Grading table:

C1

Scientific quality and production.

C2

Reputation and drawing power, integration into the environment.

C3

Laboratory life and governance.

C4

Strategy and scientific project.

A+ A -A

Overall assessment of the team : Chimie Moléculaire du Solide

Équipe dont la production, le rayonnement et le projet sont bons mais pourraient être améliorés.

Grading table:

C1

Scientific quality and production.

C2

Reputation and drawing power, integration into the environment.

C3

Laboratory life and governance.

C4

Strategy and scientific project.

B B -B

Overall assessment of the team : Bioélectrochimie et Spectroscopie

Équipe dont la production est excellente, le rayonnement et le projet sont très bons.

Grading table:

C1

Scientific quality and production.

C2

Reputation and drawing power, integration into the environment.

C3

Laboratory life and governance.

C4

Strategy and scientific project.

A+ A -A

Overall assessment of the team : Spectrométrie de Masse des Interactions et des Systèmes

Équipe dont la production et le projet sont bons mais pourraient être améliorés, le rayonnement est très bon.

Grading table:

C1

Scientific quality and production.

C2

Reputation and drawing power, integration into the environment.

C3

Laboratory life and governance.

C4

Strategy and scientific project.

B A -B

Overall assessment of the team : Chemoinformatique

Équipe dont la production, le rayonnement et le projet sont très bons.

Grading table:

C1

Scientific quality and production.

C2

Reputation and drawing power, integration into the environment.

C3

Laboratory life and governance.

C4

Strategy and scientific project.

A A -A


Report 1  Introduction Date and conduct of visit:

The site visit took place on January 11th 2011 at the Centre Européen d'Etudes du Diabète building in the Hautepierre campus, a center located closed to the lab building. It was conducted by an international evaluation panel of 7 experts in the scientific fields represented by the evaluated unit. Two months before the visit, each committee member had received a report in English including the description of the work performed during the last four years and the proposed projects for the laboratory. Overall, this report contained all the information required by AERES and enabled an efficient preparation of the visit. The visit opened by a closed-door session to prepare the review. The evaluation took place under excellent conditions in a public session with presentations and discussions with the director, group leaders, scientific staff, technical and administrative staff, post-graduate and PhD students. It was followed by a debriefing time organized by the committee at the end of the session.

History and geographical location of the unit, and overall description of its field and activities:

The current unit (MNT3) has almost the same composition as Team 2 from the current INSERM Unit 682 directed by Ms Michèle Kedinger. This unit was created in 2009 as the result of the fusion of 3 former teams, two located in Strasbourg ( U682 and U575) and one located in Basel (Switzerland) directed by Ms Gertraud Orend, who was recruited in 2008 as a DR2 INSERM. The unit gathers 23 people. The organization of an independent unit (MNT3) for the next five year-contract (2013)(2014)(2015)(2016)(2017) follows the retirement of Ms Michèle Kedinger and reflects limited interactions with the other teams forming U682. This new unit benefits from expertise about extracellular matrix and cell adhesion in development and disease in different organs (intestine, brain, pancreas, breast). The unit is focused on the role of the microenvironment and especially the impact of matrix stiffness on cell migration and angiogenesis in normal tissue homeostasis, inflammation and cancer progression. A continuum of research is proposed from the fundamental roles of tenascin in both angiogenesis and metastasis up to the generation of peptides targeting transmembrane receptors (neuropilin-1, integrin, semaphorin3A). These peptides could be potent tools in clinical applications to prevent tumoral angiogenesis and progression. This latter project has been the starting point of a spin-off company (MTP Therapeutics) with support from the regional innovative business incubator.

The unit is located in an INSERM building adjacent to the hospital allowing for supply of human samples, library set up and development of translational research. The unit has a marked and visible position in the national and international training program (cellular biology and physiology, neurosciences) in the roles of teachers or teaching program coordinator at the Universities of Strasbourg, Basel or Beyrouth. All researchers of the unit are involved in higher education.

Regional and industrial partnerships (MTP Therapeutics) have been established.

Management team:

During Ms Michèle Kedinger's direction of Unit U682 (about 70 people), the director was assisted by 2 secretaries. One of them will work for Ms Gertraud Orend's unit in the future. However institutional funding for the unit was shared between teams according to their needs and grants/external funding was raised by individual investigators.

The new research unit is governed by Ms Gertraud Orend who has already acquired management experience by leading a team in Basel and who will be assisted by a secretary, and 3 researchers responsible for computer tasks, communication and health/safety respectively. Even though each project leader is requesting external grants, acquired funding is shared within the unit. Technical personnel is allocated to the projects based on demand and expertise. Active discussions between unit members are performed at a weekly internal institute seminar. Once a month the strategy is discussed during an executive committee between members forming "the directive committee" consisting of the director, project leaders and permanent scientists.

Unit workforce:

 Assessment of the unit

Overall opinion on the unit:

The current unit aims to establish a monothematic research unit focused on the biological, biochemical and biophysical properties of the tumoral microenvironment and its associated signalling pathways through study on angiogenesis, cell dissemination and homing. The unit offers a good continuum of research from fundamental understanding of the role of tenascin-C in tumor development up to clinical applications of an original receptortargeting strategy via amphiphilic peptides that supports highly promising therapeutic developments. The unit offers strong attractiveness as examplified by the potential integration of an ATIPE/AVENIR candidate with a strong CV and a highly relevant research program on the role of caveolin in this same research field. The visiting committee considers this intention as a vibrant addition to the unit. The Hautepierre building had already proven to provide an excellent infrastructure in terms of space and facilities (secretary office, animal facility, molecular and cell biology, cell and small animal imaging). Even though some applied projects are proposed, most projects remain in the field of basic research. The unit is promising and the relevance of the questions addressed is strong in the field of tumoral microenvironment, cell adhesion and mechanotransduction. The unit is led by a scientist who is well supported by the entire team. The unit is dynamic and well-balanced with an optimal combination of permanent researchers, postdocs and students. All expertise for pursuing the project is available within the team or through collaborations. Good expertise of senior scientists is documented in the field of microenvironment, cell adhesion molecules and animal models. Unit scientific production is good in terms of quantity and quality when evaluated in relation to the time required for restructuring a laboratory.

Strengths and opportunities:

The unit is based on a good expertise of senior scientists in the field of microenvironment, cell adhesion and tumorigenesis.

The development of original transgenic mouse models (KO, tissue-specific transgenesis) for the study of tenascin-C will represent the basis of the research program.

The use of spontaneous tumor models rather than subcutaneously grafted tumor cell lines is recognized as a scientifically sound decision and a valuable effort.

The development of an experimental strategy (patented and licensed to a spin-off company) allowing specific targeting of single transmembrane receptors (neuropilin-1, integrins, tyrosine kinase receptors…) and subsequent therapeutic applications is original and creative.

The attractivity of a very complementary project on caveolin headed by a young researcher should reinforce the unit.

The unit displays a clear ability to recruit talented young scientists, to raise funds through competitive grant applications, to develop productive collaborations and to maintain a good critical mass. Basic and translational researches are conducted, together with active collaboration with a biotech company for development of inhibitory peptides.

Weaknesses and risks:

The project is ambitious but the high number of animal models developed may be seen as a threat of remaining at the level of phenotype description without pushing forward the understanding of the mechanisms of action of tenascin and related ECM molecules in tumorigenesis (receptors, signalling pathways).

A qualified animal facility is available but the housing of a large panel of transgenic animals has to be checked. The use of in vivo imaging such as MRI and PET-scan for small animals is lacking although efforts are under way to close this gap by adequate collaborations.

To avoid conflicts of interest, the project on transmembrane peptides used as therapeutic agents should be clearly distinct from the objectives of the spin-off company and focus on targets different from neuropilin-1 as proposed by the project leader.

Although, individual projects are of interest, collaborative projects and interconnectivity between research axes need to be well specified and reinforced.

All permanent scientists of the unit appeared to adhere to the leadership and scientific orientation of the Director. Some of them accepted to drop their long-term personal line of research to reinforce the workforce on tenascin-C. Still some additional efforts should be made over the next years to better interconnect the projects on tenascin-C and those on transmembrane peptides. The integration of an INSERM/AVENIR candidate would certainly help to create links between these two research projects. However, in the absence of the AVENIR/ATIP support and/or the expected arrival of the young investigator, the unit will lack expertise in mechanotransduction.

Invitations to top ranked meetings are missing.

Interactions with biophysicists need to be developed to maintain competitiveness.

Recommendations:

Given the idea to reinforce an interdisciplinary research environment based on animal models, animal imaging and biophysical studies for the future, further efforts are required to provide the basis for this very exciting concept. Unit members should more intensely communicate their results at the international level. An important recommendation is to submit and publish their results in higher impact journals, but also to increase the number of scientific presentations at international meetings. The unit needs a full support from all the institutions to decrease the teaching load of the more dynamic scientists with university commitments.

The unit has to improve its international visibility. To do that, the unit should identify a common scientific goal and establish priorities in its ongoing research with clear objectives to reach.

 Detailed assessments

Assessment of scientific quality and production:

The unit has worked on a dialog between cells and their surrounding extracellular matrix along 2 axes: (i) by elucidating the role of extracellular matrix molecules (tenascin-C) in cell migration and angiogenesis in normal homeostasis but also under inflammatory conditions and during tumoral progression and (ii) by targeting receptors involved in microenvironment-dependent signalling (neuropilin, integrins, semaphorin 3A, VEGFR) through generation of inhibitory peptides against the transmembrane domain with the aim to modify tumoral angiogenesis and progression. The unit has established several mouse and cellular models (KO and overexpression) to modulate tenascin-C expression in the microenvironment. Recent results obtained by the unit are the following:

-role of laminin in intestinal development and cancer: by RNA profiling, the unit showed that LM511 is regulating the PI3K/Akt signaling. The unit has shown the requirement of LM111 in eye development since the conditional deletion of LM111 leads to blindness, which is due not only to a defect in organization and composition of the retinal basement membrane, but also to an abnormal retinal vasculature. The requirement of LM1 in cortex development has been demonstrated whereas LM332 is involved in tumoral progression through perturbation of angiogenesis. Finally, some evidence shows the role of Laminin alpha1 and alpha5 in inflammatory bowel disease such as Crohn's disease and ulcerative colitis.

-role of tenascin in rheumatoid arthritis through Toll-like receptor 4 signalling by inducing pro-inflammatory cytokines and in tumor progression through Wnt signaling activation, and in the creation of a protective microenvironment and participation in lymph node mimicry-associated tumor evasion.

The unit has shown that a peptide mimicking the transmembrane domain of neuropilin 1 antagonizes the biological function of neuropilin and validated the antiangiogenic and tumor growth inhibitory effect in 3D assays and in preclinical mouse models of brain tumors (Oncogene 2010). Transmembrane peptides can also be used for live imaging of tumor progression.

The production of high impact publications has been hampered by the development and analysis of animal models which has been very time-consuming. The quality of internal publications is good since 44 publications have been accepted including 14 original publications (Cancer Research, Mol Biol Cell, Oncogene with a mean impact factor of 7.7 during the last past 4 years), 20 publications issued from fruitful collaborations (Nature Cell Biology, Nature Medicine, Journal of Cell Biology Small, Cancer Research…), 5 invited reviews, 5 book chapters and 3 editorials, 1 licensed patent. The unit has also successfully attracted grants (2 INCA, 3 ANR, Labex).

Unit members have been invited in 20 conferences (9 in France, 11 abroad).

Assessment of the unit's integration into its environment:

The INSERM building is physically located at the Hautepierre campus close to the Hautepierre Hospital, to the "Institut Regional du Cancer" and to the "Centre de Ressources Biologiques" which is in charge of providing biological specimens. The unit has demonstrated a good ability to raise external funding grants (3 INCA, 2 ANR, Medalis Labex) and grants based on national and international collaborations. Several collaborations with the clinics are allowed through INCA grants. The Labex Medialis, of which the unit is a founding member, will certainly help to foster the collaborations with pharmacologists. Valorisation of the research is quite impressive since a spin off has emerged from the translational research developed in the unit. Several conferences are scheduled with the involvement of unit members (Basel meeting on the tumor environment, 2nd meeting on targeting matrix in cancer, course on in vivo models in cancer for industry, NEUREX Symposium on cell migration in the brain, French society for matrix biology, FASEB conference on matricellular proteins).

Assessment of the research unit's reputation and drawing power:

The group leader enjoys national and international recognition but could be invited to more International meetings. She is very active through participations in numerous national and international calls.

Unit members have been invited to 20 conferences (9 in France, 11 abroad). The unit received the Universal Biotech Innovation Prize 2011 and 7 prizes including a "contrat d'interface", a "prix de la fédération pour la recherche sur le cerveau", an award from the European Association for cancer Research Applied Biosystems and distinctions for poster presentation and for excellent young researcher.

The unit has recruited its own team leader as an Inserm senior researcher (DR2), 4 post-doctoral fellows including 3 foreigners (India, Italy, United Kingdom). 7 PhD students from France and abroad are currently trained in the team. The unit is attractive for 3 advanced scientists want to join the team. The unit has been successful in recruiting an associated clinician who will strengthen the relationship with clinics. The head of the Neurosurgery department (University Hospital Strasbourg) will join this unit in January 2013 and therefore is included in the workforce. A talented young investigator is expected to join the research unit in summer 2012 by applying for an ATIP-AVENIR program.

In addition, the unit developed fruitful collaborations with numerous labs in France and Germany and the group leader has co-organized 6 scientific meetings in Strasbourg and a FASEB conference session in USA. All permanent scientists are involved in national (CNU, ANR) and international reviewing for grant agencies, scientific commission and scientific journals.

Assessment of the unit's governance and life:

The PI is German, offering international dynamics through the usage of English as the internal lab language. The proposed director of the unit appears to be well appreciated and respected by her colleagues. Not only charisma and expertise of senior scientists but also attractiveness towards young investigators and clinical researchers should contribute to the success of the unit. There is a good balance between staff scientists, technicians, post-docs and students. The possibility to attend international conferences is appreciated by post-docs and students. The technical staff is well supported in terms of training, preparation of competitive examinations and opportunity of recruitment in a spin off founded by one of the unit's scientists.

Assessment of the strategy and 5-year project:

The merging of the three original expertises in a monothematic research unit with an integrated fundamental and applied research program is highly relevant. The project is still focused on the interplay between cells and their microenvironment by (i) studying mechanical properties of extracellular matrix controlled by either extracellular matrix components (tenascin-C) or adhesion associated signalling pathways (integrins, neuropilin, caveolin); (ii) targeting central organizers of adhesive transmembrane receptor signaling (integrins, neuropilin-1, VEGFR, Semaphorin) with inhibiting transmembrane peptides. The goal is to understand the organization of the tumoral microenvironment, the modulation of physical and chemical properties of the tumoral microenvironment, the duality between non adhesive and adhesive extracellular components (tenascin-C versus fibronectin) leading to angiogenesis and metastasis and affecting drug responsiveness. Brain and breast cancer will be studied through experimental mouse, chicken and zebrafish models and through organotypic organ and 3D cell culture models (spheroids and biomaterials).

In a more global and academic approach, expression profiling (RNA, protein) will define matrix composition in WT tenascin-C, KO or overexpression conditions in order to reveal tenascin-C impact on matrix expression and organization, tissue stiffness (AFM, force maps of frozen tissue) and integrin signaling (including caveolin and neuropilin signalling). It will be addressed whether tenascin-C affects vascular integrity by focusing on tubulogenesis, pericyte coverage and pruning thanks to 3D collagen gels, hanging drops, bioengineered matrices, CAM assay and zebrafish angiogenesis model. The potential role of tenascin-C in the transdifferentiation of tumor cells into endothelial cells will be investigated in the orthotopic brain tumor model (glioblastoma xenografts). It will be studied whether tenascin-C matrix tubes can offer potential trafficking routes. Tumor angiogenesis will be addressed in the zebrafish model whereas the tumor metastasis, dissemination and homing will be analyzed in breast cancer NeuNT and PyMT mice. These complementary appoaches appear pertinent and competitive. The evaluation committee feels however that the unit should go far beyond the description of the phenotypes observed in these various biological contexts and attempt to decipher the molecular mechanisms (receptors, signalling pathways) by which tenascin-C mediates these distinct effects. The unit has also developed these last few years an original approach to interfere with and thus to prevent the signalling pathways initiated by the recruitment of adhesion molecules during the processes of angiogenesis and metastasis. Briefly, they use a set of hydrophobic peptides targeting the transmembrane domains of receptors for adhesion molecules. By using these original tools, the unit is studying the influence of neuropilin and others actors in the control of tumor progression. Although some questions remain to be answered concerning the specificity of action of these peptides, their bioavailability in vivo or their targeting to tumor sites, the visiting committee has been convinced by the strong potential of these components as potential therapeutic agents. The committee recommends that basic research on the understanding of the mechanism of action of these peptides (the structural studies that have been initiated through collaborations in France shoud definitely be helpful in that sense) and on the improvement of their targeting should be pursued in the laboratory while the spin-off company MTP Therapeutics will focus on the clinical applications. Also, the generalization of the concept established with neuropilin-1 to receptors of interest in the field of research of the laboratory appears as a valuable challenge.

On the basis of this peptide technology (licensed patents), the unit is developing a translational approach, in a cutting edge project in partnership with MTP Therapeutic.

Assessment of the unit's involvement in training:

The unit has a visible position in the national and international training program (cellular biology and physiology, neurosciences) as teachers or teaching program coordinator at the Universities of Strasbourg, Basel or Beyrouth since all researchers of the unit are involved in higher education. Strong implication in teaching activity and creation of a cell imaging platform on the Health and Sciences campus of Strasbourg University has been secured by positions affiliated to the university ensuring full time teaching duties. "The integration of an INSERM/AVENIR candidate would certainly help to create links between these two research projects. However, in the absence of the AVENIR/ATIP support and/or the expected arrival of the young investigator, the unit will lack expertise in mechanotransduction". The arrival of a young talented and competitive expert in biomechanics will indeed provide an integrative potential. Nevertheless, the staff scientists are experts in adhesion signaling and cover biomechanical aspects. Even if the ATIP/AVENIR candidate will not join the unit (immediately) the program is unique, innovative and competitive. The program will discover important information about signals from the tumor microenvironment relevant in driving angiogenesis and metastasis and will continue to translate this knowledge into the development of novel transmembrane peptides for targeting and live imaging of cancer.

•

It was mentioned that "...housing of a large panel of transgenic animals has to be checked." Very recently, the current team (future MN3T unit) was successful in acquiring financing through the Labex Medalis program for a new caging system that will quadruplicate the current capacity thus covering the anticipated needs.

•

It was noted that "The use of in vivo imaging such as MRI and PET-scan for small animals is lacking although efforts are under way to close this gap by adequate collaborations." Moreover, "Interactions with biophysicists need to be developed to maintain competitiveness". Through the Labex Medalis program where MN3T is a founding member we will obtain access to MRI and PET-scan in the frame of the TransImaging Equipex program that has been selected by ANR. Moreover, several collaborations with biophysicists have already been established which are supported by 2 collaborative grants (ANR, INCa, G. Orend coordinator) and a co-supervision of a PhD student by a physicist.

•

It was mentioned: "To avoid conflicts of interest, the project on transmembrane peptides used as therapeutic agents should be clearly distinct from the objectives of the spin-off company and focus on targets different from neuropilin-1." A distinct focus will certainly be given. Whereas MN3T will focus on the molecular mechanisms of action of selected transmembrane peptides, the company MTP Therapeutics will deal with aspects of ADME and strategies for translation as e.g. clinical trials, thus providing a non-competitive win-win situation for both entities.

•

"An important recommendation is to submit and publish their results in higher impact journals" Stochastic transgenic and knockout cancer models with up to half year delay of tumor development have been used in the past and will continue to be used in the future which is a well appreciated but time consuming endeavour. Moreover, physical translocation to U682 had significantly delayed mouse breeding and experiments. Nevertheless, several manuscripts with a high publication potential are in preparation or are in the submission/resubmission phase. Accepting the associated delay our declared aim is the publication of complete and comprehensive data in higher impact journals, rather than publication of only single aspects in lower impact journals. Publications in higher impact journals will also further increase invitations to international conferences.

• "The new research unit is governed by Ms Gertraud Orend who has already aqcuired management experience by leading a team in Basel..."

The team leader has obtained more than 9 years of experience in leadership both in Basel (5 years) and in Strasbourg (more than 4 years).

Sincerely yours, Gertraud Orend Strasbourg, 7. 3. 2012

N1 to N7 20 13 (24) ***** 9 * If different, indicate corresponding FTEs in brackets.

		Workforce	Number on 06/30/2011	Number on 01/01/2013	2013-2017 Number of producers* *
	N1: Professors or assistant professors	2	3	3
	N2: EPST or EPIC researchers	3	3	3
	N3: Other professors and researchers	1	0	3
	N4: Engineers, technicians and administrative staff * on a permanent position	3	7 [5.2]
	N5: Engineers, technicians and administrative staff * on a non-permanent position	2	3 ****
	N6: Postdoctoral students ***	2	3
	N7: Doctoral students	7	5
	N8: PhD defended		7
	N9: Number of Habilitations to Direct Research (HDR) defended	0
	N10: People habilitated to direct research or similar	5	6
	TOTAL **	Number of producers in the [01/01/2007-06/30/2011] period who will be present in 2013-2017.
		Definition and downloading of criteria:
		http://www.aeres-evaluation.fr/Evaluation/Evaluation-des-unites-de-recherche/Principes-d-evaluation.
	***	Numbers according to form 2.7 of the unit`s application in June 30, 2011
	**** Other personnel being present at 1. 1. 2013 is added to the shaded area and FTE of all personnel is
	presented in brackets.

5 

 5 Statistics per field : SVE au 10/05/2012

	Notes
		C2	C2		C3	C4
	Critères	Scientific quality and production.	Reputation and drawing power, integration into the environment.	Laboratory life and governance.	Strategy and scientific project.
	A+	10	14		18	16
	A	33	32		31	29
	B	13	10		6	11
	C	1	1		2	1
	Non noté	-	-		-	-
	Pourcentages
		C1	C2		C3	C4
	Critères	Scientific quality and production.	Reputation and drawing power, environment. integration into the	Laboratory life and governance.	Strategy and scientific project.
	A+	18%	25%		32%	28%
	A	58%	56%		54%	51%
	B	23%	18%		11%	19%
	C	2%	2%		4%	2%
	Non noté	-	-		-	-

Domaine SVE -Répartition des notes par critère C1 C2 C3 C4

 Grading

Once the visits for the 2011-2012 evaluation campaign had been completed, the chairpersons of the expert committees, who met per disciplinary group, proceeded to attribute a score to the research units in their group (and, when necessary, for these units' in-house teams).

This score (A+, A, B, C) concerned each of the four criteria defined by the AERES and was given along with an overall assessment.

With respect to this score, the research unit concerned by this report (and, when necessary, its in-house teams) received the overall assessment and the following grades:

 Overall assessment of the unit :

The Microenvironmental Niche in Tumorigenesis and Targeted Therapy

Unité dont la production, le rayonnement, l'organisation, l'animation et le projet sont très bons.

Grading table:

C1

Scientific quality and production.

C2

Reputation and drawing power, integration into the environment.

C3

Laboratory life and governance.

C4

Strategy and scientific project. We are grateful for the very positive evaluation and constructive recommendations made by the AERES committee and would like to comment on a few points.

• It was mentioned that the unit should improve its international visibility. "The group leader...could be invited to more international meetings. An important recommendation is......to increase the number of scientific presentations at international meetings". The current team enjoys considerable international visibility as evidenced by attracting over the past 4 years several foreign students (5), postdocs (2), and sabbatical scientists (5) with 7 different nationalities. Team members have organized meetings or sessions at meetings with international participants (5), presented research results at 20 conferences upon invitation (9 in France, 11 abroad), and delivered more than 50 presentations overall, including talks at Gordon Research and Faseb conferences. Presentations of seminars in research institutes (2 in France and 5 abroad), extensive reviewing for international funding agencies in Switzerland, Israel and USA, participation in PhD and habilitation committees in the UK, Germany, Switzerland and Austria, expert appraisal for several journals and serving as founder and chief editor of the journal "Cell Adhesion and Migration" (which is indexed with an anticipated impact factor of 4.6) has further increased international recognition. Moreover, researchers have obtained international prizes (including the Universal European Biotech Innovation Prize 2011) and are continuing to organize international meetings and sessions in the future (e.g. Neurex workshop 2012, Faseb Research conference 2013).

•

The committee has recommended that the research should be more focused and integrated and should extend on the identification of the molecular mechanisms. "Still some additional efforts should be made over the next years to better interconnect the projects on tenascin-C and those on transmembrane peptides". Since our creation in 2009 following the fusion of three teams with different but complementary expertise we have initiated projects with an integrated nature (supported by extramural funding). Further integration will be intensified in the future. We already strengthened this effort by reorienting the research program (e.g. discontinuing gastrointestinal tumor models). The future unit will focus on the role of the microenvironment on tumor angiogenesis and metastasis. Tenascin-C has been chosen as a cancer relevant extracellular matrix molecule. Biophysical and biochemical mechanisms of a tenascin-C-enriched microenvironment will be determined. Moreover perception of signals from a tenascin-C-enriched microenvironment by the cells through transmembrane receptors will be elucidated at the molecular level. Knowledge about signal integration from the tumor microenvironment is already used for the design and application of novel peptides targeting the transmembrane domain of cancer relevant adhesion and signaling receptors. This feedback approach provides a strong interconnectivity between the tenascin-Cand peptide-based parts of the project. Our publication record on the identification of molecular mechanisms of tenascin-C (e.g. Lange et al., 2007Lange et al., , 2008) ) and the mode of action of the transmembrane targeting peptides (Hubert et al., 2010) reveals that our research has been molecular and mechanism-driven in the past and this will continue to be a focus for the future.


Report 1  Introduction Date and conduct of visit:

The site visit took place on January 13th 2011 at Forum de la Faculté de Médecine de Strasbourg. Two months before the visit, each committee member had received a report in English including the description of the work performed in the last four years and the proposed projects for the team directed by Mr Thierry Massfelder. Overall, this report contained all the information required by AERES and enabled an efficient preparation of the visit.

The visit opened by a closed-door session to prepare the review. In a public session, the AERES delegate explained the AERES aims and methodology. Then, the evaluated team presented the project during one hour and fourty five minutes.

After the team presentation the committee was split into three parts to meet students and post-doctoral fellows, engineers and technicians and the researchers with permanent positions.

During lunch time, the committee had a fourty five-minutes closed meeting with representatives from the Université de Strasbourg (including Hôpitaux Universitaires de Strasbourg).

At the end, the committee had 90 minutes closed-door meeting to evaluate the team and prepare the report.

History and geographical location of the unit, and overall description of its field and activities:

Mr T. Massfelder's team is currently part of INSERM Unit 682. The Inserm Unit 682 directed by Ms Michèle Kedinger was created in January 2007 as a mixed Inserm-Strasbourg University unit. Ms Kedinger will retire at the end of her contract and the 3 teams have chosen to split.

The team of Mr T. Massfelder has now focused on the study of fibrotic and inflammatory components of chronic kidney diseases and renal cell carcinoma.

The proposed research unit that will be directed by Mr T. Massfelder corresponds to the merge of his team that will concentrate on renal cell carcinoma with another team that works on prostate cancer at the Faculty of Medicine (University of Strasbourg, EA4438). The project includes a total of 2 professors and 1 assistant-professor, 1 clinician (PH), 2 researchers, 4 engineers and technicians, 1 post-doc, 4 PhD students and 3 professors, assistant-professors and clinician (associated clinical team) with common priorities to develop an active fundamental, translational and clinical research axis in urologic cancers.

Management team:

Mr T. Massfelder is proposed as future director of the Inserm Unit.

Unit workforce:

Overall opinion on the unit:

The overall scientific level, management and facilities are very good in both entities (Inserm U682 and EA4438) that want to merge. The scientific proposal based on the development of an active fundamental translational and clinical research axis in urological cancers is scientifically relevant and coherent. Both groups have in general a very good involvement in national and european networks (ARTP, ESUR). Merging both groups should help increase scientific attractiveness and leadership in the East of France for urological cancer research. This research axis will lean in a proximate future to the Institut Régional du cancer d'Alsace, an integrated facility dedicated to patient care, clinical, translational research and closely linked to fundamental cancer research. The different group leaders want to gather their expertise in urologic field to increase their scientific cooperation, which has been already initiated. In this future project, the team wants to reinforce its basic research programs by developing high level research in the field of activated cell signalling pathways in renal cell carcinoma and prostate cancer that drive treatment resistance.

Strengths and opportunities:

The project of creation of a new research unit on urological cancers leans on the presence in Strasbourg of two teams working in close collaboration with the Urology unit, the Oncology unit and the laboratory of Pathology of the University Hospital of Strasbourg. The research program of the team benefits from numerous technological platforms (Cancéropôle Grand Est, Strasbourg University, CNRS, Inserm and Mouse Clinical Institute) in Strasbourg.

Innovative approach to identify new pathways involved in renal and prostate cancer treatment resistance.

High level of valorisation and interaction with hospital and private company.

Clear concerns for translational research.

Recently established partnerships with the pharmaceutical industry (IPSEN, Bayer), biotech societies (Urolead, Anda Biologicals), and patents already filed and delivered demonstrate the potential of the team to valorise their scientific results.

Weaknesses and risks:

The hospitalo-academics constitute an important part of the permanent staff of the team. Furthermore, the future retirement of a CNRS researcher in 2014 will weaken the research potential of the team.

Recommendations:

The project is highly supported by the committee that however recommends some prioritization for the RCC part, focusing on Lim-1 for example. The use of animal models such as specific transgenic mice will allow addressing more specifically the mechanistic basis of their findings. International collaborations should be also reinforced.

Additional full-time researchers as well as post-doctoral fellows should be hired to reinforce the scientific potential of the team. The committee highly recommends to have both original teams located on the same area in the next future.

 Detailed assessments

Assessment of scientific quality and production:

The proposed project is based on elucidating signalling pathways involved in renal cell carcinoma (RCC) and prostate cancer (PC). This project results from the combination of the recognized research expertise of both teams, which previously worked on renal cell carcinoma (Inserm U682) and prostate cancer (EA4438).

The team of Mr Thierry Massfelder has provided in the past original data showing the reactivation of nephrogenic sonic hedgehog (SHH) Gli signalling pathway in human RCC. This risky and original work demonstrated that the reactivation of SHH pathway is crucial for tumor growth, partly through the Akt and NF-kB oncogenic proteins. Using antibody arrays, they found various Gli targets including the developmental transcription factor Lim1. The follow-up of this research topic with clear objectives is highly recommended by the committee.

The other team works on constitutively activated androgen receptor that leads therapeutic resistance in PC. They developed an original yeast-based assay to detect constitutively activated androgen receptor (AR) variant in human samples. By screening different human tumors, they demonstrated the expression of truncated AR variants that lack the ligand-binding domain (LBD) in 83% of metastatic samples. These truncated receptor variants appear to be involved in the castration-resistant progression and represent an interesting target to restore hormone-sensitivity of PC. The following of this project is highly recommended by the committee.

A particular strength of this group is the close collaboration with the Urology, Oncology and Pathology units at the University Hospitals of Strasbourg that allows them to have a good collection of human samples. They took this opportunity to develop unique and original preclinical mouse models of RCC and PC in collaboration with UROLEAD, an innovative spin-off (created and developed by Mr T. Massfelder).

Quality and quantity of publications is in the good range, especially in this competitive field. The group of Mr Massfelder published 6 papers in good impact factor journals like Cancer Research (1), Oncogene (1), Carcinogenesis (3) and Molecular Cancer (1). The other group published 12 original articles also in highly ranked impact factor journals like Cancer Research (1), Endocrinology (2), American Journal of Pathology (1), Human Mutation (2) and International Journal of Cancer (2).

The international position of these groups is difficult to assess but could certainly be better (if jugded on the low number of invitations to international meetings). This is certainly a point that should be improved.

Assessment of the unit's integration into its environment:

The valorisation part of the projects is very strong with two international patents and the creation of Urolead, a spin off company aimed to provide preclinical models of kidney and prostate cancer with patient tumor xenografts in mice. The company got several awards (Oseo, FEDER, Alsace biovalley and region, Urther) and is well funded. Part of the proposed research in the Unit will benefit of the expertise, tools and financial support from this company. This is also a good way to translate the fundamental research to preclinical/clinical area as well as to industrial partners.

Both groups have a good hability to obtain external financing like InCa (2), ANR emergence and FRM « chimie pour la médecine », LNCC and ARC « subvention libre », which represent a total of 750 000 €. However, the team should reinforce its capacity to obtain more competitive grants.

Assessment of the research unit's reputation and drawing power:

Few international invitations, but the participation of both groups to the organization of national (ARTP) and European programs (ESUR) is good. The team leader is chairman of the next annual congress of the European Society for Urological Research (ESUR) and the other group leader is permanent vice-president of the ARTP meeting. However, collaboration with foreign laboratories should be reinforced in the future.

Since 2007, they have been able to recruit 2 post-docs, 7 PhD, 9 master 2 students and 14 master 1 students highlighting the good capacity to attract students, especially medical doctors.

However, although two former students are expected to come back from their post-doctoral stage in Belgium and in the US, the team should improve its capacity to attract more foreign post-docs. This merging research unit combines the better of two previously independent teams, which refocused their research. No doubt that this will be a beneficial crossfeeding with shared expertise and tools. The proposed director of the team appears to be well appreciated and respected by the members of the team.

Assessment of the strategy and 5-year project:

The research project is ambitious and innovative which rely on strong data obtained previously in both groups. The international competition on these topics is high but the expertise and hypotheses appeared original and well suited. The research staffs are adequate (4 technicians for 2 full time researchers). Recruitment of a junior researcher as scheduled will be important in the future.

The RCC program on studying the reactivation of SHH-Gli pathway is very risky and original. Only few laboratories are working on these aspects and the follow up of this project focusing on Lim-1 strategy is highly recommended by the committee. However, the program priorities regarding the inhibition of this pathway in tumor growth and invasion should be more ambitious and clarified. Interaction with the local mouse clinical institute should be reinforced in order to develop more ambitious metastatic mice models.

The PC research program based on elucidating the novel functions of the truncated AR receptor variants on gene expression is highly relevant and well structured. The first part of the project is based on elucidating the consequence of the lack of the binding domain of the AR for interaction with its partners using multi-level approach (RMN, crystallography). On the second part, they plan to assess the functions of AR variants on stroma-epithelium communication, invasion, migration and metastatic progression of PC. Lastly, in partnership with different industrial partners (Ipsen, Janssen and Bayer) they are looking for novel compounds that inhibit the interaction of the truncated AR with its regulatory co-factors.

Assessment of the unit's involvement in training:

There is a good involvement of the team in student teaching, especially for master and medical doctors training. The team is actively involved in teaching and training in the field of urology and cancer. One of the group leaders is co-responsible of the physiopathology master 2 at Strasbourg University and is coordinating the teaching of oncology courses for medical doctor at the faculty of medicine. Reputation and drawing power, integration into the environment.

Laboratory life and governance.

Strategy and scientific project.

A+

5

  Statistics per field : SVE au 10/05

Domaine SVE -Répartition des notes par critère

			10		14		18		16
	A		33		32		31		29
	B		13		10		6		11
	C		1		1		2		1
	Non noté		-		-		-		-
	Pourcentages
			C1		C2		C3	C4
	Critères	Scientific quality and production.	Reputation and drawing power, environment. integration into the	Laboratory life and governance.	Strategy and scientific project.
	A+		18%		25%		32%	28%
	A		58%		56%		54%	51%
	B		23%		18%		11%	19%
	C		2%		2%		4%	2%
	Non noté		-		-		-	-
	Nbre
	A		A		A
								A
					A+
							A+
		B	A+
	A+			B				B
						B
	5
		C	NN	C	NN	C	NN	C	NN
	0
		C1		C2		C3		C4

 Grading

Once the visits for the 2011-2012 evaluation campaign had been completed, the chairpersons of the expert committees, who met per disciplinary group, proceeded to attribute a score to the research units in their group (and, when necessary, for these units' in-house teams).

This score (A+, A, B, C) concerned each of the four criteria defined by the AERES and was given along with an overall assessment.

With respect to this score, the research unit concerned by this report (and, when necessary, its in-house teams) received the overall assessment and the following grades:

 Overall assessment of the unit :

Cell signalling and communication in kidney and prostate cancer

Unité dont la production, le rayonnement, l'organisation, l'animation et le projet sont très bons.

Grading table:

C1

Scientific quality and production.

C2

Reputation and drawing power, integration into the environment.

C3

Laboratory life and governance.

C4

Strategy and scientific project.